Precursor composition, solid dispersant and preparation method thereof, tilmicosin controlled-release preparation and preparation process and application thereof

Abstract

The present invention provides a precursor composition, a solid dispersant and a preparation method thereof, a tilmicosin controlled-release preparation and a preparation process and application thereof, and belongs to the technical field of polymer mixtures and drug sustained-release. The present invention provides a precursor composition, which is composed of the following substances: a monomer, a scaffold molecule, a surfactant and an initiator; wherein the monomer is composed of vinyl acetate, methyl acrylate, hydroxyethyl methacrylate and 2-vinylmorpholine. A novel tilmicosin controlled-release preparation can be prepared using the above-mentioned precursor composition. The tilmicosin controlled-release preparation has the advantage of better controlled release of tilmicosin drugs, thereby preventing the side effects of tilmicosin.

Description

Technical Field

[0001] The invention belongs to the technical field of polymer mixtures and drug sustained-release, and relates to a precursor composition, a solid dispersant and a preparation method thereof, a tilmicosin controlled-release preparation and a preparation process and application thereof. Background Art

[0002] Tilmicosin, also known as Tilmicosin in English, is a semi-synthetic macrolide antibiotic prepared from a hydrolysis product of tylosin. The chemical structure of Tilmicosin is as follows:

[0003]

[0004] Tilmicosin has an inhibitory effect on Gram-positive bacteria, some Gram-negative bacteria, zymoplasma, mycoplasma and spirochetes, and is a safe and effective antibacterial and growth-promoting drug commonly used in livestock and poultry. It is mainly used for infectious diseases of pigs, chickens, cattle, sheep and other animals, especially for the prevention and treatment of respiratory diseases of livestock and poultry, such as poultry actinomycetemcomitans pleuropneumonia, pasteurellosis and chicken mycoplasma. However, due to the bitter taste of tilmicosin and its strong irritation to the stomach, the problem of sick livestock and poultry refusing to eat is prominent, and the release of tilmicosin in the stomach is prone to cause serious side effects such as gastric bleeding and gastric ulcers.

[0005] Chinese patent application 202010299902.5 provides a Tilmicosin enteric solid dispersion and its preparation method and application. The Tilmicosin enteric solid dispersion provided by the technology includes 25 parts of Tilmicosin, 67.5 parts of enteric carrier and 7.5 parts of surfactant; the enteric carrier is Eudragit L100; the surfactant is polyvinyl caprolactam polyvinyl acetate polyethylene glycol graft copolymer; its preparation method includes the following steps: (1) weigh Tilmicosin, enteric carrier and surfactant according to the ratio, mix them evenly to obtain a raw material mixture; (2) add the raw material mixture to an organic solvent, stir it at 40-80°C for 0.25-1.5 hours until the raw material mixture is dissolved, and obtain a mixture solution; (3) dry the mixture solution obtained in step (2) by spray drying, collect the powder, and obtain a Tilmicosin enteric solid dispersion; the spray drying parameters are: inlet temperature 70°C, outlet temperature 50°C, atomization pressure 4kg / cm 2 , the peristaltic pump speed is 2mL / min. However, this technology fails to provide a Tilmicosin drug preparation with better controlled release effect.

[0006] Chinese patent application 202311727671.3 provides a tilmicosin dry suspension and a preparation method thereof. In terms of mass percentage, it includes the following components: 25%-40% tripalmitin, 15%-30% sodium alginate, 8%-12% sucrose, 15%-25% suspending agent, and the remainder is tilmicosin raw powder; its preparation method includes the following steps: (1) adding tripalmitin, sodium alginate, sucrose and tilmicosin raw powder to an emulsifier, adding a solvent, turning on the emulsifier and stirring evenly to obtain a first emulsion, adding a suspending agent to the emulsifier, and continuing to stir evenly to obtain a second emulsion; (2) spray drying the second emulsion in a spray dryer to obtain a tilmicosin dry suspension. However, this technology fails to provide a tilmicosin pharmaceutical preparation with better controlled release effect.

[0007] In the article "Preparation and in vitro evaluation of Tilmicosin Eudragit L100 nanoparticles" (Chinese Journal of Antibiotics, Issue 11, 2013, pp. 848-852), Du Changyu et al. used Eudragit L100 as a polymer carrier material and Tilmicosin as a model drug to prepare nanoparticles by solvent-nonsolvent method. The morphology was observed by transmission electron microscopy, the particle size distribution was determined by nanoparticle size analyzer, the encapsulation efficiency of nanoparticles was determined by dialysis bag method, and the in vitro release was studied by dynamic dialysis method. Results The prepared nanoparticles were densely structured spheres with uniform and regular structure, and the average particle size was about (45.6±4.8) nm. The encapsulation efficiency was more than 95%, and the drug loading was (20.64±0.36)%. The in vitro release of Tilmicosin nanoparticles has significant pH sensitivity and has a certain sustained release effect. Conclusion The solvent-nonsolvent method can prepare Tilmicosin nanoparticles with uniform and regular structure, high encapsulation efficiency and a certain sustained release effect. However, this technology fails to provide a tilmicosin drug preparation with better controlled release effect. Summary of the invention

[0008] In view of this, in order to address the problem that the prior art fails to provide a novel tilmicosin pharmaceutical preparation with better controlled release effect, the present invention aims to provide a precursor composition, a solid dispersant and a preparation method thereof, a tilmicosin controlled release preparation and a preparation process and application thereof.

[0009] To achieve the above object of the invention, on the one hand, the present invention provides a precursor composition, consisting of the following substances:

[0010] Monomers, scaffold molecules, surfactants and initiators;

[0011] The monomers are composed of vinyl acetate, methyl acrylate, hydroxyethyl methacrylate and 2-vinylmorpholine, and the molar ratio of vinyl acetate, methyl acrylate, hydroxyethyl methacrylate and 2-vinylmorpholine is 0.01-3:0.01-1:0.01-1:0.01-1; the scaffold molecules are selected from at least one of povidone, copovidone, methyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose.

[0012] Preferably, the molar ratio of vinyl acetate, methyl acrylate, hydroxyethyl methacrylate and 2-vinylmorpholine is 1-2: 0.35-0.9: 0.13-0.43: 0.06-0.26.

[0013] More preferably, the molar ratio of vinyl acetate, methyl acrylate, hydroxyethyl methacrylate and 2-vinylmorpholine is 1.5-1.75: 0.45-0.7: 0.25-0.4: 0.1-0.2.

[0014] More preferably, and as an embodiment of the present invention, the molar ratio of vinyl acetate, methyl acrylate, hydroxyethyl methacrylate and 2-vinylmorpholine is 1.67:0.65:0.33:0.15.

[0015] Preferably, the scaffold molecule is selected from a mixture of povidone, copovidone and methylcellulose.

[0016] Preferably, the surfactant is an anionic surfactant.

[0017] More preferably, the anionic surfactant is selected from at least one of a fatty acid salt type surfactant, a sulfonate type surfactant, a sulfate ester salt type surfactant and a phosphate ester salt type surfactant.

[0018] More preferably, and as an example of the present invention, the anionic surfactant is sodium dodecyl sulfate.

[0019] Preferably, the initiator is a free radical thermal initiator.

[0020] More preferably, the free radical thermal initiator is selected from at least one of a persulfate type initiator, an organic peroxide type initiator and an azo type initiator.

[0021] More preferably, and as an example of the present invention, the free radical thermal initiator is potassium persulfate.

[0022] Preferably, the mass ratio of the monomer, the scaffold molecule, the surfactant and the initiator is 600-1000: 100-300: 30-50: 10-20.

[0023] More preferably, the mass ratio of the monomer, the scaffold molecule, the surfactant and the initiator is 700-900:150-250:35-45:12-18.

[0024] More preferably, the mass ratio of the monomer, the scaffold molecule, the surfactant and the initiator is 800:200:40:15.

[0025] In another aspect, the present invention provides a solid dispersant precursor emulsion, which is prepared from the above precursor composition and water.

[0026] Preferably, the mass ratio of the monomer, the scaffold molecule, the surfactant, the initiator and the water is 600-1000: 100-300: 30-50: 10-20: 1500-2500.

[0027] More preferably, the mass ratio of the monomer, the scaffold molecule, the surfactant and the initiator is 700-900: 150-250: 35-45: 12-18: 1700-2300.

[0028] More preferably, the mass ratio of the monomer, the scaffold molecule, the surfactant and the initiator is 800:200:40:15:2000.

[0029] In another aspect, the present invention provides a method for preparing the solid dispersant precursor emulsion, comprising the following steps:

[0030] S1, mixing the formulated amount of scaffold molecules, surfactant, initiator and water, adjusting the temperature, and obtaining an initiating solution;

[0031] S2, mixing the formulated amounts of vinyl acetate and hydroxyethyl methacrylate to obtain a mixed monomer A, and mixing the formulated amounts of methyl acrylate and 2-vinylmorpholine to obtain a mixed monomer B;

[0032] S3, while stirring, the mixed monomer A and the mixed monomer B obtained in step S2 are added dropwise to the initiator solution obtained in step S1, respectively, to react and obtain a solid dispersant precursor emulsion.

[0033] Preferably, the reaction temperature in step S3 is 70-90° C., and the reaction time is ≤ 3 hours.

[0034] More preferably, the reaction temperature in step S3 is 80°C.

[0035] More preferably, in step S3, the reaction time is 2.5 hours.

[0036] More preferably, in step S3, the reaction refers to a reaction after the dropwise addition is completed.

[0037] In another aspect, the present invention provides a solid dispersant, the raw material of which is the solid dispersant precursor emulsion mentioned above or the solid dispersant precursor emulsion prepared by the above preparation method.

[0038] In another aspect, the present invention provides a method for preparing the above-mentioned solid dispersant, comprising the following steps:

[0039] The solid dispersant precursor emulsion is spray dried, crushed and sieved to obtain the solid dispersant.

[0040] Preferably, the spray drying is performed using a drying tower.

[0041] Preferably, the air inlet temperature of the drying tower is 130-150°C, the air outlet temperature is 70-75°C, and the induced draft fan pressure is -120 to -50Pa.

[0042] More preferably, the wind pressure of the induced draft fan is -100Pa.

[0043] Preferably, in the crushing and screening, the air inlet temperature of the crusher used is -10°C to 0°C, the air outlet temperature is 25-40°C, and the screening is through a 100-mesh sieve.

[0044] In another aspect, the present invention provides a tilmicosin controlled-release preparation, the raw materials of which include the above-mentioned solid dispersant, a plasticizer and tilmicosin.

[0045] Preferably, the plasticizer is selected from triethyl citrate and / or propylene glycol.

[0046] Preferably, the mass ratio of the solid dispersant, the plasticizer and the tilmicosin is 180-220:6-14:62-78.

[0047] More preferably, and as an example of the present invention, the mass ratio of the solid dispersant, the plasticizer and the tilmicosin is 200:10:70.

[0048] In another aspect, the present invention provides a process for preparing the above-mentioned Tilmicosin controlled-release preparation, comprising the following steps:

[0049] The solid dispersant, plasticizer and tilmicosin in a prescribed amount are mixed and hot-melt extruded to obtain the tilmicosin controlled-release preparation.

[0050] Preferably, the hot melt extrusion is performed using a hot melt extruder, with a first temperature of 70-90° C., a screw temperature of 135-165° C., and a rotation speed of 25-40 rpm.

[0051] Preferably, the hot melt extrusion is followed by pulverization.

[0052] In yet another aspect, the present invention provides the use of the above-mentioned precursor composition, solid dispersant precursor emulsion and preparation method thereof, solid dispersant and preparation method thereof, tilmicosin controlled-release preparation and preparation process thereof in pharmaceutical manufacturing.

[0053] Compared with the prior art, the present invention has the following beneficial effects:

[0054] (1) The present invention provides a new type of solid dispersant, which provides ideas for the synthesis of new drug dispersants.

[0055] (2) The present invention provides a method for preparing the above-mentioned solid dispersant and its tilmicosin controlled-release preparation. By optimizing the process parameters, the solid dispersant particles are more uniform in size, the particle yield is high, and the drug preparation has better formability, which is conducive to continuous production.

[0056] (3) In vitro controlled release experiments in simulated gastrointestinal environments of weaned piglets and chickens showed that the tilmicosin controlled-release preparation provided by the present invention has a good controlled-release effect. DETAILED DESCRIPTION

[0057] The following non-limiting examples can enable those skilled in the art to more fully understand the present invention, but do not limit the present invention in any way. The following content is only an exemplary description of the scope of the present invention, and those skilled in the art can make various changes and modifications to the invention of the present invention based on the disclosed content, and they should also fall within the scope of the present invention.

[0058] The present invention is further described below by way of specific examples. The various chemical reagents used in the examples of the present invention are obtained through conventional commercial channels unless otherwise specified. Unless otherwise specified, the contents described below are all weight contents. Unless otherwise specified, it is understood that the process is carried out at room temperature.

[0059] In the following examples and comparative examples, the instrument models used are as follows:

[0060] name Instrument Model Drying tower MD-15 grinder GH-300 Hot Melt Extruder WST-M16 S1 Experimental

[0061] In the following examples and comparative examples, the sources of raw materials are as follows:

[0062] name Manufacturer / Brand Specification Povidone K30 Shaanxi Chenming Biotechnology Co., Ltd. 99％ Copolyvinylpyrrolidone VA64 Xi'an Tianzheng Pharmaceutical Excipients Co., Ltd. 99％ Methylcellulose Adamas 400mPa·s Hydroxypropyl Cellulose Adamas HL22, HP: 5.5%-9% Sodium Carboxymethyl Cellulose Adamas 800-1200mPa·s Potassium Persulfate Greagent ≥99.5％ Tilmicosin Hongxinkang Type 85

[0063] In Examples 1-8, the raw material components and weight parts of the solid dispersant precursor emulsion are shown in the following table (unit: weight parts):

[0064]

[0065]

[0066] In Comparative Examples 1-5, the raw material components and weight parts of the solid dispersant precursor emulsion are shown in the following table (unit: weight parts):

[0067]

[0068] In Examples 1-8 and Comparative Examples 1-5, the monomers are a mixture of vinyl acetate, methyl acrylate, hydroxyethyl methacrylate and 2-vinylmorpholine in a molar ratio of 1.67:0.65:0.33:0.15.

[0069] Examples 1.1-1.4: Compared with Example 1, the ratios of the four components in the monomer are different, and the rest are the same.

[0070] In Examples 1.1-1.4, the molar ratios of the four components in the monomers are shown in the following table:

[0071]

[0072]

[0073] Comparative Examples 1.1-1.6 are different from Example 1 in terms of the components and / or proportions of the monomers, and the rest are the same.

[0074] In Comparative Examples 1.1-1.6, the types and molar ratios of the components in the monomers are shown in the following table:

[0075]

[0076] Preparation Example 1

[0077] Preparation of solid dispersant precursor emulsion

[0078] S1. Fully stir and mix the formulated amount of scaffold molecules, surfactant, initiator and water to obtain an initiating solution.

[0079] S2, mixing the formulated amounts of vinyl acetate and hydroxyethyl methacrylate to obtain a mixed monomer A, and mixing the formulated amounts of methyl acrylate and 2-vinylmorpholine to obtain a mixed monomer B;

[0080] S3. The initiator liquid is adjusted and maintained at 80° C. While stirring, the mixed monomer A and the mixed monomer B obtained in step S2 are added dropwise to the initiator liquid. After the addition is completed, the mixture is reacted for 2.5 hours to obtain a solid dispersant precursor emulsion.

[0081] The solid dispersant precursor emulsions prepared from the solid dispersant precursor emulsion raw materials described in Examples 1-8, Examples 1.1-1.4, Comparative Examples 1-5 and Comparative Example 1.1 according to the method of Preparation Example 1 are named Ee1, Ee2, Ee3, Ee4, Ee5, Ee6, Ee7, Ee8, Ee1.1, Ee1.2, Ee1.3, Ee1.4, Ec1, Ec2, Ec3, Ec4, Ec5 and Ec1.1 respectively.

[0082] Preparation Example 2

[0083] Preparation of solid dispersant precursor emulsion

[0084] S1. Fully stir and mix the formulated amount of scaffold molecules, surfactant, initiator and water to obtain an initiating solution.

[0085] S2, mixing the formulated amounts of vinyl acetate, hydroxyethyl methacrylate, methyl acrylate and 2-vinylmorpholine to obtain a mixed monomer;

[0086] S3. The initiator liquid is adjusted and maintained at 80° C. The mixed monomer obtained in step S2 is added dropwise to the initiator liquid during stirring. After the addition is completed, the mixture is reacted for 2.5 hours to obtain a solid dispersant precursor emulsion.

[0087] The solid dispersant precursor emulsion prepared from the solid dispersant precursor emulsion raw material described in Example 1 according to the method of Preparation Example 2 is named Ec6.

[0088] Preparation Example 3

[0089] Preparation of solid dispersant precursor emulsion

[0090] S1. Fully stir and mix the formulated amount of scaffold molecules, surfactant, initiator and water to obtain an initiating solution.

[0091] S2, mixing the formulated amounts of vinyl acetate and hydroxyethyl methacrylate to obtain a mixed monomer A, and mixing the formulated amounts of methyl acrylate and 2-vinylmorpholine to obtain a mixed monomer B;

[0092] S3, adjusting and maintaining the initiating liquid at 80° C., adding the mixed monomer A obtained in step S2 dropwise to the initiating liquid during stirring, then adding the mixed monomer B dropwise after the addition is complete, and reacting for 2.5 hours to obtain a solid dispersant precursor emulsion.

[0093] The solid dispersant precursor emulsion prepared from the solid dispersant precursor emulsion raw material described in Example 1 according to the method of Preparation Example 3 is named Ec7.

[0094] Preparation Example 1.2

[0095] Preparation of solid dispersant precursor emulsion

[0096] S1. Fully stir and mix the formulated amount of scaffold molecules, surfactant, initiator and water to obtain an initiating solution.

[0097] S2, mixing the formulated amounts of vinyl acetate and hydroxyethyl methacrylate to obtain a mixed monomer A;

[0098] S3. The initiator liquid is adjusted and maintained at 80° C. While stirring, the mixed monomer A obtained in step S2 and the formulated amount of methyl acrylate are added dropwise to the initiator liquid. After the addition is completed, the mixture is reacted for 2.5 hours to obtain a solid dispersant precursor emulsion.

[0099] The solid dispersant precursor emulsion prepared from the solid dispersant precursor emulsion raw material described in Comparative Example 1.2 according to the method of Preparation Example 1.2 is named Ec1.2.

[0100] Preparation Example 1.3

[0101] Preparation of solid dispersant precursor emulsion

[0102] S1. Fully stir and mix the formulated amount of scaffold molecules, surfactant, initiator and water to obtain an initiating solution.

[0103] S2, mixing the formulated amounts of methyl acrylate and 2-vinyl morpholine to obtain a mixed monomer B;

[0104] S3. The initiator liquid is adjusted and maintained at 80° C. While stirring, the mixed monomer B obtained in step S2 and the formulated amount of vinyl acetate are added dropwise to the initiator liquid. After the addition is completed, the mixture is reacted for 2.5 hours to obtain a solid dispersant precursor emulsion.

[0105] The solid dispersant precursor emulsion prepared from the solid dispersant precursor emulsion raw material described in Comparative Example 1.3 according to the method of Preparation Example 1.3 is named Ec1.3.

[0106] Preparation Example 1.4

[0107] Preparation of solid dispersant precursor emulsion

[0108] S1. Fully stir and mix the formulated amount of scaffold molecules, surfactant, initiator and water to obtain an initiating solution.

[0109] S2, mixing the formulated amounts of vinyl acetate and hydroxyethyl methacrylate to obtain a mixed monomer A, and mixing the formulated amounts of methyl acrylate, methyl methacrylate, 1-allylpiperazine and 2-vinylmorpholine to obtain a mixed monomer B;

[0110] S3. The initiator liquid is adjusted and maintained at 80° C. While stirring, the mixed monomer A and the mixed monomer B obtained in step S2 are added dropwise to the initiator liquid. After the addition is completed, the mixture is reacted for 2.5 hours to obtain a solid dispersant precursor emulsion.

[0111] The solid dispersant precursor emulsion prepared from the solid dispersant precursor emulsion raw material described in Comparative Example 1.4 according to the method of Preparation Example 1.4 is named Ec1.4.

[0112] Preparation Example 1.5

[0113] Preparation of solid dispersant precursor emulsion

[0114] S1. Fully stir and mix the formulated amount of scaffold molecules, surfactant, initiator and water to obtain an initiating solution.

[0115] S2, mixing the formulated amounts of vinyl acetate and hydroxyethyl methacrylate to obtain a mixed monomer A, and mixing the formulated amounts of methyl acrylate and 1-allylpiperazine to obtain a mixed monomer B;

[0116] S3. The initiator liquid is adjusted and maintained at 80° C. While stirring, the mixed monomer A and the mixed monomer B obtained in step S2 are added dropwise to the initiator liquid. After the addition is completed, the mixture is reacted for 2.5 hours to obtain a solid dispersant precursor emulsion.

[0117] The solid dispersant precursor emulsion prepared from the solid dispersant precursor emulsion raw material described in Comparative Example 1.5 according to the method of Preparation Example 1.5 is named Ec1.5.

[0118] Preparation Example 1.6

[0119] Preparation of solid dispersant precursor emulsion

[0120] S1. Fully stir and mix the formulated amount of scaffold molecules, surfactant, initiator and water to obtain an initiating solution.

[0121] S2, mixing the formulated amounts of vinyl acetate and methyl methacrylate to obtain a mixed monomer A, and mixing the formulated amounts of methyl acrylate and 2-vinylmorpholine to obtain a mixed monomer B;

[0122] S3. The initiator liquid is adjusted and maintained at 80° C. While stirring, the mixed monomer A and the mixed monomer B obtained in step S2 are added dropwise to the initiator liquid. After the addition is completed, the mixture is reacted for 2.5 hours to obtain a solid dispersant precursor emulsion.

[0123] The solid dispersant precursor emulsion prepared from the solid dispersant precursor emulsion raw material described in Comparative Example 1.6 according to the method of Preparation Example 1.6 is named Ec1.6.

[0124] Preparation Example 4

[0125] The solid dispersant is prepared by using a solid dispersant precursor emulsion.

[0126] The solid dispersant precursor emulsion was spray dried using a drying tower with an air inlet temperature of 140°C, an air outlet temperature of 72.5°C, and an induced draft fan pressure of -100Pa.

[0127] After spray drying, a pulverizer is used for pulverization and screening. The pulverizer air inlet temperature is -5°C, the air outlet temperature is 35°C, and the sieving is through a 100-mesh sieve.

[0128] Using solid dispersant precursor emulsions Ee1, Ee2, Ee3, Ee4, Ee5, Ee6, Ee7, Ee8, Ee1.1, Ee1.2, Ee1.3, Ee1.4, Ec1, Ec2, Ec3, Ec4, Ec5, Ec6, Ec7, Ec1.1, Ec1.2, Ec1.3, Ec1.4, Ec1.5 and Ec1.6 The solid dispersants prepared in Example 4 are respectively recorded as De1, De2, De3, De4, De5, De6, De7, De8, De1.1, De1.2, De1.3, De1.4, Dc1, Dc2, Dc3, Dc4, Dc5, Dc6, Dc7, Dc1.1, Dc1.2, Dc1.3, Dc1.4, Dc1.5 and Dc1.6.

[0129] Preparation Example 5

[0130] The solid dispersant is prepared by using a solid dispersant precursor emulsion.

[0131] The solid dispersant precursor emulsion was spray dried using a drying tower with an air inlet temperature of 130°C, an air outlet temperature of 75°C, and an induced draft fan pressure of -120Pa.

[0132] After spray drying, a pulverizer is used for pulverization and screening. The pulverizer air inlet temperature is 0°C, the air outlet temperature is 25°C, and the sieving is through a 100-mesh sieve.

[0133] Preparation Example 6

[0134] The solid dispersant is prepared by using a solid dispersant precursor emulsion.

[0135] The solid dispersant precursor emulsion was spray dried using a drying tower with an inlet air temperature of 150°C, an outlet air temperature of 70°C, and an induced draft fan pressure of -50Pa.

[0136] After spray drying, a pulverizer is used for pulverization and screening. The pulverizer has an air inlet temperature of -10°C and an air outlet temperature of 40°C. The sieving is performed through a 100-mesh sieve.

[0137] Preparation Example 7

[0138] The solid dispersant is prepared by using a solid dispersant precursor emulsion.

[0139] The solid dispersant precursor emulsion was spray dried using a drying tower with an air inlet temperature of 120°C, an air outlet temperature of 72.5°C, and an induced draft fan pressure of -100Pa.

[0140] After spray drying, a pulverizer is used for pulverization and screening. The pulverizer air inlet temperature is -5°C, the air outlet temperature is 35°C, and the sieving is through a 100-mesh sieve.

[0141] Preparation Example 8

[0142] The solid dispersant is prepared by using a solid dispersant precursor emulsion.

[0143] The solid dispersant precursor emulsion was spray dried using a drying tower with an air inlet temperature of 140°C, an air outlet temperature of 65°C, and an induced draft fan pressure of -100Pa.

[0144] After spray drying, a pulverizer is used for pulverization and screening. The pulverizer air inlet temperature is -5°C, the air outlet temperature is 35°C, and the sieving is through a 100-mesh sieve.

[0145] Preparation Example 9

[0146] The solid dispersant is prepared by using a solid dispersant precursor emulsion.

[0147] The solid dispersant precursor emulsion was spray dried using a drying tower with an air inlet temperature of 140°C, an air outlet temperature of 72.5°C, and an induced draft fan pressure of -150Pa.

[0148] After spray drying, a pulverizer is used for pulverization and screening. The pulverizer air inlet temperature is -5°C, the air outlet temperature is 35°C, and the sieving is through a 100-mesh sieve.

[0149] Preparation Example 10

[0150] The solid dispersant is prepared by using a solid dispersant precursor emulsion.

[0151] The solid dispersant precursor emulsion was spray dried using a drying tower with an air inlet temperature of 140°C, an air outlet temperature of 72.5°C, and an induced draft fan pressure of -100Pa.

[0152] After spray drying, a pulverizer is used for pulverization and screening. The pulverizer air inlet temperature is -15°C, the air outlet temperature is 35°C, and the sieving is through a 100-mesh sieve.

[0153] Preparation Example 11

[0154] The solid dispersant is prepared by using a solid dispersant precursor emulsion.

[0155] The solid dispersant precursor emulsion was spray dried using a drying tower with an air inlet temperature of 140°C, an air outlet temperature of 72.5°C, and an induced draft fan pressure of -100Pa.

[0156] After spray drying, a pulverizer is used for pulverization and screening. The pulverizer air inlet temperature is -5°C, the air outlet temperature is 50°C, and the sieving is through a 100-mesh sieve.

[0157] Effect Example 1

[0158] Screening rate test of dry pulverized solid dispersants.

[0159] The solid dispersant precursor emulsion Ee1 was dried and crushed by the drying and crushing methods of Preparation Examples 4-11. 10 g of the crushed solid dispersant was accurately weighed and passed through a 100-mesh sieve. The solid dispersant powder obtained after sieving was accurately weighed and the sieving rate was calculated according to the following formula:

[0160] Screening rate = mass of solid dispersant powder obtained after screening / mass of solid dispersant before screening × 100%

[0161] Each group of experiments was repeated 10 times, and the mean and standard deviation of the screening rate were calculated. The results are shown in the following table:

[0162] Group Screening rate / % (mean ± standard deviation) Preparation Example 4 99.64±0.02 Preparation Example 5 98.45±0.03 Preparation Example 6 98.10±0.01 Preparation Example 7 94.82±0.02 Preparation Example 8 95.38±0.02 Preparation Example 9 90.81±0.03 Preparation Example 10 91.56±0.06 Preparation Example 11 94.79±0.04

[0163] It can be seen that the preparation method of the solid dispersant provided in Preparation Example 4 by dry crushing has a higher screening rate.

[0164] Preparation Example 12

[0165] Preparation of Tilmicosin Controlled Release Preparation

[0166] The raw material composition of Tilmicosin controlled-release preparation is shown in the following table:

[0167]

[0168]

[0169] The preparation method of the Tilmicosin controlled-release preparation is as follows:

[0170] The solid dispersant, plasticizer and tilmicosin in the formula amount were fully mixed, and hot melt extruded using a hot melt extruder with a first temperature of 80° C., a screw temperature of 150° C. and a rotation speed of 30 rpm to obtain a tilmicosin controlled release preparation.

[0171] Preparation Example 13

[0172] A method for preparing a tilmicosin controlled-release preparation.

[0173] The solid dispersant, plasticizer and tilmicosin in the formula amount were fully mixed, and hot melt extruded using a hot melt extruder with a first temperature of 70° C., a screw temperature of 165° C. and a rotation speed of 40 rpm to obtain a tilmicosin controlled release preparation.

[0174] Preparation Example 14

[0175] A method for preparing a tilmicosin controlled-release preparation.

[0176] The solid dispersant, plasticizer and tilmicosin in the formula amount were fully mixed, and hot melt extruded using a hot melt extruder with a first temperature of 90° C., a screw temperature of 135° C. and a rotation speed of 25 rpm to obtain a tilmicosin controlled release preparation.

[0177] Preparation Example 15

[0178] A method for preparing a tilmicosin controlled-release preparation.

[0179] The solid dispersant, plasticizer and tilmicosin in the formula amount were fully mixed, and hot melt extruded using a hot melt extruder with a first temperature of 50° C., a screw temperature of 150° C. and a rotation speed of 30 rpm to obtain a tilmicosin controlled release preparation.

[0180] Preparation Example 16

[0181] A method for preparing a tilmicosin controlled-release preparation.

[0182] The solid dispersant, plasticizer and tilmicosin in the formula amount were fully mixed, and hot melt extruded using a hot melt extruder with a first temperature of 80° C., a screw temperature of 170° C. and a rotation speed of 30 rpm to obtain a tilmicosin controlled release preparation.

[0183] Preparation Example 17

[0184] A method for preparing a tilmicosin controlled-release preparation.

[0185] The solid dispersant, plasticizer and tilmicosin in the formula amount were fully mixed, and hot melt extruded using a hot melt extruder with a first temperature of 80° C., a screw temperature of 150° C. and a rotation speed of 55 rpm to obtain a tilmicosin controlled release preparation.

[0186] Effect Example 2

[0187] Testing of the effect of hot melt extrusion continuous production of tilmicosin controlled release preparations

[0188] (1) The preparation methods of the Tilmicosin controlled-release preparations provided in Preparation Examples 12-17 and the raw material composition of Te1 in Preparation Example 12 were respectively used to prepare the Tilmicosin controlled-release preparations using a hot melt extruder. The Tilmicosin controlled-release preparations were continuously prepared for 24 hours using the preparation methods described in each of Preparation Examples 12-17. Samples were taken after continuous production for 1 hour and 24 hours, and the particle sizes of 50 samples were counted and the average particle size was calculated after taking photos under a microscope. The particle size change rate was calculated according to the following formula.

[0189] Particle size change rate = | average particle size of the sample when continuous production for 24 hours - average particle size of the sample when continuous production for 1 hour | ÷ average particle size of the sample when continuous production for 1 hour × 100%

[0190] The smaller the particle size change rate, the more stable the continuous production.

[0191] In addition, observe and record whether adhesion, drawing, blockage or unformed phenomenon occurs during the 24-hour continuous production of each group. The continuous production results are summarized in the following table:

[0192] Group Particle size change rate / % Is there any adhesion, drawing, clogging or shapelessness? Preparation Example 12 2.39 no Preparation Example 13 4.16 no Preparation Example 14 3.58 no Preparation Example 15 12.37 yes Preparation Example 16 10.62 yes Preparation Example 17 8.80 no

[0193] (2) The raw material compositions of Te1, Te2, Te3, Te4, Te9, Te10, Te11, Te12, Tc8, Tc9 and Tc10 in Preparation Example 12 and the preparation method of the Tilmicosin controlled-release preparation provided in Preparation Example 12 were respectively used to prepare the Tilmicosin controlled-release preparation using a hot melt extruder. The characterization method was the same as that in (1) in Effect Example 2. The continuous production effects are summarized in the following table:

[0194]

[0195]

[0196] From the above two groups of effect evaluation tests, it can be seen that the selection of the various preparation process parameters of the hot melt extrusion of the Tilmicosin controlled release preparation provided in Preparation Example 12 is most conducive to continuous production. In addition, the type of solid dispersant, the type of filler and the selection of the ratio all have a certain impact on the continuous production process.

[0197] Effect Example 3

[0198] Evaluation of controlled release effect of tilmicosin controlled-release preparation under simulated gastrointestinal conditions of weaned piglets

[0199] According to the experimental method provided by the prior art "Study on the Effect of Enzymatic Soy Protein on the Digestibility of Nutrients in Weaned Piglets by In Vitro Digestion Experiment" (Conference Name: FIIF2019 Feed Industry Innovation Forum; Author: Wang Shiqi, etc.), the controlled release behavior of controlled-release preparations in the gastrointestinal tract was simulated by in vitro artificial gastric juice and artificial intestinal juice methods, and the gastrointestinal release behavior of tilmicosin controlled-release preparations was evaluated.

[0200] The experimental method is as follows:

[0201] 1. Preparation of simulated gastric juice for weaned piglets.

[0202] Take 62.5 mL of 0.1 mol / L, pH = 6 sodium phosphate buffer solution and put it in a conical flask. Add 50 mL of 0.2 mol / L hydrochloric acid and 25 mL of 220 U / mL pepsin solution while stirring. Use 1 mol / L hydrochloric acid and 1 mol / L sodium hydroxide solution to adjust the pH to 3.3 to obtain simulated gastric fluid of weaned piglets.

[0203] 2. Configuration of simulated small intestinal digestive juice for weaned piglets.

[0204] On the basis of the simulated gastric juice of weaned piglets, 50 mL of 0.2 mol / L sodium phosphate buffer with pH = 6.8 was added, and then 25 mL of 0.6 mol / L sodium hydroxide solution and 25 mL of fresh pancreatic juice (13 mg pancreatin was dissolved in 130 mL of 0.6 mol / L sodium hydroxide solution, pancreatin specific activity was 1:250, prepared immediately before use) were added, and stirred thoroughly. Finally, 1 mol / L hydrochloric acid solution and 1 mol / L sodium hydroxide solution were used to adjust the pH of the mixture to 6.8, and the simulated intestinal juice of weaned piglets was obtained.

[0205] 3. Determination of the release rate of tilmicosin controlled-release preparation in simulated gastric fluid of weaned piglets.

[0206] The tilmicosin controlled-release preparation was mixed with simulated gastric fluid of weaned piglets (the concentration of the controlled-release preparation was 1 g / L), sealed with a sealing film, and placed in a 39.5°C constant-temperature oscillator with an oscillation frequency of 120 rpm for simulated release. 5 mL of samples were taken after 1 h, 2 h, and 3 h of digestion, and quickly filtered through a 0.22 μm filter membrane. The chromatographic conditions under the determination of tilmicosin content in the method disclosed in Chinese patent application 201310566491.1 were used for determination. The release amount of each tilmicosin controlled-release preparation in the simulated gastric fluid of weaned piglets was calculated by the external standard method.

[0207] 4. Determination of the release rate of tilmicosin controlled-release preparation in simulated small intestinal digestive fluid of weaned piglets.

[0208] The tilmicosin controlled-release preparation was mixed with the simulated small intestinal digestive fluid of weaned piglets (the concentration of the controlled-release preparation was 1 g / L), sealed with a sealing film, and placed in a 39.5°C constant temperature oscillator with an oscillation frequency of 100 rpm for simulated release. 5 mL of samples were taken after 1 h, 2 h, 6 h, and 10 h of digestion, and quickly filtered through a 0.22 μm filter membrane. The chromatographic conditions under the determination of tilmicosin content in the method disclosed in Chinese patent application 201310566491.1 were used for determination. The release amount of each tilmicosin controlled-release preparation in the simulated small intestinal digestive fluid of weaned piglets was calculated by the external standard method.

[0209] The release test results of Tilmicosin controlled-release preparation in simulated gastric fluid of weaned piglets are shown in the following table:

[0210]

[0211] It can be seen that compared with Tc1-Tc10 and Tc1.1-Tc1.6, the tilmicosin controlled-release preparations of groups Te1-Te12 and Te1.1-Te1.4 have an overall lower release rate in the simulated gastric juice of weaned piglets. The lower the release rate of tilmicosin in gastric juice, the less irritation tilmicosin causes to the animal's stomach, and the less likely it is to cause side effects such as gastric bleeding.

[0212] The release test results of Tilmicosin controlled-release preparation in simulated small intestinal digestive fluid of weaned piglets are shown in the following table:

[0213]

[0214] It can be seen that compared with Tc1-Tc10 and Tc1.1-Tc1.6, the tilmicosin controlled-release preparations of groups Te1-Te12 and Te1.1-Te1.4 have higher release in the simulated small intestinal digestive fluid of weaned piglets, especially after 6 hours in the small intestine, when the small intestinal contents of weaned piglets have basically entered the large intestine. The tilmicosin controlled-release preparations of groups Te1-Te12 and Te1.1-Te1.4 were released in simulated small intestinal fluid for 6 hours, and the release rate can reach 85.96%-93.42%, which is higher than that of groups Tc1-Tc10 and Tc1.1-Tc1.6. The higher the release rate of tilmicosin in the small intestinal environment, the more complete the release of tilmicosin, which is more conducive to the efficacy of the tilmicosin controlled-release preparation.

[0215] Effect Example 4

[0216] Evaluation of controlled release effect of tilmicosin controlled release preparation under simulated chicken gastrointestinal conditions

[0217] Referring to the experimental method provided by the prior art "Study on the Effect of Exogenous Protease on In Vitro Energy and Amino Acid Digestibility of Chicken Feed" (Master's thesis, Yangzhou University, 2018.6, Wu Shiqiao), the controlled release behavior of the controlled-release preparation in the gastrointestinal tract was simulated by in vitro artificial gastric juice and artificial intestinal juice methods, and the gastrointestinal release behavior of the tilmicosin controlled-release preparation was evaluated.

[0218] The experimental method is as follows:

[0219] 1. Preparation of chicken simulated gastric juice.

[0220] Take 2.17g sodium chloride and 1.57g potassium chloride, dissolve them in 2000mL deionized water, and adjust the pH value to 2.0 with 2mol / L hydrochloric acid solution at 41°C to obtain gastric buffer solution. Dissolve 387.5kU pepsin in 250mL of pH2.0 hydrochloric acid solution to obtain gastric enzyme solution (prepared and used immediately). Mix the gastric buffer solution and the gastric enzyme solution in a volume ratio of 6:1 to obtain chicken simulated gastric fluid.

[0221] 2. Preparation of chicken simulated small intestinal digestive juice.

[0222] Take 9.35g of anhydrous disodium hydrogen phosphate, 40.09g of anhydrous sodium dihydrogen phosphate, 11.13g of sodium chloride, 3.09g of potassium chloride, and 1.6 million units of penicillin and dissolve them in 2000mL of deionized water. Adjust the pH to 6.50 with 1mol / L phosphoric acid solution and 1mol / L sodium hydroxide solution at 41°C to obtain a small intestinal buffer. Dissolve 110.40kU of amylase, 13.55kU of trypsin, and 3.11kU of chymotrypsin in 25mL of deionized water and dissolve them completely to obtain a small intestinal enzyme solution. Mix the small intestinal buffer and the small intestinal enzyme solution in a volume ratio of 8:1 to obtain a chicken simulated small intestinal digestive fluid.

[0223] 3. Determination of the release rate of tilmicosin controlled-release preparation in chicken simulated gastric fluid.

[0224] The tilmicosin controlled-release preparation was mixed with chicken simulated gastric fluid (the concentration of the controlled-release preparation was 1 g / L), sealed with a sealing film, and placed in a 41°C constant-temperature oscillator with an oscillation frequency of 120 rpm for simulated release. 5 mL of samples were taken after 1 h, 2 h, and 4 h of digestion, and quickly filtered through a 0.22 μm filter membrane. The chromatographic conditions under the tilmicosin content determination item in the method disclosed in Chinese patent application 201310566491.1 were used for determination. The release amount of each tilmicosin controlled-release preparation in chicken simulated gastric fluid was calculated by the external standard method.

[0225] 4. Determination of the release rate of tilmicosin controlled-release preparation in chicken simulated small intestinal digestive fluid.

[0226] The tilmicosin controlled-release preparation was mixed with chicken simulated small intestinal digestive fluid (the concentration of the controlled-release preparation was 1 g / L), sealed with a sealing film, and placed in a 41°C constant temperature oscillator with an oscillation frequency of 100 rpm for simulated release. 5 mL of samples were taken after 3 h, 6 h, 12 h, and 18 h of digestion, and quickly filtered through a 0.22 μm filter membrane. The chromatographic conditions under the tilmicosin content determination item in the method disclosed in Chinese patent application 201310566491.1 were used for determination. The release amount of each tilmicosin controlled-release preparation in the chicken simulated small intestinal digestive fluid was calculated by the external standard method.

[0227] The release test results of Tilmicosin controlled-release preparation in chicken simulated gastric fluid are shown in the following table:

[0228]

[0229]

[0230] It can be seen that compared with Tc1-Tc10 and Tc1.1-Tc1.6, the tilmicosin controlled-release preparations of groups Te1-Te12 and Te1.1-Te1.4 have an overall lower release rate in chicken simulated gastric juice. The lower the release rate of tilmicosin in gastric juice, the less irritation tilmicosin causes to the animal's stomach, and the less likely it is to cause side effects such as gastric bleeding.

[0231] The release test results of Tilmicosin controlled-release preparation in chicken simulated small intestinal digestive fluid are shown in the following table:

[0232]

[0233] It can be seen that compared with Tc1-Tc10 and Tc1.1-Tc1.6, the Tilmicosin controlled-release preparations of groups Te1-Te12 and Te1.1-Te1.4 have higher release in the simulated small intestinal digestive fluid of chickens, especially at 6 hours in the small intestine (anterior small intestine), the release can reach 58.17%-65.70%, and at 12 hours in the small intestine (posterior small intestine), the release can reach 78.78%-87.40%, both higher than groups Tc1-Tc10 and Tc1.1-Tc1.6. The higher the release of Tilmicosin in the small intestine environment, the more complete the release of Tilmicosin, which is more conducive to the efficacy of Tilmicosin controlled-release preparations.

[0234] Effect Example 5

[0235] Accelerated stability evaluation of tilmicosin controlled release preparation

[0236] The test was conducted according to the test method recorded in the 2015 edition of the Veterinary Pharmacopoeia of the People's Republic of China. The samples of each group were placed under the conditions of 45℃±2℃ and 85%±5% relative humidity for 6 months, and the test results are summarized in the following table:

[0237]

[0238] It can be seen that compared with Tilmicosin controlled-release preparations Tc1-10 and Tc1.1-1.6, Tilmicosin controlled-release preparations Te1-12 and Te1.1-1-4 have better accelerated stability overall. This shows that the solid dispersant component, plasticizer component and their content in the controlled-release preparation have a certain influence on the accelerated stability of the Tilmicosin controlled-release preparation.

[0239] Effect Example 6

[0240] Evaluation of long-term stability of tilmicosin controlled-release preparations

[0241] The test was conducted according to the test method recorded in the 2015 edition of the Veterinary Pharmacopoeia of the People's Republic of China. The samples of each group were placed at a temperature of 15-25°C and a relative humidity of 45%-60% for 24 months, and the test results are summarized in the following table:

[0242]

[0243] It can be seen that compared with Tilmicosin controlled-release preparations Tc1-10 and Tc1.1-1.6, Tilmicosin controlled-release preparations Te1-12 and Te1.1-1-4 have better long-term stability overall. This shows that the solid dispersant component, the plasticizer component and their content in the controlled-release preparation have a certain influence on the long-term stability of the Tilmicosin controlled-release preparation.

[0244] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A tilmicosin controlled-release preparation, characterized in that: The raw materials include solid dispersant, plasticizer and tilmicosin. The raw material of the solid dispersant is a solid dispersant precursor emulsion; The solid dispersant precursor emulsion is made from a precursor composition and water; The precursor composition consists of the following substances: Monomers, scaffold molecules, surfactants and initiators; The monomers are composed of vinyl acetate, methyl acrylate, hydroxyethyl methacrylate and 2-vinyl morpholine, and the molar ratio of vinyl acetate, methyl acrylate, hydroxyethyl methacrylate and 2-vinyl morpholine is 1-2: 0.35-0.9: 0.13-0.43: 0.06-0.26; the scaffold molecule is selected from at least one of povidone, copovidone, methyl cellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose, and the surfactant is an anionic surfactant; The mass ratio of the monomer, the scaffold molecule, the surfactant, the initiator and the water is 600-1000: 100-300: 30-50: 10-20: 1500-2500; The preparation method of the solid dispersant precursor emulsion comprises the following steps: S1, mixing the formulated amount of scaffold molecules, surfactant, initiator and water, adjusting the temperature, and obtaining an initiating solution; S2, mixing the formulated amounts of vinyl acetate and hydroxyethyl methacrylate to obtain a mixed monomer A, and mixing the formulated amounts of methyl acrylate and 2-vinylmorpholine to obtain a mixed monomer B; S3, while stirring, simultaneously adding the mixed monomer A and the mixed monomer B obtained in step S2 to the initiating solution obtained in step S1, and reacting them to obtain a solid dispersant precursor emulsion; The plasticizer is selected from triethyl citrate and / or propylene glycol; the mass ratio of the solid dispersant, the plasticizer and the tilmicosin is 180-220:6-14:62-78.

2. The tilmicosin controlled-release preparation according to claim 1, characterized in that: The molar ratio of vinyl acetate, methyl acrylate, hydroxyethyl methacrylate and 2-vinylmorpholine is 1.5-1.75: 0.45-0.7: 0.25-0.4: 0.1-0.

2.

3. The tilmicosin controlled-release preparation according to claim 2, characterized in that: The molar ratio of vinyl acetate, methyl acrylate, hydroxyethyl methacrylate and 2-vinylmorpholine is 1.67:0.65:0.33:0.

15.

4. The tilmicosin controlled-release preparation according to claim 1, characterized in that: The scaffold molecule is a mixture of povidone, copovidone and methylcellulose; and the initiator is a free radical thermal initiator.

5. The Tilmicosin controlled-release preparation according to claim 4, characterized in that: The surfactant is sodium dodecyl sulfate, and the initiator is potassium persulfate.

6. The Tilmicosin controlled-release preparation according to claim 1, characterized in that: The reaction temperature in step S3 is 70-90° C., and the reaction time is ≤3 hours.

7. The Tilmicosin controlled-release preparation according to claim 1, characterized in that: The preparation method of the solid dispersant comprises the following steps: The solid dispersant precursor emulsion is spray dried, crushed and sieved to obtain the solid dispersant.

8. The Tilmicosin controlled-release preparation according to claim 7, characterized in that: The spray drying is carried out using a drying tower; the inlet air temperature of the drying tower is 130-150°C, the outlet air temperature is 70-75°C, and the induced draft fan pressure is -120~-50Pa.

9. The Tilmicosin controlled-release preparation according to claim 7, characterized in that: In the crushing and screening, the air inlet temperature of the crusher used is -10°C~0°C, the air outlet temperature is 25-40°C, and the screening is through a 100-mesh sieve.

10. The process for preparing the Tilmicosin controlled-release preparation according to any one of claims 1 to 9, characterized in that: The following steps are involved: The solid dispersant, plasticizer and tilmicosin in a prescribed amount are mixed and hot-melt extruded to obtain the tilmicosin controlled-release preparation.

11. The preparation process according to claim 10, characterized in that: The hot melt extrusion is performed using a hot melt extruder, with a first temperature of 70-90° C., a screw temperature of 135-165° C., and a rotation speed of 25-40 rpm.

12. Use of the tilmicosin controlled-release preparation according to any one of claims 1 to 9 in the preparation of antibacterial drugs.

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