CN110327348A - Compound long-acting injection and preparation method thereof containing Enrofloxacin and Meloxicam - Google Patents
Compound long-acting injection and preparation method thereof containing Enrofloxacin and Meloxicam Download PDFInfo
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- CN110327348A CN110327348A CN201910655012.0A CN201910655012A CN110327348A CN 110327348 A CN110327348 A CN 110327348A CN 201910655012 A CN201910655012 A CN 201910655012A CN 110327348 A CN110327348 A CN 110327348A
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- CN
- China
- Prior art keywords
- meloxicam
- polyoxyethylene
- enrofloxacin
- stearate
- macromolecule
- Prior art date
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- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 title claims abstract description 109
- 229960001929 meloxicam Drugs 0.000 title claims abstract description 109
- SPFYMRJSYKOXGV-UHFFFAOYSA-N Baytril Chemical compound C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 SPFYMRJSYKOXGV-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 229960000740 enrofloxacin Drugs 0.000 title claims abstract description 74
- 238000002347 injection Methods 0.000 title claims abstract description 55
- 239000007924 injection Substances 0.000 title claims abstract description 55
- 150000001875 compounds Chemical class 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims description 17
- 239000007962 solid dispersion Substances 0.000 claims abstract description 32
- 229920002521 macromolecule Polymers 0.000 claims abstract description 21
- 239000003340 retarding agent Substances 0.000 claims abstract description 21
- 239000000080 wetting agent Substances 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 10
- -1 aluminium distearate Chemical compound 0.000 claims description 62
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 43
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 27
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 claims description 18
- 229920001983 poloxamer Polymers 0.000 claims description 14
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- 239000002245 particle Substances 0.000 claims description 11
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- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 2
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- FFJCNSLCJOQHKM-CLFAGFIQSA-N (z)-1-[(z)-octadec-9-enoxy]octadec-9-ene Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCCCCCCC\C=C/CCCCCCCC FFJCNSLCJOQHKM-CLFAGFIQSA-N 0.000 claims description 2
- PZJWYUDBXNNVLZ-UHFFFAOYSA-N 1-cyclopropyl-7-(4-ethylpiperazin-1-yl)-6-fluoro-4-oxoquinoline-3-carboxylic acid;hydrochloride Chemical compound Cl.C1CN(CC)CCN1C(C(=C1)F)=CC2=C1C(=O)C(C(O)=O)=CN2C1CC1 PZJWYUDBXNNVLZ-UHFFFAOYSA-N 0.000 claims description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- XDOFQFKRPWOURC-UHFFFAOYSA-N 16-methylheptadecanoic acid Chemical class CC(C)CCCCCCCCCCCCCCC(O)=O XDOFQFKRPWOURC-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
The invention discloses a kind of compound long-acting injection containing Enrofloxacin and Meloxicam, including Enrofloxacin and/or its salt, in a dispersed form existing Meloxicam, Meloxicam solid dispersions, macromolecule retarding agent, wetting agent, decentralized medium；Every 1000mL injection contains: 20~250g of Enrofloxacin and/or its salt (in terms of Enrofloxacin), in a dispersed form 5~50g of existing Meloxicam, 5~30g of macromolecule retarding agent, 5~20g of wetting agent, surplus is decentralized medium；Wherein, the mass ratio of Meloxicam existing for discrete form and Meloxicam solid dispersions (in terms of Meloxicam) is 5:1~1:1.Injection formulation quality of the present invention is stable, drug release slowly, safely and effectively, a course for the treatment of is only administered 1~2 time, can treating both manifestation and root cause of disease, and maintain effective blood drug concentration 3~7 days；It only injects 1 needle 1 time, enhances animal compliance, reduce Animal stress, be more advantageous to prognosis of disease and prognosis.
Description
Technical field
The invention belongs to animal specific field of pharmaceutical preparations, are related to a kind of compound long-acting containing Enrofloxacin and Meloxicam
Injection and preparation method thereof.
Background technique
Enrofloxacin (Enrofloxacin) also known as Ethyl Ciprofloxacin, Enrofloxacin.Its has a broad antifungal spectrum, sterilizing power is strong,
There is very strong effect to gram-positive bacteria, negative bacterium, mycoplasma, certain anaerobic bacterias etc., especially to gram-Negative bacillus
Effect is strong, sensitive bacteria include staphylococcus aureus, streptococcus, Actinomyces pyogenes, Escherichia coli, detection of Salmonella, Pasteurella, gram
The primary bacterium of thunder, proteus, pseudomonas aeruginosa, haemophilus, Podbielniak bacterium, erysipelas bacillus；There is special efficacy to mycoplasma, effect is better than
Tylosin, colistin, still valid to the two drug resistance mycoplasma, anti-chicken Deficiency Mycoplasma has better effect；Also have to mycobacterium
Certain effect.Enrofloxacin has obvious antibacterial aftereffect to sensitive bacteria, and antibacterial activity is in concentration dependent, to resting stage and growth
The bacterium of phase is effective.
Enrofloxacin absorbs rapidly, and intramuscular injection good absorbing relatively for oral administration, widely distributed in vivo, Tissue is higher than blood plasma,
Be conducive to treat the infectious diseases of whole body and each system or tissue, mainly de- ethyl still has at Ciprofloxacin for metabolism in vivo
Powerful activity, pig body is interior to be lacked ethoxyresorufin O-deethylase and directly inactivates, and about 15%~50% is discharged with original shape from urine.Elimination half-life period exists
Different genera animal and different way of administration have larger difference, intravenous half-life period (h): pigeon 3.8, chicken 5.26~10.3, turkey
4.1, rabbit 2.2~2.5, dog 2.4, pig 3.45, ox 1.7~2.3, horse 4.4, camel 3.6.Intramuscular injection half-life period (h): pig 4.06, milk
Ox 5.9, horse 9.9, camel 6.4.
Since listing, Enrofloxacin is widely applied in veterinary clinic.It is mainly used for breathing caused by sensitive bacteria
Road, enteron aisle, the urinary tract and skin soft-tissue infection, as E.coli of calf disease and salmonellosis, pleuropneumonia, mazoitis and
Hysteritis etc.；Pig dysentery characterized by white mucous stool, oedema, Bronchopneumonia, mazoitis-hysteritis-agalasisa syndrome；Dog, the bacterium of cat or branch are former
Breathing caused by body-sensing dye, digestion, urogenital system, it is also effective to skin infection, otitis externa, uterus suppuration, pyoderma treatment；
Treatment infectious coryza of chicken, dysentery characterized by white mucous stool, avian hemorrhagic septicemia and the various mycoplasma infections of poultry etc. also have excellent results.
Meloxicam (Meloxicam, MEL) is a kind of non-steroid anti-inflammatory drug of enol amides, mainly passes through inhibition
The activity of epoxidase (COX) reduces the synthesis of prostaglandin (PGs) and plays antipyretic-antalgic anti-inflammatory effect, can additionally reduce
The inflammatory tissue of granulocyte infiltrates.Because it can selectively inhibit epoxy coated steel strand (COX-2), and the suppression to cyclooxygenase 1 (COX-1)
It is weaker therefore weaker to the adverse reaction of gastrointestinal tract or kidney to make use.
Meloxicam is taken orally with tablet or with injection intramuscular injection, subcutaneous administration, absorption is rapidly and relatively complete, is distributed in more
In blood plasma, plasma protein binding rate is greater than 97%, is metabolized as the metabolism of the alcohol, acid derivative and various polarity of parmacodynamics-less activity
Object, about 75% drug are drained through excrement, and remainder is drained through urine, and antalgic and inflammation relieving onset time is 30 minutes.Dog is subcutaneous
It reaches maximum plasma concentration within injection about 2.5 hours, there is linear close within the scope of therapeutic dose, between dosage and blood concentration
System, volume of distribution 0.3L/kg；Cat, which is subcutaneously injected about 1.5 hours, reaches maximum plasma concentration, within the scope of therapeutic dose, administration
There are linear relationship, volume of distribution 0.09L/kg, the Meloxicam bioconversions in cat body between dosage and blood concentration
Main path is oxidation, and about 21% drug is drained (2% is original shape Meloxicam, and 19% is its metabolin) through urine, 79%
Through excrement excretion (49% is original shape Meloxicam, and 30% is its metabolin).
Meloxicam is widely used in veterinary clinic.Ox: often sharing with suitable antimicrobial, adjuvant treatment of acute respiratory tract
It infects to alleviate the clinical symptoms of ox, assists in the treatment of the diarrhea clinical symptoms of calf and the non-cow in milk of black ox, adjuvant treatment of acute
Mammitis, hysteritis and Postpartum Analgesia.Pig often shares with suitable antimicrobial, adjuvant treatment puerperal septiemia and toxaemia and
Few newborn syndrome of mammitis-hysteritis-etc..Pet: dog be mainly used for alleviate acute and chronic musculoskeletal disease caused by inflammation and
Pain and verifying after pain and orthopaedics or operation on soft tissue, cat are mainly used for alleviating oophorohysterectomy and small-sized soft
Organize the postoperative pain of operation.
In clinical application, Meloxicam is often combined with antimicrobial, alleviates heat, pain and inflammatory symptom that infection causes.But mesh
Before have no the compound preparation approval listing of Meloxicam and antimicrobial, when practical application, generally requires to inject 2 needles respectively, expends
Manpower and material resources increase Animal stress simultaneously.
Currently, the enrofloxacin injection of China's approved listing is solution, it is to give for 1 day that specification, which recommends dosage regimen,
It is medicine 2 times, successive administration 3 days to 7 days, time-consuming and laborious, and easily cause Animal stress.The Meloxicam injection of approved listing is also molten
Liquor, it is to share with appropriate antibiotics that specification, which recommends dosage regimen, a secondary amounts, every 1kg weight, ox 0.5mg, pig 0.4mg, if
It needs, is injected again after 24 hours primary.
105213402 A of Chinese patent CN discloses a kind of livestock and poultry compound enrofloxacin Meloxicam soluble powder, solvable
Property powder be suitable for the poultry of intensive culture, but because pig, dog, cat, ox, sheep, horse drinking-water waste are more, clinical application is inconvenient,
And multiple dosing is needed, it is time-consuming and laborious to be unfavorable for drug effect performance.
Summary of the invention
The purpose of the present invention is being directed to prior art defect, a kind of compound injection containing Enrofloxacin and Meloxicam is provided
Liquid, for Enrofloxacin bulk pharmaceutical chemicals through ultramicro crushing treatment, Control granularity D90≤5 μm are suspended in dispersion in the form of drug microparticles
In medium；Meloxicam bulk pharmaceutical chemicals are directly suspended in decentralized medium through ultramicro crushing treatment, Control granularity D90≤5 μm, a part
In, remainder is prepared into solid dispersions and is added in decentralized medium, while improving the dissolution and absorption of Meloxicam, meaning
The outer redispersibility for finding to can be improved the long-acting injection, effectively prevent the caking phenomenon of Enrofloxacin.Injection of the present invention
Prepare simple, easy to use, the quality of the pharmaceutical preparations is stable, drug release slowly, safely and effectively, Enrofloxacin, which effectively presses down, kills pathogen, Mei Luo
Former times health alleviates clinical symptoms in time, and a course for the treatment of is only administered 1~2 time, treating both manifestation and root cause of disease can be realized, and maintain effective blood drug concentration
3~7 days；It only injects 1 needle 1 time, enhances animal compliance, reduce Animal stress, be more advantageous to prognosis of disease and prognosis.
The purpose of the present invention is achieved through the following technical solutions:
A kind of compound long-acting injection containing Enrofloxacin and Meloxicam, including Enrofloxacin and/or its salt, with dispersion
Meloxicam existing for form, Meloxicam solid dispersions, macromolecule retarding agent, wetting agent, decentralized medium；Every 1000mL note
Liquid is penetrated to contain: 30~250g of Enrofloxacin and/or its salt (in terms of Enrofloxacin), in a dispersed form existing Meloxicam 5~
50g, 5~30g of macromolecule retarding agent, 5~20g of wetting agent, surplus is decentralized medium；Wherein, U.S. Lip river former times existing for discrete form
The mass ratio of health and Meloxicam solid dispersions (in terms of Meloxicam) is 5:1~1:1.
Preferably, every 1000mL injection contains: 100~200g of Enrofloxacin and/or its salt (in terms of Enrofloxacin), with
10~25g of Meloxicam existing for discrete form, 15~20g of macromolecule retarding agent, 4~10g of wetting agent, surplus are that dispersion is situated between
Matter；Wherein, the mass ratio of Meloxicam existing for discrete form and Meloxicam solid dispersions (in terms of Meloxicam) is 2:1
~1:1.
The enrofloxacin salt is any one in Enrofloxacin sodium, Enrofloxacin HCL and Enrofloxacin
Kind.
The Enrofloxacin or its salt must not detect 25 μm through ultramicro crushing treatment, Control granularity D90≤5 μm
Above particle.
The Meloxicam must not detect 25 μm or more of grain through ultramicro crushing treatment, Control granularity D90≤5 μm
Son.
The Meloxicam solid dispersions are prepared using solvent-fusion method, comprising: carrier auxiliary material heating water bath
To melting；Meloxicam through ultramicro crushing treatment is stirred evenly with dimethylformamide, after 0.5~1h of ultrasound, is added to molten
It in the carrier auxiliary material melted, stirs 0.5~1 hour, fusant, which is poured on the cooling stainless steel disc of frost, to be made its fast cooling, coagulate
Gu after cooling and solidifying, pulverizing and sieving to get Meloxicam solid dispersions.Wherein, the Meloxicam, dimethyl formyl
The weight ratio of amine and carrier auxiliary material is 1:1:3~5；The carrier auxiliary material is selected from poloxamer and/or polyethylene glycol, preferably
The combination of poloxamer or poloxamer and polyethylene glycol；The carrier auxiliary material is the combination of poloxamer and polyethylene glycol
When, the mass ratio of poloxamer and polyethylene glycol is 1:2~1:5；The polyethylene glycol be Macrogol 4000,6000,
8000,12000,20000, the poloxamer is PLURONICS F87,407.
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, monostearate are sweet
Grease and polyoxyethylene (75) stearate mixture, Unigly GO 102S, any one in pegoxol 7 stearate
Or it is a variety of；Preferably, the macromolecule retarding agent is rilanit special, is selected from aluminum monostearate, aluminium distearate and tristearin
At least one of sour aluminium and/or combination selected from least one of polyvinyl alcohol, Chinese wax, microwax and beeswax.
The wetting agent is selected from lecithin, soybean lecithin, hydroxylated lecithin, tween (20,40,60,80), poloxamer
(124,188,237,338,407), sapn (20,40,60,65,80,85), propylene glycol diacetate, propylene glycol monostearate,
Sodium lactate, stearic acid sodium lactate, four oleyl ether of polyoxyethylene (30EO) sorbierite, polyoxyethylene (60EO) sorbierite four are stearic
Ether, four oleic acid ether of polyoxyethylene (40EO) sorbierite, four oleate of polyoxyethylene (60EO) sorbierite, polyoxyethylene (8,12,
24,40,50,100,110) stearate, polyoxyethylene (10,30,40,50,60) rilanit special, polyoxyethylene (10,35,
40,60,80,90,100) castor oil, polyoxyethylene (300,400,600) monoleate, castor oil, caprylic capric polyethylene glycol
Glyceride, Sefsol 218, propylene glycol monolaurate, Unigly GO 102S, -3 pairs of isostearates of polyglycereol, tristearin
Sour polyoxyethylene glyceride, lauric acid polyoxyethylene glyceride, oleoyl polyoxyethylene glyceride, sub- oleoyl polyoxyethylene glycerol
Ester, three ceteareth -4- phosphate, ethylene glycol stearate and diethylene glycol stearate mixture etc. it is any one
Kind is a variety of；Preferably, the wetting agent is selected from one of lecithin and hydroxylated lecithin, is selected from tween, sapn, the moon
The combination of at least one of cinnamic acid polyoxyethylene glyceride.
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 of the present invention to provide the systems of the compound long-acting injection containing Enrofloxacin and Meloxicam
Preparation Method, comprising:
(a), decentralized medium is heated to 150~180 DEG C, and continues 1~1.5h；
(b), when the macromolecule retarding agent used for rilanit special and is selected from aluminum monostearate, aluminium distearate, tristearin
When at least one of sour aluminium, hydrogenated castor is added into 120~140 DEG C of decentralized media for accounting for injection volume 60%~70%
Oil and be selected from least one of aluminum monostearate, aluminium distearate, aluminum stearate, and at 120~140 DEG C maintain 1~2h,
Make the complete gelatinization of macromolecule retarding agent；Let cool to 40-60 DEG C, add except aluminum monostearate, aluminium distearate, aluminum stearate,
Macromolecule retarding agent, wetting agent, Enrofloxacin and/or its salt outside rilanit special, in a dispersed form existing Meloxicam,
Meloxicam solid dispersions successively use high speed disperser equal with revolving speed 8000~30000 revs/min of 0.5~2h of shearing, high pressures
Matter machine 10000~26000psi homogeneous, 0.5~2h uses 10000~26000psi of high pressure homogenizer homogeneous, 1~2h or use
High speed disperser is with 8000~30000 revs/min of 1~2h of shearing of revolving speed；The decentralized medium being cooled to room temperature is taken, is settled to
1000mL；
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 volume 60%~70% is taken, is let cool to 40~60 DEG C, macromolecule resistance is added into decentralized medium
There is Meloxicam, Meloxicam solid dispersions in stagnant dose, wetting agent, Enrofloxacin and/or its salt, successively in a dispersed form
Use high speed disperser with revolving speed 8000~30000 revs/min of 0.5~2h of shearing, high pressure homogenizer 10000~26000psi homogeneous
0.5~2h or use high pressure homogenizer 10000~26000psi homogeneous, 0.5~2h or use high speed disperser with revolving speed 8000~
30000 revs/min of 0.5~2h of shearing；The decentralized medium being cooled to room temperature is taken, 1000mL is settled to；
(c), granularity, related substance and content are detected；Packing is after qualification to get the compound containing Enrofloxacin and Meloxicam
Long-acting injection.
The beneficial effects of the present invention are:
(1) the compound long-acting injection of the invention containing Enrofloxacin and Meloxicam, preparation process is simple, repeatability between batch
It is good；
(2) the compound long-acting injection of the invention containing Enrofloxacin and Meloxicam, Enrofloxacin and Meloxicam raw material
Through ultramicro crushing treatment, Control granularity D90≤5 μm, preparation suspension performance is good.
(3) the compound long-acting injection of the invention containing Enrofloxacin and Meloxicam, part Meloxicam raw material are prepared as
Solid dispersions are added, and meloxicam absorption is good, and bioavilability is high, while can be improved the redisperse of the long-acting injection
Property, it effectively prevent the caking phenomenon of Enrofloxacin.
(4) the compound long-acting injection containing Enrofloxacin and Meloxicam of the invention, a course for the treatment of are only administered 1~2 time, and 1
It is secondary only to inject 1 time, can 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, promotees
Into with improve disease lapse to and prognosis.
Specific embodiment
Technical solution of the present invention is described further below by specific embodiment.
In specific embodiment:
Enrofloxacin or its salt must not detect 25 μm or more of grain through ultramicro crushing treatment, Control granularity D90≤5 μm
Son.
Meloxicam must not detect 25 μm or more of particle through ultramicro crushing treatment, Control granularity D90≤5 μm.
Ultramicro crushing treatment process is as follows:
Hierarchy system is pulverized using fluidized bed supersonic airstream, material inlet is controlled in 60~80g.Material is in powder
Broken chamber is mutually with mutually self head-on collision of 2.5 Mach velocities, fast-crushing.Particle through crushing rises to grading room with air-flow, closes
The particle of lattice enters cyclone separator with air-flow, finally obtains required product, and tail gas enters deduster discharge.Biggish particle exists
It under grader effect, falls pulverizing chamber after rise again, is crushed again, until obtaining qualified product.Granularity fineness is become by grader
Frequency controls.Equipment runs major parameter are as follows: power pressure 0.8MPa sorts frequency 30Hz, and pulse instrument is between moving in circles pulse
Every time 20s.
Embodiment 1:
Prescription
Wherein, Meloxicam solid dispersions are as made from following methods: 100.0g Meloxicam is added to
In 100.0g dimethylformamide, it is uniformly mixed, and ultrasound 1h；It is husky to be added to the 50.0g pool Lip river melted completely at 65 DEG C
In nurse 188 and 250.0g Macrogol 6000 mixture, 0.5h is stirred；Fusant is poured on the cooling stainless steel disc of frost,
After cooling and solidifying, pulverize and sieve to get Meloxicam solid dispersions, it is spare.
The preparation method of long-acting injection containing Enrofloxacin and Meloxicam:
It takes isopropyl myristate appropriate, is heated to 150-180 DEG C, and continue 1h；Pork and beans after taking 700mL to heat
Cool isopropyl propionate is cooled to 120-140 DEG C, and aluminum monostearate, rilanit special is added, and maintains 1-2h, makes aluminum monostearate, hydrogen
Change the complete gelatinization of castor oil；It lets cool to 40-60 DEG C, Chinese wax, sorbester p18, lecithin, Enrofloxacin, Meloxicam solid point is added
Meloxicam existing for granular media and discrete form, successively through high speed disperser with 25000 revs/min of shearing 1h of revolving speed, equal with high pressure
Matter machine 10000psi homogeneous 1.5h, takes the isopropyl myristate being cooled to room temperature, is settled to 1000mL；It detects granularity and contains
Amount；Packing carries out external performance evaluation to it to get the long-acting injection containing Enrofloxacin and Meloxicam after qualification, including
Character, granularity, 3h sedimentation volume ratio, the measurement such as redispersibility, syringeability, content, measurement result are shown in Table 1.
Granularity inspection: according to one annex 0982 of " Chinese veterinary pharmacopoeia " version in 2015, " granularity and determination of particle size distribution "
First method: microscopic method.Diameter of particle D90≤5 μm should not detect 50 μm or more of particle.
Sedimentation volume ratio measurement: according to " Chinese veterinary pharmacopoeia " annex page 25 of version one in 2015, apparatus plug graduated cylinder, which measures, to be supplied
Test product 50mL, close plug firmly shake 1 minute, write down the beginning height H of suspended matter0, stand, suspended matter is final when writing down 3h
Height H is calculated: sedimentation volume ratio=H/H according to the following formula0。
Redispersibility measurement: suspension is placed in 100mL tool plug graduated cylinder, close plug rights again after being inverted graduated cylinder
(one anti-one positive calculation is primary, firmly uniform when stirring), the sediment of graduated cylinder bottom should be uniformly dispersed again.With the heavy of graduated cylinder bottom
It is fewer that drop object stirs number needed for being uniformly dispersed, and shows that redispersibility is better.Excellent suspension shakes again after storage, answers
It can disperse again quickly, can guarantee the accuracy of the uniformity and divided dose when application.* to represent redispersibility poorer more.
Syringeability measurement: investigating the syringeability of preparation with the syringe for being connected with 9# syringe needle, and "+" represents that syringeability is good, and "+" is got over
It is better to represent syringeability more；It is poor that "-" represents syringeability, and "-", and to represent syringeability poorer.
Assay: 2006~2011 editions methods of veterinary medical quality standard compendium carry out Enrofloxacin and analgesic-antipyretic
Assay.
Embodiment 2:
Prescription
Wherein, Meloxicam solid dispersions are as made from following methods: 100.0g Meloxicam is added to
In 100.0g dimethylformamide, it is uniformly mixed, and ultrasound 1h；It is husky to be added to the 100.0g pool Lip river melted completely at 65 DEG C
In 12000 mixture of nurse 188 and 200.0g polyethylene glycol, 1h is stirred；Fusant is poured on the cooling stainless steel disc of frost, cold
But it after solidifying, pulverizes and sieves to get Meloxicam solid dispersions, it is spare.
The preparation method of long-acting injection containing Enrofloxacin and Meloxicam: it takes soybean oil appropriate, is heated to 150-180
DEG C, and continue 1h；Soybean oil after taking 700mL to heat is cooled to 120-140 DEG C, and aluminum monostearate, hydrogenated castor is added
Oil maintains 1-2h, makes the complete gelatinization of aluminum monostearate, rilanit special；It lets cool to 40-60 DEG C, polyvinyl alcohol, tween is added
80, lauric acid polyoxyethylene glyceride, hydroxylated lecithin, Enrofloxacin sodium, Enrofloxacin, Meloxicam solid dispersions
And Meloxicam takes successively through (25000 revs/min) shearing 0.5h of high speed disperser, with high pressure homogenizer 10000psi homogeneous 1h
The soybean oil being cooled to room temperature, is settled to 1000mL；Detect granularity and content；It is dispensed after qualification to get Enrofloxacin and beauty is contained
The long-acting injection of Luo Xikang, carries out external performance evaluation, including character, granularity, 3h sedimentation volume ratio to it, redispersibility,
The measurement such as syringeability, content.For external method of evaluating performance with implementing 1, measurement result is shown in Table 1.
Embodiment 3:
Prescription
Wherein, Meloxicam solid dispersions are as made from following methods: 100.0g Meloxicam is added to
In 100.0g dimethylformamide, it is uniformly mixed, and ultrasound 0.5h；It is added to the 300.0g pool Lip river melted completely at 60 DEG C
In husky nurse 188,1h is stirred；Fusant is poured on the cooling stainless steel disc of frost, after cooling and solidifying, is pulverized and sieved to get beauty
Lip river former times health solid dispersions, it is spare.
The preparation method of long-acting injection containing Enrofloxacin and Meloxicam: it takes ethyl oleate appropriate, is heated to 150-
180 DEG C, and continue 1h；Ethyl oleate after taking 700mL to heat is cooled to 120-140 DEG C, and aluminum monostearate, hydrogen is added
Change castor oil, maintains 1-2h, make the complete gelatinization of aluminum monostearate, rilanit special；It lets cool to 40-60 DEG C, microwax is added, spits
Beauty existing for temperature 80, hydroxylated lecithin, Enrofloxacin sodium, Enrofloxacin, Meloxicam solid dispersions and discrete form
Luo Xikang takes cooling successively through (25000 revs/min) shearing 1h of high speed disperser, with high pressure homogenizer 15000psi homogeneous 1.5h
To the ethyl oleate of room temperature, it is settled to 1000mL；Detect granularity and content；It is dispensed after qualification to get Enrofloxacin and Mei Luo is contained
The long-acting injection of former times health, external performance evaluation, including character, granularity, 3h sedimentation volume ratio are carried out to it, and redispersibility is led to
The measurement such as needle, content.For external method of evaluating performance with implementing 1, measurement result is shown in Table 1.
Embodiment 4:
Prescription
Preparation method: taking ethyl oleate appropriate, is heated to 150-180 DEG C, and continue 1h；After taking 700mL to heat
Ethyl oleate is cooled to 120-140 DEG C, and aluminum stearate, rilanit special is added, and maintains 1-2h, makes aluminum stearate, hydrogenated castor
The complete gelatinization of oil；It lets cool to 40-60 DEG C, beeswax, Tween 80, sorbester p18 and lecithin, Enrofloxacin, Meloxicam solid is added
Meloxicam existing for dispersion (with embodiment 3) and discrete form is taken and is cooled to high pressure homogenizer 15000psi homogeneous 1h
The ethyl oleate of room temperature, is settled to 1000mL；Detect granularity and content；It is dispensed after qualification to get Enrofloxacin and Mei Luo former times is contained
The long-acting injection of health carries out external performance evaluation, including character, granularity, 3h sedimentation volume ratio, redispersibility, cleansing pin to it
Property, the measurement such as content.For external method of evaluating performance with implementing 1, measurement result is shown in Table 1.
Embodiment 5:
Prescription
Wherein, Meloxicam solid dispersions are as made from following methods: 100.0g Meloxicam is added to
In 100.0g dimethylformamide, it is uniformly mixed, and ultrasound 0.5h；It is added to the 100.0g pool Lip river melted completely at 60 DEG C
In husky nurse 188 and 300.0g PEG 8000 mixture, 1h is stirred；Fusant is poured on the cooling stainless steel disc of frost,
After cooling and solidifying, pulverize and sieve to get Meloxicam solid dispersions, it is spare.
The preparation method of long-acting injection containing Enrofloxacin and Meloxicam: it takes medium chain fatty acid appropriate, is heated to
150-180 DEG C, and continue 1h；Medium chain fatty acid after taking 700mL to heat is cooled to 120-140 DEG C, and stearic acid is added
Aluminium, rilanit special maintain 1-2h, make the complete gelatinization of aluminum stearate, rilanit special；It lets cool to 40-60 DEG C, tween is added
80, U.S. Lip river former times existing for span 85, lecithin, Enrofloxacin, Enrofloxacin sodium, Meloxicam solid dispersions and discrete form
Health, with high pressure homogenizer 10000psi homogeneous 1.5h, takes after (25000 revs/min) shearing 0.5h of high speed disperser and is cooled to room
The medium chain fatty acid of temperature, is settled to 1000mL；Detect granularity and content；It is dispensed after qualification to get Enrofloxacin and Mei Luo former times is contained
The long-acting injection of health carries out external performance evaluation, including character, granularity, 3h sedimentation volume ratio, redispersibility, cleansing pin to it
Property, the measurement such as content.For external method of evaluating performance with implementing 1, measurement result is shown in Table 1.
The outer performance evaluation of 1. injecting fluid of table
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, under the conditions of being placed in high temperature (60 DEG C), Qiang Guang (4500 ± 500lx of intensity of illumination)
Under the conditions of and high humidity (relative humidity 90% ± 5%) under the conditions of, place 10 days, with 0 day compare, carry out sample stability tentatively examine
It examines, the results are shown in Table 2.As can be seen from Table 2, placing 10 days, each index meets regulation, with comparison in 0 day without significant change, shows compound
Enrofloxacin injection quality meets regulation, and preparation stabilization.
2. compound enrofloxacin injection influence factor test result of table
Influence of the Meloxicam solid dispersions to injection suspension performance
Sample prepared by Example 1, as test sample.Existing Meloxicam substitutes Meloxicam in a dispersed form
Solid dispersions, other components and dosage and embodiment 1 are consistent, and prepare sample according to the preparation method of embodiment 1, as right
Product in the same old way.
Sedimentation volume ratio and redispersibility after detection placement for 24 hours.
It takes test sample and each 10mL of control sample to be respectively placed in 25mL centrifuge tube respectively, respectively does 3 in parallel.With every point
The revolving speed that 1500 turns of clock is centrifuged 30 minutes, and identical dynamics vibrates centrifuge tube out, and can observation medical fluid be uniformly mixed and mix again
The time required to uniformly.It the results are shown in Table 3.
Seen from table 3, Meloxicam is prepared as Meloxicam solid dispersions to be added in system, for 24 hours settling volume
Than increasing, redispersibility is good, and can effectively avoid the caking phenomenon of system drug particles.
Influence of the 3. Meloxicam solid dispersions of table to injection suspension performance
Note: * represents redispersibility energy, and the fewer redispersibility of * is better.
The sustained release performance of long-acting injection containing Enrofloxacin and Meloxicam 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 by the commercially available conventional enrofloxacin injection (aqueous solution of 5mg/kg.B.W. dosage (in terms of Enrofloxacin) single intramuscular injection
Agent, Bayer A.G)；2nd group: having been listed by 0.5mg/kg.B.W. dosage (in terms of Meloxicam) single intramuscular injection
Meloxicam (solution, Labiana life science pharmaceutical factory)；3rd group by 20mg/kg.B.W. dosage (with En Nuosha
Star meter), i.e., 2mg/kg.B.W. dosage (in terms of Meloxicam), single intramuscular injection embodiment 5 contain Enrofloxacin and Mei Luo former times
The compound long-acting injection of health.
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 foreleg vein, about 4mL, is placed in heparin sodium heparin tube every time
In.Acquisition blood sample is centrifuged 10min through 4000r/min, draws upper plasma in PA tube, and after label, sealing is protected from light, -20
DEG C preservation is to be measured.Using the plasma sample of HPLC measuring method detection different time points, blood concentration-time data, warp are obtained
5.2 software of WinNonlin carries out pharmacokinetic parameters analysis, and pharmacokinetic parameters are shown in Table 4 and table 5.
4. Enrofloxacin of table is in the test intracorporal pharmacokinetic parameter of dog (n=6)
5. Meloxicam of table is in the test intracorporal pharmacokinetic parameter of dog (n=6)
By table 4 and table 5 as it can be seen that being compared with conventional formulation pharmacokinetic parameters, the present invention is containing Enrofloxacin and Meloxicam
After compound long-acting injection administered intramuscular, either Enrofloxacin or Meloxicam the intracorporal blood concentration of dog and often
Commercial preparation no significant difference is advised, but elimination half-life period and residence time significantly extend, and show excellent slow release effect.
Claims (10)
1. a kind of compound long-acting injection containing Enrofloxacin and Meloxicam, it is characterised in that including Enrofloxacin and/or its
Salt, in a dispersed form existing Meloxicam, Meloxicam solid dispersions, macromolecule retarding agent, wetting agent, decentralized medium；
Every 1000mL injection contains: 20~250g of Enrofloxacin and/or its salt (in terms of Enrofloxacin), in a dispersed form existing beauty
Lip river 5~50g of former times health, 5~30g of macromolecule retarding agent, 5~20g of wetting agent, surplus is decentralized medium；Wherein, discrete form exists
Meloxicam and Meloxicam solid dispersions (in terms of Meloxicam) mass ratio be 5:1~1:1.
2. compound long-acting injection according to claim 1, it is characterised in that every 1000mL injection contains: Enrofloxacin
And/or 100~200g of its salt (in terms of Enrofloxacin), in a dispersed form existing 10~25g of Meloxicam, macromolecule retarding agent
15~20g, 4~10g of wetting agent, surplus are decentralized medium；Wherein, Meloxicam existing for discrete form and Meloxicam solid
The mass ratio of dispersion (in terms of Meloxicam) is 2:1~1:1.
3. compound long-acting injection according to claim 1 or 2, it is characterised in that the enrofloxacin salt is selected from grace promise
Any one in husky star sodium, Enrofloxacin HCL and Enrofloxacin.
4. compound long-acting injection according to claim 1 or 2, it is characterised in that the Enrofloxacin or its salt are through super
Crushing of Ultrafine processing, Control granularity D90≤5 μm, and 25 μm or more of particle must not be detected；
The Meloxicam must not detect 25 μm or more of particle through ultramicro crushing treatment, Control granularity D90≤5 μm.
5. compound long-acting injection according to claim 1 or 2, it is characterised in that the Meloxicam solid dispersions
It is prepared using solvent-fusion method, comprising: carrier auxiliary material heating water bath to melting；Meloxicam through ultramicro crushing treatment
It is stirred evenly with dimethylformamide, after 0.5~1h of ultrasound, is added into the carrier auxiliary material of melting, stirs 0.5~1 hour, it will
Fusant is poured on the cooling stainless steel disc of frost, after cooling and solidifying, is pulverized and sieved to get Meloxicam solid dispersions.
6. compound long-acting injection according to claim 5, it is characterised in that the Meloxicam, dimethylformamide
Weight ratio with carrier auxiliary material is 1:1:3~5；The carrier auxiliary material is selected from poloxamer and/or polyethylene glycol.
7. compound long-acting injection according to claim 1 or 2, it is characterised in that the macromolecule retarding agent is selected from poly-
Vinyl alcohol, hypromellose, hyetellose, hydroxypropylcellulose, sodium carboxymethylcellulose, hyaluronic acid, xanthan gum, shell
Glycan, sodium alginate, gelatin, chitin, carboxymethyl chitosan, stearic acid, aluminum monostearate, aluminium distearate, aluminum stearate,
Rilanit special, beeswax, microwax, yellow wax, Chinese wax, polylactic acid, poly lactide-glycolide acid, polycaprolactone, polyoxy second
Alkene beeswax, tristerin, glycerin monostearate and polyoxyethylene (75) stearate mixture, Unigly GO 102S,
Any one or more in pegoxol 7 stearate；Preferably, the macromolecule retarding agent be rilanit special,
Selected from least one of aluminum monostearate, aluminium distearate and aluminum stearate and/or it is selected from polyvinyl alcohol, Chinese wax, microwax
With the combination of at least one of beeswax.
8. compound long-acting injection according to claim 1 or 2, it is characterised in that the wetting agent be selected from lecithin,
Soybean lecithin, hydroxylated lecithin, polysorbas20, polysorbate40, polysorbate60, Tween 80, Pluronic/Lutrol F 44, PLURONICS F87, pool Lip river
Husky nurse 237, Pluronic/Lutrol F 108, poloxamer188, span 20, span 40, sorbester p18, sorbester p38, sorbester p17, span 85, third
Glycol diethyl ester, propylene glycol monostearate, sodium lactate, stearic acid sodium lactate, four oleyl ether of polyoxyethylene (30EO) sorbierite,
Four stearyl ether of polyoxyethylene (60EO) sorbierite, four oleic acid ether of polyoxyethylene (40EO) sorbierite, polyoxyethylene (60EO) sorb
Four oleate of alcohol, polyoxyethylene (8) stearate, polyoxyethylene (12) stearate, polyoxyethylene (24) stearate, polyoxy
Ethylene (40) stearate, polyoxyethylene (50) stearate, polyoxyethylene (100) stearate, polyoxyethylene (110) are stearic
Acid esters, polyoxyethylene (30) rilanit special, polyoxyethylene (40) rilanit special, gathers polyoxyethylene (10) rilanit special
Ethylene oxide (50) rilanit special, polyoxyethylene (60) rilanit special, polyoxyethylene (10) castor oil, polyoxyethylene (35) castor
Sesame oil, polyoxyethylene (40) castor oil, polyoxyethylene (60) castor oil, polyoxyethylene (80) castor oil, polyoxyethylene (90) castor
Sesame oil, polyoxyethylene (100) castor oil, polyoxyethylene (300) monoleate, 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 polyoxyethylene glyceride, lauric acid polyoxyethylene glyceride,
Oleoyl polyoxyethylene glyceride, sub- oleoyl polyoxyethylene glyceride, three ceteareth -4- phosphate, ethylene glycol are stearic
Any one or more in acid esters and diethylene glycol stearate mixture；Preferably, the wetting agent is selected from lecithin
One of rouge and hydroxylated lecithin, the combination selected from least one of tween, sapn, lauric acid polyoxyethylene glyceride.
9. compound long-acting injection according to claim 1 or 2, it is characterised in that 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, oleic acid
Ethyl ester, N,N-dimethylformamide, triacetyl glycerine, medium chain fatty acid, Ergol, isopropyl myristate, formaldehyde
Contracting glycerol, glyceryl monooleate, any one or more in Masine 35-1.
10. the preparation method of the compound long-acting injection described in claim 1 containing Enrofloxacin and Meloxicam, feature exist
In including:
(a), decentralized medium is heated to 150~180 DEG C, and continues 1~1.5h；
(b), when the macromolecule retarding agent used for rilanit special and is selected from aluminum monostearate, aluminium distearate, aluminum stearate
At least one of when, into 120~140 DEG C of decentralized media for account for injection volume 60%~70% be added rilanit special and
Selected from least one of aluminum monostearate, aluminium distearate, aluminum stearate, and 1~2h is maintained at 120~140 DEG C, make height
The complete gelatinization of molecule retarding agent；It lets cool to 40-60 DEG C, adds except aluminum monostearate, aluminium distearate, aluminum stearate, hydrogenation
Macromolecule retarding agent, wetting agent, Enrofloxacin and/or its salt outside castor oil, in a dispersed form existing Meloxicam, Mei Luo
Former times health solid dispersions successively shear 0.5~2h, 0.5~2h of high pressure homogenizer homogeneous using high speed disperser or use high pressure
0.5~2h of homogenizer homogeneous shears 0.5~2h using high speed disperser；The decentralized medium being cooled to room temperature is taken, is settled to
1000mL；
When the macromolecule retarding agent of use does not include aluminum monostearate, aluminium distearate, aluminum stearate, rilanit special, take
The decentralized medium for accounting for injection volume 60%~70% is let cool to 40~60 DEG C, into decentralized medium be added macromolecule retarding agent,
There is Meloxicam, Meloxicam solid dispersions in wetting agent, Enrofloxacin and/or its salt, successively using height in a dispersed form
Fast dispersion machine shears 0.5~2h, 0.5~2h of high pressure homogenizer homogeneous or uses 0.5~2h of high pressure homogenizer homogeneous, or using high
Fast dispersion machine shears 0.5~2h；The decentralized medium being cooled to room temperature is taken, 1000mL is settled to.
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| CN201910655012.0A CN110327348A (en) | 2019-07-19 | 2019-07-19 | Compound long-acting injection and preparation method thereof containing Enrofloxacin and Meloxicam |
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| CN117530922A (en) * | 2024-01-09 | 2024-02-09 | 中国农业大学 | High-stability compound injection for livestock and preparation method and application thereof |
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| CN117530922A (en) * | 2024-01-09 | 2024-02-09 | 中国农业大学 | High-stability compound injection for livestock and preparation method and application thereof |
| CN117530922B (en) * | 2024-01-09 | 2024-04-26 | 中国农业大学 | High-stability compound injection for livestock and preparation method and application thereof |
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