CN110251481A - A kind of veterinary tilmicosin taste masking slow-releasing granules and its preparation process - Google Patents
A kind of veterinary tilmicosin taste masking slow-releasing granules and its preparation process Download PDFInfo
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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Abstract
The invention belongs to new veterinary medicine field, it is related to a kind of veterinary tilmicosin taste masking sustained-release granular formulation and its preparation process.Preparation step includes: to combine nanotechnology, wet granulation and film coating, and the ingredient in granule is formulated after mixing by mass/mass are as follows: Tilmicosin 5~30.0%；Solid lipid or fluid oil 10.0~45.0%；Surfactant 1.0~10.0%；Diluent 10.0~40.0%；Corrigent 1.0%~20.0%；Coating material 5.0%~20.0%.Optimize formula and technique.Granule appearance is white or faint yellow, and granularity 0.2-2mm, loss on drying is less than 2%；4h dissolution rate is less than 50% in pH=2 simulate the gastric juice, and 4h dissolution rate is less than 90% in pH=8 simulate the gastric juice.The present invention overcomes simple coating taste maskings not exclusively with the simple unconspicuous defect of nano controlled-release effect, effectively reduces stimulation of the Tilmicosin to stomach lining.
Description
Technical field
The present invention relates to new veterinary medicine preparation fields, and in particular to a kind of veterinary tilmicosin taste masking sustained-release granular formulation and
Its preparation process.
Background technique
Tilmicosin is the dedicated antibiotic of livestock and poultry synthesized by the hydrolysate of tylosin.For oral administration and subcutaneous injection absorbs
Fastly, apparent volume of distribution is big, and penetration into tissue is strong, and the drug concentration in lung tissue is more than ten times of serum.It can be rapid and complete
Enter mammary gland from blood entirely, it is 10-30 times of serum that newborn drug concentration is high, and length of holding time, reachable 1-2d.It is this
Special characteristics of pharmacokinetics is especially suitable for the treatment of the infectious diseases such as domestic animal pneumonia and mazoitis, is clinically widely used in chest
Animal respiratory disease caused by mould Actinobacillus, Pasteurella, mycoplasma, staphylococcus aureus etc. and mazoitis it is anti-
Control.But because Tilmicosin bitter taste is big, oral administration influences animal (especially pig) to the intake of drug, pierces to animal stomach lining
Swash big, the deficiencies of drug administration by injection safety low (irritation of such as cardiac toxic and injection site), seriously constrains Tilmicosin
In the compliance of animal diseases control application.Also, spice administration is also poor to the compliance of feeding personnel.
Granted Tilmicosin dosage form include Tilmicosin soluble powder, tilmicosin solution, Tilmicosin pre-mixing agent,
Tilmicosin injection also all suffers from the challenge of palatability or safety.And Tilmicosin enteric coated granule agent granted in the recent period
Though the palatability of Tilmicosin can be improved, because Tilmicosin in gastric juice environment the very big therefore simple enteric material of solubility
Material coating can not significantly reduce it in the release of stomach, while increase in intestinal segment pH value, and coatings dissolution, Tilmicosin is very
It can release fastly, because Tilmicosin is higher fat-soluble, rapid decrease after blood concentration increases rapidly, and Tilmicosin is length
Antibacterial aftereffect type antibiotic, the time that the performance of maximum drug effect requires effective blood drug concentration to maintain is longer, this simple intestines
Molten dosage form is not appropriate for the performance of the maximum drug effect of Tilmicosin, and the blood medicine peak valley phenomenon of superelevation also results in unnecessary wave
Take.In addition, some technique, which only considered, improves its palatability, and stimulation of the Tilmicosin ignored to stomach lining, such as patent (CN
104958764) it is coated in using stomach dissolution type material, can be released quickly in stomach Tilmicosin, be unfavorable for improving dynamic
The compliance of object.
After drug is wrapped up nanosizing, carrier material can hide the property of Tilmicosin, completely cut off itself and taste bud
Contact, to improve its palatability, nanometer small particle will not generate feeling of grittiness when oral；Secondly because carrier material is dredged
Aqueous, nanoparticle often has very strong sustained release performance, is suitble to prepare medicament slow release delivery system, avoids the peak valley of drug existing
As playing the drug effect of drug to greatest extent and reducing administration number of times.But because its drugloading rate is low, caused by packaging medicine is incomplete
The deficiencies of taste masking is insufficient and liquid dosage form is not easy storage transport also limits it in the use of field of veterinary to a certain extent.It will
Contact of the drug with taste bud can be reduced after drug coating, completely cut off direct projection of the natural light to drug, and through water-insoluble or enteric
Property the functional materials coating such as material after can assign the performance that drug is discharged in gastrointestinal tract specific target site, packaging technique in recent years
It in the palatability for improving drug, prepares and is widely used in enteron aisle positioning release medicine transmission system, but is also common simple in producing
Be coated taste masking not exclusively and the inapparent phenomenon of slow release effect.In consideration of it, the present invention for the first time innovatively joint nanotechnology and
Wet granulation packaging technique, the advantages of combining two kinds of technologies, overcome nanometer encapsulating and taste masking are incomplete, liquid dosage form is unsuitable
It stores transport and is coated the defect that taste masking is incomplete and sustained release performance is bad merely.The made Tilmicosin taste masking sustained release of the present invention
Granule not only has the advantages that traditional coated granule taste masking, targeting, also has the advantages that emerging Nano medication is long-acting.
The present invention is combined into oil with one of palm oil, glyceryl palmitostearate, cottonseed oil, peanut oil or other groups
It is living to be combined into surface with one of Brij35, Tween-60, Myrj 52, Crodaret or other groups for phase carrier
Property, diluent is combined into one of dextrin, calcium monohydrogen phosphate, low-substituted hydroxypropyl cellulose, magnesium carbonate or other groups, with apple
One of acid, saccharin, mannitol, maltose, menthol or other groups are combined into corrigent.With hypromellose, propylene
One of acid resin, oil with hydrogenated soybean, cellulose acetate-phthalate or other groups are combined into coating material.Utilize hot melt cream
Change excusing from death method and prepare Tilmicosin nanoparticle, then diluent and corrigent are added into the Tilmicosin nanoparticle prepared, warp
A kind of veterinary tilmicosin taste masking sustained-release granular formulation is made in wet granulation coating.The present invention is ingenious to combine nanotechnology and coating
The advantages of two kinds of technologies of technology, the palatability of Tilmicosin is not only significantly improved, prepares and can be used for what animal mixed feeding took orally
The novel taste masked particle agent of Tilmicosin, reduces stimulation of the Tilmicosin to animal stomach lining, improves animal Tilmicosin
Compliance also adds the interior of Tilmicosin while imparting Tilmicosin apparent sustained release performance with commercially available pre-mixing agent ratio
Clothes absorb.This undoubtedly will be helpful to use when Tilmicosin prevents and treats zoosis in clinic, achieve the purpose that be reduced synergy.
Summary of the invention
It is an object of the invention to overcome the deficiencies of existing technologies, provide it is a kind of with good conformability and palatability,
The veterinary tilmicosin taste masking sustained-release granular formulation of bioavilability can be significantly improved.The present invention uses single factor test method, with drug
Solubility in oily phase carrier is index, is screened to the type and dosage of oily phase carrier；Using orthogonal design, to receive
Grain of rice drugloading rate is that type, volume, the concentration of inspection target Surfactant are screened；With the price of coating material and
Cumulative release in simulate the gastric juice and intestinal juice is that index screens the type and dosage of coating material；It is searched for food with the day of pig
Amount is index, is screened to the type and dosage of the corrigent of Tilmicosin taste masking sustained-release granular formulation.Successfully develop one
Kind formula is reasonable, simple process, the veterinary tilmicosin taste masking sustained-release granular formulation of quality safety.Veterinary tilmicosin of the present invention is covered
The granularity of flavor sustained-release granular preparation is 0.2-2mm, and loss on drying is less than 2%, the 4h cumulative release in the simulate the gastric juice of pH=2
Less than 50%, 4h cumulative release is greater than 90% in the simulate the gastric juice of pH=8.Veterinary tilmicosin taste masking sustained release of the invention
The granularity of granula preparation, loss on drying, dissolution in vitro, melting meet " Republic of China Veterinary Pharmacopoeia " to for animals
The relevant regulations of granula；It degrades under high temperature, high humidity, high light conditions is no more than 3%, and palatability is good, and it is mixed to can be used for pig
Oral administration is raised, is the 2 times or more of commercially available pre-mixing agent in the oral administration biaavailability of pig.
A kind of palatability provided by the invention, which is got well and had sustained release performance and improves for animals of Tilmicosin oral absorption, to be covered
Flavor sustained-release granule, the release being substantially reduced in the bitter taste stomach function regulating of Tilmicosin, improve animal to the compliance of Tilmicosin and
Tilmicosin keeps use of the Tilmicosin in clinic more cost-effective in the ability of intestinal segment positioning release medicine.
Specific address, it is described that technical scheme is as follows:
A kind of veterinary tilmicosin taste masking sustained-release granular formulation, the granule are to be made by the steps to obtain,
Preparation step includes that the oil of solid lipid or liquid is carried out nanosizing processing, is combined with wet granulation and with film coating
Prepared by method, the ingredient in granule is that (W/W) mixed formulation components (are constituted after mixing based on mass/mass
Preparation) as described below:
(1) Tilmicosin 5.0~30.0%；
(2) oily phase 10.0~45.0%；
(3) surfactant 1.0~10.0%；
(4) diluent 10.0~40.0%；
(5) corrigent 1.0%~20.0%；
(6) coating material 5.0%~20.0%；
It prepares according to the following steps:
(1) Tilmicosin is added in 100 DEG C of formula ratio of oily phase by formula ratio, Tilmicosin is made to be dissolved in oily phase after stirring
In, obtain solution 1；
(2) aqueous surfactant solution is preheated to 100 DEG C by formula ratio, is added in the resulting solution 1 of step (1),
Using nanosuspension made of supersound method, the ultrasound condition are as follows: probe diameter 6-13mm, ultrasonic time 3-
10min；
(3) corrigent and diluent for taking formula ratio after mixing, are added in the nanosuspension of step (2) preparation,
It is being stirred continuously and after mixing, is drying and softwood is made；
(4) partial size is made in the sieve that step (3) resulting softwood crosses the aperture 1mm with oscillating granulator is 0.2-2mm's
Particle；
(5) by after step (4) resulting particle drying, the coating material for weighing formula ratio is dissolved in coating solution, with coating
Machine is coated, and obtains veterinary tilmicosin taste masking sustained-release granular formulation；
Wherein:
The oil is mutually selected from palm oil, glyceryl palmitostearate, one of cottonseed oil or peanut oil or its group
It closes；
The surfactant be selected from Brij35, Tween-60, Myrj 52, one of Crodaret or
A combination thereof；
The diluent be selected from dextrin, calcium monohydrogen phosphate, one of low-substituted hydroxypropyl cellulose or magnesium carbonate or its
Combination；
The corrigent is selected from malic acid, saccharin, mannitol, maltose, one of menthol or combinations thereof；
The coating material is selected from hypromellose, acrylic resin, oil with hydrogenated soybean or phthalic acid esters
One of acid cellulose or combinations thereof；
The coating solution is selected from 95% ethyl alcohol or methylene chloride.
Preferably, the composition of veterinary tilmicosin taste masking sustained-release granular formulation of the invention is based on mass/mass
Component proportion is as follows:
(1) Tilmicosin 10.0~25.0%；
(2) oily phase 15.0~40.0%；
(3) surfactant 2.0~9.0%；
(4) diluent 15.0~35.0%；
(5) corrigent 2.5%~16.0%；
(6) coating material 6.0%~18.0%.
The oil is mutually selected from palm oil, one of glyceryl palmitostearate or cottonseed oil；
The surfactant is selected from Brij35, one of Tween-60 or Crodaret；
The diluent is selected from dextrin, one of low-substituted hydroxypropyl cellulose or magnesium carbonate；
The corrigent is selected from malic acid or maltose crosses one of menthol；
The coating material is in hypromellose, oil with hydrogenated soybean or cellulose acetate-phthalate
It is a kind of；
In the ethyl alcohol or methylene chloride that the coating solution is 95%.
Optimal preferred embodiment of the invention is system of the veterinary tilmicosin taste masking sustained-release granular formulation based on mass/mass
Agent component is as described below:
(1) Tilmicosin 15.0%；
(2) oily phase 30.0%；
(3) surfactant 3.0%；
(4) diluent 27.0%；
(5) corrigent 15.0%；
(6) coating material 10.0%；
The oil is mutually selected from palm oil or glyceryl palmitostearate；
The surfactant is selected from Crodaret or Tween-60；
The diluent is selected from dextrin or magnesium carbonate；
The corrigent is selected from maltose or menthol；
The coating material is selected from cellulose acetate-phthalate or polyacrylic resin；
The ethyl alcohol that the coating solution is 95%.
The appearance of veterinary tilmicosin taste masking sustained-release granular formulation of the invention is coffee-like to brown, granularity 0.2-2mm,
Loss on drying is less than 2%.
The veterinary tilmicosin taste masking sustained-release granular formulation of the invention 4h Accumulation dissolution in the simulate the gastric juice of pH=2 is less than
50%, 4h accumulative releasing degree is greater than 90% in the simulate the gastric juice of pH=8.
Beneficial effects of the present invention are as described below:
Veterinary tilmicosin taste masking sustained-release granular formulation prepared by the present invention innovatively combines nanotechnology and wet for the first time
Legal system grain packaging technique has good palatability and sustained release performance, on the one hand solves because Tilmicosin bitter taste is big, to pig mouthful
The problem of clothes administration food refusal, on the other hand reduces Tilmicosin in the release of stomach, be significantly sustained imparting Tilmicosin
While performance, the oral administration biaavailability of Tilmicosin and holding time for internal effectively Mlc are significantly improved, it will
Advantageously reduce the administration number of times and frequency of Tilmicosin.Meanwhile the dosage combination nanotechnology and packaging technique, it combines
Nano medication partial size is small, surface area is big and packaging technique taste masking and the advantages of intestinal segment positioning release medicine, and granule obtained is not only right
The infection of enteron aisle sensitive bacteria has remarkable result, also overcomes nanometer a liquid forms storage, transport, disadvantage inconvenient for use, city
Have a extensive future, can mixed feeding take orally the lung for preventing and treating the pig as caused by Actinobacillus pleuropneumoniae, Pasteurella, mycoplasma etc.
The scorching and Proliferative Enteritis as caused by lawsonia intracellularis.
Detailed description of the invention
Fig. 1: the pictorial diagram and schematic diagram of veterinary tilmicosin taste masking sustained-release granular formulation prepared by the present invention.Appended drawing reference is said
Bright: the A figure in Fig. 1 is the pictorial diagram of veterinary tilmicosin taste masking sustained-release granular formulation prepared by the present invention, and the B figure in Fig. 1 is this
Invent the schematic diagram of the veterinary tilmicosin taste masking sustained-release granular formulation of preparation.
Fig. 2: the optical microphotograph of Tilmicosin nanoparticle in veterinary tilmicosin taste masking sustained-release granular formulation prepared by the present invention
Mirror figure.Picture size is 10 × 20.
Fig. 3: the scanning mirror of the middle Tilmicosin nanoparticle of veterinary tilmicosin taste masking sustained-release granular formulation prepared by the present invention
Figure.
Fig. 4: the pharmacokinetics Drug-time curve figure of veterinary tilmicosin taste masking sustained-release granular formulation prepared by the present invention.
Specific embodiment
Below by specific embodiment, the invention will be further described, but embodiment does not do any form to the present invention
Restriction, those skilled in the art can enumerate several embodiments according to limited range, therefore not depart from this hair
Change and modification under bright general plotting should belong within protection scope of the present invention.
The prescription 1 and its cumulative in vitro of 1 veterinary tilmicosin taste masking sustained-release granular formulation of embodiment discharge
The prescription 1 of veterinary tilmicosin taste masking sustained-release granular formulation of the invention is shown in Table 1, the granule shape and mode of preparation
Figure is as shown in Figure 1, the cumulative in vitro release of Tilmicosin taste masking sustained-release granular formulation prepared by prescription 1 is shown in Table 2.
The prescription 1 of 1 veterinary tilmicosin taste masking sustained-release granular formulation of table
The preparation method of veterinary tilmicosin taste masking sustained-release granular formulation:
(1) 10g Tilmicosin raw material powder, 15g palm oil and 15g glyceryl palmitostearate are taken, by palm oil and firmly
Tilmicosin is added in resin acid tripalmitin after dissolving by heating, stirring is completely dissolved Tilmicosin mutually in oil.
The release in vitro of granule at various ph values in 2 embodiment 1 of table
(2) solution of the Brij35 of 75ml 3%, 2% Myrj 52 is taken to be added in above-mentioned solution, (6mm probe, surpasses ultrasound
Sound 6min) emulsification, 1000nm nanoparticle below is formed, the light microscopic and electron microscope of the nanoparticle of preparation are as shown in Figures 2 and 3.
(3) 30g dextrin, 0.03g saccharin and 9.97g mannitol are taken after mixing, is added in the suspension in (2), no
Disconnected stirring, after mixing, is placed in 55 DEG C of dryings in baking oven and conventional softwood is made.
(4) step (3) resulting softwood is made up to the particle of 0.2-2mm with oscillating granulator of the sieve of 1mm.
(5) after 55 DEG C of dry whole grains, dry granule is placed in seed-coating machine into baking oven for particle in step (4),
95% ethanol solution for spraying into the polyacrylic resin of 500ml 3% is coated, and obtains veterinary tilmicosin taste masking sustained release
Granule.
As can be seen from Table 2 in the environment of simulate the gastric juice (pH=2), Tilmicosin bulk pharmaceutical chemicals are averagely emptied in pig stomach
It is almost discharged in 4h, Tilmicosin taste masking sustained-release granular formulation can be sustained up to 12h in simulate the gastric juice, had sustained release and reduced
Stimulation to stomach.Simultaneously as granule has released 70% when pig stomach is averaged emptying time 4h, released in stomach
Medicine can be metabolized by gastric acid part, will be unfavorable for the absorption of Tilmicosin, and it is released in 4h in the environment of simulated intestinal fluid
Entirely, this drug release feature will be unfavorable for the Tilmicosin blood concentration of time dependence and long antibacterial aftereffect maintenance and its most
The performance of big drug effect.
The prescription 2 and its cumulative in vitro of 2 veterinary tilmicosin taste masking sustained-release granular formulation of embodiment discharge
The prescription 2 of veterinary tilmicosin taste masking sustained-release granular formulation is shown in Table 3, Tilmicosin nanometer suspension prepared by prescription 2
The release of the cumulative in vitro of liquid and veterinary tilmicosin taste masking sustained-release granular formulation is shown in Table 4.
The prescription 2 of 3 veterinary tilmicosin taste masking sustained-release granular formulation of table
The preparation method of veterinary tilmicosin taste masking sustained-release granular formulation:
(1) 15g Tilmicosin raw material powder and 30g cottonseed oil are taken, Tilmicosin is added in cottonseed oil, heating stirring makes molten
Solution.
(2) the Tween-60 solution of suitable 75ml 5% is taken to be added in above-mentioned solution, ultrasound (2mm probe, ultrasonic 6min)
Emulsification forms 1000nm nanoparticle below.
(3) 20g low-substituted hydroxypropyl cellulose, 10g magnesium carbonate, 7g malic acid and 3g menthol are taken after mixing, is added
Enter in the suspension in (2), be stirred continuously, after mixing, is placed in drying in 55 DEG C of baking ovens and conventional softwood is made.
The release in vitro of granule at various ph values in 4 embodiment 2 of table
(4) softwood in (3) is made up to the particle of 0.2-2mm with oscillating granulator of 1mm sieve.
(5) by the particle in (4) into baking oven 55 DEG C of dry whole grains, dry granule is placed in seed-coating machine, spray into
The cellulose acetate-phthalate ethanol solution of 333ml3% is coated, and obtains veterinary tilmicosin taste masking slow-releasing granules
Agent.
As can be seen from Table 4 in the environment of simulate the gastric juice (pH=2), 3 institute of prescription compared with Tilmicosin bulk pharmaceutical chemicals
The Tilmicosin taste masking sustained-release granular formulation of preparation can be sustained up to 36h, 28% only be discharged when pig is averaged gastric emptying time 4h, in mould
Slow-release time is too long (36h) in the environment of quasi- intestinal juice.It can be seen that Tilmicosin taste masking sustained-release granular formulation tool prepared by the present invention
There are the irritation for substantially reducing stomach and good sustained release performance.Since Tilmicosin taste masking sustained-release granular formulation is in simulated intestinal fluid
36h just discharges completely, may result in the Tilmicosin in Tilmicosin granule do not fully absorb be just discharged it is external and
Cause unnecessary waste.
The prescription 3 and its cumulative in vitro of 3 veterinary tilmicosin taste masking sustained-release granular formulation of embodiment discharge
The prescription 3 of veterinary tilmicosin taste masking sustained-release granular formulation is shown in Table 5, Tilmicosin nanometer suspension prepared by prescription 3
The release of the cumulative in vitro of liquid and veterinary tilmicosin taste masking sustained-release granular formulation is shown in Table 6.
The prescription 3 of 5 veterinary tilmicosin taste masking sustained-release granular formulation of table
The preparation method of veterinary tilmicosin taste masking sustained-release granular formulation:
(1) 20g Tilmicosin raw material powder, 40g palm oil are taken, Tilmicosin is added in palm oil, heating stirring makes molten
Solution.
(2) the Crodaret solution of 150ml 3% is taken to be added in above-mentioned solution, (2mm probe, surpasses ultrasound
Sound 6min) emulsification, form 1000nm nanoparticle below.
The release in vitro of granule at various ph values in 6 embodiment 3 of table
(3) 20g dextrin and 7g mannitol are taken after mixing, is added in the suspension in step (2), is stirred continuously, is mixed
After closing uniformly, it is placed in drying in baking oven and softwood is made.
(4) with oscillating granulator by after the soft material granulation in step (3), until dry whole grain in baking oven, by dry particle
Agent is placed in seed-coating machine, and the carbon dichloride Coating Solution for spraying into the oil with hydrogenated soybean of 500ml is coated, and is obtained for animals for rice
Examine star taste masking sustained-release granular formulation.
As can be seen from Table 6 in the environment of simulate the gastric juice (pH=2), prescription 3 is made compared with Tilmicosin bulk pharmaceutical chemicals
Standby Tilmicosin taste masking sustained-release granular formulation can be sustained up to for 24 hours, only discharge 40% when pig is averaged gastric emptying time 4h, and its
Slow-release time is also more appropriate (12h) in the environment of simulated intestinal fluid, while ensure that sustained release, more drugs can small intestine extremely
Jejunal segment is absorbed, and is beneficial to the performance of Tilmicosin maximum drug effect.
Preparation of the embodiment 4 containing the not veterinary tilmicosin taste masking sustained-release granular formulation of same amount corrigent
The prescription of 7 granule 1 of table
The preparation method of granule 1:
(1) Tilmicosin of 15g is added after dissolving by heating 30g glyceryl palmitostearate, stirring makes Tilmicosin
It is dissolved in the glyceryl palmitostearate of melting.
(2) the Crodaret solution of 150ml 3% is preheated to 100 DEG C, is added in above-mentioned (1) solution,
1000nm nanosuspension below is made in ultrasonic emulsification (6mm probe, ultrasonic 6min).
(3) dextrin and 10g mannitol for taking 32g respectively after mixing, are added in the nanosuspension in step (2),
It is stirred continuously, after mixing, makes conventional softwood in 50 DEG C of drying.
(4) softwood in step (3) is made to the particle of 0.2-2mm with oscillating granulator of the sieve in the aperture 1mm.
(5) it by after the particle drying of step (4) preparation, weighs 20g oil with hydrogenated soybean and is dissolved in 500mL carbon dichloride, with packet
Clothing machine is coated, and obtains veterinary tilmicosin taste masking sustained-release granular formulation 1.
The prescription of 8 granule 2 of table
The preparation method of granule 2:
(1) Tilmicosin of 15g is added after dissolving by heating 30g glyceryl palmitostearate, stirring makes Tilmicosin
It is dissolved in the glyceryl palmitostearate of melting；
(2) the Crodaret solution of 150ml 3% is preheated to 100 DEG C, above-mentioned steps (1) solution is added
In, 1000nm nanosuspension below is made in ultrasonic emulsification (6mm probe, ultrasonic 6min)；
(3) dextrin and 15g mannitol for taking 27g respectively after mixing, are added in the nanosuspension in step (2),
It is stirred continuously, after mixing, makes conventional softwood in 50 DEG C of drying.
(4) softwood in step (3) is made to the particle of 0.2-2mm with oscillating granulator of the sieve in the aperture 1mm.
(5) it by after the particle drying of (4) preparation, weighs 10g oil with hydrogenated soybean and is dissolved in 500mL carbon dichloride, use seed-coating machine
It is coated, obtains veterinary tilmicosin taste masking sustained-release granular formulation 2.
The Tilmicosin taste masking sustained-release granular formulation containing different flavoring agent contents of 5 embodiment 4 of embodiment preparation is fitted
Mouth property
9 test material of table and experimental animal
1. test method
(1) Tilmicosin raw material, two kinds of Tilmicosin taste masking sustained-release granular formulations containing different content corrigent.
(2) feed and preparation
To be uniformly mixed drug with feed, feed is clayed into power shape in advance with ball mill, replaces rice by States Pharmacopoeia specifications
Tilmicosin raw material and granule are prepared with feed, make to raise by the maximum recommended dosage 400mg/kg feed for examining star mixed feeding
The content of Tilmicosin is 400mg/kg in material, is stored spare.
(3) experimental animal
It is tested under the premise of strictly observing animal welfare principle, during which guarantees proper temperature, feed is sufficient, drinking-water
Freely.By the pig of 15 weight 15-20kg, it is randomly divided into blank group, Tilmicosin spice group, directly coating group, granule group
1,5 groups of granule group 2 etc., every group 3.Stable breeding can independently search for food in 5, in the pigsty drunk water respectively, carry out 8 days by a definite date suitable
Mouth property test, wherein first 3 days being the laundering period.The weight that pig is weighed when on-test, empties hopper, and sufficient blank is added and raises
Material, 6
The palatability testing (Mean ± SD, n=3) of the different Tilmicosin granules of table 9
Note: granule 1 is to prepare in embodiment 5 with granule 2.A: there is significant difference (p < 0.01) with blank group ratio；
B: there were significant differences (p < 0.01) with mixed raw material group ratio；C: there were significant differences (p < 0.01) with simple coating group ratio.
It is observed after hour once, remaining feed in blow tank is cleaned after 24 hours, weigh and calculate every group of day feeding
Amount, test weigh the weight of pig after repeating 3 days, 3 days.After the laundering period, hopper is emptied, addition etc. respectively in corresponding group
Measure the granule and sky of sufficient preprepared mixed Tilmicosin raw material, simple coated granule, different flavoring agent contents
White feed is observed once after 6 hours, remaining feed in blow tank is cleaned after 24 hours, and every group of day feeding is weighed and calculate
Amount, test repeat 5 days.The weight of a pig is weighed after 5 days again, calculates 5 days feedstuff-meat ratios of each group pig.Above data is recorded in
In the table prepared in advance, preservation is put on record.
2. test results and analysis
The laundering period daily ingestion amount of each group pig is normal as can be seen from Table 9, meets the feeding range of the age in days pig, illustrates each
Group pig is in a good state of health, and also demonstrates the credibility of test data.Table 9 the result shows that Tilmicosin mix fodder will affect pig
Feeding also demonstrate the present invention and prepare Tilmicosin taste masking sustained-release granular formulation to influence intake of the pig to Tilmicosin
Necessity.Do not prepare nanoparticle and before directly granulating coated group of pig the feeding of 3d significantly reduce, it was demonstrated that simple coating also without
The problem of method very good solution Tilmicosin palatability difference.And the content of the prescription corrigent of granule group 1 and granule group 2 is not
Together, feed intake has certain difference, it is seen that corrigent influences whether that pig complies with Tilmicosin feeding to a certain extent
Property.
The pharmaceutical evaluation of 6 Tilmicosin taste masking sustained-release granular formulation 2 of embodiment
1. test method
(1) granularity checkout facility
According to, to the regulation of granule granularity inspection, weighing replacing for tri- parts of different batches of 8.00g under veterinary drug allusion quotation granule item
Meter Kao Xing taste masking sustained-release granular formulation carries out granularity inspection using double sieve methods, cannot be sieved and can be sieved by No. five total by No.1
With no more than for the 15% of examination amount.
(2) loss on drying is tested
According to, to the regulation of granule loss on drying, weighing replacing for tri- parts of different batches of 8.00g under veterinary drug allusion quotation granule item
Meter Kao Xing taste masking sustained-release granular formulation (because containing low melting point lipid carrier or corrigent in prescription, is not pressed then in 40 DEG C of oven dryings
According to the regulation that granules of sugar agent should be dried under reduced pressure in 80 DEG C), it is dry for 24 hours, until constant weight, reducing weight must not exceed 2.0%.
(3) melting is tested
Dissolution in vitro examination is carried out to the granule in example 4, according to beast States Pharmacopoeia specifications, enteric is no longer carried out then and tests
Card and melting inspection.
2. test results and analysis
10 each batch granule granularity of table and loss on drying examination
The granule of unqualified granularity is respectively less than for the 15% of examination amount in 3 batch samples as can be seen from Table 10, it is seen that this
The Tilmicosin taste masking sustained-release granular formulation of invention preparation meets the granularity requirements of veterinary drug allusion quotation granule, and 3 batches as can be seen from Table 10
The loss on drying of secondary sample meets the loss on drying requirement of veterinary drug allusion quotation granule within 2.0%.In conclusion of the invention
Successfully it is made that a kind of palatability is good, novel Tilmicosin taste masking slow-releasing granules with significant slow-release capability and up-to-standard
Agent.
The pharmacokinetic trial of 7 Tilmicosin taste masking sustained-release granular formulation 2 of embodiment
1. materials and methods
(1) medicament sources: Tilmicosin pre-mixing agent is commercial product, and Tilmicosin taste masking sustained-release granular formulation is embodiment 4
Preparation.
(2) experimental animal: tri-crossbreeding, 12, weight 15-20kg, subfield stable breeding is in country, Hua Zhong Agriculture University beast
Medicine remains datum Laboratory.
(3) instrument configuration: supercentrifuge, liquid chromatograph (commercial product).
(4) test method
It is tested under the premise of strictly observing animal welfare principle, during which guarantees proper temperature, feed is sufficient, drinking-water
Freely.By the pig of 12 weight 15-20kg, it is randomly divided into Tilmicosin pre-mixing agent group and Tilmicosin taste masking sustained-release granular formulation
Group.By 200g/ tons of feed gastric infusions of pharmacopeia recommended dose.After administration 0.5,1,2,4,6,8,12,24,36,48,72,
96,120h collects the blood sample of pig, takes supernatant after centrifugation, with Tilmicosin in liquid chromatographic detection blood after pre-treatment
Content, and draw Drug-time curve.
The pharmacokinetic parameters of table 11 Tilmicosin pre-mixing agent and taste masking sustained-release granular formulation
Note: T1/2β: eliminate half-life period；Cmax: maximum plasma concentration；Tmax: peak time；F: relative bioavailability.
2. test results and analysis
The Drug-time curve and medicine of commercially available Tilmicosin pre-mixing agent and Tilmicosin taste masking enteric coated granule prepared by the present invention
Dynamic data of learning are as shown in Fig. 4 and table 11.As can be seen from Table 11, the area under the drug-time curve of granule is commercially available pre-mixing agent
2.72 times, i.e., relative bioavailability is up to 272.46%, and blood concentration is rapider than increasing with pre-mixing agent, this may be that will receive
After grain of rice enteric coating, less drug is metabolized by gastric acid, and more drugs are transported to intestinal segment and absorb, and Tilmicosin nanometer
The grain suction-operated to the intestinal mucosa and slow release in intestinal segment, extend Tilmicosin in body drug release time.
Delay in conclusion the present invention successfully prepares the Tilmicosin taste masking that a kind of palatability is good, oral bio dynamics is high
Granule is released, effective Mlc can be rapidly achieved while slow-release capability is strong, this is undoubtedly beneficial to Tilmicosin most
The performance of big drug effect, be also beneficial to Tilmicosin in veterinary clinic to control and prevention of disease when application.
Claims (5)
1. a kind of veterinary tilmicosin taste masking sustained-release granular formulation, which is characterized in that the granule is to make as follows
Standby to obtain, the preparation step includes that the oil of solid or liquid is mutually carried out nanosizing processing, with wet granulation and uses film
It is coated the method combined to be prepared, the mixed formulation components based on mass/mass of the ingredient in granule are as described below:
(1) Tilmicosin 5.0~30.0%；
(2) oily phase 10.0~45.0%；
(3) surfactant 1.0~10.0%；
(4) diluent 10.0~40.0%；
(5) corrigent 1.0%~20.0%；
(6) coating material 5.0%~20.0%.
It prepares according to the following steps:
(1) Tilmicosin is added in 100 DEG C of formula ratio of oily phase by formula ratio, is dissolved in Tilmicosin in oily phase,
Obtain solution 1；
(2) aqueous surfactant solution is preheated to 100 DEG C by formula ratio, be added in the resulting solution 1 of step (1), utilized
Nanosuspension made of supersound method, the ultrasound condition are as follows: probe diameter 6-13mm, ultrasonic time 3-
10min；
(3) corrigent and diluent for taking formula ratio after mixing, are added in the nanosuspension of step (2) preparation, not
With after mixing, softwood is made in drying for disconnected stirring；
(4) particle that partial size is 0.2-2mm is made in the sieve that step (3) resulting softwood crosses the aperture 1mm with oscillating granulator；
(5) by after step (4) resulting particle drying, the coating material for weighing formula ratio is dissolved in coating solution, with seed-coating machine into
Row coating, obtains veterinary tilmicosin taste masking sustained-release granular formulation；
Wherein:
The oil is mutually selected from palm oil, glyceryl palmitostearate, one of cottonseed oil or peanut oil or combinations thereof；
The surfactant is selected from Brij35, Tween-60, Myrj 52, one of Crodaret or its group
It closes；
The diluent is selected from dextrin, calcium monohydrogen phosphate, one of low-substituted hydroxypropyl cellulose or magnesium carbonate or combinations thereof；
The corrigent is selected from malic acid, saccharin, mannitol, maltose, one of menthol or combinations thereof；
The coating material is selected from hypromellose, and acrylic resin, oil with hydrogenated soybean or phthalic acid acetic acid are fine
Tie up one of element or combinations thereof；
The coating solution is selected from 95% ethyl alcohol or methylene chloride.
2. veterinary tilmicosin taste masking sustained-release granular formulation according to claim 1, it is characterised in that the composition of preparation presses matter
Amount/quality meter component proportion is as follows:
(1) Tilmicosin 10.0~25.0%；
(2) oily phase 15.0~40.0%；
(3) surfactant 2.0~8.0%；
(4) diluent 15.0~35.0%；
(5) corrigent 2.5%~16.0%；
(6) coating material 6.0%~18.0%.
The oil is mutually selected from palm oil, one of glyceryl palmitostearate or cottonseed oil；
The surfactant is selected from Brij35, one of Tween-60 or Crodaret；
The diluent is selected from dextrin, one of low-substituted hydroxypropyl cellulose or magnesium carbonate；
The corrigent is selected from malic acid or maltose crosses one of menthol；
The coating material is selected from hypromellose, and one in oil with hydrogenated soybean or cellulose acetate-phthalate
Kind；
The ethyl alcohol or methylene chloride that the coating solution is 95%.
3. veterinary tilmicosin taste masking sustained-release granular formulation according to claim 2, which is characterized in that based on mass/mass
Formulation components it is as described below:
(1) Tilmicosin 15.0%；
(2) oily phase 30.0%；
(3) surfactant 3.0%；
(4) diluent 27.0%；
(5) corrigent 15.0%；
(6) coating material 10.0%；
The oil is mutually selected from palm oil or glyceryl palmitostearate；
The surfactant is selected from Crodaret or Tween-60；
The diluent is selected from dextrin or magnesium carbonate；
The corrigent is selected from maltose or menthol；
The coating material is selected from cellulose acetate-phthalate or polyacrylic resin；
The ethyl alcohol that the coating solution is 95%.
4. veterinary tilmicosin taste masking sustained-release granular formulation according to claim 1, which is characterized in that described is for animals for rice
Examining star taste masking sustained-release granular formulation appearance is coffee color to brown, and granularity 0.2-2mm, loss on drying is less than 2%.
5. veterinary tilmicosin taste masking sustained-release granular formulation according to claim 1, which is characterized in that described is for animals for rice
Examining star taste masking sustained-release granular formulation, 4h Accumulation dissolution is less than 50% in the simulate the gastric juice of pH=2, in the simulate the gastric juice of pH=8
4h accumulative releasing degree is greater than 90%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110693814A (en) * | 2019-10-09 | 2020-01-17 | 华中农业大学 | Veterinary tilmicosin nano-gel breast perfusion agent and preparation method thereof |
| CN117398347A (en) * | 2023-12-15 | 2024-01-16 | 山东国邦药业有限公司 | Tilmicosin dry suspension and preparation method thereof |
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| CN101422432A (en) * | 2008-07-09 | 2009-05-06 | 西北农林科技大学 | A kind of tilmicosin nano-emulsion antibacterial drug and preparation method thereof |
| CN103083281A (en) * | 2013-01-15 | 2013-05-08 | 广州格雷特生物科技有限公司 | Enteric-coated tilmicosin slow-release micro-capsule preparation and preparation method thereof |
| CN107375247A (en) * | 2017-08-25 | 2017-11-24 | 重庆市畜牧科学院 | Tilmicosin film control enteric-coated sustained-release preparation and preparation method thereof |
| WO2019032057A1 (en) * | 2017-08-11 | 2019-02-14 | Vet Products Research And Innovation Center Company Limited | Method for preparing nano-particle of tilmicosin and product thereof |
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2019
- 2019-07-17 CN CN201910646734.XA patent/CN110251481A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101422432A (en) * | 2008-07-09 | 2009-05-06 | 西北农林科技大学 | A kind of tilmicosin nano-emulsion antibacterial drug and preparation method thereof |
| CN103083281A (en) * | 2013-01-15 | 2013-05-08 | 广州格雷特生物科技有限公司 | Enteric-coated tilmicosin slow-release micro-capsule preparation and preparation method thereof |
| WO2019032057A1 (en) * | 2017-08-11 | 2019-02-14 | Vet Products Research And Innovation Center Company Limited | Method for preparing nano-particle of tilmicosin and product thereof |
| CN107375247A (en) * | 2017-08-25 | 2017-11-24 | 重庆市畜牧科学院 | Tilmicosin film control enteric-coated sustained-release preparation and preparation method thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110693814A (en) * | 2019-10-09 | 2020-01-17 | 华中农业大学 | Veterinary tilmicosin nano-gel breast perfusion agent and preparation method thereof |
| CN117398347A (en) * | 2023-12-15 | 2024-01-16 | 山东国邦药业有限公司 | Tilmicosin dry suspension and preparation method thereof |
| CN117398347B (en) * | 2023-12-15 | 2024-03-19 | 山东国邦药业有限公司 | Tilmicosin dry suspension and preparation method thereof |
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Application publication date: 20190920 |