CN108743541A - Water-soluble veterinary drug preparation and preparation method thereof - Google Patents
Water-soluble veterinary drug preparation and preparation method thereof Download PDFInfo
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- CN108743541A CN108743541A CN201810656717.XA CN201810656717A CN108743541A CN 108743541 A CN108743541 A CN 108743541A CN 201810656717 A CN201810656717 A CN 201810656717A CN 108743541 A CN108743541 A CN 108743541A
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- water
- florfenicol
- veterinary drug
- preparation
- drug preparation
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
The present invention discloses a kind of water-soluble veterinary drug preparation and preparation method thereof, including following mass fraction than component：Florfenicol 20-25%, inclusion agents 71.9-76.9% dissolve out agent 1.5-2.3%, dispersant 0.7-0.9%, cosolvent 0.4-0.7%.Water solubility veterinary drug preparation disclosed by the invention and preparation method thereof, pass through molecule inclusion technology, solve the problems, such as that Florfenicol is undissolved in water, greatly improve the bioavilability of product, common centrifugal spray handicraft product heap density is improved by the improvement of technological parameter simultaneously, so that product heap density has been reached and is more suitable for Feed Enterprise and cultivates the level that terminal uses, while improving product mobility, packaging material usage amount is saved, significant economic results in society are created.
Description
Technical field
The invention belongs to field of veterinary medicine preparation, more particularly, to a kind of water-soluble veterinary drug preparation and preparation method thereof.
Background technology
Florfenicol is also known as Florfenicol, is a kind of excellent animal specific broad-spectrum antibiotic, has has a broad antifungal spectrum, inhales
It keeps well, be distributed the features such as wide, safe and efficient in vivo, be especially a cancellation the shortcomings that chloramphenicol destroys hemopoietic function of bone marrow, without latent
Induced aplastic anemia, teratogenesis, carcinogenic and mutagenesis.The poultry being widely used on veterinary clinic caused by sensitive bacteria
The treatment of bacterial disease in poultry, and significant effect, no residual chloromycetin problem, are not likely to produce drug resistance, be Thiamphenicol most
Good substitute.But Florfenicol raw material is almost insoluble in water, and common process product bioavilability is low, seriously affects clinical fortune
With.Therefore, the maximum technical barrier of florfenicol formulations is to improve product solubility in water, and formulation products are in water not
Molten, can not especially drink water use on poultry.Even if in addition often heap density is very low for conventional water-soluble formulation products, cause
Inconvenient for use and drug waste, threatening environment safety；Secondly, the vitro Drug dissolution rate of florfenicol formulations is slower, animal
It needs that the long period is waited for can be only achieved haemoconcentration after suitable edible, and then be easy to cause that medication is uncontrolled, and medicine is residual larger.Institute
The solubility of florfenicol formulations in water is improved, for improving its bioavilability, dissolution rate and expanding clinical application
Range is of great significance.
Invention content
The present invention for overcome the deficiencies in the prior art, provides the water solubility that a kind of solubility is high, In vitro dissolution rate is fast
Veterinary drug preparation and preparation method thereof.
To achieve the goals above, the present invention uses following technical scheme：A kind of water solubility veterinary drug preparation, including following matter
Measure the component of score ratio：Florfenicol 20-25%, inclusion agents 71.9-76.9% dissolve out agent 1.5-2.3%, dispersant 0.7-
0.9%, cosolvent 0.4-0.7%.
Use inclusion agents in the present invention, realize the stability of material by molecule inclusion technology, it is non-degradable it is non-discolouring not
Caking, high degree improve properties of product.
Further, the dissolution agent is the mixture of Macrogol 4000 and Macrogol 6000
Further, the inclusion agents are the mixture of beta-cyclodextrin and HYDROXYPROPYL BETA-CYCLODEXTRIN；The beta-cyclodextrin
Mass ratio with HYDROXYPROPYL BETA-CYCLODEXTRIN is 5:1.
Further, the dispersant is the combination of one or both of propylene glycol block polyether, poly glycol monomethyl ether.
Further, the cosolvent is the combination of one or more of dimethyl sulfoxide (DMSO), sodium succinate, glycerine.
The invention also discloses the preparation methods of the water-soluble veterinary drug preparation, include the following steps：
A, to weigh Florfenicol, inclusion agents, dispersant and cosolvent respectively by the mass fraction percentage spare；
B, Florfenicol and inclusion agents are uniformly mixed, are stirred continuously in 80~83 DEG C of hot water of input and can be obtained molecule packet
Close liquid, ratio of water to material 2:1；
C, when molecule inclusion liquid temperature in step b is stablized in 80~83 DEG C of ranges, input dispersant, cosolvent, clarification
Stirring heat preservation 1h afterwards, then carries out it centrifugal spray drying processing using drying machine with centrifugal spray, crosses 80 mesh sieve, you can obtain
Finished product.
Further, in the step c during centrifugal spray drying by the size controlling of water-soluble veterinary drug preparation 120
~160 μm.
Further, the inlet air temperature in the step c when centrifugal spray drying is 175~180 DEG C, leaving air temp 90
±2℃。
The present invention uses molecule inclusion technology in preparation process so that molecular state can be presented in material, with molecularity
State is being completely dissolved in water, and solubility is high, and water-soluble ability is strong, efficiently solves the problems, such as that the water-soluble speed of traditional pulvis is slow；
Secondly, pulvis upon dissolution, can be realized and be long placed in no precipitation, can meet the use demand of poultry drinking-water and domestic animal spice simultaneously；
Powder processed is carried out by the way of centrifugal spray, efficiently solves Florfenicol indissoluble solution and low bulk density Clinical practice in water
Limited problem, the product heap density being prepared is high, and then effectively enhances the water solubility of product, and it is slow both to have solved water-soluble speed
Slow problem, and solve the problems, such as that product heap is low density, avoiding conventional water-soluble Florfenicol, routinely production heap density is low
The phenomenon that occur, have prodigious technical advantage；Secondly, the stability of drug character is improved by molecule inclusion technology, is made
Pulvis it is non-degradable it is non-discolouring do not lump, be less prone to rotten situation, improve that pulvis is edible to obtain safety；Dissolving out agent can
Synergistic effect is generated with Florfenicol, the bioactivity of Florfenicol is improved, improves its dissolution rate in vitro, is ensured few
The effect of just capable of being rapidly reached effective blood concentration on the basis of the use of amount Florfenicol raw material medicine, play Florfenicol.
The present invention uses centrifugal spray technique productions water solubility veterinary drug preparation, and it is convenient that technological approaches is realized, production capacity is high, cost
It is low, it is produced suitable for Industrialization；This product solubility is high, dissolving is rapid, heap appropriate density, high production capacity low cost fluorobenzene Buddhist nun
Preparation is examined, Clinical practice is facilitated, being truly realized cost efficiency in cultivation terminal is of great significance.
In conclusion the present invention has the following advantages：By molecule inclusion technology, it is insoluble in water to solve Florfenicol
The problem of solution, greatly improves the bioavilability of product, while improving common centrifugation spray by the improvement of technological parameter
Mist handicraft product heap density makes product heap density reach and is more suitable for Feed Enterprise and cultivates the level that terminal uses, carries simultaneously
High product mobility, saves packaging material usage amount；The external dissolution rate of Florfenicol is effectively increased, fluorobenzene is well played
The effect of Buddhist nun examines.
Description of the drawings
After Fig. 1 takes 2 drug of experimental group, control group 1 and control group orally for chicken single dose (30mg.kg-1) in control experiment 2
The relational graph of blood mass concentration and time.
Fig. 2 be in control experiment 3 after 1 drug of pig spice feeding Florfenicol original powder and embodiment blood mass concentration and when
Between relational graph.
Fig. 3 is Florfenicol in control experiment 4 in rat vivo medicine concentration-time plot.
Fig. 4 is the structural schematic diagram of the drying machine with centrifugal spray in the present invention.
Fig. 5 is the lateral partial structurtes sectional view of the drying machine with centrifugal spray in the present invention.
Fig. 6 is enlarged drawing at A in Fig. 4.
Fig. 7 is enlarged drawing at A in Fig. 5.
Fig. 8 is enlarged drawing at B in Fig. 5
Sectional view when Fig. 9 is shaft and connection axis connection in the drying machine with centrifugal spray in the present invention.
Figure 10 is the cooperation schematic diagram between upper metate in the present invention.
Specific implementation mode
In order to make those skilled in the art be better understood from the present invention program, below in conjunction in the embodiment of the present invention
Attached drawing, technical solution in the embodiment of the present invention carry out clear, complete description.
Embodiment 1：
If producing 100kg water solubility veterinary drug preparations, comprise the steps of：
(1) Florfenicol 21kg is weighed, beta-cyclodextrin and HYDROXYPROPYL BETA-CYCLODEXTRIN are respectively that 64.4kg and 11.8kg (are pressed
Active ingredient meter), Macrogol 4000 and Macrogol 6000 are respectively 0.9kg and 0.6kg (based on active ingredient), propylene glycol
Block polyether 0.9kg, dimethyl sulfoxide (DMSO) 0.4kg, it is spare；
(2) Florfenicol, beta-cyclodextrin and HYDROXYPROPYL BETA-CYCLODEXTRIN are uniformly mixed, are put into 80~83 DEG C of hot water not
Disconnected stirring can be obtained molecule inclusion liquid, ratio of water to material 2:1；
(3) when molecule inclusion liquid temperature in step (2) is stablized in 80~83 DEG C of ranges, input propylene glycol block polyether,
Dimethyl sulfoxide (DMSO), stirring heat preservation 1h, then carries out centrifugal spray drying processing using drying machine with centrifugal spray to it after clarification；Into
One step, by atomizing disk variable frequency adjustment to 15-25hz, the particle size range of powder material obtained is made to control at 120~160 μm,
Then material is crossed into 80 mesh sieve to get to water-soluble veterinary drug preparation.
Specifically, as shown in figs. 4 through 10, the drying machine with centrifugal spray includes tower body 1, doing in the tower body 1
Dry chamber 11 and percussion device for hitting the tower body 1,11 top of the drying chamber are equipped with centrifugal atomizing disk 3 and hot blast pipe 4,
4 outlet end of the hot blast pipe be equipped with outlet nozzle 43, the percussion device include supporting rack 2, be set to support frame as described above on and according to
More shafts 6 of secondary drive connection, the cam 61 being respectively arranged in the more shafts 6, on 1 outer wall of the tower body
Multiple fixed blocks 7, the active tunnel 71 on the fixed block 7, one end be inserted in the active tunnel 71 with it is described convex
Take turns matched ram 8, the return unit being sheathed on the ram 89 and for driving the more shafts 6 to rotate
Driving part, the return unit 9 are spring, which is connected with fixed block 7, and the other end is connected with ram 8；Institute
The more shafts 6 stated are enclosed outside the tower body 1, when liquid via centrifugal atomizing disk 3 be atomized into droplet spray after, drop with
Hot-air current contacting out of hot blast pipe 4, the moisture in drop are evaporated, and then obtain Florfenicol powder preparation, however
Florfenicol powder preparation due in the drying process to be completely dried easily is attached on the inner wall of drying chamber to occur
Powder formulation bonds blocking situation, and coking easily occurs, to influence the quality of powder formulation；And it can by setting
The percussion device for hitting 1 outer wall of tower body, so that tower body 1 vibrates, and then will be attached to the object on 11 inner wall of drying chamber
Material vibrates, and effectively prevents the blocking problem of powder bonding.
Specifically, support frame as described above 2 be disposed around metal ring on 1 outer wall of tower body, further, the metal ring and
There is certain gap, which is evenly arranged with 4 support legs along the circumferentially-spaced of annulus between 1 outer wall of tower body
25,25 bottom end of the support leg is fixed by screws on ground, since supporting rack is no and tower body is directly connected to, and then works as tower
When body vibrates, so the vibration effect that supporting rack 2 is subject to is smaller.The more shafts are arranged in the upper of the metal ring
Surface, the number of the shaft 7 is 8 in this present embodiment, and described 8 shafts 6 are in the octagon-shaped with an opening
It is disposed around outside tower body 1, it is 8 pieces that the fixed block 7, which is made of metal material its number also, and described 8 pieces of fixed blocks 7 are outside tower body
Wall is provided at circumferentially spaced, and the active tunnel 71 is horizontally disposed, and the ram 8 is made of metal material, packet
Cylindrical portion and globular part are included, described cylindrical portion one end is plugged in the active tunnel 71 of fixed block 7, and the cam 61 is in rotation
It can be in contact with globular part and globular part is pushed to be moved to close to the direction of fixed block 7, and then cylindrical portion is pushed to hit tower body 1
Outer wall is so that tower body 1 vibrates, further, corresponding to being set respectively at the position of every shaft 6 on support frame as described above 2
There are two first bearing seats 10, every 6 left and right ends of shaft to be threaded through respectively in the first bearing seat 10, as shown in figure 5, I
To define the shaft 6 being arranged in 1 directly to the right of tower body be first shaft, and define with first shaft be press it is clockwise
Other 7 shafts that direction is set gradually are respectively second, third root, the 4th, the 5th, the six roots of sensation, the 7th, the 8th
Root shaft, when 8 shafts rotate respectively under the driving effect of driving part, the cam 61 that is arranged in shaft 6 can be with
Shaft 6 rotates together and ram 8 is pushed constantly to hit 1 outer wall of tower body, so that tower body can vibrate, due to 8
Root shaft is disposed around outside tower body, and then when 8 shafts rotate, can hit tower body on 8 positions of tower body outer wall, to
The percussion device Oscillation Amplitude that tower body occurs when hitting tower body is improved, dry cavity wall will can be more effectively attached to
On material vibrating get off, be sequentially connected successively additionally, due to more shafts, and more shafts ensure when mounted it is same
Cam under time in every shaft relative to the position of ram and different, i.e., be not under the same time cam all
Ram can be pushed to strike the outer wall of tower body 1, i.e. 8 rams hit tower body in intermittent state, to one
8 cams in the section time in 8 shafts can push corresponding ram to hit tower body outer wall respectively, can be to tower body eight not
Successively eight shocks are carried out at same position respectively, not only expand the vibration area of tower body, and generated after hitting for this eight times
Vibration wave can be overlapped mutually, and then the further vibrating effect for enhancing tower body, further be convenient for that drying will be attached to
Material vibrating on cavity wall gets off.
Further, it is realized and is sequentially connected by a drive mechanism between adjacent two shaft 6, specifically, described
Drive mechanism includes the mounting base 21 being arranged on supporting rack 2, is set in the mounting base 21 and intermeshing two first umbrella
Gear 22, supplies described shaft one end to be inserted at the connecting shaft 23 on first bevel gear in the connecting shaft 23
Inserting groove 231, the rotation stop groove 232 on 231 inner wall of the inserting groove are set in the shaft 6 and 232 phase of the rotation stop groove
The anti-rotation block 61 of cooperation and in the mounting base 21 and 23 matched second bearing seat 24 of the connecting shaft；The rotation stop
There is certain gap, the diameter of the connecting shaft 6 to be less than the maximum of the first bevel gear 22 between 232 inner wall of block 61 and rotation stop groove
Diameter；By being respectively set connecting shaft 23 on two intermeshing first bevel gears, and in mounting base 21 setting with it is described
The second bearing seat 24 of connecting shaft interference fit, and then can ensure when supporting rack 2 vibrates, two first bevel gears according to
Old to keep intermeshing state, in addition shaft passes through anti-rotation block and the rotation stop groove mating two being arranged in connecting shaft
Realize the rotation stop cooperation of shaft and connecting shaft, and due to having certain gap, Jin Er between anti-rotation block and rotation stop groove inner wall
When cam in shaft pushes ram 8 to hit tower body outer wall and vibrate, due to the presence in the gap make shaft with
While cooperation certain offset can also occur relative to connecting shaft for connecting shaft rotation stop, that is, the vibration in shaft is prevented to involve
Onto the first bevel gear, to which two bevel gears ensured in mounting base can remain the state of engagement, and then 8 are ensure that
Shaft can realize drive connection always.
Further, the driving component includes the transmission shaft 63 being sequentially connected with a wherein shaft 6 and for driving
The driving motor 64 that the dynamic transmission shaft 63 rotates, specifically, the driving motor 64 is the general electricity directly bought in the market
Machine, structure and operation principle are that therefore not to repeat here for the prior art, and the driving motor 64 is mounted on supporting rack 2, described
Transmission shaft 63 is by the output axis connection of shaft coupling and driving motor 64, on one end of the separate driving motor of the transmission shaft 63
If there are one the second bevel gear 65, set that there are one the second bevel gears on the described one end of first shaft far from the first bevel gear 62
65, two the second bevel gear 65 intermeshings；And then when driving motor works, 8 shafts 6 can finally be driven to turn together
It is dynamic, eight different locations of tower body can be hit by a driving motor and bring it about 8 vibrations, to subtract
Lack energy consumption, reduces production cost.
Preferably, the percussion device is two groups, described two groups of percussion devices in setting up and down on the outer wall of tower body,
By the way that percussion device is set as two groups, the rum point to tower body is further increased, i.e., further expands the vibration of tower body
Range is vibrated to improve the vibrating effect of tower body conducive to by the material being attached on dry cavity wall completely.
Further, the centrifugal atomizing disk 3 is connected by conveying pipeline 31 with a liquid storing barrel 32, on the conveying pipeline 31
It is provided with charging pump 33, the centrifugal atomizing disk 3 and charging pump 33 all can directly be bought from the market, therefore this will not be repeated here,
When feed liquid is placed in liquid storing barrel, by charging pump can by feed liquid extract out and via centrifugal atomizing disk be ejected in drying chamber with
Hot-air current contacting, and then realize drying purpose.
Further, the hot blast pipe 4 is connected with a heater box 41, and heating wire is equipped in the heater box 41, described
41 side of heater box is equipped with air blower 42, and then when air blower 42 works can be transported to the hot-air in heater box 41 dry
It is in contact in dry chamber 11 and then with the drop sprayed through centrifugal atomizing disk and desiccation is played to it.
Further, the tower body 1 is equipped with the conical discharge port 12 being connected with the drying chamber 11；The tower body 1
It is equipped with the conical discharge port 12 that is connected with the drying chamber 11, and then the Florfenicol powder preparation after drying enters taper
Discharge port 12, under the action of suction ventilator 103, powder and particulate matter enter sieve bucket 101 by connecting tube 100, in going out for sieve bucket
Mouth setting strainer makes powder pass through sieve bucket and enters storage bin 103, and particulate matter falls in sieve bucket 101, entered by feed opening 107
Among upper metate, the rotation of the second driving motor 104 drives rotation axis 105, rotation axis 105 to drive metate 107 to rotate, pass through
Effect particulate matter between mano 106 and metate 107 is ground as powder, and under the action of suction ventilator, powder passes through discharging
Mouth 111 and connecting tube enter storage tank 103.
The present invention operation principle be：Liquid is atomized into via centrifugal atomizing disk 3 after droplet sprays, drop with from hot wind
Hot-air current contacting in pipe 4, the moisture in drop are evaporated, and then obtain Florfenicol powder preparation, however due to
It is that the Florfenicol powder preparation being completely dried easily is attached on the inner wall of drying chamber to powder system occur in drying process
Agent bonds blocking situation, and coking easily occurs, to influence the quality of powder formulation；And tower can be hit by setting
The percussion device of 1 outer wall of body so that tower body 1 vibrates, and then will be attached to the material vibrating on 11 inner wall of drying chamber
Get off.Florfenicol powder preparation after drying enters conical discharge port 12, under the action of suction ventilator 103, powder and particle
Object enters sieve bucket 101 by connecting tube 100, and strainer is arranged in the outlet of sieve bucket, so that powder is passed through sieve bucket and enters storage bin 103,
Particulate matter is fallen in sieve bucket 101, is entered among upper metate by feed opening 107, and the rotation of the second driving motor 104 drives rotation
Axis 105, rotation axis 105 drive metate 107 to rotate, are ground by the effect particulate matter between mano 106 and metate 107
For powder, under the action of suction ventilator, powder enters storage tank 103 by discharge port 111 and connecting tube.
Embodiment 2：
If producing 100kg water solubility veterinary drug preparations, comprise the steps of：
(1) Florfenicol 20kg is weighed, beta-cyclodextrin and HYDROXYPROPYL BETA-CYCLODEXTRIN are respectively that 64.2kg and 12.4kg (are pressed
Active ingredient meter), Macrogol 4000 and Macrogol 6000 are respectively 1.4kg and 0.6kg (based on active ingredient), propylene glycol
Block polyether and each 0.4kg of poly glycol monomethyl ether, sodium succinate and glycerine each 0.3kg, it is spare；
(2) Florfenicol and beta-cyclodextrin, HYDROXYPROPYL BETA-CYCLODEXTRIN are uniformly mixed, and are put into 80~83 DEG C of hot water constantly
Stirring can be obtained molecule inclusion liquid, ratio of water to material 2:1；
(3) when molecule inclusion liquid temperature in step (2) is stablized in 80~83 DEG C of ranges, input propylene glycol block polyether,
Poly glycol monomethyl ether, sodium succinate and glycerine, stirring heat preservation 1h, then carries out it using drying machine with centrifugal spray after clarification
Centrifugal spray drying processing；Further, by atomizing disk variable frequency adjustment to 15-25hz, make the grain size model of powder material obtained
System is contained at 120~160 μm, material is then crossed into 80 mesh sieve to get to water-soluble veterinary drug preparation.
Embodiment 3：
If producing 100kg water solubility veterinary drug preparations, comprise the steps of：
Weigh Florfenicol 25kg, beta-cyclodextrin and HYDROXYPROPYL BETA-CYCLODEXTRIN are respectively 60.6kg and 10.7kg (by having
Imitate ingredient meter), Macrogol 4000 and Macrogol 6000 are respectively 1.6kg and 0.6kg (based on active ingredient), and propylene glycol is embedding
Section polyethers and each 0.45kg of poly glycol monomethyl ether, dimethyl sulfoxide (DMSO) and glycerine each 0.3kg, it is spare；
(2) Florfenicol and beta-cyclodextrin, HYDROXYPROPYL BETA-CYCLODEXTRIN are uniformly mixed, and are put into 80~83 DEG C of hot water constantly
Stirring can be obtained molecule inclusion liquid, ratio of water to material 2:1；
(3) when molecule inclusion liquid temperature in step (2) is stablized in 80~83 DEG C of ranges, input propylene glycol block polyether,
Poly glycol monomethyl ether, sodium succinate and glycerine, stirring heat preservation 1h, then carries out it using drying machine with centrifugal spray after clarification
Centrifugal spray drying processing；Further, by atomizing disk variable frequency adjustment to 15-25hz, make the grain size model of powder material obtained
System is contained at 120~160 μm, material is then crossed into 80 mesh sieve to get to water-soluble veterinary drug preparation.
Embodiment 4：
If producing 100kg water solubility veterinary drug preparations, comprise the steps of：
Weigh Florfenicol 25kg, beta-cyclodextrin and HYDROXYPROPYL BETA-CYCLODEXTRIN are respectively 60.6kg and 10.7kg (by having
Imitate ingredient meter), Macrogol 4000 and Macrogol 6000 are respectively 1.6kg and 0.6kg (based on active ingredient), polyethylene glycol
Monomethyl ether 0.9kg, sodium succinate and glycerine each 0.6kg, it is spare；
(2) Florfenicol and beta-cyclodextrin, HYDROXYPROPYL BETA-CYCLODEXTRIN are uniformly mixed, and are put into 80~83 DEG C of hot water constantly
Stirring can be obtained molecule inclusion liquid, ratio of water to material 2:1；
(3) when molecule inclusion liquid temperature in step (2) is stablized in 80~83 DEG C of ranges, input propylene glycol block polyether,
Poly glycol monomethyl ether, sodium succinate and glycerine, stirring heat preservation 1h, then carries out it using drying machine with centrifugal spray after clarification
Centrifugal spray drying processing；Further, by atomizing disk variable frequency adjustment to 15-25hz, make the grain size model of powder material obtained
System is contained at 120~160 μm, material is then crossed into 80 mesh sieve to get to water-soluble veterinary drug preparation.
Above example be by the technology implementation process certain embodiments lifted more effective and being illustrated for illustrating the present invention and
, the limitation carried out to the application range of the present invention is not it.As long as what is done on the basis of the present invention is not significantly
Improvement all can be considered the row in protection scope of the present invention.
Control experiment 1：
Water solubility veterinary drug preparation produced by the invention sells product in solubility, solution rate, solute effect etc. with city
Carry out Experimental Comparison.
Experimental group：Water-soluble veterinary drug preparation (the specification that embodiment 1 and embodiment 2 produce：100:20).
Control group：Florfenicol powder 1 is sold in city and 2 (specification of florfenicol powder is sold in city：100:20).
Experimental method：
A, 1L normal-temperature waters (25 ± 2 DEG C) are modulated, 200ml normal-temperature waters are respectively contained in 4 250ml beakers of A1, A2, B1, B2, it is standby
With；
B, be separately added into A1 and A2 beakers embodiment 1 and each 3g of the water-soluble veterinary drug preparation of embodiment 2 (15g/l,
3000ppm), stirring is until clarification completely, records mixing time；
C, city's pin florfenicol powder 1 and 2 each 3g (15g/l, 3000ppm) is separately added into B1 and B2 beakers, stirring until
Clarification completely records mixing time；
D, above 4 sample heap density are measured respectively, and observe mobility, are compared.
Experimental result：
1 experimental group of table is with control group in solubility, solution rate, solute effect etc. comparing result
It is above-mentioned the experimental results showed that, it is produced by the invention water solubility the veterinary drug preparation stirring and dissolving time all within 1min,
It is significantly faster than that product is sold in the cities Liang Ge；And dissolving clarity highly-water-soluble is up to 15g/l, i.e. 3000ppm, and it is not muddy, without floating
Object and precipitation stand 48h and are cooled to 15 DEG C and still clarify molten, no precipitate completely, and solute effect is good；Product heap of the present invention
For density in 0.40g/ml or more, mobility is good, and animal clinical preferably uses.
Control experiment 2：
Water solubility veterinary drug preparation produced by the invention becomes with blood concentration of the external two Florfenicol products in chicken body
Change situation comparison, to judge the bioavilability of different product.
Experimental method：
1, medication and blood sampling time
36 Sanhuang chickens, every chicken single dose are selected to be administered by 30mg.kg-1 (in terms of Florfenicol) spice.Refer to table 1.
(0h) strength venous blood collection about 4mL is as blank control before perfusion.5 after perfusion, 15,30min and 1,2,4,6,8,10,12, it is each for 24 hours
Blood sampling 1 time, take a blood sample about 4mL every time.It places it in the centrifuge tube containing heparin, 3000r/min, centrifugation 10min, separated plasma ,-
It is preserved under the conditions of 20 DEG C, it is to be measured.
Experimental group：1 florfenicol powder of the embodiment of the present invention, specification 100:20
Control group 1：Certain external company's florfenicol powder, specification 100:10
Control group 2：Certain external company's florfenicol powder, specification 100:2
2, blood serum sample pre-processes
It is accurate to pipette plasma sample 0.5mL and be placed in 10mL centrifuge tubes, add 10 μ L of Thiamphenicol internal standard solution (1g.L-1) and
The PES liquid (pH=7.0) of 0.5mL, whirlpool 3min are mixed well.Then 3.0mL ethyl acetate is added, whirlpool 3min is fully mixed
5min is centrifuged after even, draws ethyl acetate supernatant in another test tube.Same method repeats extraction 1 time, merges second twice
Acetoacetic ester extracting solution evaporates into draught cupboard dry.In residue plus 1.0mL mobile phases, whirling motion 1min, ultrasonic 5min, 0.45 μm
After membrane filtration, 25 μ L sample introductions are drawn, measure blood concentration.
Experimental result：
2 chicken single dose of table takes blood concentration (mg.L-1) after 2 drug of experimental group, control group 1 and control group orally.
Chicken single dose (30mg.kg-1) take orally after 2 drug of experimental group, control group 1 and control group blood mass concentration and when
Between relationship, see Fig. 1.
As shown in Table 2, the peak concentration of drug of experimental group, control group 1 and control group 2 is respectively 7.36mg.L-1,6.47mg.L-
1 and 6.37mg.L-1, peak time are respectively 0.25,0.5 and 0.5h, and the area under the drug-time curve being calculated (AUC) is respectively
For 29.0mg.L-1/h, 20.0mg.L-1/h and 22.4mg.L-1/h.
Compare and can be seen that, after single dose takes 2 drug of experimental group, control group 1 and control group orally, the pharmacokinetic parameters of three have
Difference.Peak concentration of drug, the area under the drug-time curve of experimental group are above control group 1 and control group 2, and peak time is below separately
Two groups.Wherein peak concentration of drug is 1.14 and 1.16 times of control group 1 and knob control group 2 respectively, and area under the drug-time curve is respectively
1.45 and 1.29 times.Illustrate water-soluble veterinary drug preparation produced by the invention in chicken body up to higher blood concentration, when medicine, is bent
Area bigger under line can play long-acting.
Control experiment 3：
Efficiently water-soluble Florfenicol product of the invention is probed into compared with original powder, drug is in terms of pharmacokinetics the case where.
Experimental method：
The big pig 18 of selection health, age in days, weight are close, and male and female is fifty-fifty, are randomly divided into 2 groups, every group 9, every group of 3 weights
It is multiple.It routinely raises, free water and feeding.Feed is the full price mash diet without antibacterials.Clinical observation 2 before experiment
Week.16h fasting, only free water before administration, are administered free water and feeding after 6h.Following determination of plasma concentration process is the same as control
Experiment 2.
3 experimental design of table
Experimental result：
The blood mass concentration of pig spice feeding Florfenicol original powder and different time after 1 drug of embodiment is shown in Table 4 and figure
2。
The blood mass concentration mg.L of different time after 4 pig spice feeding Florfenicol original powder of table and 1 drug of embodiment-1
As shown in Table 4, the peak concentration of drug of Florfenicol original powder and fluorine pleasure sweet smell is respectively 2.85mg.L-1And 10.14mg.L-1,
Peak time is 2h, and the area under the drug-time curve (AUC) being calculated is respectively 14.55mg.L-1/ h and 72.78mg.L-1/
h。
Compare and can be seen that, after spice feeds Florfenicol original powder and fluorine pleasure sweet smell, there were significant differences for the pharmacokinetic parameters of the two.
The fragrant peak concentration of drug of fluorine pleasure is 3.56 times of Florfenicol original powder, and area under the drug-time curve is 5.00 times of Florfenicol original powder.
Illustrate the fragrant peak concentration of drug higher of spice feeding fluorine pleasure, area under the drug-time curve bigger, elimination is slower, can play more long-acting
Effect.
Control experiment 4：
The main purpose of pharmacokinetics experiment of the Florfenicol in rat body, this experiment is the different system of research
Influence of the agent method processing to Florfenicol function and effect.
Experimental method：
12 rats are selected in experiment, and every rat gavages Florfenicol original powder respectively with 30mg/kg dosage, the present invention is implemented
1 florfenicol powder of example, certain external renowned company's florfenicol formulations, (0h) acquires blood by femoral artery before rats gavaged administration
Liquid makees blank control.5min, 15min after perfusion, 30min, 1h, 2h, 4h, 6h, 8h, 10h, blood is acquired for 24 hours.It will be collected
Fresh blood sample be placed in heparin sodium centrifuge tube, 3min is centrifuged with 9000r/min, separated plasma is simultaneously stored in -80 DEG C, so
After measure blood concentration.Florfenicol is drawn in rat vivo medicine concentration-time plot, such as Fig. 3.
Test result shows that area is significantly high under the Cmax and drug-time curve of 1 florfenicol powder of the embodiment of the present invention
In Florfenicol original powder and certain external renowned company's florfenicol formulations, show florfenicol powder produced by the invention in rat body
Interior infiltration rate is fast, degree of absorption is significantly higher than Florfenicol original powder and certain external renowned company's product.1 fluorobenzene Buddhist nun of embodiment
Examine half-life period (t1/2) and mean residence time (MRT) of the powder in rat body be also significantly greater than Florfenicol original powder and it is external certain
Renowned company's product shows that florfenicol powder produced by the invention residence time in rat body is longer, is conducive to send out for a long time
Wave its drug effect.
Obviously, described embodiment is only a part of the embodiment of the present invention, instead of all the embodiments.It is based on
Embodiment in the present invention, it is obtained by those of ordinary skill in the art without making creative efforts every other
Embodiment should all belong to the scope of protection of the invention.
Claims (6)
1. a kind of water solubility veterinary drug preparation, it is characterised in that：Including following mass fraction than component：Florfenicol 20-25%,
Inclusion agents 71.9-76.9% dissolves out agent 1.5-2.3%, dispersant 0.7-0.9%, cosolvent 0.4-0.7%.
2. a kind of water-soluble veterinary drug preparation according to claim 1, it is characterised in that：The inclusion agents be beta-cyclodextrin and
The mixture of HYDROXYPROPYL BETA-CYCLODEXTRIN；The mass ratio of beta-cyclodextrin and HYDROXYPROPYL BETA-CYCLODEXTRIN is 5:1.
3. a kind of water-soluble veterinary drug preparation according to claim 1, it is characterised in that：The dissolution agent is polyethylene glycol
4000 and Macrogol 6000 mixture.
4. a kind of water-soluble veterinary drug preparation according to claim 1, it is characterised in that：The dispersant is propylene glycol block
One or both of polyethers, poly glycol monomethyl ether combine.
5. a kind of water-soluble veterinary drug preparation according to claim 1, it is characterised in that：The cosolvent is that dimethyl is sub-
One or more of sulfone, sodium succinate, glycerine combine.
6. a kind of preparation method of water-soluble veterinary drug preparation as described in any one in claim 1-5, it is characterised in that：Including with
Lower step：
A, by the mass fraction percentage weigh respectively Florfenicol, inclusion agents, dissolution agent, dispersant and cosolvent it is spare；
Florfenicol and inclusion agents are uniformly mixed, is stirred continuously in 80~83 DEG C of hot water of input and can be obtained molecule inclusion liquid,
Ratio of water to material is 2:1；
When molecule inclusion liquid temperature in step b is stablized in 80~83 DEG C of ranges, input dissolution agent, dispersant, cosolvent, clarification
Stirring heat preservation 1h afterwards, then carries out it centrifugal spray drying processing using drying machine with centrifugal spray, crosses 80 mesh sieve, you can obtain
Finished product；Inlet air temperature when centrifugal spray drying is 175~180 DEG C, and leaving air temp is 90 ± 2 DEG C.
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| CN113398094A (en) * | 2021-05-11 | 2021-09-17 | 湖北龙翔药业科技股份有限公司 | Insoluble veterinary drug nanosuspension and preparation method thereof |
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