Microcapsule coated tilmicosin premix and preparation method thereof

Abstract

The invention relates to a micro-capsule coated tilmicosin premix which is prepared from the following raw materials in parts by weight: 15-25 parts of tilmicosin, 0.5-1 part of a flavoring agent, 1-8 parts of a sweetening agent, 15-25 parts of an antioxidant, 5-10 parts of a plasticizer, 1-5 parts of a tackifier and 40-55 parts of an emulsifier. The premix is simple in preparation process and remarkable in curative effect, and the problems that an existing tilmicosin premix is large in irritation, poor in palatability, poor in mixing uniformity, poor in curative effect and the like can be effectively solved.

Description

Technical Field

[0001] The invention belongs to the technical field of drug preparation, and particularly relates to a microcapsule-coated tilmicosin premix and a preparation method thereof. Background Art

[0002] Tilmicosin is a semi-synthetic macrolide antibiotic for animals. Its antibacterial effect is similar to that of tylosin. Sensitive Gram-positive bacteria include Staphylococcus aureus (including penicillin-resistant Staphylococcus aureus), Pneumococcus, Streptococcus, Bacillus anthracis, Erysipelothrix rhizopus, Listeria, Clostridium perfringens, Clostridium emphysema, etc. Sensitive Gram-negative bacteria include Haemophilus, Neisseria meningitidis, Pasteurella, etc. It is also effective against mycoplasma. It is more active than tylosin against Actinobacillus pleuropneumoniae, Pasteurella, and Mycoplasma of livestock and poultry. 95% of hemolytic Pasteurella strains are sensitive to this product.

[0003] Tilmicosin has a strong antibacterial effect and excellent pharmacokinetic characteristics, and can also improve the immunity of animals. In addition, the latest research shows that Tilmicosin also has an antiviral effect in the prevention and treatment of individual pig diseases. Moreover, there is no cross-resistance between Tilmicosin and other commonly used antibiotics in clinical practice, and it has achieved remarkable results in the clinical treatment of various animal diseases. Compared with tylosin, it has a small dosage, lasting effect, small side effects, low body residue, and is safe and non-toxic. It is an economical, safe and effective new veterinary drug commonly used for antibacterial and growth promotion in livestock and poultry. In the current state of complex and atypical animal diseases, it brings new ideas and methods for clinical medication. Therefore, Tilmicosin will play a more important role in the control of livestock and poultry diseases in the future and has broad application prospects.

[0004] At present, various enterprises and research institutes have conducted many studies on Tilmicosin products, but the research progress is slow, and the defects of Tilmicosin-related products have not been effectively improved. Although the efficacy of Tilmicosin products has been improved to a certain extent, customers of pig farms and chicken farms often report that the Tilmicosin series products are bitter, which affects the animal's feed intake and makes the animals unwilling to eat; the drug concentration is unevenly distributed, and it is easy to settle at the bottom of the pellet feed, resulting in uneven distribution of the effective drug concentration. In addition, Tilmicosin preparations are easily destroyed by gastric acid after oral administration, resulting in incomplete absorption and poor antibacterial effect; they are highly irritating to the gastrointestinal tract and may have toxic side effects on the heart. At present, in order to facilitate medication, farms use products for mixing feeds. Tilmicosin series products mainly use Tilmicosin premixes, and most of the products on the market are directly mixed with raw materials and filling excipients. It has many shortcomings in application, which are listed as follows: 1) The drug concentration is unevenly distributed. It is easy to settle at the bottom of the pellet feed, resulting in uneven distribution of the drug's effective concentration; 2) When the finished product of Tilmicosin premix is ​​opened and used, dust is raised, which is extremely irritating to the human respiratory tract; 3) The tilmicosin premix comes into full contact with the animal's mouth when consumed, and has a distinct bitter taste, which affects the animal's feed intake and makes the animal unwilling to eat; 4) Oral administration can easily be destroyed by gastric acid, resulting in incomplete absorption and poor antibacterial effect. It is also highly irritating to the gastrointestinal tract and may have toxic side effects on the heart.

[0005] Therefore, it is urgent to research and develop a tilmicosin product with strong applicability to improve the defects of the above-mentioned prior art. Summary of the invention

[0006] The present invention aims to overcome the defects of the prior art and provide a microcapsule coated tilmicosin premix granule. The premix has a simple preparation process, significant efficacy, and can effectively solve the problems of the existing tilmicosin premix, such as high irritation, poor palatability, poor mixing uniformity, and poor efficacy.

[0007] The present invention also provides a method for preparing the microcapsule-coated tilmicosin premix.

[0008] To achieve the above object, the present invention adopts the following technical solution: A microcapsule-coated tilmicosin premix is ​​prepared from the following raw materials in parts by weight: 15-25 parts of tilmicosin, 0.5-1 parts of flavoring agent, 1-8 parts of sweetener, 15-25 parts of antioxidant, 5-10 parts of plasticizer, 1-5 parts of tackifier and 40-55 parts of emulsifier.

[0009] As a preferred embodiment, the above-mentioned microencapsulated tilmicosin premix is ​​made of the following raw materials in parts by weight: 20 parts of tilmicosin, 1 part of flavoring agent, 5 parts of sweetener, 20 parts of antioxidant, 5 parts of plasticizer, 1 part of viscosity enhancer, and 48 parts of emulsifier.

[0010] Specifically, the flavoring agent includes but is not limited to at least one of butyl acetate, ethyl lactate, 2-methylbutyl acetate, γ-nonalactone, clove oil, ethyl vanillin, ethyl maltol, and the like.

[0011] Specifically, the sweetener includes but is not limited to at least one of aspartame, sucralose, saccharin sodium, steviol glycosides, mogroside, neotame, xylitol, dipotassium glycyrrhizinate, and the like.

[0012] Specifically, the antioxidant includes but is not limited to at least one of polyethylene glycol 4000, polyethylene glycol 6000, phosphoglyceride, glycerol fatty acid ester, alkyl acrylate, sodium carboxymethyl cellulose and the like.

[0013] Specifically, the plasticizer includes but is not limited to at least one of triethyl citrate, triacetin, castor oil, diethyl phthalate, dibutyl phthalate, acetylated glycerate, epoxidized soybean oil, and the like.

[0014] Specifically, the viscosity enhancer includes but is not limited to at least one of sodium carboxymethyl cellulose, sodium hydroxyethyl cellulose, carrageenan, xanthan gum, guar gum, and the like.

[0015] Specifically, the emulsifier includes but is not limited to at least one of monoglycerol and diglycerol fatty acid esters, ethoxylated glycerol monoesters, ethoxylated glycerol monoesters, carnauba wax, hydrogenated soybean oil, hydrogenated palm oil, stearic acid, etc.

[0016] The present invention also provides a method for preparing the above-mentioned microcapsule-encapsulated tilmicosin premix, which comprises the following steps: 1) Mix flavoring agent, sweetener, antioxidant, plasticizer, tackifier and emulsifier according to proportion, heat until completely melted, then add tilmicosin, stir and emulsify until completely melted; 2) Use hot melt cold spray technology or spray drying technology for granulation; 3) Collect the materials and sieve them to obtain Tilmicosin premix granules.

[0017] The inventors of the present application have found that the above-mentioned shortcomings of the prior art are caused by the following reasons: 1) The odor of the raw material of Tilmicosin is extremely irritating and bitter. Direct use will affect the feed intake of livestock and poultry, resulting in poor drug effect; 2) Powder products are prone to dust after opening the bag; 3) Oral administration is easily destroyed by gastric acid, affecting the efficacy; 4) The density of common tilmicosin preparations on the market is very different from that of feed, resulting in uneven mixing The above disadvantage 1) can be improved by adding flavoring ingredients and sweetener ingredients to the formula. Flavoring agents and sweeteners can correct the taste and have an appetizing effect. The above disadvantages 2), 3), and 4) can be improved by preparing the product into particles through microencapsulation technology.

[0018] Compared with the prior art, the present invention has the following beneficial effects: The present invention adopts the above two methods to effectively solve the shortcomings of the existing tilmicosin, such as bad smell, strong irritation, poor palatability, poor mixing uniformity, and poor efficacy. By adding flavoring agents and sweeteners, not only can the irritating smell be effectively reduced and suppressed, the bitterness of the raw materials be concealed, but also the food inducing effect can be achieved, and the feed intake of livestock can be increased, and the physical strength of the affected livestock can be quickly restored. Through the microcapsule coating process, the disadvantage of powder-type products being easy to raise dust is solved, and the density of the tilmicosin granule product is close to that of the feed, which is easier to mix and more uniform. Through the microcapsule coating process, the drug is prevented from being destroyed in the gastrointestinal tract, the efficacy is increased, and the irritation of the drug to the gastrointestinal tract can be reduced. That is, the tilmicosin granules of the present invention can reduce gastric irritation, and are not easily destroyed by gastric acid, and the efficacy is significantly increased compared to the powder. In addition, the microcapsule coating process can achieve the effects and functions of sustained release of drugs, improve stability, reduce side effects, and increase bioavailability, and has obvious practical value. DETAILED DESCRIPTION

[0019] The technical solution of the present invention is further described in detail below in conjunction with the embodiments, but the protection scope of the present invention is not limited thereto.

[0020] In the following examples, unless otherwise specified, the raw materials used are common commercial products that can be directly purchased, or can be prepared using conventional techniques in the art.

[0021] Example 1 A microcapsule-coated tilmicosin premix is ​​prepared from the following raw materials in parts by weight: 20 parts of tilmicosin, 1 part of clove oil, 5 parts of aspartame, 19 parts of polyethylene glycol 4000, 5 parts of epoxidized soybean oil, 2 parts of sodium carboxymethyl cellulose, 40 parts of mono- and di-glycerol fatty acid esters, and 8 parts of carnauba wax.

[0022] The preparation method of the microcapsule-encapsulated tilmicosin premix comprises the following steps: 1) Heat the hot water tank to 50~60℃ in advance, and start the hot water circulation to keep the melting tank and the tank to be sprayed warm; 2) Add flavoring agent, sweetener, antioxidant, plasticizer, tackifier and emulsifier to the melting tank in proportion, heat the materials in the melting tank, control the material temperature to 90-100°C, stir at 15Hz until completely melted, then add tilmicosin, after the feeding is completed, the temperature naturally drops to 75-80°C, turn on the stirring and emulsification function, stir and emulsify until completely melted, and transfer to the spray tank; 3) Start stirring the spray tank, and control the speed to 5Hz. After running for 10 minutes, steam flush the spray gun pipeline, and start cold spraying for granulation. During cold spraying, set the air inlet temperature to 7℃, control the high-pressure pump speed to 35~40Hz, and the tower pressure to -30~-50MPa; 4) Collect the material with a vibrating screen, and after screening, obtain the tilmicosin premix granules.

[0023] Example 2 A microcapsule coated tilmicosin premix is ​​prepared from the following raw materials in parts by weight: 20 parts of tilmicosin, 0.8 parts of flavoring agent 2-methylbutyl acetate, 3 parts of sweetener sucralose, 10 parts each of antioxidants polyethylene glycol 4000 and polyethylene glycol 6000, 6 parts of plasticizer triacetin, 2 parts of thickener carrageenan, and 48.2 parts of emulsifier mono- and di-glycerol fatty acid esters.

[0024] The preparation method of the microcapsule-encapsulated tilmicosin premix comprises the following steps: 1) Heat the hot water tank to 50~60℃ in advance, and start the hot water circulation to keep the melting tank and the tank to be sprayed warm; 2) Add flavoring agent, sweetener, antioxidant, plasticizer, tackifier and emulsifier into the melting tank in proportion, heat the materials in the melting tank until they are completely melted, then add tilmicosin, start the stirring and emulsification function, and stir and emulsify until they are completely melted; 3) After complete melting, start the cold air circulation, adjust the spray dryer inlet air temperature to 30-45°C, the speed to 20-30Hz, and start the spray drying tower for spray drying and granulation; 4) Collect the material with a vibrating screen, and after screening, obtain the tilmicosin premix granules.

[0025] Example 3 A microcapsule-coated tilmicosin premix is ​​prepared from the following raw materials in parts by weight: 15 parts of tilmicosin, 1 part of clove oil as a flavoring agent, 5 parts of aspartame as a sweetener, 15 parts of glycerol fatty acid ester as an antioxidant, 8 parts of castor oil as a plasticizer, 2 parts of sodium carboxymethyl cellulose as a viscosity enhancer, and 54 parts of hydrogenated soybean oil as an emulsifier.

[0026] The preparation method of the above-mentioned microcapsule-encapsulated tilmicosin premix is ​​referred to Example 1.

[0027] Example 4 A microcapsule coated tilmicosin premix is ​​prepared from the following raw materials in parts by weight: 25 parts of tilmicosin, 1 part of butyl acetate, a flavoring agent, 5 parts of neotame, 8 parts each of polyethylene glycol 4000 and polyethylene glycol 6000, an antioxidant, 5 parts of triethyl citrate, a plasticizer, 4 parts of sodium carboxymethyl cellulose, and 44 parts of ethoxylated monoglyceride, an emulsifier.

[0028] The preparation method of the above-mentioned microcapsule-encapsulated tilmicosin premix is ​​referred to Example 2.

[0029] Example 5 A microcapsule coated tilmicosin premix is ​​prepared from the following raw materials in parts by weight: 22 parts of tilmicosin, 0.5 parts of flavoring agent γ-nonalactone, 3 parts of sweetener stevioside, 15 parts of antioxidant polyethylene glycol 6000, 5 parts of antioxidant alkyl acrylate, 5 parts of plasticizer dibutyl phthalate, 2 parts of tackifier sodium carboxymethyl cellulose, and 47.5 parts of emulsifier hydrogenated palm oil.

[0030] The preparation method of the above-mentioned microcapsule-encapsulated tilmicosin premix is ​​referred to Example 2.

[0031] Example 6 A microcapsule coated tilmicosin premix is ​​prepared from the following raw materials in parts by weight: 18 parts of tilmicosin, 0.5 parts of ethyl malt powder as a flavoring agent, 5 parts of saccharin sodium as a sweetener, 20 parts of polyethylene glycol 6000 as an antioxidant, 5 parts of triethyl citrate as a plasticizer, 2 parts of xanthan gum as a viscosity enhancer, and 49.5 parts of mono- and di-glycerol fatty acid esters as an emulsifier.

[0032] The preparation method of the above-mentioned microcapsule-encapsulated tilmicosin premix is ​​referred to Example 1.

[0033] Example 7 A microcapsule-coated tilmicosin premix is ​​prepared from the following raw materials in parts by weight: 20 parts of tilmicosin, 0.8 parts of clove oil as a flavoring agent, 2 parts of dipotassium glycyrrhizinate as a sweetener, 15 parts of phosphoglyceride as an antioxidant and 3 parts of sodium carboxymethyl cellulose as an antioxidant, 5 parts of epoxidized soybean oil as a plasticizer, 1 part of guar gum as a viscosity enhancer, and 53.2 parts of hydrogenated palm oil as an emulsifier.

[0034] The preparation method of the above-mentioned microcapsule-encapsulated tilmicosin premix is ​​referred to Example 1.

[0035] Example 8 A microcapsule-coated tilmicosin premix is ​​prepared from the following raw materials in parts by weight: 23 parts of tilmicosin, 1 part of ethyl vanillin as a flavoring agent, 8 parts of xylitol as a sweetener, 15 parts of alkyl acrylate as an antioxidant, 8 parts of castor oil as a plasticizer, 1 part of sodium carboxymethyl cellulose as a viscosity enhancer, and 44 parts of hydrogenated soybean oil as an emulsifier.

[0036] The preparation method of the above-mentioned microcapsule-encapsulated tilmicosin premix is ​​referred to Example 2.

[0037] Comparative Example 1 A method for preparing tilmicosin premix particles is carried out according to the method of Example 1, except that the following raw materials are used in parts by weight: 20 parts of tilmicosin and an emulsifier is used as filler.

[0038] Preparation method: see Example 1 Comparative Example 2 A method for preparing a tilmicosin premix comprises the following raw materials in parts by weight: 20 parts of tilmicosin and anhydrous glucose as a filler.

[0039] The above-mentioned Tilmicosin premix is ​​not granulated but directly mixed into powder.

[0040] The following is a performance and animal experiment on the premix prepared above.

[0041] In vitro dissolution The in vitro dissolution and in vivo absorption of tilmicosin preparations were compared. The cumulative dissolution amount of tilmicosin at different times was determined by slurry method using 0.1 mol / L hydrochloric acid and 0.2 mol / L sodium phosphate solution as dissolution media, respectively, to evaluate the in vitro dissolution characteristics of different tilmicosin preparations. The results are shown in Table 1.

[0042] Table 1 Cumulative dissolution of tilmicosin test preparations in 0.1 mol / L hydrochloric acid and 0.2 mol / L sodium phosphate solutions (%) It can be seen from the results in Table 1 that: compared with Comparative Examples 1 and 2, the solubility of the tilmicosin premix of each embodiment of the present invention in 0.1 mol / L hydrochloric acid for 2 h does not exceed 25.98%, which is much lower than the solubility of 83.26% and 93.84% of Comparative Examples 1 and 2; at the same time, the solubility of the tilmicosin premix of each embodiment of the present invention in 0.2 mol / L sodium phosphate solution for 2 h and 4 h is also significantly lower than the solubility of Comparative Examples 1 and 2.

[0043] Clinical comparison of taste masking effect Table 2 below shows the taste masking comparison of the tilmicosin preparations of each embodiment and the comparative example. From the results in Table 2, it can be seen that the tilmicosin preparations of comparative examples 1 and 2 have no sweet taste and are obviously irritating, while the tilmicosin premixes of each embodiment of the present invention have a sweet fragrance and are not obviously irritating. Compared with the comparative example, the tilmicosin premixes of each embodiment of the present invention have better palatability and are easier for animals to eat.

[0044] Table 2 Comparison of taste masking of tilmicosin preparations in various examples and comparative examples Mixing uniformity test Comparison of the mixing uniformity of the tilmicosin preparation and the feed: 20 g of the tilmicosin preparation was weighed and mixed with 10 kg of feed. After 10 min, 5 points were selected to detect the tilmicosin content and the RSD value was calculated. The results are shown in Table 3.

[0045] It can be seen from the results in Table 3 that the Tilmicosin premixes of the embodiments of the present invention have good mixing uniformity and can be well mixed with feed.

[0046] Table 3 Mixing uniformity of tilmicosin preparations of various examples and comparative examples Animal testing 60 healthy piglets of similar size (about 50 kg, feed intake of about 2 kg) were selected and randomly divided into 10 groups, 6 pigs in each group, and administered with a single centralized feed mixing dose of 20 mg / (kg·bw). The average feed intake of each group was calculated. The results are shown in Table 4.

[0047] Table 4 Effects of Tilmicosin preparations in various examples and comparative examples on feed intake of piglets It can be seen from the results in Table 4 that, compared with the comparative example, the tilmicosin premixes of the embodiments of the present invention have better palatability and can significantly increase the feed intake of piglets.

Claims

1. A microencapsulated tilmicosin premix, characterized in that: The invention is prepared from the following raw materials in parts by weight: 15-25 parts of tilmicosin, 0.5-1 parts of flavoring agent, 1-8 parts of sweetener, 15-25 parts of antioxidant, 5-10 parts of plasticizer, 1-5 parts of tackifier and 40-55 parts of emulsifier.

2. The microencapsulated tilmicosin premix according to claim 1, characterized in that: The invention is prepared from the following raw materials in parts by weight: 20 parts of tilmicosin, 1 part of flavoring agent, 5 parts of sweetener, 20 parts of antioxidant, 5 parts of plasticizer, 1 part of tackifier and 48 parts of emulsifier.

3. The microencapsulated tilmicosin premix according to claim 1, characterized in that: The flavoring agent is at least one of butyl acetate, ethyl lactate, 2-methylbutyl acetate, γ-nonalactone, clove oil, ethyl vanillin and ethyl maltol.

4. The microencapsulated tilmicosin premix according to claim 1, characterized in that: The sweetener is at least one of aspartame, sucralose, saccharin sodium, stevioside, mogroside, neotame, xylitol and dipotassium glycyrrhizinate.

5. The microencapsulated tilmicosin premix according to claim 1, characterized in that: The antioxidant is at least one of polyethylene glycol 4000, polyethylene glycol 6000, phosphoglyceride, glycerol fatty acid ester, alkyl acrylate and sodium carboxymethyl cellulose.

6. The microencapsulated tilmicosin premix according to claim 1, characterized in that: The plasticizer is at least one of triethyl citrate, triacetin, castor oil, diethyl phthalate, dibutyl phthalate, acetylated glycerate and epoxidized soybean oil.

7. The microencapsulated tilmicosin premix according to claim 1, characterized in that: The viscosity enhancer is at least one of sodium carboxymethyl cellulose, sodium hydroxyethyl cellulose, carrageenan, xanthan gum and guar gum.

8. The microencapsulated tilmicosin premix according to claim 1, characterized in that: The emulsifier is at least one of monoglycerol and diglycerol fatty acid esters, ethoxylated glycerol monoesters, ethoxylated glycerol monoesters, carnauba wax, hydrogenated soybean oil, hydrogenated palm oil, and stearic acid.

9. The method for preparing the microcapsule-encapsulated tilmicosin premix according to any one of claims 1 to 8, characterized in that: The steps include: 1) Mix flavoring agent, sweetener, antioxidant, plasticizer, tackifier and emulsifier according to proportion, heat until completely melted, then add tilmicosin, stir and emulsify until completely melted; 2) Use hot melt cold spray technology or spray drying technology for granulation; 3) Collect the materials and sieve them to obtain Tilmicosin premix granules.

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