CN106511355A - Florfenicol gel implant for veterinary use and preparation method of florfenicol gel implant - Google Patents
Florfenicol gel implant for veterinary use and preparation method of florfenicol gel implant Download PDFInfo
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- CN106511355A CN106511355A CN201610979562.4A CN201610979562A CN106511355A CN 106511355 A CN106511355 A CN 106511355A CN 201610979562 A CN201610979562 A CN 201610979562A CN 106511355 A CN106511355 A CN 106511355A
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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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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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
- A61K31/65—Tetracyclines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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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
- A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
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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
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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Abstract
The invention relates to a florfenicol gel implant for veterinary use. The florfenicol gel implant is prepared from the following raw materials in parts by weight: 2-5 parts of florfenicol, 4-10 parts of doxycycline hydrochloride, 8-12 parts of polylactic acid, 8-12 parts of PLGA, 70-90 parts of nitrogen-methyl pyrrolidone, 0.01-5 parts of poloxamer 188, 0.01-2 parts of monoethanolamine and 5-20 parts of benzyl alcohol. According to the florfenicol gel implant for veterinary use provided by the invention, through the combined application of the florfenicol and the doxycycline hydrochloride, a synergistic effect is achieved among the medicines, and the gel implant is prepared into the form of a sustained-release injection, so that an antibacterial effect is enhanced and a curative effect is improved; the appearance of drug-resistance bacteria is delayed or relieved; an antibacterial scope is widened for mixed infections; the doses of some medicines can be reduced, so that toxic and side reactions are relieved; and in addition, the cost of the florfenicol, which is used in a single mode, can be reduced.
Description
Technical field
The invention belongs to technical field of veterinary, more particularly to a kind of veterinary florfenicol gel implant and its preparation
Method.
Background technology
Florfenicol（Florfenicol, FF）, fluprofen is also called, Florfenicol, by elder generation of U.S. Ling-Bao Ya
（Schering-Plough）Company was succeeded in developing in 1988, was a kind of new chloromycetin broad spectrum antibiotic for animals, to various
Gram positive bacteria and gram negative bacteria and mycoplasma（Including cattle, the haemophiluss of pig, shigella dysenteriae, Salmonella,
Escherichia coli, streptococcus pneumoniae, hemophilus influenza, streptococcus, staphylococcus aureuses, chlamydia, leptospira, rickettsia
Deng）Bacterial disease, the especially respiratory system to poultry and the intestinal infection effect is significants such as caused pig, chicken, cattle, fish.
Florfenicol can suppress antibacterial 70S ribosomes, with the A positions receptor binding on ribosomal 50S subunits, suppress
The cruel based transferase of peptide, makes the extension of peptide chain be inhibited, and in making antibacterial, protein synthesis are disturbed, thus equal to G+ and G- bacterium
There is inhibitory action.Thiamphenicol can typically produce the cruel transferring enzyme of second with the Resistant strain of chloromycetin, and this enzyme is propagated with plasmid, and
Can make thiamphenicol that secondization reaction occur with chloromycetin, main portions occur on-the OH on its Alpha-Methyl position, make pharmacology live
Property disappear.Because-F instead of the-OH on thiamphenicol Alpha-Methyl in florfenicol so that Acetylase cannot be destroyed, because
This florfenicol is still sensitive with the bacterial strain of chloromycetin to resistance to thiamphenicol.Therefore florfenicol will not yellow bright to contain similar chlorine mould
, by plasmid-mediated produced drug resistance, many chloramphenicol resistance bacterial strains are still sensitive to florfenicol for element, thiamphenicol, therefore its
It is all effective to the bacterial strain of chloromycetin, thiamphenicol, oxytetracycline, sulfanilamide or ampicillin-resistant.
Florfenicol absorb it is rapid, in vivo widely distributed, has a broad antifungal spectrum, be not likely to produce drug resistance, and route of administration is more
Sample, takes orally and intramuscular injection is well-tolerated, but florfenicol is insoluble in water, and utilization rate is low, it is impossible to give full play to drug effect.And
Due to sick, animal appetite, drink are intended to decline even refusing to eat, drinking refusal, and impact is orally taken the photograph medicine, affected the treatment then；Florfenicol is noted
Though penetrating liquid improves utilization rate, during Clinical practice, frequent drug administration, arresting and easily causing to move in injection process
Thing stress, or even cause new disease, affect lapsing to for curative effect of medication and disease.Current fluorobenzene Buddhist nun wide variety of at home
Examining preparation mainly has injection, pre-mixing agent and a soluble powder, florfenicol durative action preparation for example aqueouss suspensoid injectio, microsphere,
Microemulsion, liposome, suspension emulsion, in-situ gel etc. also have been reported that, but they are all present, and preparation stability is poor, preparation process is multiple
It is miscellaneous, the shortcomings of side effect is larger.
The content of the invention
Present invention aim to overcome that the deficiencies in the prior art and a kind of veterinary florfenicol gel that provides is planted
Enter agent and preparation method thereof.
The object of the present invention is achieved like this：A kind of veterinary florfenicol gel implant, it is characterised in that：Including with
The raw material composition of lower parts by weight：2 ~ 5 parts of florfenicol, 4 ~ 10 parts of doxycycline hydrochloride, 8 ~ 12 parts of polylactic acid, PLGA 8-12
Part, 70 ~ 90 parts of n-methlpyrrolidone, 0.01 ~ 5 part of Poloxamer 188,0.01 ~ 2 part of monoethanolamine, 5 ~ 20 parts of benzyl alcohol.
A kind of veterinary florfenicol gel implant, it is characterised in that：Constitute including the raw material of following parts by weight：Fluorobenzene
Buddhist nun examine 3 ~ 4 parts, 6 ~ 8 parts of doxycycline hydrochloride, 9 ~ 11 parts of polylactic acid, PLGA 9-11 parts, 75 ~ 85 parts of n-methlpyrrolidone,
1 ~ 4 part of Poloxamer 188,0.5 ~ 1.5 part of monoethanolamine, 10 ~ 15 parts of benzyl alcohol.
A kind of veterinary florfenicol gel implant, it is characterised in that：Constitute including the raw material of following parts by weight：Fluorobenzene
Buddhist nun examine 3.5 parts, 7 parts of doxycycline hydrochloride, 10 parts of polylactic acid, 10 parts of PLGA, 80 parts of n-methlpyrrolidone, poloxamer
188 3 parts, 1 part of monoethanolamine, 12 parts of benzyl alcohol.
A kind of preparation method of veterinary florfenicol gel implant, it is characterised in that：Have steps of：
Step 1）, the n-methlpyrrolidone that takes deal described in 70% ~ 80% be put in dense preparing tank, be heated to 30 ~ 60 degrees Celsius,
The polylactic acid and PLGA of the deal is added while stirring, adds polylactic acid and PLGA later in the environment of 30 ~ 60 degrees Celsius
Insulation 10 ~ 14 hours, while insulation, is stirred, and obtains mixed liquor 1；
Step 2）, take deal described in 10% ~ 15% n-methlpyrrolidone be put into cleaning container in, take the fluorine of the deal
Benzene Buddhist nun examines and is added in n-methlpyrrolidone, stirs 20 ~ 40 minutes, is completely dissolved n-methlpyrrolidone, is mixed
Close liquid 2；
Step 3）, mixed liquor 2 is added to into step 1）The mixed liquor 1 of middle acquisition）In, mixed liquor 3 is obtained, by 3 constant temperature of mixed liquor
To 35 ~ 65 degrees Celsius, and 1 ~ 3 hour is stirred in the state of 35 ~ 65 degrees Celsius, make 3 mix homogeneously of mixed liquor；
Step 4）, mixed liquor 3 carried out into coarse filtration using filter, the mixed liquor 3 after coarse filtration is put in dilute preparing tank, take remaining 10% ~
The n-methlpyrrolidone of 15% deal is by step 1）In dense preparing tank, step 2）In container and filter in the mixing that remains
Liquid 1, mixed liquor 2 and mixed liquor 3 are punched in dilute preparing tank, then circulation stirring 5 ~ 10 minutes；Obtain medicinal liquid 1；
Step 5）, by medicinal liquid 1 be placed on oscillator shake 1 ~ 5 minute, then doxycycline hydrochloride is added in medicinal liquid 1, plus
It is stirred while entering, obtains medicinal liquid 2；
Step 6）, by medicinal liquid 2 be placed on oscillator shake 1 ~ 5 minute, then monoethanolamine is added in medicinal liquid 2, addition
It is stirred simultaneously, the pH value of medicinal liquid 1 is scheduled on into 3.2 ~ 4.3；Obtain medicinal liquid 3；
Step 7）, the benzyl alcohol of the deal and Poloxamer 188 be added in medicinal liquid 2, side is stirred while addition,
Place at room temperature 20 ~ 30 hours after fully dissolving, then filtered using microporous filter membrane, after filtration, can obtain described
Veterinary florfenicol gel implant.
Step 2）Described in container be stainless steel cask；Step 5）Described in oscillator be turbula shaker.
The use in conjunction of florfenicol and doxycycline hydrochloride can be subtracted in the present invention collaboration that plays medicine and by its
Slow releasing injection is prepared into, antibacterial action can be strengthened and improved curative effect；Delay or reduce the appearance of fastbacteria；Can to mixed infection
Expand antibacterial range；Individual drugs dosage can be reduced, so as to reduce toxicity；On the other hand florfenicol can be reduced alone
Cost.
Description of the drawings
Fig. 1 is florfenicol standard curve.
Fig. 2 is impact of the different carriers to florfenicol release in vitro rate.
Fig. 3 is impact of the different carriers to florfenicol preparation.
Specific embodiment
Embodiment 1：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：3.5 grams of florfenicol, 7 grams of doxycycline hydrochloride, 10 grams of polylactic acid, 10 grams of PLGA, 80 grams of n-methlpyrrolidone,
3 grams of Poloxamer 188,1 gram of monoethanolamine, 12 grams of benzyl alcohol.
A kind of preparation method of veterinary florfenicol gel implant, it is characterised in that：Have steps of：
Step 1）, the n-methlpyrrolidone that takes deal described in 70% be put in dense preparing tank, be heated to 37 degrees Celsius, while stirring
The polylactic acid and PLGA of the deal is added, and after adding polylactic acid and PLGA, 12 hours is incubated in the environment of 37 degrees Celsius,
While insulation, it is stirred, obtains mixed liquor 1；
Step 2）, take deal described in 15% n-methlpyrrolidone be put into cleaning stainless steel cask in, take the fluorine of the deal
Benzene Buddhist nun examines and is added in n-methlpyrrolidone, stirs 30 minutes, is completely dissolved n-methlpyrrolidone, obtains mixed liquor
2；
Step 3）, mixed liquor 2 is added to into step 1）The mixed liquor 1 of middle acquisition）In, mixed liquor 3 is obtained, by 3 constant temperature of mixed liquor
To 40 degrees Celsius, and 2 hours are stirred in the state of 40 degrees Celsius, make 3 mix homogeneously of mixed liquor；
Step 4）, mixed liquor 3 carried out into coarse filtration using filter, the mixed liquor 3 after coarse filtration is put in dilute preparing tank, takes remaining 15%
The n-methlpyrrolidone of deal is by step 1）In dense preparing tank, step 2）In container and filter in the mixed liquor that remains
1st, mixed liquor 2 and mixed liquor 3 are punched in dilute preparing tank, then circulation stirring 8 minutes；Obtain medicinal liquid 1；
Step 5）, by medicinal liquid 1 be placed on turbula shaker shake 3 minutes, then doxycycline hydrochloride is added in medicinal liquid 1,
It is stirred while addition, obtains medicinal liquid 2；
Step 6）, by medicinal liquid 2 be placed on turbula shaker shake 3 minutes, then monoethanolamine is added in medicinal liquid 2, add
While be stirred, the pH value of medicinal liquid 1 is scheduled on into 3.5；Obtain medicinal liquid 3；
Step 7）, the benzyl alcohol of the deal and Poloxamer 188 be added in medicinal liquid 2, side is stirred while addition,
Place at room temperature 24 hours after fully dissolving, then filtered using microporous filter membrane, 0.45 μm of filtering with microporous membrane of first Jing
Device coarse filtration, then Jing after 0.22 μm of filtering with microporous membrane, you can obtain described veterinary florfenicol gel implant.
The present invention substantially reduces frequency injection, reduce animal injection stress, strengthen the compliance that medicine is used.Times for spraying
Reduction, ensured administration time, it is to avoid developing rapidly for Resistant strain, can extend then the service life of novel chiral synthon.
Medicine blood drug level is improved, the total using dosage of medicine is reduced；Effective blood drug concentration can be chronically at, drug effect can be improved.Blood medicine
Concentration curve can reduce the toxic and side effects of medicine without obvious Wave crest and wave trough, reduce animal and use upper risk.Medicine can be passed
Site of action is delivered to, is eliminated and is reduced side effect.
Experiment 1：The quality stability of veterinary florfenicol gel implant.
The preparation of florfenicol standard curve
Precision weighs florfenicol standard substance 0.0104g, is placed in 100mL volumetric flasks, plus mobile phase constant volume is to 100ml, configuration
Into the storing liquid that concentration is 100 μ g/mL, after shaking up, be taken out 1 respectively, 2,4,6,8,10mL be placed in 100mL volumetric flasks,
Plus distilled water constant volume is to 100mL, peak area, 10 μ L of each sample introduction, Mei Yinong after shaking up, is surveyed respectively on high performance liquid chromatograph
Degree is determined 3 times, takes peak area meansigma methodss, draws standard curve；As a result such as Fig. 1.
The screening of prescription
The preparation and evaluation of florfenicol gel implant
Polylactic acid and PLGA are slowly added in the 10mL glass centrifuge tubes of appropriate n-methlpyrrolidone, are careful not to
Polylactic acid is adhered on tube wall.Then mixed liquor is placed on into 24h in 37 DEG C of electro-heating standing-temperature cultivators, then by the fluorine of precise
Benzene Buddhist nun is examined in the polymer solution for adding own Jing dissolvings, vibrates 2min, be supplemented with n-methlpyrrolidone and arrive on spiral agitator
Full dose, and 2min is vibrated on turbula shaker again, medicine is sufficiently mixed and dissolving, then this solution is placed at room temperature
Storage 24h.
Vitro release is determined
It is slowly dropped into containing 5 mL release medium through 0.2 mL of preparation of room temperature storage（Phosphate buffered solution pH 7.4 adds
The methanol that 0.5% Tween 80 adds 5%）Glass centrifuge tube in, screw lid, the constant temperature that glass centrifuge tube is placed into 37 DEG C shaken
Swing in incubator, setting hunting speed is 30 rpm.Release medium is slowly withdrawn in different interval times, is released with fresh
Put medium to be changed, METHOD FOR CONTINUOUS DETERMINATION one week, every time each sample determination 3 times, detect the release in vitro of each time period of gel
Rate and accumulative release rate.
Outward appearance（Character, clarity are determined）And syringeability（Viscosimetric analysis）
The In-situ forming gel implant of preparation is positioned under the daylight lamp that illuminance is 2000 LX, visual observations, solution presents clear
Bright state, foreign.It is with 1 mL syringe draw solutions, slow to extract out, observe the syringeability of gel.
Gel formation time situation
The florfenicol In-situ forming gel implant liquid-transfering gun deposited through room temperature is drawn into 0.2 mL, is slowly dropped into and is filled 10
ML phosphate buffers（pH=7.4）Glass centrifuge tube in, while with timer timing gel formation time.Experimental result：It is solidifying
Glue implant forms white gels granule in release medium, and is deposited to the bottom of glass centrifuge tube（Gelling time is shown in Table 3）.
The screening of prescription
Orthogonal test is carried out using orthogonal table, 1,2 are shown in Table.Optimum prescription is filtered out according to result.
1 factor of table and level
| Level | A1 solvents | B1 concentration |
| 1 | Acetone | 8% |
| 2 | N-methlpyrrolidone | 12% |
| 3 | DMSO | 10% |
Table 2 tests orthogonal packet
| Tested number | A | B |
| 1 | 1 | 1 |
| 2 | 1 | 2 |
| 3 | 2 | 1 |
| 4 | 2 | 2 |
The results are shown in Table 3
Table 3 tests orthogonal result
| Tested number | Outward appearance and syringeability | Gelling time |
| 1 | Well | 45s |
| 2 | Well | 42s |
| 3 | It is bad | 56s |
| 4 | Well | 44s |
As a result show, 8% acetone and 10% DMSO are used as solvent, although the florfenicol situ-gel outward appearance prepared and logical
Pin is good, but has phenomenon of burst release in the early stage（Such as Fig. 2）, and at the 6th day or so, the preparation of medicine is up to more than 90%.With
12% n-methlpyrrolidone is that florfenicol situ-gel prepared by solvent, not only outward appearance and syringeability are good, and without prominent
Phenomenon is released, drug release rate is slow（Such as Fig. 3）.Therefore, polylactic acid is selected as microcarrier, 12% n-methlpyrrolidone
The gel effect prepared as the solvent of polylactic acid is best.
Experiment 2：The formational situation of veterinary florfenicol gel implant and production.
The preparation of florfenicol gel implant and design of scheme
Appropriate n-methlpyrrolidone is added in electrical heating Agitation Tank and is heated, 2400 g polylactic acid of precise and 2400
G PLGA are added to simultaneously heated and stirred extremely dissolving in the Agitation Tank for fill n-methlpyrrolidone；Then 4000 g of precise again
Florfenicol has been added in the fully solution of dissolving, is stirred to fully dissolving, is supplemented with n-methlpyrrolidone to full dose i.e. 20
L, makes medicine be sufficiently mixed and dissolving, then this solution placement is deposited 24 h, sampling detection at room temperature.
4 factor of table and level
Table 5 tests orthogonal result
Evaluation index and result
Table 6 tests orthogonal result
| Tested number | Mixing situation | Release time | Outward appearance and cleansing pin situation | Gelling time |
| 1 | Well | Discharge to 72h | Well | 9s |
| 2 | Well | Discharge to 90h | Well | 8s |
| 3 | Well | Discharge to 68h | It is bad | 9s |
| 4 | Well | Discharge to 96h | Well | 24s |
| 5 | Well | Discharge to 82h | Well | 20s |
| 6 | Well | Discharge to 74h | It is bad | 25s |
| 7 | Well | Discharge to 98h | Well | 10s |
| 8 | Well | Discharge to 84h | It is bad | 9s |
| 9 | Well | Discharge to 70h | It is bad | 12s |
Result of the test shows, according to the prescription that laboratory stage determines, during according to the temperature of Workshop Production situation setting with mixing
Between, show 8 h-50 DEG C, 12 h-37 DEG C, 24 h-37 DEG C（Time-temperature）Requirement can be reached, it is contemplated that mixing time is to knot
Fruit has no significant effect, and it is ideal that mixing time is set to 12h by preferably cost-effective and increase production yield.
Product is using report：
2 months 2016, Henan assist source animal husbandry cultivation company limited reflection weather anomaly caused the child care swinery of a collection of 20kg or so
Cough phenomenon, morning serious symptom, at night patrol can often hear cough, are thought that wind-engaging flu becomes not shown interest in and only exist
Reduce ventilation time daytime, find that sick pig spirit is depressed afterwards, body temperature up to 41 DEG C ~ 42 DEG C, cough, loss of appetite or useless exhausted, by hair
Thick disorderly rapid breathing, height are difficult, and with ventral breathing, nose disk and ear cyanosis, mouth and nose flow out foam sample secretions,
Serious death by suffocation.Dissect the clearly visible pathological changes of dead sick pig and be mainly pneumonia pleuritis.Pneumonia mostly is both sides property pneumonia can
See that fibrous substance attaches to surface.There are a large amount of liquid with blood in thoracic cavity, lungs have adhesion with pleura.Mesenteric lymph node is bright
Aobvious enlargement, splenomegaly, softness, other organs have no significant change.Pig transmissible pleura is diagnosed as according to clinical manifestation and dissection
Pneumonia, after take pulmonary lymph nodes smear after the pleural effusion of sick pig, Gram’s staining, microscopy, it is seen that negative red bead
Bacillus.Every 3mL of intramuscular injection of the present invention is being used, is being administered once, symptom is being substantially achieved control from the 3rd day, and death do not occur yet, 5
After it, swinery recovers normal.Prove that the present invention has good Clinical practice curative effect.
In following examples, the preparation method of veterinary florfenicol gel implant is same as Example 1, repeats no more.
Embodiment 2：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 7 grams of doxycycline hydrochloride, 10 grams of polylactic acid, 10 grams of PLGA, 80 grams of n-methlpyrrolidone, pool
188 3 grams of Luo Shamu, 1 gram of monoethanolamine, 12 grams of benzyl alcohol.
Embodiment 3：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：2 grams of florfenicol, 4 grams of doxycycline hydrochloride, 8 grams of polylactic acid, 8 grams of PLGA, 70 grams of n-methlpyrrolidone, pool Lip river
188 0.01 grams of husky nurse, 0.01 gram of monoethanolamine, 5 grams of benzyl alcohol.
Embodiment 4：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 10 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 12 grams of PLGA, 90 grams of n-methlpyrrolidone, pool
188 5 grams of Luo Shamu, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 5：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：20 grams of florfenicol, 40 grams of doxycycline hydrochloride, 80 grams of polylactic acid, 80 grams of PLGA, 700 grams of n-methlpyrrolidone,
0.1 gram of Poloxamer 188,0.1 gram of monoethanolamine, 50 grams of benzyl alcohol.
Embodiment 6：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：Florfenicol 200,400 grams of doxycycline hydrochloride, 800 grams of polylactic acid, 800 grams of PLGA, n-methlpyrrolidone
70000 grams, 1 gram of Poloxamer 188,1 gram of monoethanolamine, 500 grams of benzyl alcohol.
Embodiment 7：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 4 grams of doxycycline hydrochloride, 8 grams of polylactic acid, 8 grams of PLGA, 70 grams of n-methlpyrrolidone, pool Lip river
188 0.01 grams of husky nurse, 0.01 gram of monoethanolamine, 5 grams of benzyl alcohol.
Embodiment 8：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：2 grams of florfenicol, 10 grams of doxycycline hydrochloride, 8 grams of polylactic acid, 8 grams of PLGA, 70 grams of n-methlpyrrolidone, pool Lip river
188 0.01 grams of husky nurse, 0.01 gram of monoethanolamine, 5 grams of benzyl alcohol.
Embodiment 9：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：2 grams of florfenicol, 4 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 8 grams of PLGA, 70 grams of n-methlpyrrolidone, pool Lip river
188 0.01 grams of husky nurse, 0.01 gram of monoethanolamine, 5 grams of benzyl alcohol.
Embodiment 10：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：2 grams of florfenicol, 4 grams of doxycycline hydrochloride, 8 grams of polylactic acid, 12 grams of PLGA, 70 grams of n-methlpyrrolidone, pool Lip river
188 0.01 grams of husky nurse, 0.01 gram of monoethanolamine, 5 grams of benzyl alcohol.
Embodiment 11：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：2 grams of florfenicol, 4 grams of doxycycline hydrochloride, 8 grams of polylactic acid, 8 grams of PLGA, 90 grams of n-methlpyrrolidone, pool Lip river
188 0.01 grams of husky nurse, 0.01 gram of monoethanolamine, 5 grams of benzyl alcohol.
Embodiment 12：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：2 grams of florfenicol, 4 grams of doxycycline hydrochloride, 8 grams of polylactic acid, 8 grams of PLGA, 70 grams of n-methlpyrrolidone, pool Lip river
188 5 grams of husky nurse, 0.01 gram of monoethanolamine, 5 grams of benzyl alcohol.
Embodiment 13：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：2 grams of florfenicol, 4 grams of doxycycline hydrochloride, 8 grams of polylactic acid, 8 grams of PLGA, 70 grams of n-methlpyrrolidone, pool Lip river
188 0.01 grams of husky nurse, 2 grams of monoethanolamine, 5 grams of benzyl alcohol.
Embodiment 14：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：2 grams of florfenicol, 4 grams of doxycycline hydrochloride, 8 grams of polylactic acid, 8 grams of PLGA, 70 grams of n-methlpyrrolidone, pool Lip river
188 0.01 grams of husky nurse, 0.01 gram of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 15：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 10 grams of doxycycline hydrochloride, 8 grams of polylactic acid, 8 grams of PLGA, 70 grams of n-methlpyrrolidone, pool Lip river
188 0.01 grams of husky nurse, 0.01 gram of monoethanolamine, 5 grams of benzyl alcohol.
Embodiment 16：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 4 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 8 grams of PLGA, 70 grams of n-methlpyrrolidone, pool Lip river
188 0.01 grams of husky nurse, 0.01 gram of monoethanolamine, 5 grams of benzyl alcohol.
Embodiment 17：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：2 grams of florfenicol, 4 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 12 grams of PLGA, 70 grams of n-methlpyrrolidone, pool
188 0.01 grams of Luo Shamu, 0.01 gram of monoethanolamine, 5 grams of benzyl alcohol.
Embodiment 18：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 10 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 12 grams of PLGA, 90 grams of n-methlpyrrolidone, pool
188 5 grams of Luo Shamu, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 19：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 10 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 12 grams of PLGA, 90 grams of n-methlpyrrolidone, pool
188 5 grams of Luo Shamu, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 20：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 10 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 12 grams of PLGA, 90 grams of n-methlpyrrolidone, pool
188 5 grams of Luo Shamu, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 21：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 10 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 12 grams of PLGA, 90 grams of n-methlpyrrolidone, pool
188 5 grams of Luo Shamu, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 22：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 10 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 12 grams of PLGA, 90 grams of n-methlpyrrolidone, pool
188 5 grams of Luo Shamu, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 23：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：50 grams of florfenicol, 100 grams of doxycycline hydrochloride, 120 grams of polylactic acid, 120 grams of PLGA, n-methlpyrrolidone 900
Gram, 50 grams of Poloxamer 188,20 grams of monoethanolamine, 200 grams of benzyl alcohol.
Embodiment 24：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：500 grams of florfenicol, 1000 grams of doxycycline hydrochloride, 1200 grams of polylactic acid, 1200 grams of PLGA, nitrogen-crassitude
9000 grams of ketone, 500 grams of Poloxamer 188,200 grams of monoethanolamine, 2000 grams of benzyl alcohol.
Embodiment 25：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：2 grams of florfenicol, 10 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 12 grams of PLGA, 90 grams of n-methlpyrrolidone, pool
188 5 grams of Luo Shamu, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 26：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 4 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 12 grams of PLGA, 90 grams of n-methlpyrrolidone, pool
188 5 grams of Luo Shamu, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 27：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 10 grams of doxycycline hydrochloride, 8 grams of polylactic acid, 12 grams of PLGA, 90 grams of n-methlpyrrolidone, pool
188 5 grams of Luo Shamu, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 28：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 10 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 8 grams of PLGA, 90 grams of n-methlpyrrolidone, pool
188 5 grams of Luo Shamu, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 29：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 10 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 12 grams of PLGA, 70 grams of n-methlpyrrolidone, pool
188 5 grams of Luo Shamu, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 30：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 10 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 12 grams of PLGA, 90 grams of n-methlpyrrolidone, pool
188 0.01 grams of Luo Shamu, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 31：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 10 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 12 grams of PLGA, 90 grams of n-methlpyrrolidone, pool
188 5 grams of Luo Shamu, 0.01 gram of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 32：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 10 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 12 grams of PLGA, 90 grams of n-methlpyrrolidone, pool
188 5 grams of Luo Shamu, 2 grams of monoethanolamine, 5 grams of benzyl alcohol.
Embodiment 33：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：2 grams of florfenicol, 4 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 12 grams of PLGA, 90 grams of n-methlpyrrolidone, pool
188 5 grams of Luo Shamu, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 34：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：2 grams of florfenicol, 10 grams of doxycycline hydrochloride, 8 grams of polylactic acid, 12 grams of PLGA, 90 grams of n-methlpyrrolidone, pool
188 5 grams of Luo Shamu, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 35：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：2 grams of florfenicol, 10 grams of doxycycline hydrochloride, 12 grams of polylactic acid, 8 grams of PLGA, 90 grams of n-methlpyrrolidone, pool
188 5 grams of Luo Shamu, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 36：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 10 grams of doxycycline hydrochloride, 8 grams of polylactic acid, 8 grams of PLGA, 90 grams of n-methlpyrrolidone, pool Lip river
188 5 grams of husky nurse, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Embodiment 37：A kind of veterinary florfenicol gel implant, it is characterised in that：Including the raw material of following parts by weight
Composition：5 grams of florfenicol, 4 grams of doxycycline hydrochloride, 8 grams of polylactic acid, 12 grams of PLGA, 70 grams of n-methlpyrrolidone, pool Lip river
188 5 grams of husky nurse, 2 grams of monoethanolamine, 20 grams of benzyl alcohol.
Claims (5)
1. a kind of veterinary florfenicol gel implant, it is characterised in that：Constitute including the raw material of following parts by weight：Fluorobenzene Buddhist nun
Examine 2 ~ 5 parts, 4 ~ 10 parts of doxycycline hydrochloride, 8 ~ 12 parts of polylactic acid, PLGA 8-12 parts, 70 ~ 90 parts of n-methlpyrrolidone, pool
188 0.01 ~ 5 parts of Luo Shamu, 0.01 ~ 2 part of monoethanolamine, 5 ~ 20 parts of benzyl alcohol.
2. a kind of veterinary florfenicol gel implant, it is characterised in that：Constitute including the raw material of following parts by weight：Fluorobenzene Buddhist nun
Examine 3 ~ 4 parts, 6 ~ 8 parts of doxycycline hydrochloride, 9 ~ 11 parts of polylactic acid, PLGA 9-11 parts, 75 ~ 85 parts of n-methlpyrrolidone, pool
188 1 ~ 4 parts of Luo Shamu, 0.5 ~ 1.5 part of monoethanolamine, 10 ~ 15 parts of benzyl alcohol.
3. a kind of veterinary florfenicol gel implant, it is characterised in that：Constitute including the raw material of following parts by weight：Fluorobenzene Buddhist nun
Examine 3.5 parts, 7 parts of doxycycline hydrochloride, 10 parts of polylactic acid, 10 parts of PLGA, 80 parts of n-methlpyrrolidone, Poloxamer 188
3 parts, 1 part of monoethanolamine, 12 parts of benzyl alcohol.
4. a kind of preparation method of veterinary florfenicol gel implant, it is characterised in that：Have steps of：
Step 1）, the n-methlpyrrolidone that takes deal described in 70% ~ 80% be put in dense preparing tank, be heated to 30 ~ 60 degrees Celsius,
The polylactic acid and PLGA of the deal is added while stirring, adds polylactic acid and PLGA later in the environment of 30 ~ 60 degrees Celsius
Insulation 10 ~ 14 hours, while insulation, is stirred, and obtains mixed liquor 1；
Step 2）, take deal described in 10% ~ 15% n-methlpyrrolidone be put into cleaning container in, take the fluorine of the deal
Benzene Buddhist nun examines and is added in n-methlpyrrolidone, stirs 20 ~ 40 minutes, is completely dissolved n-methlpyrrolidone, is mixed
Close liquid 2；
Step 3）, mixed liquor 2 is added to into step 1）The mixed liquor 1 of middle acquisition）In, mixed liquor 3 is obtained, by 3 constant temperature of mixed liquor
To 35 ~ 65 degrees Celsius, and 1 ~ 3 hour is stirred in the state of 35 ~ 65 degrees Celsius, make 3 mix homogeneously of mixed liquor；
Step 4）, mixed liquor 3 carried out into coarse filtration using filter, the mixed liquor 3 after coarse filtration is put in dilute preparing tank, take remaining 10% ~
The n-methlpyrrolidone of 15% deal is by step 1）In dense preparing tank, step 2）In container and filter in the mixing that remains
Liquid 1, mixed liquor 2 and mixed liquor 3 are punched in dilute preparing tank, then circulation stirring 5 ~ 10 minutes；Obtain medicinal liquid 1；
Step 5）, by medicinal liquid 1 be placed on oscillator shake 1 ~ 5 minute, then doxycycline hydrochloride is added in medicinal liquid 1, plus
It is stirred while entering, obtains medicinal liquid 2；
Step 6）, by medicinal liquid 2 be placed on oscillator shake 1 ~ 5 minute, then monoethanolamine is added in medicinal liquid 2, addition
It is stirred simultaneously, the pH value of medicinal liquid 1 is scheduled on into 3.2 ~ 4.3；Obtain medicinal liquid 3；
Step 7）, the benzyl alcohol of the deal and Poloxamer 188 be added in medicinal liquid 2, side is stirred while addition,
Place at room temperature 20 ~ 30 hours after fully dissolving, then filtered using microporous filter membrane, after filtration, can obtain described
Veterinary florfenicol gel implant.
5. the preparation method of veterinary florfenicol gel implant according to claim 4, it is characterised in that：Step 2）In
Described container is stainless steel cask；Step 5）Described in oscillator be turbula shaker.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610979562.4A CN106511355A (en) | 2016-11-08 | 2016-11-08 | Florfenicol gel implant for veterinary use and preparation method of florfenicol gel implant |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610979562.4A CN106511355A (en) | 2016-11-08 | 2016-11-08 | Florfenicol gel implant for veterinary use and preparation method of florfenicol gel implant |
Publications (1)
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| CN106511355A true CN106511355A (en) | 2017-03-22 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201610979562.4A Pending CN106511355A (en) | 2016-11-08 | 2016-11-08 | Florfenicol gel implant for veterinary use and preparation method of florfenicol gel implant |
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| CN (1) | CN106511355A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103202802A (en) * | 2013-04-22 | 2013-07-17 | 南京农业大学 | In-situ gel formulation for florfenicol injection and preparation method thereof |
| CN103830162A (en) * | 2012-11-23 | 2014-06-04 | 青岛康地恩动物药业有限公司 | Preparation method of doxycycline gel |
| CN105012320A (en) * | 2015-07-20 | 2015-11-04 | 济南亿民动物药业有限公司 | Preparation technology for compound solution of florfenicol and doxycycline |
-
2016
- 2016-11-08 CN CN201610979562.4A patent/CN106511355A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103830162A (en) * | 2012-11-23 | 2014-06-04 | 青岛康地恩动物药业有限公司 | Preparation method of doxycycline gel |
| CN103202802A (en) * | 2013-04-22 | 2013-07-17 | 南京农业大学 | In-situ gel formulation for florfenicol injection and preparation method thereof |
| CN105012320A (en) * | 2015-07-20 | 2015-11-04 | 济南亿民动物药业有限公司 | Preparation technology for compound solution of florfenicol and doxycycline |
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