CN114983944A - Preparation method of tiamulin fumarate soluble powder - Google Patents
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Abstract
The invention discloses a preparation method of tiamulin fumarate soluble powder, belonging to the technical field of veterinary drugs, and the preparation method comprises the following steps: preparing a binder, preparing a mixture and preparing tiamulin fumarate soluble powder; the method for preparing the tiamulin fumarate soluble powder comprises the steps of taking anhydrous citric acid and sodium chloride, sieving, adding the sieved anhydrous citric acid and the sieved sodium chloride into a mixture, adding the anhydrous citric acid and the sieved sodium chloride into a mixing barrel together, and starting a hopper mixer to mix to obtain the tiamulin fumarate soluble powder; the invention can avoid the use of organic solvent, prolong the drug effect, avoid irritant gas and paralysis of the tiamulin fumarate soluble powder, improve the content and water solubility of active substances in the tiamulin fumarate soluble powder and reduce the sensitivity of the tiamulin fumarate soluble powder to water quality.
Description
Technical Field
The invention relates to the technical field of veterinary drugs, and in particular relates to a preparation method of tiamulin fumarate soluble powder.
Background
The tiamulin fumarate is fumarate of tiamulin, white or white-like crystalline powder, odorless and tasteless, and can be used for treating chronic respiratory diseases of chicken, mycoplasma pneumonia of swine and hemophilus pleuropneumonia of Haemophilus, and dysentery caused by treponema suis; in addition, tiamulin fumarate is extremely sensitive to mycoplasma, and is one of the most effective drugs for treating mycoplasmosis at present.
However, the use of tiamulin fumarate currently has the following problems: organic solvents are frequently used in preparation of the preparation, so that on one hand, the problem of organic solvent residue exists, which affects animal health, and on the other hand, the problem of safety needs to be considered when the organic solvents are used in preparation, so that the investment cost and the production complexity are increased; materials such as a filling agent, an adhesive and the like are adopted in the preparation, the prepared preparation product cannot fully cover the pungent smell of the raw materials, and after the preparation product is dissolved, the pungent smell can be further released, so that the feeding and drinking amount of animals are influenced; the tiamulin fumarate has large molecular weight, and the molecules are too large to completely enter a cavity of beta-cyclodextrin, so that the inclusion effect is poor, the stability is poor, the content of raw materials is limited, and soluble powder with high material content cannot be prepared; the tiamulin fumarate is sensitive to water quality in a drinking water administration process, underground well water or common tap water is mostly used in a culture site, the water quality is poor, effective components are separated out and wasted, and the use effect is influenced.
The current main solution to the above problems is to use an enteric coating material, but the enteric coating material is insoluble under acidic and neutral conditions, can only be used for mixing and administration, is not suitable for the current situation of drinking water administration in poultry cultivation, and cannot solve the problems that soluble powder with high raw material content cannot be prepared and the water quality is sensitive in the drinking water administration process.
In chinese patent CN100337622C, a tiamulin fumarate-containing solid dispersion and a preparation method thereof are disclosed, wherein tiamulin fumarate and a medical water-soluble carrier are heated and melted under the condition of an organic solvent, then cooled and solidified, then crushed, and dried to remove the organic solvent; the patent has the following defects: the preparation process uses organic solvent, and the prepared solid dispersible tablet can generate pungent odor after being dissolved.
Chinese patent CN104146949A discloses a tiamulin fumarate premix and a preparation method thereof, which comprises the steps of crushing, mixing, granulating and screening a tiamulin fumarate raw material and gelatin to obtain a final premix; the patent has the following defects: the prepared tiamulin fumarate premix can generate pungent smell after being dissolved.
Chinese patent CN104490788B discloses tiamulin fumarate granules and a preparation method thereof, wherein a filler and an adhesive are added into a tiamulin fumarate raw material, boiling granulation is carried out, then the prepared granules are added into a coating solution for coating, the adhesive is at least one of pregelatinized starch or hydroxypropyl methyl cellulose, the filler is at least one of soluble starch, lactose and glucose, and the coating agent is HPMC, PEG, Tween-80, talcum powder and ethanol; the patent has the following defects: the preparation process uses organic solvent, and the prepared tiamulin fumarate particles can generate pungent odor after being dissolved.
Chinese patent CN105878228B discloses a tiamulin fumarate soluble powder and a preparation method thereof, which adopts beta-cyclodextrin as an inclusion agent, dissolves tiamulin fumarate in ethanol, adds a saturated aqueous solution of the beta-cyclodextrin, separates out the inclusion compound by cooling and adding excessive ethanol, dries after filtering, and adds EDTA, sodium dodecyl sulfate and a filler to obtain the final soluble powder; the patent has the following defects: the preparation process uses an organic solvent, has poor coating effect and poor stability, limits the content of raw materials, and cannot prepare tiamulin fumarate soluble powder with high raw material content.
Chinese patent CN111419823B discloses a tiamulin fumarate enteric-coated pellet, a preparation method and application thereof, wherein the tiamulin fumarate is added into PEG6000 in a molten state, and then the mixture is cooled, solidified and crushed into particles, and then enteric-coated, wherein the coating liquid is HP-55, talcum powder and ethanol water; the patent has the following defects: organic solvents were used in the preparation.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of tiamulin fumarate soluble powder, which can avoid the use of organic solvents, prolong the drug effect, avoid irritant gas and paralytic feeling of the tiamulin fumarate soluble powder, improve the content and water solubility of active substances in the tiamulin fumarate soluble powder and reduce the sensitivity of the tiamulin fumarate soluble powder to water quality.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a preparation method of tiamulin fumarate soluble powder comprises the following steps: preparing a binder, preparing a mixture and preparing tiamulin fumarate soluble powder;
the method for preparing the adhesive comprises the steps of adding PVP-K30 into water, stirring and fully dissolving, then adding water-soluble acrylic resin LT-206, and stirring uniformly to obtain the adhesive;
the manufacturer of the water-soluble acrylic resin LT-206 is New Material Co., Ltd of Fushan City meaningful ways;
in the adhesive, the weight ratio of PVP-K30, water and water-soluble acrylic resin LT-206 is 3-5:25: 5-10;
the method for preparing the mixture comprises adding tiamulin fumarate into a fluidized bed granulator, starting the fluidized bed granulator, and controlling the air intake at 50-75m 3 The air inlet temperature is 50-80 ℃, the adhesive is added through the peristaltic pump, the rated rotating speed of the peristaltic pump is controlled to be 20-50%, and the adhesion is finishedAfter the agent is added, the air intake is adjusted to 60-90m 3 Drying for 15-20min at air inlet temperature of 70-90 deg.C to obtain mixture;
in the prepared mixture, the weight ratio of the tiamulin fumarate to the binder is 60-80: 33-40;
the method for preparing the tiamulin fumarate soluble powder comprises the steps of taking anhydrous citric acid and sodium chloride, processing the anhydrous citric acid and the sodium chloride with 30-mesh and 80-mesh sieves respectively, taking the middle part of 30-mesh to 80-mesh sieves to obtain the sieved anhydrous citric acid and the sieved sodium chloride, adding the sieved anhydrous citric acid and the sieved sodium chloride into a mixture, adding the mixture into a mixing barrel together, starting a hopper mixer to mix, controlling the rotating speed to be 50-100rpm, and mixing for 15-20min to obtain the tiamulin fumarate soluble powder;
in the preparation of the tiamulin fumarate soluble powder, the weight ratio of the sieved anhydrous citric acid to the sieved sodium chloride to the mixture is 0.5-1:4-31.4: 93-120.
Compared with the prior art, the invention has the following beneficial effects:
(1) the preparation method of the tiamulin fumarate soluble powder can avoid the use of an organic solvent and solve the problem of organic solvent residue;
(2) the preparation method of the tiamulin fumarate soluble powder can avoid irritant gas and paralytic feeling of the tiamulin fumarate soluble powder, increase water intake, dissolve the tiamulin fumarate soluble powder prepared by the invention in tap water according to 1 ten thousand ppm of tiamulin fumarate, feel with tongue tip, have no obvious paralytic feeling, dissolve the tiamulin fumarate soluble powder prepared by the invention according to 125ppm of tiamulin fumarate, carry out drinking water administration on white feather broilers, continuously use for 5 days, and the daily average water intake is 151mL of 142-;
(3) the preparation method of the tiamulin fumarate soluble powder can improve the water solubility of the tiamulin fumarate soluble powder, the tiamulin fumarate soluble powder prepared by the invention is added into tap water at room temperature according to 1 ten thousand ppm of tiamulin fumarate, and the mixture is stirred for 3min after being added, wherein the turbidity is 8.9-13.5 NTU;
(4) the preparation method of the tiamulin fumarate soluble powder can improve the stability of the tiamulin fumarate soluble powder and reduce the sensitivity of the tiamulin fumarate soluble powder to water quality, the tiamulin fumarate soluble powder prepared by the method is dissolved in tap water at 20 ℃ according to 1 ten thousand ppm of tiamulin fumarate, and after standing for 24 hours, the liquid is clear, no precipitate and no floating matter exist, and the effective content of the supernatant is 97.5-98.2%;
(5) the preparation method of the tiamulin fumarate soluble powder can prolong the drug effect of the tiamulin fumarate soluble powder, improve the blood concentration of chickens after drinking water administration, and improve the blood concentration by more than 14% compared with the existing product.
Drawings
Fig. 1 is a graph comparing the blood concentration in vivo of tiamulin fumarate soluble powders prepared in examples 1 to 4 and comparative examples 1 to 3.
Detailed Description
In order to more clearly understand the technical features, objects, and effects of the present invention, specific embodiments of the present invention will now be described.
Example 1
A preparation method of tiamulin fumarate soluble powder comprises the following steps:
1. adding PVP-K30 into water, stirring and fully dissolving, then adding water-soluble acrylic resin LT-206, and stirring uniformly to obtain an adhesive;
the manufacturer of the water-soluble acrylic resin LT-206 is New Material Co., Ltd of Fushan City meaningful ways;
wherein the weight ratio of the PVP-K30 to the water-soluble acrylic resin LT-206 is 3:25: 5;
2. adding tiamulin fumarate into fluidized bed granulator, starting the fluidized bed granulator, and controlling air intake at 75m 3 The inlet air temperature is 60 ℃, the adhesive is added through the peristaltic pump, the rated rotating speed of the peristaltic pump is controlled to be 25%, and after the adhesive is added, the inlet air volume is adjusted to be 90m 3 Drying for 17min at the air inlet temperature of 70 ℃ to obtain a mixture;
the weight ratio of the tiamulin fumarate to the adhesive is 60: 33;
3. taking anhydrous citric acid and sodium chloride, respectively processing the anhydrous citric acid and the sodium chloride by using a 30-mesh sieve and a 80-mesh sieve, taking the middle part of 30-mesh sieve to 80-mesh sieve to obtain the sieved anhydrous citric acid and the sieved sodium chloride, adding the sieved anhydrous citric acid and the sieved sodium chloride into the mixture, then adding the mixture into a mixing barrel together, starting a hopper mixer to mix, controlling the rotating speed to be 50rpm, and mixing for 15min to obtain tiamulin fumarate soluble powder;
wherein the weight ratio of the sieved anhydrous citric acid to the sieved sodium chloride to the mixture is 0.6:31.4: 93.
Example 2
A preparation method of tiamulin fumarate soluble powder comprises the following steps:
1. adding PVP-K30 into water, stirring and fully dissolving, then adding water-soluble acrylic resin LT-206, and stirring uniformly to obtain an adhesive;
the manufacturer of the water-soluble acrylic resin LT-206 is New Material Co., Ltd of Fushan City meaningful ways;
wherein the weight ratio of the PVP-K30 to the water-soluble acrylic resin LT-206 is 5:25: 10;
2. adding tiamulin fumarate into fluidized bed granulator, starting the fluidized bed granulator, and controlling air intake at 75m 3 The air inlet temperature is 70 ℃, the adhesive is added through the peristaltic pump, the rated rotating speed of the peristaltic pump is controlled to be 20%, and after the adhesive is added, the air inlet quantity is adjusted to be 90m 3 Drying for 20min at 75 deg.C to obtain mixture;
the weight ratio of the tiamulin fumarate to the adhesive is 80: 40;
3. taking anhydrous citric acid and sodium chloride, respectively processing the anhydrous citric acid and the sodium chloride by using a 30-mesh sieve and a 80-mesh sieve, respectively taking the middle part of 30-80 meshes to obtain the sieved anhydrous citric acid and the sieved sodium chloride, respectively weighing the sieved anhydrous citric acid, adding the sieved sodium chloride into the mixture, then adding the mixture into a mixing barrel together, starting a hopper mixer to mix, controlling the rotating speed to be 70rpm, and mixing for 20min to obtain tiamulin fumarate soluble powder;
wherein the weight ratio of the sieved anhydrous citric acid to the sieved sodium chloride to the mixture is 1:4: 120.
Example 3
A preparation method of tiamulin fumarate soluble powder comprises the following steps:
1. adding PVP-K30 into water, stirring and fully dissolving, then adding water-soluble acrylic resin LT-206, and stirring uniformly to obtain an adhesive;
the manufacturer of the water-soluble acrylic resin LT-206 is New Material Co., Ltd of Fushan City meaningful ways;
wherein the weight ratio of the PVP-K30 to the water-soluble acrylic resin LT-206 is 3.5:25: 7.5;
2. adding tiamulin fumarate into fluidized bed granulator, starting the fluidized bed granulator, and controlling air intake at 75m 3 The air inlet temperature is 50 ℃, the adhesive is added through the peristaltic pump, the rated rotating speed of the peristaltic pump is controlled to be 30%, and after the adhesive is added, the air inlet volume is adjusted to be 90m 3 The air inlet temperature is 90 ℃, and the mixture is obtained after drying for 15 min;
the weight ratio of the tiamulin fumarate to the adhesive is 75: 36;
3. taking anhydrous citric acid and sodium chloride, respectively processing the anhydrous citric acid and the sodium chloride by using a 30-mesh sieve and a 80-mesh sieve, respectively taking the middle part of 30-80 meshes to obtain the sieved anhydrous citric acid and the sieved sodium chloride, respectively weighing the sieved anhydrous citric acid, adding the sieved sodium chloride into the mixture, then adding the mixture into a mixing barrel together, starting a hopper mixer to mix, controlling the rotating speed to be 100rpm, and mixing for 20min to obtain tiamulin fumarate soluble powder;
wherein the weight ratio of the sieved anhydrous citric acid to the sieved sodium chloride is 0.5:13.5: 111.
Example 4
A preparation method of tiamulin fumarate soluble powder comprises the following steps:
1. adding PVP-K30 into water, stirring and fully dissolving, then adding water-soluble acrylic resin LT-206, and stirring uniformly to obtain an adhesive;
the manufacturer of the water-soluble acrylic resin LT-206 is New Material Co., Ltd of Fushan City meaningful ways;
wherein the weight ratio of the PVP-K30 to the water-soluble acrylic resin LT-206 is 3.2:25: 6.5;
2. weighing tiamulin fumarate, adding into a fluidized bed granulator, starting the fluidized bed granulator, and controlling the air intake to be 50m 3 The air inlet temperature is 80 ℃, the adhesive is added through the peristaltic pump, the rated rotating speed of the peristaltic pump is controlled to be 50%, and after the adhesive is added, the air inlet quantity is adjusted to be 60m 3 Drying for 18min at the air inlet temperature of 80 ℃ to obtain a mixture;
the weight ratio of the tiamulin fumarate to the adhesive is 65: 34.7;
3. taking anhydrous citric acid and sodium chloride, respectively processing the anhydrous citric acid and the sodium chloride by using a 30-mesh sieve and a 80-mesh sieve, respectively taking the middle part of the 30-mesh sieve to the 80-mesh sieve to obtain the sieved anhydrous citric acid and the sieved sodium chloride, respectively weighing the sieved anhydrous citric acid, adding the sieved sodium chloride into the mixture, adding the mixture into a mixing barrel, starting a hopper mixer to mix, controlling the rotating speed to be 100rpm, and mixing for 15min to obtain tiamulin fumarate soluble powder;
wherein the weight ratio of the sieved anhydrous citric acid to the sieved sodium chloride is 0.9:24.4: 99.7.
Example 5
A preparation method of tiamulin fumarate soluble powder comprises the following steps:
1. adding PVP-K30 into water, stirring and fully dissolving, then adding water-soluble acrylic resin LT-206, and stirring uniformly to obtain an adhesive;
the manufacturer of the water-soluble acrylic resin LT-206 is New Material Co., Ltd of Fushan City meaningful ways;
wherein the weight ratio of the PVP-K30 to the water-soluble acrylic resin LT-206 is 4:25: 7;
2. adding tiamulin fumarate into fluidized bed granulator, starting the fluidized bed granulator, and controlling air intake at 60m 3 The air inlet temperature is 60 ℃, and the adhesive is added through a peristaltic pumpControlling the rated rotating speed of the peristaltic pump to be 25%, and adjusting the air intake to be 80m after the adhesive is added 3 Drying for 17min at the air inlet temperature of 80 ℃ to obtain a mixture;
the weight ratio of the tiamulin fumarate to the adhesive is 70: 35;
3. taking anhydrous citric acid and sodium chloride, respectively processing the anhydrous citric acid and the sodium chloride by using a 30-mesh sieve and a 80-mesh sieve, taking the middle part of the mixture from 30 meshes to 80 meshes to obtain the sieved anhydrous citric acid and the sieved sodium chloride, adding the sieved anhydrous citric acid and the sieved sodium chloride into the mixture, then adding the mixture into a mixing barrel together, starting a hopper mixer to mix, controlling the rotating speed to be 70rpm, and mixing for 17min to obtain tiamulin fumarate soluble powder;
wherein the weight ratio of the sieved anhydrous citric acid to the sieved sodium chloride to the mixture is 0.6:28: 100.
Comparative example 1
A preparation method of tiamulin fumarate soluble powder comprises the following steps:
1. weighing tiamulin fumarate and medicinal gelatin, adding into a mixing barrel, starting mixing at 100rpm for 20min, and taking out to obtain a primary mixture;
the weight ratio of the tiamulin fumarate to the medicinal gelatin is 80: 20;
2. transferring the primary mixture into a grinder, starting the grinder, controlling the rotating speed to be 3000rpm, grinding for 3min to obtain ground materials, sieving the ground materials with a 80-mesh sieve, and taking undersize materials as a mixture;
3. adding the mixture into a wet granulator, adding purified water for wet granulation to obtain wet granules, transferring the wet granules into a fluidized bed, drying, and drying to obtain tiamulin fumarate soluble powder;
the weight ratio of the mixed material to the purified water is 100: 30.
Comparative example 2
A commercial tiamulin fumarate premix, manufacturer: loyang Henrel Biotech, Inc., lot number 2108033, content specification 80%;
comparative example 3
A commercial tiamulin fumarate premix, manufacturer: shanghai Shenya health products Limited, lot number 21120803, content specification 80%;
test example 1
The water solubility of tiamulin fumarate soluble powders prepared in examples 1 to 4 and comparative examples 1 to 3 was tested, and the test method and test results were as follows:
the test results of examples 1 to 4 and comparative examples 1 to 3 were as follows, in which 1 ten thousand ppm of tiamulin fumarate was added to room temperature tap water, stirred for 3min after the addition, and the turbidity after the dissolution was measured:
from the above results, it can be seen that the water solubility of the tiamulin fumarate soluble powders prepared in examples 1-4 was better than that of the tiamulin fumarate soluble powders of comparative examples 1-3.
Test example 2
The taste masking effect of the tiamulin fumarate soluble powders prepared in examples 1 to 4 and comparative examples 1 to 3 was tested, and the test method and test results were as follows:
dissolving tiamulin fumarate in tap water according to the proportion of 1 ten thousand ppm, and then using the tongue tip to feel whether paralysis is caused or not, wherein the results are as follows:
in order to further compare and mask the taste effect, 800 white feather broilers aged 30 days are selected and divided into 8 groups, each group comprises 100 white feather broilers, the tiamulin fumarate soluble powder prepared in examples 1-5 and comparative examples 1-3 is dissolved according to 125ppm of tiamulin fumarate, drinking water administration is respectively carried out on each group of white feather broilers, the white feather broilers are continuously used for 5 days, the water intake of each day is recorded at the same time, the average water intake of 5 days is calculated, and the calculation result is as follows:
from the above results, the tiamulin fumarate soluble powder prepared in examples 1-5 can ensure that the daily water intake of poultry is 142-.
Test example 3
The stability of the tiamulin fumarate soluble powders prepared in examples 1 to 5 and comparative examples 1 to 3 was tested, and the test method and test results were as follows:
dissolving 1 ten thousand ppm of tiamulin fumarate in 20 ℃ tap water, standing for 24h, observing the dissolved state after 24h, taking supernatant liquid, and detecting the effective content, so as to compare the stability of the product after dissolution, wherein the detection result is as follows:
the above data show that the product prepared by the scheme of the invention can maintain better stability within 24 hours, does not precipitate and float, is clear, the effective content of the upper layer is still maintained at 97.5-98.2%, and the product of the comparative example precipitates and precipitates to different degrees, so that the effective content of the upper layer is reduced and is 3.3-14.5% lower than that of the scheme of the invention.
Test example 4
The in vivo absorption effect of the tiamulin fumarate soluble powder prepared in examples 1 to 3 and comparative examples 1 to 3 was tested, and the test method and test results were as follows:
in order to further verify the difference of absorption effects in vivo, 600 white feather broilers of 30 days old are selected and equally divided into 6 groups, each group is 100, each group is administered with drinking water after the tiamulin fumarate soluble powder prepared in examples 1-3 and comparative examples 1-3 is dissolved according to 125ppm of tiamulin fumarate, blood plasma of the chickens starts to be collected 0.5h after administration to detect the blood plasma concentration, and the contrast graph of the obtained blood plasma concentration in vivo is shown in figure 1 after detection till 24h after administration;
as can be seen from the comparison of the in vivo blood concentration in figure 1, the bioavailability of the examples 1 and 3 in vivo is greatly improved compared with that of the comparative examples 1-3, the AUC is improved by more than 14%, the peak reaching time is close, but the effective blood concentration is maintained for a longer time, which indicates that the time for exerting the drug effect is longer.
All percentages used in the present invention are mass percentages unless otherwise indicated.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (2)
1. The preparation method of tiamulin fumarate soluble powder is characterized by comprising the following steps: preparing a binder, preparing a mixture and preparing tiamulin fumarate soluble powder;
the method for preparing the adhesive comprises the steps of adding PVP-K30 into water, stirring and fully dissolving, then adding water-soluble acrylic resin LT-206, and stirring uniformly to obtain the adhesive;
in the adhesive, the weight ratio of PVP-K30, water and water-soluble acrylic resin LT-206 is 3-5:25: 5-10;
the method for preparing the mixture comprises adding tiamulin fumarate into a fluidized bed granulator, starting the fluidized bed granulator, and controlling the air intake at 50-75m 3 The inlet air temperature is 50-80 ℃, the adhesive is added through the peristaltic pump, the rated rotating speed of the peristaltic pump is controlled to be 20-50%, and after the adhesive is added, the inlet air volume is adjusted to be 60%-90m 3 Drying for 15-20min at air inlet temperature of 70-90 deg.C to obtain mixture;
in the prepared mixture, the weight ratio of the tiamulin fumarate to the binder is 60-80: 33-40;
the method for preparing the tiamulin fumarate soluble powder comprises the steps of taking anhydrous citric acid and sodium chloride, processing the anhydrous citric acid and the sodium chloride with 30-mesh and 80-mesh sieves respectively, taking the middle part of 30-mesh to 80-mesh sieves to obtain the sieved anhydrous citric acid and the sieved sodium chloride, adding the sieved anhydrous citric acid and the sieved sodium chloride into a mixture, adding the mixture into a mixing barrel together, starting a hopper mixer to mix, controlling the rotating speed to be 50-100rpm, and mixing for 15-20min to obtain the tiamulin fumarate soluble powder;
in the preparation of the tiamulin fumarate soluble powder, the weight ratio of the sieved anhydrous citric acid to the sieved sodium chloride to the mixture is 0.5-1:4-31.4: 93-120.
2. The method for preparing tiamulin fumarate soluble powder according to claim 1, wherein the manufacturer of the water-soluble acrylic resin LT-206 is New Material of meaningful No. of Foshan.
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| CN202210838306.9A Active CN114983944B (en) | 2022-07-18 | 2022-07-18 | Preparation method of tiamulin fumarate soluble powder |
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