CN115645376B - Efficient double-layer coated tilmicosin pellets and preparation method thereof - Google Patents
Efficient double-layer coated tilmicosin pellets and preparation method thereof Download PDFInfo
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- CN115645376B CN115645376B CN202211320346.0A CN202211320346A CN115645376B CN 115645376 B CN115645376 B CN 115645376B CN 202211320346 A CN202211320346 A CN 202211320346A CN 115645376 B CN115645376 B CN 115645376B
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- JTSDBFGMPLKDCD-XVFHVFLVSA-N tilmicosin Chemical compound O([C@@H]1[C@@H](C)[C@H](O)CC(=O)O[C@@H]([C@H](/C=C(\C)/C=C/C(=O)[C@H](C)C[C@@H]1CCN1C[C@H](C)C[C@H](C)C1)CO[C@H]1[C@@H]([C@H](OC)[C@H](O)[C@@H](C)O1)OC)CC)[C@@H]1O[C@H](C)[C@@H](O)[C@H](N(C)C)[C@H]1O JTSDBFGMPLKDCD-XVFHVFLVSA-N 0.000 title claims abstract description 139
- 229960000223 tilmicosin Drugs 0.000 title claims abstract description 137
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- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 6
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- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02W—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO WASTEWATER TREATMENT OR WASTE MANAGEMENT
- Y02W90/00—Enabling technologies or technologies with a potential or indirect contribution to greenhouse gas [GHG] emissions mitigation
- Y02W90/10—Bio-packaging, e.g. packing containers made from renewable resources or bio-plastics
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an efficient double-layer coated pellet of tilmicosin, belonging to the technical field of animal medicines. The pill core is prepared by adopting a solid dispersion melting method, and tilmicosin is uniformly dispersed in the partner-type composite auxiliary materials at a molecular level, so that the bioavailability is higher; the quick-release drug coating layer makes the release speed faster; the taste-masking coating masks the peculiar smell of the medicine and can not refusal to eat. The product has round appearance, good fluidity, no bitter taste or dust, and uniform solid administration and stirring. The pharmacokinetic test comparison proves that the product has the advantages of quick absorption speed, quick response, high blood concentration and good curative effect in vivo after oral administration.
Description
Technical Field
The invention relates to the technical field of animal medicines, in particular to an efficient double-layer coated tilmicosin pellet and a preparation method thereof.
Background
Tilmicosin is a special drug for animals, has inhibiting effect on gram-positive bacteria, certain gram-negative bacteria, mycoplasma, spirochetes and the like, is clinically used for preventing and treating livestock pneumonia (caused by infection of actinobacillus pleuropneumoniae, pasteurella, mycoplasma and the like), poultry mycoplasma disease and mastitis of lactating animals, and has extremely wide application prospect in animal health care. Tilmicosin is indissolvable in water, and liquid preparations such as injection, solution and the like which are clinically related are all required to be added with a large amount of organic solvents as solubilizers and stability, so that the addition of the organic solvents is extremely easy to generate harm such as organism allergy or toxicity, has higher cost and pollutes the environment, and is contrary to the green environmental protection and maintenance concept advocated by the state.
The tilmicosin premix in the current market is two, one is a powder preparation which is directly mixed with auxiliary materials, the bitter taste is high, the bitter taste is diffused in the material mixing process, the powder dust inhaled by the mouth and nose of a feeding person is easy to generate anaphylaxis, the medicine has irritation to the stomach, and the animal does not want to eat; the other is tilmicosin granules, and the problems of uneven stirring, inaccurate dosage, diffuse dust, easy occurrence of adverse reaction by operators and the like are caused by uneven granule sizes. Tilmicosin has poor water solubility, and oral in vivo drug crystals are insoluble and non-dispersible, so that gastrointestinal mucosa is stimulated to influence transmembrane transport and absorption, thus leading to the fact that blood concentration reaches peak time late, the bioavailability is low, and a large amount of drug prototypes are discharged out of the body through intestines, thus causing waste and environmental pollution. Along with the development of large-scale breeding industry, development of efficient tilmicosin preparation suitable for clinical first-line use is urgently needed.
Therefore, it is a technical problem to be solved by those skilled in the art to provide a tilmicosin preparation which is highly stable, efficient, free of bitter taste and capable of being easily mixed uniformly.
Disclosure of Invention
In view of the above, the invention provides an efficient double-layer coated pellet of tilmicosin and a preparation method thereof.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
the tilmicosin high-efficiency double-layer coated micropill comprises a pill core, a quick-release medicine coating layer and a taste masking coating layer; wherein, the pill core comprises the following components in weight ratio: quick release drug coating: taste masking coating = 50-80:10-30:1-10;
wherein, the pill core comprises the following raw materials in parts by weight: 10-20 parts of tilmicosin, 25-50 parts of solid dispersing agent, 5-20 parts of inclusion agent and 1-10 parts of surfactant;
the quick-release medicine coating comprises the following raw materials in parts by weight: 1-10 parts of tilmicosin, 0-10 parts of solid dispersing agent, 10-20 parts of coating agent and 2-3 parts of coating material;
the taste masking coating layer comprises the following raw materials in parts by weight: 1-5 parts of coating material, 1-2 parts of sweetener and 1-3 parts of lubricant.
Preferably, the components are in weight proportion as a pill core: quick release drug coating: taste masking coating =(60-80):(20-30):(1-5)。
Further, the solid dispersing agent is a companion type composite auxiliary material solid dispersing agent.
Further, the solid dispersing agent of the mate composite auxiliary material is one or more of polyethylene glycol 8000, polyethylene glycol 6000, poloxamer 188, mono-diglycerol fatty acid ester, hydrogenated castor oil and copovidone.
The beneficial effects of adopting the further scheme are as follows: the adopted companion type composite auxiliary material solid dispersing agent is a medicine or food grade material, is safe and reliable, and has no side effect.
Further, the inclusion agent is one or more of beta cyclodextrin, hydroxypropyl beta cyclodextrin, polyethylene glycol, carbomer and hypromellose.
The beneficial effects of adopting the further scheme are as follows: the inclusion agent is cyclodextrin, and the inclusion technology is to use the barrel-shaped cavity space in the molecular structure and to use the novel solid dispersion technology to directionally disperse and include the medicine molecules in the barrel-shaped cavity space in the molecular structure to form stable solid dispersion microcapsules or pellets, which are also called as molecular capsules. The cyclodextrin has good non-toxic safety, more than 6 glucose are connected through alpha-1, 4 glycosidic bonds to form a barrel-shaped cavity space structure, and the cyclodextrin has the specificity of 'outer hydrophilcity and inner hydrophilcity', and according to the principle of compatibility of similar people, the outer hydrophilcity enables the cyclodextrin to be easily dissolved in water, and the inner hydrophilcity enables the cyclodextrin to attract and contain indissolvable drug molecules to enter the barrel-shaped cavity space structure to form a stable solid dispersion. The solid dispersion improves the solubility, stability and in vivo bioavailability of the medicine in water, and particularly can quickly release the medicine in animals to generate high blood concentration and bombardment sterilization effect on pathogenic bacteria. The technology has been applied in human pharmaceutical preparations for many years, and is mainly used for covering up the peculiar smell of the medicine, increasing the solubility and stability of insoluble medicine, improving the bioavailability of the medicine and the like.
Further, the surfactant is polyoxyethylene hydrogenated castor oil, and one or more of tween, sodium dodecyl sulfate and propylene glycol are mixed.
The beneficial effects of adopting the further scheme are as follows: the surfactant adopted by the invention can accelerate the release and dissolution of the medicine, and realize the function and curative effect of the medicine as soon as possible.
Further, the coating material is one or more of hypromellose, copovidone, polyacrylic resin latex and acrylic resin No. 2;
the sweetener is steviosin and the lubricant is talcum powder.
The beneficial effects of adopting the further scheme are as follows: the coating material adopted by the invention can effectively mask the peculiar smell of the medicine and increase the stability of the medicine.
The invention also provides a preparation method of the efficient tilmicosin double-layer coated pellet, which comprises the following steps:
(1) Weighing the raw materials according to the parts by weight;
(2) Heating and melting a solid dispersing agent and an inclusion agent in the pellet core material to obtain a melt 1;
(3) Adding tilmicosin into the melt 1, stirring and dissolving until the tilmicosin is clear, and then adding a surfactant, stirring, dissolving and clarifying to obtain a solution 2;
(4) Stirring the solution 2 at 70-80 ℃ until all components are uniformly dispersed, filtering the solution 2, setting the air inlet temperature to be 0-10 ℃, and preparing the tilmicosin pill core by a high-speed centrifugal atomizer and a cold spraying mode;
(5) Sieving tilmicosin pill core, taking 24-65 mesh, dissolving quick-release medicine coating material in ethanol solution, setting air inlet temperature at 45-55deg.C, and spray coating quick-release medicine coating on pill core by fluidized bed bottom;
(6) Dissolving the taste masking coating material in water to form latex with mass fraction of 30%, setting air inlet temperature at 45-55deg.C, and spray coating the latex to the surface of quick-release drug coating layer by fluidized bed to obtain tilmicosin high-efficiency double-layer coated pellet.
The method has the beneficial effects that: experiments show that the tilmicosin high-efficiency pellets prepared by the method have the advantages of no bitter taste, no peculiar smell, remarkably improved solubility and dissolution speed, uniform particle size, good flowability, no dust in the process of mixing materials, and easy uniform mixing with feed.
Further, the heating temperature in the step (2) is 60-90 ℃;
step (2) further comprises adding an inclusion agent in the pellet core material to melt 1.
Further, in the step (4), the stirring speed is 100-200r/min, and the stirring time is 20-180min.
Further, the volume fraction of the ethanol solution in the step (5) is 20%.
Compared with the prior art, the invention has the beneficial effects that:
(1) The tilmicosin high-efficiency double-layer coated pellet is prepared by combining a solid dispersion technology and an inclusion technology and adopting a melt atomization method, has no liquid solvent, short heat preservation time, does not need heat energy during spraying, is prepared only by a cold spraying mode, is simple and convenient to operate and low in cost compared with similar preparations, and is suitable for large-scale industrial production.
(2) The invention relates to an efficient double-layer coated pellet of tilmicosin, which consists of a pellet core, a quick-release medicine coating layer and a taste masking coating layer. The pill core is prepared by adopting a solid dispersion melting method, and tilmicosin is uniformly dispersed in the partner-type composite auxiliary materials at a molecular level, so that the bioavailability is higher; the quick-release medicine coating makes the release speed faster, and realizes the high-efficiency functional pill.
(3) The tilmicosin high-efficiency double-layer coated pellet changes insoluble medicines into soluble preparations, the inclusion process covers the peculiar smell of the medicines, the solid dispersion and the inclusion process are combined, the dissolution rate and the bioavailability of the medicines are greatly improved, various requirements of clinical mixing, drinking and concentrated preparation application can be met, and the tilmicosin high-efficiency double-layer coated pellet is convenient for clinical application and popularization.
(4) The tilmicosin high-efficiency double-layer coated pellet disclosed by the invention is green and safe in all of solid dispersing agents, inclusion agents, surfactants and the like, does not contain hormone, antibiotics and the like to influence food safety components, and is suitable for popularization and application in large-scale pig farms and industrialization.
(5) The invention discloses a tilmicosin high-efficiency double-layer coated pellet, which is found by comparing pharmacokinetics tests, and has the advantages of high absorption speed, quick response, high blood concentration and good curative effect in oral administration. The graph shows that the impact effect of the anti-biological drug blood drug peak sterilization can be achieved, and a plurality of parameter indexes all achieve the ideal effect of oral anti-biological drug treatment, so that the clinical drug application can be satisfied.
(6) The invention combines the solid dispersion technology and the cyclodextrin inclusion technology, the inclusion technology covers peculiar smell, the solid dispersion technology increases solubility and dissolution, the pollution-free and liquid solvent-free technology is adopted in the preparation process, the convenient cold spraying technology is used for preparing the efficient tilmicosin pellets for animals, and the pellets are subjected to secondary coating, so that the pellets have no peculiar smell completely. The preparation process has the advantages of low energy consumption, low cost, large production batch, green and pollution-free properties and the like. The prepared inclusion microcapsule has no bitter taste, improves the palatability of tilmicosin, reduces the irritation of tilmicosin to animal gastric mucosa, improves the compliance of animals to tilmicosin, has high dissolution rate, quick effect, high blood concentration, good curative effect and good stability, can completely meet the detection requirements of national standards, and practically solves the problems of inconvenient medicine use and the like in the large-scale cultivation process from the clinical point of view, and humanized meets the medicine use habit of a cultivator. The invention also provides a preparation method of the tilmicosin high-efficiency pellets for animals.
Drawings
FIG. 1 is a high-efficiency pellet of tilmicosin prepared by the invention;
FIG. 2 is a high-efficiency pellet of tilmicosin from company A;
FIG. 3 is a tilmicosin high-efficiency pellet from company B;
FIG. 4 is a graph showing the dissolution profile of tilmicosin pellets prepared according to the present invention in water;
FIG. 5 is a graph (0-72 hours) comparing the average drug time of tilmicosin and tilmicosin enteric coated particles of example 2 of the present invention;
FIG. 6 is a graph (0-36 hours) comparing the average drug time of tilmicosin and tilmicosin enteric coated particles of example 2 of the present invention;
FIG. 7 is a graph (0-24 hours) comparing the average drug time of tilmicosin and tilmicosin enteric coated particles of example 2 of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The product prepared in example 1 was used in the test examples of the present invention.
Example 1
Efficient double-layer coated tilmicosin pellets
(1) Weighing the core material: 150kg of tilmicosin, 6000250kg of polyethylene glycol, 188180kg of poloxamer, 100kg of betacyclodextrin and 20kg of sodium dodecyl sulfate;
quick release drug coating material: 50kg of tilmicosin, 50kg of beta-cyclodextrin, 6000100kg of polyethylene glycol, 60kg of hypromellose and 20kg of copovidone;
taste masking coating material: 10kg of hydroxypropyl methylcellulose; 7kg of polyacrylic resin; 2kg of talcum powder; steviosin 1kg;
(2) Heating and melting a solid dispersing agent in the pill core material, and then adding a coating agent in the pill core material to obtain a melt 1;
(3) Adding tilmicosin into the melt 1, stirring and dissolving until the tilmicosin is clear, and then adding a surfactant, stirring, dissolving and clarifying to obtain a solution 2;
(4) Stirring solution 2 at 75deg.C for 30min under stirring at 100r/min, filtering solution 2, setting air inlet temperature at 5deg.C, and preparing tilmicosin pill core by high-speed centrifugal atomizer and cold spraying;
(5) Sieving tilmicosin pill core to obtain 30-65 mesh pill core, dissolving quick-release medicine coating material in ethanol solution, setting air inlet temperature at 50deg.C, and spray coating quick-release medicine coating on pill core by fluidized bed bottom;
(6) Dissolving the taste masking coating material in water to form latex with the mass fraction of 30%, setting the air inlet temperature to be 50 ℃, and coating the latex on the surface of the quick-release drug coating layer through the bottom spray of a fluidized bed to obtain the tilmicosin high-efficiency double-layer coated micropill.
Example 2
Efficient double-layer coated tilmicosin pellets
(1) Weighing the core material: 150kg of tilmicosin; 100kg of mono-diglyceride fatty acid ester; 250kg of hydrogenated castor oil; 188130kg of poloxamer; 100kg of hydroxypropyl betacyclodextrin; tween 80 20kg.
Quick release drug coating material: 50kg of tilmicosin; 70kg of beta-cyclodextrin; 100kg of hydroxypropyl methylcellulose; 20kg of copovidone;
taste masking coating material: 5kg of hydroxypropyl methylcellulose; 3kg of polyacrylic resin; talcum powder 1kg; steviosin 1kg;
(2) Heating and melting a solid dispersing agent in the pill core material, and then adding a coating agent in the pill core material to obtain a melt 1;
(3) Adding tilmicosin into the melt 1, stirring and dissolving until the tilmicosin is clear, and then adding a surfactant, stirring, dissolving and clarifying to obtain a solution 2;
(4) Stirring solution 2 at 70deg.C for 30min under 200r/min, dispersing uniformly, filtering solution 2, setting air inlet temperature at 3deg.C, and preparing tilmicosin pill core by high-speed centrifugal atomizer and cold spraying;
(5) Sieving tilmicosin pill core to obtain 65 mesh pill core, dissolving quick-release medicine coating material in ethanol solution, setting air inlet temperature at 55deg.C, and spray coating quick-release medicine coating on pill core by fluidized bed bottom;
(6) Dissolving the taste masking coating material in water to form latex with the mass fraction of 30%, setting the air inlet temperature to 55 ℃, and coating the latex on the surface of the quick-release drug coating layer through the bottom spray of a fluidized bed to obtain the tilmicosin high-efficiency double-layer coated pellet.
Example 3
Efficient double-layer coated tilmicosin pellets
(1) Weighing the core material: 120kg of tilmicosin; 140kg of copovidone; 8000150kg of polyethylene glycol; 188200kg of poloxamer; 40kg of polyoxyethylene hydrogenated castor oil;
quick release drug coating material: 80kg of tilmicosin; polyethylene glycol 600080kg; 80kg of hydroxypropyl methylcellulose; 30kg of hydroxypropyl betacyclodextrin; 30kg of copovidone;
taste masking coating material: 25kg of hydroxypropyl methylcellulose; 12kg of polyacrylic resin; 6kg of steviosin; 7kg of talcum powder;
(2) Heating and melting a solid dispersing agent in a pill core material to obtain a melt 1;
(3) Adding tilmicosin into the melt 1, stirring and dissolving until the tilmicosin is clear, and then adding a surfactant, stirring, dissolving and clarifying to obtain a solution 2;
(4) Stirring solution 2 at 80deg.C for 30min under 140r/min, dispersing uniformly, filtering solution 2, setting air inlet temperature at 2deg.C, and preparing into tilmicosin pill core by high-speed centrifugal atomizer and cold spraying;
(5) Sieving tilmicosin pill core to obtain 24 mesh pill core, dissolving quick-release medicine coating material in ethanol solution, setting air inlet temperature at 45deg.C, and spray coating quick-release medicine coating on pill core by fluidized bed bottom;
(6) Dissolving the taste masking coating material in water to form latex with the mass fraction of 30%, setting the air inlet temperature to 45 ℃, and coating the latex on the surface of the quick-release drug coating layer through the bottom spray of a fluidized bed to obtain the tilmicosin high-efficiency double-layer coated pellet.
Test example 1 drug particle size test:
the test method comprises the following steps: referring to a particle size determination method of tilmicosin premix of 2015 edition of Chinese animal pharmacopoeia, combining with internal control of products, selecting 24-mesh and 65-mesh sieves, weighing samples of different manufacturers, performing particle size screening on the medicines by the same method, evaluating the medicines with a qualification rate of 24-65 meshes, and optimizing the qualification rate of 24-65 meshes. The results of the particle size measurement are shown in Table 1 below.
TABLE 1 results of particle size determination of tilmicosin premix from different manufacturers
Product name | The invention relates to a high-efficiency pellet of tilmicosin group | A enterprise product | B Enterprise product |
Yield of percent of pass | 100% | 64% | 79% |
Test results: by comparison, the tilmicosin-containing high-efficiency pellets have full and bright particles, uniform granularity and no fine powder, can provide a good mixing environment, and are easy to uniformly mix with granular medicines. Test example 2 drug bitter test:
the test method comprises the following steps: a small amount of tilmicosin premix drug was taken and placed at the tip of the tongue for taste, and evaluated within 5 seconds, with the results shown in table 2 below.
TABLE 2 bitter taste detection results of 20% tilmicosin premix from different manufacturers
Product name | The invention relates to a high-efficiency pellet of tilmicosin group | A enterprise product | B Enterprise product |
Taste and flavor of taste | No bitter and peculiar smell | The bitter taste is intense | Is especially sweet |
Test results: by comparison, the tilmicosin-containing high-efficiency pellets are not bitter within 5 seconds, so that the inclusion pellets are completely included, the taste masking effect is good, and the problem of drug irritation is solved.
Test example 3 alignment of pharmaceutical traits
(1) The test method comprises the following steps: the tilmicosin samples of 3 different manufacturers are respectively weighed, respectively placed under 100 times of electro-optical mirrors, observed and photographed, and the results are shown in figures 1, 2 and 3.
The tilmicosin high-efficiency pellets are round pellets, have smooth appearance, are uniform and compact in size and are not adhered to each other.
The product of enterprise A is irregular pill, which has unsmooth appearance, uneven and loose size and adhesion.
The product of enterprise B is irregular pill, its appearance is not smooth, its size is not symmetric and loose and is adhered mutually.
Test example 4 dissolution test
The test method comprises the following steps: according to the dissolution rate measurement method of China veterinary Pharmacopeia 2015, the high-efficiency tilmicosin pellets of examples 1, 2 and 3 are weighed, the samples of different factories are operated in the same method, the dissolution rate in water is measured, and the samples are sampled at 0, 5, 10, 15, 30, 45, 75 and 120 minutes, and the dissolution rate measurement results are shown in the following table 3 and fig. 4.
TABLE 3 comparative test results of dissolution in water of efficient tilmicosin pellets
Stability test
The high-efficiency tilmicosin pellets in example 2 are subjected to a normal temperature placement test and a 40 ℃ heat acceleration test according to the drug stability test guidelines under the 2015 item of Chinese animal pharmacopoeia, the normal temperature test is observed for 24 months, the 40 ℃ heat acceleration test is observed for 6 months, all quality indexes are in a qualified range, and the stability results are shown in the following table 4.
Table 4 florfenicol tilmicosin high-efficiency pellet microcapsule 40 ℃ stability test observation
In summary, the efficient tilmicosin pellets for animals are obviously superior to similar products in terms of bitterness, properties, granularity, dissolution rate, stability and the like, and the above description is further made in combination with specific preferred embodiments, and the specific implementation of the present invention is not to be considered as limited to these descriptions, and all similar processes and equivalent changes to the present invention should be considered as falling within the scope of protection of the present invention.
Test example 5
The invention discloses a high-efficiency pellet of tilmicosin, which is prepared from the following components in example 2 (Shennitimixin for short):
the tilmicosin high-efficiency pellets (abbreviated as Shenniu tilmicosin) prepared in the embodiment 2 of the invention and the domestic first-time tilmicosin enteric-coated particles are entrusted to the institute of animal husbandry and veterinary medicine in Lanzhou of China academy of agricultural sciences, and the absorption and metabolism characteristics of tilmicosin and enteric-coated particles are compared and evaluated in pig body in a pharmacokinetics comparison test, so that a basis is provided for preparing a reasonable clinical medication scheme.
5.1 Experimental protocol
Healthy three-way pigs, 16 pigs, are randomly divided into 2 groups (Shenniu tilmicin group; tilmicosin enteric granule control group), 8 of each group, and male and female are half. The administration dosage refers to the clinical recommended dosage and usage of tilmicosin pigs, and the feeding amount of the early-stage actual feed is combined to determine that each pig is 60mg/kgBW, and each group is subjected to one-time gastric lavage administration. Each pig blood sampling point is 20 time points of 0min, 15min, 30min, 45min, 1h, 1.25h, 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 10h, 12h, 24h, 36h, 48h, 72h and the like. The sample is anticoagulated by EDTA, plasma is separated, a Waters2695 high performance liquid chromatography system is adopted for detection, the experimental data are processed and counted by utilizing the full-automatic pharmacokinetic analysis software of Phoenix WinNonLin8.2, the AUC and Cmax are subjected to logarithmic transformation, and then the analysis of variance, double single-side t-test and calculation of relative bioavailability are carried out. Methodology studies showed that the regression equation was y= 26971x-196608, r 2 The linear range is 50-5000 ng/mL, the quantitative limit is 50ng/mL, the precision is less than 5%, the average recovery rate under the three concentrations of low, medium and high is 96.5+/-2.53%, 96.88 +/-1.25%, 105.3+/-1.85%, and the RSD% is less than 5%.
5.2 pharmacokinetic experiments
5.2.1 concentration at time of drug and Curve at time of drug
Determining and calculating the content of tilmicosin in pig plasma samples at different time points, and obtaining the results shown in Table 1; drawing a medicine time curve chart of tilmicosin by taking time as an x axis and tilmicosin concentration as a y axis, wherein the medicine time curve chart of tilmicosin in different time periods is shown in fig. 5 and 6.
TABLE 5 concentration of tilmicosin and tilmicosin enteric coated particles in pig plasma traditional Chinese medicine (. Mu.g/mL)
5.2.2 pharmacokinetic parameters
The experiment adopts a high performance liquid phase detection method to determine main parameters of pharmacokinetics of tilmicosin and tilmicosin enteric-coated particles in pigs, and a curve of the tilmicosin and tilmicosin enteric-coated particles accords with a non-atrioventricular model when the pigs are administrated in a single dose.
Tilmicosin and tilmicosin enteric granule reference drug main pharmacokinetic parameters, average maximum blood concentration C max 2.1+ -1.1 and 1.2+ -0.7 respectively; the delay time TLag is respectively 0.8+/-0.4 and 3.2+/-1.5; peak time T max 4.4+ -1.0 and 6.5+ -0.5 respectively; average drug elimination half-life T 1/2 8.4+ -6.3, 17.5+ -12.6, respectively; the average area under the curve AUC (0-24) is 14.77+ -4.48, 9.94+ -6.8, and the average area under the curve AUC (0-infinity) is 15.74+ -5.7, 12.1+ -9.5 respectively; the clearance CL/F is respectively as follows; 4.32+ -3.41, 3.01+ -2.81; the apparent distribution volumes V_F were 44.31.+ -. 34.26 and 66.41.+ -. 50.54, respectively, and the average residence times MRTlast were 8.5.+ -. 1.2 and 12.1.+ -. 3.1, respectively.
5.3 summary of experimental data
The above experimental parameters and data are summarized in Table 6, and the time-of-drug curve (0-24 hours) is shown in FIG. 7.
TABLE 6 results of comparative study of pharmacokinetics of tilmicosin and tilmicosin enteric coated particles
5.4 comprehensive analysis of Experimental data
5.4.1 absorption, distribution, metabolism
The peak time of the blood concentration of the Shennitimixing and tilmicosin enteric-coated particles is respectively 4.4 hours and 6.5 hours; half-lives were 8.4 hours, 17.5 hours, respectively; the clearance rate is respectively 4 hours and 3 hours; the average residence time was 8.5 hours and 12 hours, respectively. The data show that tilmicosin has quick response compared with tilmicosin enteric granule, wherein the peak time of the tilmicosin is 2 hours earlier; the oral clearance rate reaches 4 hours, the half-life reaches 8 hours, and the method accords with the drug release rule of oral antibiotics.
5.4.2 time and blood concentration
The highest blood concentration Cmax of the tilmicosin enteric-coated particles is 2.1 and 1.2 mug/ml respectively, and the data show that the blood concentration of the tilmicosin enteric-coated particles is up to 175%; the area under the curve when the oral administration was counted according to different time periods is shown in table 7.
TABLE 7 Curve area of tilmicosin and tilmicosin enteric coated granule
Description of data: tilmicosin is an enteric-coated particle of tilmicosin with a treatment effect of more than 2 times within 0-12 hours of oral administration; 1.5 times in the interval of 0-24 hours; the time period between 0 and 48 hours is 1.3 times.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (3)
1. The preparation method of the tilmicosin double-layer coated pellet is characterized by comprising the following steps of:
(1) Weighing the core material: 150kg of tilmicosin, 6000 kg of polyethylene glycol 250kg, 188 kg of poloxamer 188 kg, 100kg of betacyclodextrin and 20kg of sodium dodecyl sulfate;
quick release drug coating material: 50kg of tilmicosin, 50kg of betacyclodextrin, 6000 kg of polyethylene glycol, 60kg of hypromellose and 20kg of copovidone;
taste masking coating material: 10kg of hydroxypropyl methylcellulose; 7kg of polyacrylic resin; 2kg of talcum powder; steviosin 1kg;
(2) Heating and melting solid dispersing agent polyethylene glycol 6000 and poloxamer 188 in the pill core material, and then adding inclusion agent beta-cyclodextrin in the pill core material to obtain melt 1;
(3) Adding tilmicosin into the melt 1, stirring and dissolving until the tilmicosin is clear, and then adding surfactant sodium dodecyl sulfate, stirring, dissolving and clarifying to obtain a solution 2;
(4) Stirring solution 2 at 75deg.C for 30min under stirring at 100r/min, filtering solution 2, setting air inlet temperature at 5deg.C, and preparing tilmicosin pill core by high-speed centrifugal atomizer and cold spraying;
(5) Sieving tilmicosin pill core to obtain 30-65 mesh pill core, dissolving quick-release medicine coating material in ethanol solution, setting air inlet temperature at 50deg.C, and spray coating quick-release medicine coating on pill core by fluidized bed bottom;
(6) Dissolving the taste masking coating material in water to form latex with the mass fraction of 30%, setting the air inlet temperature to be 50 ℃, and coating the latex on the surface of the quick-release drug coating layer through the bottom spray of a fluidized bed to obtain the tilmicosin double-layer coated pellet.
2. The preparation method of the tilmicosin double-layer coated pellet is characterized by comprising the following steps of:
(1) Weighing the core material: 150kg of tilmicosin; 100kg of mono-diglyceride fatty acid ester; 250kg of hydrogenated castor oil; poloxamer 188 kg 130; 100kg of hydroxypropyl betacyclodextrin; tween 80 20kg;
quick release drug coating material: 50kg of tilmicosin; 70kg of beta-cyclodextrin; 100kg of hydroxypropyl methylcellulose; 20kg of copovidone;
taste masking coating material: 5kg of hydroxypropyl methylcellulose; 3kg of polyacrylic resin; talcum powder 1kg; steviosin 1kg;
(2) Heating and melting solid dispersing agent mono-diglycerol fatty acid ester, hydrogenated castor oil and poloxamer 188 in the pellet core material, and then adding inclusion agent hydroxypropyl betacyclodextrin in the pellet core material to obtain melt 1;
(3) Adding tilmicosin into the melt 1, stirring and dissolving until the tilmicosin is clear, and then adding a surfactant Tween 80, stirring, dissolving and clarifying to obtain a solution 2;
(4) Stirring solution 2 at 70deg.C for 30min under 200r/min, dispersing uniformly, filtering solution 2, setting air inlet temperature at 3deg.C, and preparing tilmicosin pill core by high-speed centrifugal atomizer and cold spraying;
(5) Sieving tilmicosin pill core to obtain 65 mesh pill core, dissolving quick-release medicine coating material in ethanol solution, setting air inlet temperature at 55deg.C, and spray coating quick-release medicine coating on pill core by fluidized bed bottom;
(6) Dissolving the taste masking coating material in water to form latex with the mass fraction of 30%, setting the air inlet temperature to 55 ℃, and coating the latex on the surface of the quick-release drug coating layer through the bottom spray of a fluidized bed to obtain the tilmicosin double-layer coated pellet.
3. The preparation method of the tilmicosin double-layer coated pellet is characterized by comprising the following steps of:
(1) Weighing the core material: 120kg of tilmicosin; 140kg of copovidone; polyethylene glycol 8000150kg; poloxamer 188200kg; 40kg of polyoxyethylene hydrogenated castor oil;
quick release drug coating material: 80kg of tilmicosin; polyethylene glycol 600080kg; 80kg of hydroxypropyl methylcellulose; 30kg of hydroxypropyl betacyclodextrin; 30kg of copovidone;
taste masking coating material: 25kg of hydroxypropyl methylcellulose; 12kg of polyacrylic resin; 6kg of steviosin; 7kg of talcum powder;
(2) Heating and melting solid dispersing agent copolyvidone, polyethylene glycol 8000 and poloxamer 188 in the pill core material to obtain melt 1;
(3) Adding tilmicosin into the melt 1, stirring and dissolving until the tilmicosin is clear, and then adding a surfactant polyoxyethylene hydrogenated castor oil, stirring, dissolving and clarifying to obtain a solution 2;
(4) Stirring solution 2 at 80deg.C for 30min under 140r/min, dispersing uniformly, filtering solution 2, setting air inlet temperature at 2deg.C, and preparing into tilmicosin pill core by high-speed centrifugal atomizer and cold spraying;
(5) Sieving tilmicosin pill core to obtain 24 mesh pill core, dissolving quick-release medicine coating material in ethanol solution, setting air inlet temperature at 45deg.C, and spray coating quick-release medicine coating on pill core by fluidized bed bottom;
(6) Dissolving the taste masking coating material in water to form latex with the mass fraction of 30%, setting the air inlet temperature to 45 ℃, and coating the latex on the surface of the quick-release drug coating layer through the bottom spray of a fluidized bed to obtain the tilmicosin double-layer coated pellet.
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