CN115645376A - Tilmicosin efficient double-layer coated pellet and preparation method thereof - Google Patents
Tilmicosin efficient double-layer coated pellet and preparation method thereof Download PDFInfo
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- CN115645376A CN115645376A CN202211320346.0A CN202211320346A CN115645376A CN 115645376 A CN115645376 A CN 115645376A CN 202211320346 A CN202211320346 A CN 202211320346A CN 115645376 A CN115645376 A CN 115645376A
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Images
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- 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
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a high-efficiency double-layer coated tilmicosin pellet, belonging to the technical field of animal medicines. The pill core is prepared by adopting a solid dispersion and fusion method technology, and the tilmicosin is uniformly dispersed in the mate type composite auxiliary material in a molecular level, so that the bioavailability is higher; the quick-release drug coating layer ensures that the release speed is higher; the taste masking coating layer masks the peculiar smell of the medicine and does not refuse to eat. The product has round appearance, good fluidity, no bitter taste, no dust, and uniform solid administration. The comparison of pharmacokinetic experiments proves that the oral administration of the product has the advantages of fast absorption speed, fast effect, high blood concentration and good curative effect.
Description
Technical Field
The invention relates to the technical field of animal medicines, in particular to a tilmicosin high-efficiency double-layer coated pellet and a preparation method thereof.
Background
Tilmicosin is a special medicine for animals, has an inhibiting effect on gram-positive bacteria, certain gram-negative bacteria, mycoplasma, spirochetes and the like, is mainly clinically used for preventing and treating livestock pneumonia (caused by infection of actinobacillus pleuropneumoniae, pasteurellosis, mycoplasma and the like), avian mycoplasmosis and mastitis of lactating animals, and has a very wide application prospect in animal health care. Tilmicosin is difficult to dissolve in water, a large amount of organic solvents are required to be added into clinically related liquid preparations such as injection, solution and the like as solubilizers and stability, the organic solvents are very easy to cause harm such as organism allergy or toxicity and the like, the cost is high, the environment is polluted, and the tilmicosin is in contradistinction with the green and environment-friendly culture idea advocated by the state.
The tilmicosin premix on the market at present is two, one is a powder preparation directly mixed with auxiliary materials, the bitterness is large, the bitterness is diffused in the process of mixing materials, the phenomenon that the mouth and the nose of feeding personnel inhale medicine dust is easy to cause allergy, the medicine is irritating to the stomach, and animals are unwilling to eat and the like; the other is tilmicosin granules, and the problems of uneven material mixing, inaccurate dosage of used medicament, diffuse dust, easy occurrence of adverse reaction by operators and the like are caused by uneven particle size. Tilmicosin has poor water solubility, and oral in-vivo medicine crystals are insoluble and non-dispersible, and stimulate gastrointestinal mucosa to influence transmembrane transport and absorption, so that the blood concentration peak time is late, the bioavailability is low, and a large amount of prototype medicines are discharged out of the body through intestines, thereby causing waste and environmental pollution. With the development of the large-scale breeding industry, the development of a high-efficiency tilmicosin preparation suitable for the first line of clinical application is urgently needed.
Therefore, the technical problem to be solved by the technical personnel in the field is urgently needed to provide a tilmicosin preparation which is high in stability, high in efficiency, free of bitter taste and easy to mix uniformly.
Disclosure of Invention
In view of this, the invention provides a tilmicosin high-efficiency double-layer coated pellet and a preparation method thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
a tilmicosin high-efficiency double-layer coated pellet comprises a pellet core, a quick-release drug coating layer and a taste-masking coating layer; wherein, the components are as follows according to the weight ratio: the quick-release drug coating layer: taste-masking layer =50-80:10-30:1-10;
wherein the pellet core comprises the following raw materials in parts by weight: 10-20 parts of tilmicosin, 25-50 parts of a solid dispersing agent, 5-20 parts of an inclusion agent and 1-10 parts of a surfactant;
the quick-release drug coating layer comprises the following raw materials in parts by weight: 1-10 parts of tilmicosin, 0-10 parts of solid dispersant, 10-20 parts of coating agent and 2-3 parts of coating material;
the taste masking coating comprises the following raw materials in parts by weight: 1-5 parts of coating material, 1-2 parts of sweetening agent and 1-3 parts of lubricating agent.
Preferably, the pill core comprises the following components in parts by weight: the quick-release drug coating layer: taste masking coating =(60-80)：(20-30)：(1-5)。
Further, the solid dispersant is a mate type composite auxiliary material solid dispersant.
Furthermore, the mate type composite auxiliary material solid dispersant is one or a mixture of polyethylene glycol 8000, polyethylene glycol 6000, poloxamer 188, mono-diglycerol fatty acid ester, hydrogenated castor oil and copovidone.
The beneficial effect of adopting the further scheme is as follows: the mate type composite auxiliary material solid dispersing agent adopted by the invention is a medicine or food grade material, is safe and reliable, and has no side effect.
Further, the clathrating agent is one or more of betacyclodextrin, hydroxypropyl betacyclodextrin, polyethylene glycol, carbomer and hydroxypropyl methylcellulose.
The beneficial effect of adopting the above further scheme is that: the inclusion agent is cyclodextrin as an example, and the inclusion technology is that drug molecules are directionally dispersed and included in a barrel-shaped cavity space in a molecular structure by utilizing the barrel-shaped cavity space in the molecular structure and adopting a novel solid dispersion technology to form stable solid dispersion microcapsules or pellets, which are also called molecular capsules. The cyclodextrin is non-toxic and good in safety, more than 6 glucose are connected through alpha-1, 4 glycosidic bonds to form a barrel-shaped cavity space structure, the cyclodextrin has the particularity of 'external hydrophilicity and internal hydrophobicity', according to the compatibility principle of the similar people, the cyclodextrin is easy to dissolve in water by the external hydrophilicity, and the cyclodextrin can attract and contain indissolvable drug molecules into the barrel-shaped cavity space structure by the internal hydrophobicity to form a stable solid dispersion. The solid dispersion improves the solubility, stability and in-vivo bioavailability of the medicament in water, particularly can quickly release the medicament in an animal body to generate high blood concentration, and has bombardment sterilization effect on pathogenic bacteria. The technology has been applied to 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 medicines, improving the bioavailability of the medicine and the like.
Further, the surfactant is one or more of polyoxyethylene hydrogenated castor oil, tween, sodium dodecyl sulfate and propylene glycol.
The beneficial effect of adopting the further scheme is as follows: the surfactant adopted by the invention can accelerate the release and dissolution of the medicament and realize the function and curative effect of the medicament as soon as possible.
Further, one or more of hydroxypropyl methylcellulose, copovidone, polyacrylic resin emulsion and acrylic resin No. 2 are mixed as the coating material;
the sweetening agent is stevioside, and the lubricating agent is talcum powder.
The beneficial effect of adopting the further scheme is as follows: the coating material adopted by the invention can effectively cover up the peculiar smell of the medicine and increase the stability of the medicine.
The invention also provides a preparation method of the tilmicosin efficient double-layer coated pellet, which comprises the following steps of:
(1) Weighing the raw materials in parts by weight;
(2) Heating and melting the solid dispersing agent and the inclusion agent in the pill core material to obtain molten liquid 1;
(3) Adding tilmicosin into the molten liquid 1, stirring and dissolving until the mixture is clear, then adding a surfactant, stirring and dissolving until the mixture is clear, and obtaining a solution 2;
(4) Stirring the solution 2 at the temperature of 70-80 ℃ until all components are uniformly dispersed, then filtering the solution 2, setting the air inlet temperature to be 0-10 ℃, and preparing a tilmicosin pill core in a cold spraying mode by using a high-speed centrifugal atomizer;
(5) Sieving tilmicosin pill core to obtain 24-65 mesh, dissolving the quick-release drug coating layer material in ethanol solution, setting air inlet temperature at 45-55 deg.C, and spray coating the quick-release drug coating layer on the pill core via fluidized bed;
(6) Dissolving the taste-masking coating material in water to form a latex solution with the mass fraction of 30%, setting the air inlet temperature to be 45-55 ℃, and performing bottom spraying coating on the latex solution to the surface of the quick-release drug coating layer through a fluidized bed to obtain the tilmicosin efficient double-layer coated pellet.
The method of the invention has the beneficial effects that: experiments show that the tilmicosin high-efficiency pellet prepared by the method has no bitter taste and peculiar smell, the solubility and the dissolution speed are obviously improved, the particle size is uniform, the free-running property is good, no dust appears in the material mixing process, and the tilmicosin high-efficiency pellet is very easy to be uniformly mixed with feed.
Further, the heating temperature in the step (2) is 60-90 ℃;
the step (2) also comprises the step of adding the inclusion agent in the pill core material into the melt 1.
Further, in the step (4), the stirring speed is 100-200r/min, and the stirring time is 20-180min.
Further, the ethanol solution in the step (5) has a volume fraction of 20%.
Compared with the prior art, the invention has the beneficial effects that:
(1) The high-efficiency double-layer coated tilmicosin pellet disclosed by the invention combines a solid dispersion technology and an inclusion technology, is prepared by adopting a melting atomization method, does not contain any liquid solvent, is short in heat preservation time, does not need heat energy during spraying, is prepared only by adopting 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 a tilmicosin high-efficiency double-layer coated pellet which consists of a pellet core, a quick-release drug coating layer and a taste masking coating layer. The pill core is prepared by adopting a solid dispersion and fusion method technology, and the tilmicosin is uniformly dispersed in the mate type composite auxiliary material in a molecular level, so that the bioavailability is higher; the quick-release drug coating layer ensures that the release speed is higher, and the high-efficiency functional pill is realized.
(3) The tilmicosin high-efficiency double-layer coated pellet changes insoluble medicines into soluble preparations, covers peculiar smell of the medicines by the inclusion process, combines the solid dispersion and the inclusion process, greatly improves the dissolution rate and the bioavailability of the medicines, can simultaneously meet various requirements of clinical mixing, drinking water and concentrated preparation application, and is convenient for clinical application and popularization.
(4) The solid dispersing agent, the inclusion agent, the surfactant and the like used by the tilmicosin high-efficiency double-layer coating pellet are green and safe, do not contain ingredients such as hormone, antibiotics and the like which influence food safety, and are suitable for popularization and application and industrialization of large-scale pig farms.
(5) The high-efficiency double-layer coated tilmicosin micro-pill has the advantages of high absorption speed, quick response, high blood concentration and good curative effect in oral administration bodies, which is found by comparison of pharmacokinetic experiments. The time curve chart shows that the bombardment effect of peak sterilization of the anti-biologic drug blood can be achieved, a plurality of parameter indexes achieve the ideal effect of oral anti-biologic drug treatment, and clinical medication can be met.
(6) The invention adopts the combination of the solid dispersion technology and the cyclodextrin inclusion technology, the inclusion technology covers the peculiar smell, the solid dispersion technology increases the solubility and the dissolution rate, the nuisanceless and liquid-state menstruum is adopted in the preparation process, the convenient cold spraying technology is used for preparing the tilmicosin high-efficiency pellet for animals, and the pellet is coated for the second time and has no peculiar smell completely. The preparation process has the advantages of low energy consumption, low cost, large production batch, greenness, no pollution and the like. The prepared inclusion microcapsule has no bitter taste, improves the palatability of tilmicosin, reduces the stimulation of the tilmicosin to the gastric mucosa of animals, improves the compliance of the animals to the tilmicosin, has high dissolution rate, quick response, high blood concentration, good curative effect and good stability of the high-efficiency tilmicosin pellets, can completely meet the detection requirements of national standards, practically solves the problems of inconvenient medication and the like in the large-scale culture process from the clinical perspective, and can humanizedly meet the medication habits of culturists. The invention also provides a preparation method of the tilmicosin high-efficiency pellet for animals.
Drawings
FIG. 1 shows a tilmicosin high-efficiency pellet prepared by the invention;
FIG. 2 shows a high-performance tilmicosin pellet from company A;
FIG. 3 shows a high-performance tilmicosin pellet from company B;
FIG. 4 is a water dissolution curve of the tilmicosin high-efficiency pellet prepared by the invention;
FIG. 5 is a graph comparing the mean drug time curves of tilmicosin and tilmicosin enteric particles of example 2 of the present invention (0-72 hours);
FIG. 6 is a graph comparing the mean drug time curves of tilmicosin and tilmicosin enteric-coated particles of example 2 of the present invention (0-36 hours);
FIG. 7 is a graph comparing the mean dosing time curves of enteric particles of tilmicosin and tilmicosin (0-24 hours) in example 2 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The test was carried out using the product prepared in example 1 in all of the test examples of the present invention.
Example 1
High-efficiency double-layer coated tilmicosin pellet
(1) Weighing the pill core material: 150kg of tilmicosin, 6000250kg of polyethylene glycol, 188180kg of poloxamer, 100kg of beta-cyclodextrin and 20kg of sodium dodecyl sulfate;
quick-release drug coating material: 50kg of tilmicosin, 50kg of betacyclodextrin, 6000100kg of polyethylene glycol, 60kg of hydroxypropyl methylcellulose and 20kg of copovidone;
taste masking coating material: 10kg of hydroxypropyl methylcellulose; 7kg of polyacrylic resin; 2kg of talcum powder; 1kg of stevioside;
(2) Heating and melting the solid dispersing agent in the pill core material, and then adding the inclusion agent in the pill core material to obtain molten liquid 1;
(3) Adding tilmicosin into the molten liquid 1, stirring and dissolving until the mixture is clear, then adding a surfactant, stirring and dissolving until the mixture is clear, and obtaining a solution 2;
(4) Stirring the solution 2 at the temperature of 75 ℃ for 30min at the speed of 100r/min, uniformly dispersing, filtering the solution 2, setting the air inlet temperature to be 5 ℃, and preparing tilmicosin pill cores in a cold spraying mode through a high-speed centrifugal atomizer;
(5) Sieving tilmicosin pill cores, taking 30-65 mesh pill cores, dissolving a quick-release medicine coating layer material in an ethanol solution, setting the air inlet temperature to be 50 ℃, and spraying a quick-release medicine coating layer on the pill cores through a fluidized bed;
(6) Dissolving the taste-masking coating material in water to form a latex solution with the mass fraction of 30%, setting the air inlet temperature to be 50 ℃, and performing bottom spraying coating on the latex solution to the surface of the quick-release drug coating layer through a fluidized bed to obtain the tilmicosin efficient double-layer coated pellet.
Example 2
High-efficiency double-layer coated tilmicosin pellet
(1) Weighing the pill core material: 150kg of tilmicosin; 100kg of mono-diglycerol fatty acid ester; 250kg of hydrogenated castor oil; poloxamer 188130kg; 100kg of hydroxypropyl betacyclodextrin; tween 80 (20 kg).
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; 1kg of talcum powder; 1kg of stevioside;
(2) Heating and melting the solid dispersing agent in the pill core material, and then adding the inclusion agent in the pill core material to obtain molten liquid 1;
(3) Adding tilmicosin into the molten liquid 1, stirring and dissolving until the mixture is clear, then adding a surfactant, stirring and dissolving until the mixture is clear, and obtaining a solution 2;
(4) Stirring the solution 2 at 200r/min for 30min under the heat preservation of 70 ℃, uniformly dispersing, filtering the solution 2, setting the air inlet temperature to be 3 ℃, and preparing tilmicosin pill cores in a cold spraying mode through a high-speed centrifugal atomizer;
(5) Screening a tilmicosin pill core, taking a 65-mesh pill core, dissolving a quick-release medicine coating layer material in an ethanol solution, setting the air inlet temperature to be 55 ℃, and spraying a quick-release medicine coating layer on the pill core through a fluidized bed;
(6) Dissolving the taste-masking coating material in water to form a latex solution with the mass fraction of 30%, setting the air inlet temperature to be 55 ℃, and performing bottom spraying coating on the latex solution to the surface of the quick-release drug coating layer through a fluidized bed to obtain the tilmicosin efficient double-layer coated pellet.
Example 3
High-efficiency double-layer coated tilmicosin pellet
(1) Weighing a pill 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 the solid dispersing agent in the pellet core material to obtain molten liquid 1;
(3) Adding tilmicosin into the molten liquid 1, stirring and dissolving until the mixture is clear, then adding a surfactant, stirring and dissolving until the mixture is clear, and obtaining a solution 2;
(4) Stirring the solution 2 at the temperature of 80 ℃ for 30min at the speed of 140r/min, uniformly dispersing, filtering the solution 2, setting the air inlet temperature to be 2 ℃, and preparing tilmicosin pill cores in a cold spraying mode through a high-speed centrifugal atomizer;
(5) Sieving tilmicosin pill cores, taking 24-mesh pill cores, dissolving the quick-release drug coating layer material in an ethanol solution, setting the air inlet temperature to be 45 ℃, and spraying the quick-release drug coating layer on the pill cores through a fluidized bed;
(6) Dissolving the taste-masking coating material in water to form a latex solution with the mass fraction of 30%, setting the air inlet temperature to be 45 ℃, and performing bottom spraying coating on the latex solution to the surface of the quick-release drug coating layer through a fluidized bed to obtain the tilmicosin efficient double-layer coated pellet.
Test example 1 drug particle size test:
the test method comprises the following steps: according to a particle size determination method of tilmicosin premix in 'Chinese veterinary pharmacopoeia' 2015 edition, by combining with product internal control, 24-mesh and 65-mesh sieves are selected, samples of different manufacturers are weighed, the method is operated, the drug is subjected to particle size sieving, the qualification rate between 24 meshes and 65 meshes is evaluated, and the highest qualification rate between 24 meshes and 65 meshes is the best. The results of the particle size measurements are shown in Table 1 below.
TABLE 1 particle size determination results for tilmicosin premix from different manufacturers
| Product name | The invention relates to a high-efficiency Titilmicosin micro-pill | Product of A Enterprise | Product of B Enterprise |
| Percent of |
100％ | 64％ | 79％ |
And (3) test results: compared with the prior art, the tilmicosin high-efficiency pellet has full and bright particles, uniform granularity and no fine powder, can provide a good material mixing environment, and is very easy to be uniformly mixed with granular medicines. Test example 2 bitter taste test of drug:
the test method comprises the following steps: a small amount of the tilmicosin premix medicament is taken and placed on the tongue tip for tasting, and the judgment is carried out within 5 seconds, and the judgment result is shown in the following table 2.
Table 2 bitter taste detection results of 20% tilmicosin premix from different manufacturers
| Product name | The invention relates to a high-efficiency Titilmicosin micro-pill | Product of A Enterprise | B Enterprise product |
| Taste and flavor | Has no bitter and peculiar smell | Strong bitter taste | Is especially sweet |
And (3) test results: compared with the prior art, the high-efficiency Timicosin pellet is not bitter within 5 seconds, shows that the inclusion pellet is completely included, has good taste masking effect and improves the problem of drug irritation.
Test example 3 drug property comparison
(1) The test method comprises the following steps: weighing 3 tilmicosin samples of different manufacturers respectively, placing the samples under a 100-fold electrooptical mirror respectively, observing and taking pictures, wherein the results are shown in figures 1, 2 and 3.
The tilmicosin high-efficiency pellet is a round pellet, has smooth appearance and uniform and compact size, and is not adhered to each other.
The product of the A enterprise is irregular pills, the external surface is not smooth, the size is not uniform and loose, and the pills are adhered to each other.
The products of the B enterprises are irregular pills, the external surfaces of which are not smooth, the sizes of which are not uniform and loose and are adhered to each other.
Test example 4 dissolution test
The test method comprises the following steps: according to the determination method of dissolution rate in 'Chinese veterinary pharmacopoeia' 2015 edition, the tilmicosin high-efficiency pellets in examples 1, 2 and 3 and samples from different manufacturers are weighed and operated in the same method, the dissolution rate in water is determined, the samples are respectively sampled at 0, 5, 10, 15, 30, 45, 75 and 120 minutes, and the determination dissolution rate result is shown in the following table 3 and fig. 4.
TABLE 3 comparative test results of water dissolution rate of tilmicosin high-efficiency pellets
Stability test
The normal-temperature standing test and the 40-DEG C thermal acceleration test are carried out according to the drug stability test guiding principle under the item of 'Chinese veterinary pharmacopoeia' 2015 edition in the embodiment 2 of the tilmicosin high-efficiency pellet, the normal-temperature test is observed for 24 months, the 40-DEG C thermal acceleration is observed for 6 months, all quality indexes are in a qualified range, and the stability result is shown in the following table 4.
TABLE 4 florfenicol tilmicosin high-efficiency pellet microcapsule stability test observation at 40 DEG C
In summary, the efficient tilmicosin pellets for animals of the present invention are obviously superior to similar products in the market in terms of bitterness, properties, particle size, dissolution rate, stability, etc., the above description is a further detailed description of the present invention in conjunction with specific preferred embodiments, and the specific implementation of the present invention is not considered to be limited to these descriptions, and all processes similar to the present invention and equivalent changes made should fall within the protection scope of the present invention.
Test example 5
Example 2 (short for saint tilmicosin) pharmacokinetic test of the tilmicosin high-efficiency pellet of the invention:
the method is characterized in that a research institute of animal husbandry and veterinary medicine, lanzhou academy of agricultural sciences, china, and the high-efficiency tilmicosin pellets (short for Shenniuzosin) prepared in the embodiment 2 of the invention and domestic first-minded tilmicosin enteric-coated granules are subjected to pharmacokinetic comparison tests in pigs, and the absorption and metabolism characteristics of the tilmicosin and the enteric-coated granules are compared and evaluated, so that a basis is provided for formulating a reasonable clinical medication scheme.
5.1 protocol
Healthy three-way crossbred pigs, 16 pigs, were randomly divided into 2 groups (Shenniuzemicin group; tilmicosin enteric granule control group), each group had 8 pigs, and female and male half. The administration dosage refers to the clinical recommended dosage and use of tilmicosin pigs, the actual feed feeding amount in the early stage is combined, each pig is determined to be 60mg/kgBW, and each group is subjected to intragastric administration once. The blood sampling points of each pig are 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. Performing EDTA anticoagulation on a sample, separating plasma, detecting by using a Waters2695 high performance liquid chromatography system, processing and counting experimental data by using PhoenixWinLin8.2 full-automatic pharmacokinetic analysis software, performing logarithmic transformation on AUC and Cmax by using EXCEL, and performing variance analysis, double-single-side t test and calculation of relative bioavailability. Methodology studies have shown that the regression equation is y =26971x-196608 2 =0.9996, a linear range of 50-5000 ng/mL, a quantitative limit of 50ng/mL, precision less than 5%, average recovery rates of 96.5 +/-2.53%, 96.88 +/-1.25% and 105.3 +/-1.85% at low, medium and high concentrations, respectively, and RSD% less than 5%.
5.2 pharmacokinetic experiments
5.2.1 time-of-drug concentration vs. time-of-drug curve
The content of tilmicosin in the pig plasma samples at different time points is measured and calculated, and the obtained result is shown in table 1; the drug time curve of the tilmicosin is drawn by taking time as an x-axis and taking the concentration of the tilmicosin as a y-axis, and the drug time curves of different time periods are shown in a figure 5 and a figure 6.
TABLE 5 concentration of tilmicosin and tilmicosin enteric-coated granules in porcine plasma traditional Chinese medicine (μ g/mL)
5.2.2 pharmacokinetic parameters
The test adopts a high performance liquid detection method to determine the main pharmacokinetic parameters of the tilmicosin and tilmicosin enteric-coated particles in the pig body, and the curve of the tilmicosin and tilmicosin enteric-coated particles after the pig single-dose administration conforms to a non-atrioventricular model.
Temmicin and tilmicosin enteric-coated particles control main pharmacokinetic parameters of the medicine, and average maximum blood concentration C max 2.1 plus or minus 1.1 and 1.2 plus or minus 0.7 respectively; the delay time TLag is 0.8 plus or minus 0.4 and 3.2 plus or minus 1.5 respectively; time to peak T max 4.4 plus or minus 1.0 and 6.5 plus or minus 0.5 respectively; mean drug elimination half-life T 1/2 8.4 +/-6.3 and 17.5 +/-12.6 respectively; the AUC (0-24) of the area under the curve at the time of average medication is 14.77 + -4.48 and 9.94 + -6.8, and the AUC (0- ∞) of the area under the curve at the time of average medication is 15.74 + -5.7 and 12.1 + -9.5 respectively; the clearance rates CL/F are respectively; 4.32 plus or minus 3.41 and 3.01 plus or minus 2.81; the apparent volume V _ F of the distribution is 44.31 + -34.26 and 66.41 + -50.54 respectively, and the average residence time MRTlast is 8.5 + -1.2 and 12.1 + -3.1 respectively.
5.3 summary of Experimental data
The above experimental parameters and data are combined in Table 6, and the time curve (0-24 hours) is shown in FIG. 7.
TABLE 6 comparative study results of pharmacokinetics of tilmicosin and tilmicosin enteric-coated particles of Apis cerana
5.4 comprehensive analysis of Experimental data
5.4.1 absorption, distribution, metabolism
The blood concentration peak time of the Shenniuzmicin enteric-coated particles and the blood concentration peak time of the Timicosin enteric-coated particles are 4.4 hours and 6.5 hours respectively; the half-life periods are 8.4 hours and 17.5 hours respectively; the clearance rates are 4 hours and 3 hours respectively; the average residence times were 8.5 hours and 12 hours, respectively. The data show that the effect is fast when the blood concentration peak time of tilmicosin enteric-coated particles is 2 hours earlier than that of tilmicosin enteric-coated particles; the oral clearance rate reaches 4 hours, the half-life period reaches 8 hours, and the oral administration drug release rule is met.
5.4.2 time and blood concentration
The highest blood concentration Cmax of the deinococcus bullosa and the tilmicosin enteric-coated granules is 2.1 and 1.2 mu g/ml respectively, and the data show that the blood concentration of the tilmicosin enteric-coated granules is up to 175 percent higher than that of the tilmicosin enteric-coated granules; the area under the curve when the drugs were administered orally at different time intervals is shown in Table 7.
TABLE 7 Curve area of the Shenniu tilmicosin and tilmicosin enteric-coated granule
Description of the data: the tilmicosin enteric-coated particles have more than 2 times of treatment effect of tilmicosin enteric-coated particles within 0-12 hours after oral administration; 1.5 times in the interval of 0-24 hours; is 1.3 times in the interval of 0-48 hours.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (10)
1. A tilmicosin high-efficiency double-layer coated pellet is characterized by comprising a pellet core, a quick-release drug coating layer and a taste-masking coating layer; wherein, the components are as follows according to the weight ratio: the quick-release drug coating layer: taste-masking layer = (50-80): (10-30): (1-10);
wherein the pellet core comprises the following raw materials in parts by weight: 10-20 parts of tilmicosin, 25-50 parts of a solid dispersant, 5-20 parts of a coating agent and 1-10 parts of a surfactant;
the quick-release drug coating layer comprises the following raw materials in parts by weight: 1-10 parts of tilmicosin, 0-10 parts of solid dispersant, 10-20 parts of coating agent and 2-3 parts of coating material;
the taste masking coating comprises the following raw materials in parts by weight: 1-5 parts of coating material, 1-2 parts of sweetening agent and 1-3 parts of lubricating agent.
2. The tilmicosin high-efficiency double-layer coated pellet as claimed in claim 1, wherein the weight proportions of the pellet core of the components are as follows: the quick-release drug coating layer: taste-masking layer =60-80:20-30:1-5.
3. The tilmicosin high-efficiency double-layer coated pellet as claimed in claim 1, wherein the solid dispersant is a mate type composite auxiliary solid dispersant which is one or more of polyethylene glycol 8000, polyethylene glycol 6000, poloxamer 188, mono-diglycerol fatty acid ester, hydrogenated castor oil and copovidone.
4. The tilmicosin high-efficiency double-layer coated pellet as claimed in claim 1, wherein the coating agent is one or more of betacyclodextrin, hydroxypropyl betacyclodextrin, polyethylene glycol, carbomer and hypromellose.
5. The tilmicosin high-efficiency double-layer coated pellet as claimed in claim 1, wherein the surfactant is one or more of polyoxyethylene hydrogenated castor oil, tween, sodium dodecyl sulfate and propylene glycol.
6. The tilmicosin high-efficiency double-layer coated pellet as claimed in claim 1, wherein the coating materials are one or more of hypromellose, copovidone, polyacrylic resin emulsion and acrylic resin No. 2;
the sweetener is stevioside, and the lubricant is talcum powder.
7. A preparation method of a tilmicosin high-efficiency double-layer coating pellet is characterized by comprising the following steps:
(1) Weighing the raw materials in parts by weight according to any one of claims 1 to 6;
(2) Heating and melting the solid dispersing agent and the inclusion agent in the pill core material to obtain molten liquid 1;
(3) Adding tilmicosin into the molten liquid 1, stirring and dissolving until the mixture is clear, then adding a surfactant, stirring and dissolving until the mixture is clear, and obtaining a solution 2;
(4) Stirring the solution 2 at the temperature of 70-80 ℃ until all components are uniformly dispersed, then filtering the solution 2, setting the air inlet temperature to be 0-10 ℃, and preparing a tilmicosin pill core in a cold spraying mode by using a high-speed centrifugal atomizer;
(5) Sieving tilmicosin pellet cores to obtain 24-65 meshes, dissolving the quick-release drug coating layer material in an ethanol solution, setting the air inlet temperature to be 45-55 ℃, and spraying the quick-release drug coating layer on the pellet cores through a fluidized bed;
(6) Dissolving the taste-masking coating material in water to form latex solution with the mass fraction of 30%, setting the air inlet temperature to be 45-55 ℃, and spraying and coating the latex solution on the surface of the quick-release drug coating layer through a fluidized bed to obtain the tilmicosin efficient double-layer coated pellet.
8. The method for preparing the tilmicosin high-efficiency double-layer coated pellet as claimed in claim 7, wherein the heating temperature in the step (2) is 60-90 ℃;
the step (2) also comprises the step of adding the inclusion agent in the pill core material into the molten liquid 1.
9. The method for preparing a tilmicosin high-efficiency double-layer coated pellet as claimed in claim 7, wherein the stirring speed in the step (4) is 100-200r/min, and the stirring time is 20-180min.
10. The method for preparing a tilmicosin high-efficiency double-layer coated pellet as claimed in claim 7, wherein the ethanol solution in the step (5) is 20% by volume.
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| CN115645376B (en) | 2023-10-31 |
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