A kind of sustained-release erythromycin thiocyanate soluble powder and preparation method thereof

Abstract

The invention provides a sustained-release erythromycin thiocyanate soluble powder and a preparation method thereof, belonging to the technical field of veterinary drug preparations; the preparation method comprises gelatin amination, chitosan carboxymethylation, preparation of modified chitosan, coating and mixing steps; in the coating, erythromycin thiocyanate, glycerol and deionized water are mixed, the temperature is raised to 63-67 DEG C for stirring, and a mixed solution 1 is prepared after the stirring is completed; the modified chitosan and an acetic acid solution are mixed, and the mixed solution 2 is uniformly stirred to prepare a mixed solution; the mixed solution 2 is added to the mixed solution 1, sucrose stearate is added after the stirring is uniform, ultrasonic treatment is performed, and then a functional agent is added, and ultrasonic treatment is performed again, and after the ultrasonic treatment is completed, the mixture is stirred for reaction, and after the reaction is completed, the mixture is filtered, washed and dried to prepare sustained-release erythromycin thiocyanate particles; the product prepared by the method of the invention avoids adding a large amount of acidic reagents, has excellent sustained-release performance, is stable in the acidic environment of gastric juice, and has good drug efficacy.

Description

Technical Field

[0001] The invention belongs to the technical field of veterinary drug preparations, and particularly relates to a sustained-release erythromycin thiocyanate soluble powder and a preparation method thereof. Background Art

[0002] Erythromycin thiocyanate belongs to the macrolide antibiotics. It is the thiocyanate of erythromycin and is a veterinary drug used for infections of Gram-positive bacteria and mycoplasma. It is more often used as a starting material for the synthesis of macrolide antibiotics such as erythromycin, roxithromycin, azithromycin, and clarithromycin.

[0003] Erythromycin thiocyanate has a stronger effect on Gram-positive bacteria such as Staphylococcus aureus, Streptococcus, and Pneumococcus, and also has a certain effect on Gram-negative bacteria such as Pasteurella and Brucella. In addition, this product is also effective against Mycoplasma, Rickettsia, Leptospira, Actinomycetes, and Nocardia, but has no effect on enteric-negative bacteria such as Escherichia coli and Salmonella.

[0004] Erythromycin thiocyanate is mainly administered to animals through drinking water. When administering, it is necessary to prepare a high-concentration drug solution that is dozens of times the clinical dosage in a waterer and then dilute it for administration. However, erythromycin thiocyanate has poor water solubility. When administering, the drug solution will quickly settle to the bottom of the solution, which is not conducive to uniform administration and can easily cause blockage of the waterer, affecting the treatment effect.

[0005] CN105147620A discloses an erythromycin thiocyanate soluble powder and a preparation method thereof. The erythromycin thiocyanate soluble powder comprises, by mass percentage, 1-20% of erythromycin thiocyanate, 2-40% of sodium citrate, 1-20% of citric acid, 1-5% of sodium dihydrogen phosphate, and the remainder is auxiliary materials;

[0006] The patent improves the solubility of erythromycin thiocyanate soluble powder, and its solubility in water is 5g / L. However, the patent adds a large amount of acidic reagents. During the preparation process, the acidity of the drug solution is strong and the pH value is low, which destroys the molecular structure of the drug and seriously affects the antibacterial performance. In the subsequent administration process, after dilution with a large amount of water, the pH value increases, causing the precipitation of erythromycin thiocyanate, affecting the treatment effect.

[0007] Furthermore, the currently available erythromycin thiocyanate soluble powder is rapidly absorbed and utilized after being delivered into the animal body, and has a short duration of action, which affects the therapeutic effect;

[0008] In this regard, CN106176613A discloses a veterinary sustained-release erythromycin thiocyanate soluble powder and a preparation method thereof, wherein the erythromycin thiocyanate soluble powder with sustained-release effect comprises 10-40% erythromycin thiocyanate, 5-40% coating component, 2-3% suspending agent, and the remainder is auxiliary materials;

[0009] The erythromycin thiocyanate prepared by the method is clear when dissolved in water at a dose twice the clinical dose, and is in a uniform suspension state when dissolved in water at a dose higher than twice the clinical dose, and can maintain a stable release of the blood drug concentration, thereby avoiding the problem of rapid absorption and metabolism after entering the body once. However, the erythromycin thiocyanate soluble powder prepared by the method still has the problem of poor sustained-release effect and instability under acidic conditions such as gastric juice, which affects clinical use. Summary of the invention

[0010] In order to solve the technical problems existing in the prior art, the present invention provides a sustained-release erythromycin thiocyanate soluble powder and a preparation method thereof, which avoids adding a large amount of acidic reagents, has excellent sustained-release performance, is stable in the acidic environment of gastric juice, and has good efficacy.

[0011] In order to solve the above technical problems, the present invention adopts the following technical solutions:

[0012] A method for preparing a sustained-release erythromycin thiocyanate soluble powder, the operating steps are as follows:

[0013] 1. Gelatin amination

[0014] The gelatin is placed in a phosphate buffer solution, stirred at 28-32°C, and after being stirred evenly, a gelatin solution is obtained, an amino compound is added, and after being stirred evenly, a hydrochloric acid solution is added to adjust the pH to 4.8-5.2, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is added, and the temperature is raised to 37-40°C and stirred for 9.0-10.5 hours. After the stirring is completed, the solution is filled into a dialysis bag and dialyzed for 3 days, and deionized water is replaced 3 times a day. After the dialysis is completed, the solution is freeze-dried, and the freezing temperature is -27 to -24°C, and the freezing time is 23-25 ​​hours to obtain amino gelatin;

[0015] The mass volume ratio of the gelatin, phosphate buffer, amino compound, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 2.8-3.2 g:146-155 mL:8.6-8.8 g:1.18-1.23 g;

[0016] The pH of the phosphate buffer is 4.8-5.2;

[0017] The mass concentration of the hydrochloric acid solution is 15-18wt%;

[0018] The amino compound is a mixture of 1,6-hexanediamine and diethylenetriamine, and the mass ratio of the 1,6-hexanediamine to diethylenetriamine is 1:2.2-2.5.

[0019] 2. Carboxymethylation of chitosan

[0020] The chitosan is placed in isopropanol, stirred evenly, and then sodium hydroxide solution and sodium castor oil sulfonate are added for ultrasonic treatment. The ultrasonic time is 18-22 minutes, the ultrasonic power is 136-145W, and the ultrasonic frequency is 20-25kHz. After the ultrasonic treatment, the temperature is increased to 43-47°C, and the stirring reaction is performed for 1.6-1.8 hours. After the stirring reaction is completed, chloroacetic acid and coconut oil diethanolamide are added, and the stirring is continued at 43-47°C for 2.4-2.6 hours. After the stirring is completed, the mixture is filtered and washed, and then dried at 92-96°C for 5.8-6.2 hours to obtain carboxymethyl chitosan;

[0021] The mass concentration of the sodium hydroxide solution is 42-45%;

[0022] The mass volume ratio of the chitosan, isopropanol, sodium hydroxide solution, sodium castor oil sulfonate, chloroacetic acid and coconut oil diethanolamide is 3.2-3.8 g: 36-43 mL: 9.6-10.3 mL: 0.5-0.7 g: 66-72 mL: 0.6-1.0 g.

[0023] 3. Preparation of Modified Chitosan

[0024] Place carboxymethyl chitosan in deionized water, stir evenly, add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, stir at 135-146 rpm for 0.8-1.2 h, add amino gelatin after stirring, react at room temperature for 9.5-10.5 h, wash and dry after the reaction to obtain modified chitosan;

[0025] The mass volume ratio of the carboxymethyl chitosan, deionized water, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide and amino gelatin is 8.7-9.3 g: 900-1050 mL: 2.5-2.7 g: 1.8-2.2 g: 10.1-10.3 g.

[0026] 4. Wrapping

[0027] Mix erythromycin thiocyanate, glycerol and deionized water, raise the temperature to 63-67°C and stir for 42-48 minutes at a stirring speed of 210-230 rpm, and obtain a mixed solution 1 after the stirring is completed; mix the modified chitosan and the acetic acid solution, stir evenly, and obtain a mixed solution 2; add the mixed solution 2 to the mixed solution 1, stir evenly, add sucrose stearate, and perform ultrasonic treatment for 27-33 minutes, an ultrasonic power of 226-233 W, and an ultrasonic frequency of 40-45 kHz. After the ultrasonic treatment is completed, add a functional agent, continue the ultrasonic treatment, control the frequency and power unchanged, and the ultrasonic treatment time is 17-22 minutes. After the ultrasonic treatment is completed, stir and react for 5.8-6.3 hours. After the reaction is completed, filter, wash, and dry to obtain sustained-release erythromycin thiocyanate particles;

[0028] In the mixed solution 1, the mass ratio of erythromycin thiocyanate, glycerol and deionized water is 9.7-10.3:0.8-1.2:116-125;

[0029] In the second mixed solution, the mass ratio of modified chitosan to acetic acid solution is 1.0-1.4:28-32;

[0030] The mass concentration of the acetic acid solution is 18-22%;

[0031] The mass ratio of the mixed solution 2, the mixed solution 1, sucrose stearate, and the functional agent is 34.5-35.5:130-134:1.1-1.3:1.6-1.8;

[0032] The preparation method of the functional agent is as follows: adding β-cyclodextrin into deionized water, raising the temperature to 46-50° C., stirring, and after stirring evenly, lowering the temperature to room temperature, adding sodium periodate, stirring at 292-310 rpm for 2.3-2.8 hours, and after the stirring is completed, filtering, washing, and drying to obtain the functional agent;

[0033] The mass ratio of the β-cyclodextrin, deionized water and sodium periodate is 4.8-5.2:105-116:9.4-9.8.

[0034] 5. Mix

[0035] The sustained-release erythromycin thiocyanate granules were mixed with deionized water, Tween 20, PVP K30, anhydrous glucose and xanthan gum were added, and the mixture was stirred at 770-790 rpm for 38-42 minutes. After the stirring was completed, the mixture was spray-dried to obtain a sustained-release erythromycin thiocyanate soluble powder;

[0036] The mass ratio of the sustained-release erythromycin thiocyanate granules, deionized water, Tween 20, PVP K30, anhydrous glucose and xanthan gum is 15.3-15.8:63-66:2.3-2.7:0.8-1.2:78-82:0.7-1.3.

[0037] A sustained-release erythromycin thiocyanate soluble powder is prepared by the above preparation method.

[0038] Compared with the prior art, the present invention has achieved the following beneficial effects:

[0039] 1. The present invention performs an amination treatment on gelatin so that the surface of gelatin contains amino groups, thereby improving the adhesiveness of gelatin. Then, chitosan is carboxymethylated, wherein the sodium castor oil sulfonate and coconut oil diethanolamide can respectively increase the alkalinity and carboxylation degree of chitosan, thereby making the carboxylation of chitosan more complete. The surface of chitosan contains carboxyl groups, and the carboxymethyl chitosan is modified by amination gelatin. The two react so that the chitosan and gelatin are firmly connected to form a stable network structure. During the coating process, glycerol It can interact with erythromycin thiocyanate, reducing its direct contact with water molecules and reducing its insolubility in water. Chitosan and gelatin have good film-forming properties. The functional agent made by combining β-cyclodextrin is used as a cross-linking agent, so that erythromycin thiocyanate is coated in a stable cross-linked network structure, achieving the sustained release performance of erythromycin thiocyanate. It still maintains stable sustained release performance under the acidic conditions of gastric juice, and basically achieves complete release of the drug within 12 hours, which is not only conducive to improving drug utilization, but also can timely carry out drug action and absorption;

[0040] 2. The cumulative release rate of the product prepared by the method of the present invention was tested in simulated gastric fluid at pH = 6.2. The release rate at 0h was 0, the cumulative release rate at 2h was 9.5-9.8%, the cumulative release rate at 4h was 15.8-16.5%, the cumulative release rate at 6h was 33.1-34.7%, the cumulative release rate at 8h was 67.4-98.2%, and the cumulative release rate at 12h was 97.2-98.7%. DETAILED DESCRIPTION

[0041] In order to more clearly understand the technical features, purposes and effects of the present invention, specific embodiments of the present invention are now described.

[0042] Example 1

[0043] 1. Gelatin amination

[0044] 3.0 g of gelatin was placed in 150 mL of phosphate buffer, stirred at 30° C., and after being stirred evenly, a gelatin solution was obtained. 8.7 g of an amino compound was added, and after being stirred evenly, a 16 wt % hydrochloric acid solution was added to adjust the pH to 5.0, and then 1.20 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added, and the temperature was raised to 38° C. and stirred for 10 hours. After the stirring was completed, the solution was filled into a dialysis bag and dialyzed for 3 days, with deionized water replaced 3 times a day. After the dialysis was completed, the solution was freeze-dried at a freezing temperature of -25° C. and a freezing time of 24 hours to obtain amino gelatin.

[0045] The amino compound is a mixture of 1,6-hexanediamine and diethylenetriamine, and the mass ratio of the 1,6-hexanediamine to diethylenetriamine is 1:2.3.

[0046] 2. Carboxymethylation of chitosan

[0047] 3.5 g of chitosan was placed in 40 mL of isopropanol, stirred evenly, and then 10 mL of 43 wt% sodium hydroxide solution and 0.6 g of sodium castor oil sulfonate were added for ultrasonic treatment. The ultrasonic time was 20 min, the ultrasonic power was 140 W, and the ultrasonic frequency was 22 kHz. After the ultrasonic treatment, the temperature was raised to 45 ° C, and the reaction was stirred for 1.7 h. After the stirring reaction was completed, 70 mL of chloroacetic acid and 0.8 g of coconut oil diethanolamide were added, and the stirring was continued at 45 ° C for 2.5 h. After the stirring was completed, it was filtered and washed, and then dried at 94 ° C for 6.0 h to obtain carboxymethyl chitosan.

[0048] 3. Preparation of Modified Chitosan

[0049] 9.0 g of carboxymethyl chitosan was placed in 1000 mL of deionized water, and after stirring evenly, 2.6 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.0 g of N-hydroxysuccinimide were added, and stirred at 140 rpm for 1.0 h. After the stirring, 10.3 g of amino gelatin was added, and the mixture was reacted at room temperature for 10 h. After the reaction was completed, the mixture was washed and dried to obtain modified chitosan.

[0050] 4. Wrapping

[0051] 10g of erythromycin thiocyanate, 1.0g of glycerol and 120g of deionized water were mixed, the temperature was raised to 65°C and stirred for 45min at a stirring speed of 220rpm. After the stirring, a mixed solution 1 was obtained; 1.2g of modified chitosan and 30g of 20wt% acetic acid solution were mixed and stirred evenly to obtain a mixed solution 2; 35.0g of the mixed solution 2 was added to 132g of the mixed solution 1, and 1.2g of sucrose stearate was added after stirring evenly, and ultrasonic treatment was performed for 30min, 230W of ultrasonic power, and 42kHz of ultrasonic frequency. After the ultrasonic treatment, 1.7g of functional agent was added, and ultrasonic treatment was continued, the frequency and power were kept constant, the ultrasonic treatment time was 20min, and after the ultrasonic treatment, the reaction was stirred for 6.0h. After the reaction, the particles were filtered, washed and dried to obtain sustained-release erythromycin thiocyanate particles;

[0052] The preparation method of the functional agent is as follows: 5.0g of β-cyclodextrin is added into 110g of deionized water, the temperature is raised to 48°C, and the mixture is stirred. After the mixture is stirred evenly, the temperature is lowered to room temperature, 9.6g of sodium periodate is added, and the mixture is stirred at 300rpm for 2.5h. After the stirring is completed, the mixture is filtered, washed, and dried to obtain the functional agent.

[0053] 5. Mix

[0054] 15.6 g of sustained-release erythromycin thiocyanate granules were mixed with 65 g of deionized water, and 2.5 g of Tween 20, 1.0 g of PVPK30, 80 g of anhydrous glucose and 1.0 g of xanthan gum were added, and the mixture was stirred at 780 rpm for 40 min. After the stirring was completed, the mixture was spray-dried to obtain a sustained-release erythromycin thiocyanate soluble powder.

[0055] Example 2

[0056] 1. Gelatin amination

[0057] 2.8 g of gelatin was placed in 146 mL of pH = 4.8 phosphate buffer, stirred at 28 ° C, and after stirring evenly, a gelatin solution was obtained, 8.6 g of an amino compound was added, and after stirring evenly, a 15 wt% hydrochloric acid solution was added to adjust the pH to 4.8, and then 1.18 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added, and the temperature was raised to 37 ° C and stirred for 9.0 hours. After the stirring was completed, the solution was filled into a dialysis bag and dialyzed for 3 days, and the deionized water was replaced 3 times a day. After the dialysis was completed, freeze-dried, the freezing temperature was -27 ° C, and the freezing time was 23 hours, to obtain amino gelatin;

[0058] The amino compound is a mixture of 1,6-hexanediamine and diethylenetriamine, and the mass ratio of the 1,6-hexanediamine to diethylenetriamine is 1:2.2.

[0059] 2. Carboxymethylation of chitosan

[0060] 3.2 g of chitosan was placed in 36 mL of isopropanol, stirred evenly, and then 9.6 mL of 42 wt% sodium hydroxide solution and 0.5 g of sodium castor oil sulfonate were added for ultrasonic treatment. The ultrasonic time was 18 min, the ultrasonic power was 136 W, and the ultrasonic frequency was 20 kHz. After the ultrasonic treatment, the temperature was raised to 43 ° C, and the reaction was stirred for 1.6 h. After the stirring reaction was completed, 66 mL of chloroacetic acid and 0.6 g of coconut oil diethanolamide were added, and the stirring was continued at 43 ° C for 2.4 h. After the stirring was completed, it was filtered and washed, and then dried at 92 ° C for 5.8 h to obtain carboxymethyl chitosan.

[0061] 3. Preparation of Modified Chitosan

[0062] 8.7 g of carboxymethyl chitosan was placed in 900 mL of deionized water, and after stirring evenly, 2.5 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 1.8 g of N-hydroxysuccinimide were added, and stirred at 135 rpm for 0.8 h. After the stirring was completed, 10.1 g of amino gelatin was added, and the mixture was reacted at room temperature for 9.5 h. After the reaction was completed, the mixture was washed and dried to obtain modified chitosan.

[0063] 4. Wrapping

[0064] 9.7g of erythromycin thiocyanate, 0.8g of glycerol and 116g of deionized water were mixed, the temperature was raised to 63°C and stirred for 42min at a stirring speed of 210rpm. After the stirring, a mixed solution 1 was obtained; 1.0g of modified chitosan and 28g of 18wt% acetic acid solution were mixed and stirred evenly to obtain a mixed solution 2; 34.5g of the mixed solution 2 was added to 130g of the mixed solution 1, and 1.1g of sucrose stearate was added after stirring evenly, and ultrasonic treatment was performed. The ultrasonic time was 27min, the ultrasonic power was 226W, and the ultrasonic frequency was 40kHz. After the ultrasonic treatment, 1.6g of a functional agent was added, and the ultrasonic treatment was continued, and the frequency and power were kept constant. The ultrasonic time was 17min. After the ultrasonic treatment, the reaction was stirred for 5.8h. After the reaction, the particles were filtered, washed and dried to obtain sustained-release erythromycin thiocyanate particles.

[0065] The preparation method of the functional agent is as follows: 4.8g of β-cyclodextrin is added into 105g of deionized water, the temperature is raised to 46°C, and the mixture is stirred. After the mixture is stirred evenly, the temperature is lowered to room temperature, 9.4g of sodium periodate is added, and the mixture is stirred at 292rpm for 2.3h. After the stirring is completed, the mixture is filtered, washed, and dried to obtain the functional agent.

[0066] 5. Mix

[0067] 15.3 g of sustained-release erythromycin thiocyanate granules were mixed with 63 g of deionized water, and 2.3 g of Tween 20, 0.8 g of PVPK30, 78 g of anhydrous glucose and 0.7 g of xanthan gum were added, and the mixture was stirred at 770 rpm for 38 min. After the stirring was completed, the mixture was spray-dried to obtain a sustained-release erythromycin thiocyanate soluble powder.

[0068] Example 3

[0069] 1. Gelatin amination

[0070] 3.2 g of gelatin was placed in 155 mL of pH = 5.2 phosphate buffer, stirred at 32 ° C, and after stirring evenly, a gelatin solution was obtained, 8.8 g of an amino compound was added, and after stirring evenly, an 18 wt% hydrochloric acid solution was added to adjust the pH to 5.2, and then 1.23 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added, and the temperature was raised to 40 ° C and stirred for 10.5 hours. After the stirring was completed, the solution was filled into a dialysis bag and dialyzed for 3 days, and the deionized water was replaced 3 times a day. After the dialysis was completed, freeze-dried, the freezing temperature was -24 ° C, and the freezing time was 25 hours, to obtain amino gelatin;

[0071] The amino compound is a mixture of 1,6-hexanediamine and diethylenetriamine, and the mass ratio of the 1,6-hexanediamine to diethylenetriamine is 1:2.5.

[0072] 2. Carboxymethylation of chitosan

[0073] 3.8 g of chitosan was placed in 43 mL of isopropanol, and after stirring evenly, 10.3 mL of 45 wt% sodium hydroxide solution and 0.7 g of sodium castor oil sulfonate were added for ultrasonic treatment. The ultrasonic time was 22 min, the ultrasonic power was 145 W, and the ultrasonic frequency was 25 kHz. After the ultrasonic treatment, the temperature was raised to 47 ° C, and the reaction was stirred for 1.8 h. After the stirring reaction was completed, 72 mL of chloroacetic acid and 1.0 g of coconut oil diethanolamide were added, and stirring was continued at 47 ° C for 2.6 h. After the stirring was completed, it was filtered and washed, and then dried at 96 ° C for 6.2 h to obtain carboxymethyl chitosan.

[0074] 3. Preparation of Modified Chitosan

[0075] 9.3 g of carboxymethyl chitosan was placed in 1050 mL of deionized water, and after stirring evenly, 2.7 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.2 g of N-hydroxysuccinimide were added, and stirred at 146 rpm for 1.2 h. After stirring, 10.3 g of amino gelatin was added, and the mixture was reacted at room temperature for 10.5 h. After the reaction was completed, the mixture was washed and dried to obtain modified chitosan.

[0076] 4. Wrapping

[0077] 10.3g of erythromycin thiocyanate, 1.2g of glycerol and 125g of deionized water were mixed, the temperature was raised to 67°C and stirred for 48min at a stirring speed of 230rpm. After the stirring, a mixed solution 1 was obtained; 1.4g of modified chitosan and 32g of 22wt% acetic acid solution were mixed and stirred evenly to obtain a mixed solution 2; 35.5g of the mixed solution 2 was added to 134g of the mixed solution 1, and 1.3g of sucrose stearate was added after stirring evenly, and ultrasonic treatment was performed. The ultrasonic time was 33min, the ultrasonic power was 233W, and the ultrasonic frequency was 45kHz. After the ultrasonic treatment, 1.8g of a functional agent was added, and the ultrasonic treatment was continued, and the frequency and power were kept constant. The ultrasonic time was 22min. After the ultrasonic treatment, the reaction was stirred for 6.3h. After the reaction, the particles were filtered, washed and dried to obtain sustained-release erythromycin thiocyanate particles.

[0078] The preparation method of the functional agent is as follows: 5.2g of β-cyclodextrin is added into 116g of deionized water, the temperature is raised to 50°C, and the mixture is stirred. After the mixture is stirred evenly, the temperature is lowered to room temperature, 9.8g of sodium periodate is added, and the mixture is stirred at 310rpm for 2.8h. After the stirring is completed, the mixture is filtered, washed, and dried to obtain the functional agent.

[0079] 5. Mix

[0080] 15.8 g of sustained-release erythromycin thiocyanate granules were mixed with 66 g of deionized water, and 2.7 g of Tween 20, 1.2 g of PVPK30, 82 g of anhydrous glucose and 1.3 g of xanthan gum were added, and the mixture was stirred at 790 rpm for 42 min. After the stirring was completed, the mixture was spray-dried to obtain a sustained-release erythromycin thiocyanate soluble powder.

[0081] Comparative Example 1

[0082] Based on Example 1, the changes are as follows:

[0083] The steps of gelatin amination and chitosan carboxylmethylation are omitted, and gelatin and chitosan without any treatment are used in the step of preparing modified chitosan;

[0084] The preparation method of the modified chitosan is as follows: placing chitosan in 1000 mL of deionized water, stirring evenly, adding 10.3 g of gelatin, stirring evenly at room temperature, washing and drying, and obtaining the modified chitosan;

[0085] The rest of the operations are the same.

[0086] Comparative Example 2

[0087] Based on Example 1, the changes are as follows:

[0088] In the chitosan carboxymethylation step, sodium castor oil sulfonate and coconut oil diethanolamide were replaced with deionized water in equal amounts;

[0089] In the coating step, the operation steps of "adding 2.3 g of functional agent, continuing ultrasonic treatment, controlling the frequency and power to be constant, the ultrasonic time to be 20 min, stirring the reaction for 6.0 h after the ultrasonic treatment, filtering, washing and drying after the reaction is completed" were omitted;

[0090] The rest of the operations are the same.

[0091] Performance Testing

[0092] 5 g of the products prepared in Examples 1-3 and Comparative Examples 1-2 were respectively placed in a beaker, 100 mL of simulated gastric fluid was added, the temperature was controlled at 37° C. and constant temperature stirring was performed at a stirring speed of 50 rpm, and the cumulative release rates at different times were tested respectively;%

[0093] The simulated gastric fluid is prepared by adding 0.19 g of pepsin and 0.12 g of sodium chloride to 60 mL of deionized water, and after fully dissolving, adding 1 mol / L hydrochloric acid solution to adjust the pH to 6.2 to obtain the simulated gastric fluid;

[0094] The specific test results are as follows:

[0095]

[0096] The invention performs an amination treatment on gelatin so that the surface of gelatin contains amino groups, thereby improving the adhesiveness of gelatin. Then, chitosan is carboxymethylated, wherein the sodium castor oil sulfonate and the coconut oil diethanolamide can respectively improve the alkalinity and carboxylation degree of chitosan, thereby making the carboxylation of chitosan more complete. The surface of chitosan contains carboxyl groups, and the amination gelatin is used to modify the carboxymethyl chitosan. The two react so that the chitosan and gelatin are firmly connected to form a stable network structure. In the coating process, glycerol can It interacts with erythromycin thiocyanate, reduces its direct contact with water molecules, and reduces its insolubility in water. Chitosan and gelatin have good film-forming properties. Combined with the functional agent made from β-cyclodextrin as a cross-linking agent, erythromycin thiocyanate is coated in a stable cross-linked network structure, achieving the sustained-release performance of erythromycin thiocyanate. It still maintains stable sustained-release performance under the acidic conditions of gastric juice, and basically achieves complete release of the drug within 12 hours, which is beneficial to improve drug utilization and can also carry out drug action and absorption in a timely manner.

[0097] In Comparative Example 1, the steps of gelatin amination and chitosan carboxylmethylation were omitted, and gelatin and chitosan without any treatment were mixed. The connection between the two was unstable and the binding force was weak. The cross-linking with the functional agent was insufficient, and the coating of erythromycin thiocyanate was incomplete, resulting in a faster initial release of sustained-release erythromycin thiocyanate, and the release of the drug was basically achieved in the 8th hour, resulting in low drug utilization. In Comparative Example 2, the carboxylmethylation of chitosan was incomplete, resulting in an insufficient reaction between chitosan and gelatin, and the functional agent was omitted during the coating process, so that erythromycin thiocyanate could not be coated in a stable cross-linked network structure, thereby accelerating the initial release rate of the product and affecting the sustained-release performance.

[0098] Unless otherwise specified, all ratios and percentages described in the present invention are by mass ratios and percentages are by mass percentages.

[0099] Finally, it should be noted that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing a sustained-release erythromycin thiocyanate soluble powder, characterized in that: The method comprises the steps of gelatin amination, chitosan carboxymethylation, preparation of modified chitosan, coating and mixing; The chitosan carboxymethylation step comprises placing chitosan in isopropanol, stirring evenly, adding sodium hydroxide solution and sodium castor oil sulfonate, and performing ultrasonic treatment for 18-22 minutes. After the ultrasonic treatment, stirring is performed once. After the stirring is completed, chloroacetic acid and coconut oil diethanolamide are added, and stirring is performed twice. After the stirring is completed, filtering, washing, and drying are performed to obtain carboxymethyl chitosan. The step of preparing the modified chitosan is as follows: placing carboxymethyl chitosan in deionized water, stirring evenly, adding 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and N-hydroxysuccinimide, stirring at a speed of 135-146 rpm for 0.8-1.2 hours, adding amino gelatin after the stirring, reacting at room temperature for 9.5-10.5 hours, and washing and drying after the reaction to obtain the modified chitosan; The coating step comprises: mixing erythromycin thiocyanate, glycerol and deionized water, raising the temperature to 63-67° C. and stirring for 42-48 min at a stirring speed of 210-230 rpm, and obtaining a first mixed solution after the stirring is completed; mixing the modified chitosan and the acetic acid solution, and stirring evenly to obtain a second mixed solution; adding the second mixed solution to the first mixed solution, stirring evenly, and then adding sucrose stearate, and performing an ultrasonic treatment once; after the ultrasonic treatment is completed, adding a functional agent, and performing a second ultrasonic treatment; after the ultrasonic treatment is completed, stirring and reacting for 5.8-6.3 h; after the reaction is completed, filtering, washing and drying are performed to obtain sustained-release erythromycin thiocyanate particles; The preparation method of the functional agent is as follows: adding β-cyclodextrin into deionized water, raising the temperature to 46-50° C., stirring, and after stirring evenly, lowering the temperature to room temperature, adding sodium periodate, stirring at 292-310 rpm for 2.3-2.8 hours, and after the stirring is completed, filtering, washing, and drying to obtain the functional agent; The mixing step comprises mixing the sustained-release erythromycin thiocyanate particles with deionized water, adding Tween 20, PVP K30, anhydrous glucose and xanthan gum, stirring at 770-790 rpm for 38-42 minutes, and after the stirring is completed, spray drying to obtain the sustained-release erythromycin thiocyanate soluble powder.

2. The method for preparing a sustained-release erythromycin thiocyanate soluble powder according to claim 1, characterized in that: The gelatin amination step comprises placing gelatin in a phosphate buffer, stirring at 28-32° C., and obtaining a gelatin solution after uniform stirring. An amino compound is added, and after uniform stirring, a hydrochloric acid solution is added to adjust the pH to 4.8-5.2, and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is added, and the temperature is raised to 37-40° C. and stirred for 9.0-10.5 hours. After the stirring is completed, the solution is filled into a dialysis bag and dialyzed for 3 days, and the deionized water is replaced 3 times a day. After the dialysis is completed, the solution is freeze-dried, and the freezing temperature is -27 to -24° C. and the freezing time is 23-25 ​​hours to obtain the amino gelatin.

3. The method for preparing a sustained-release erythromycin thiocyanate soluble powder according to claim 2, characterized in that: The mass volume ratio of the gelatin, phosphate buffer, amino compound, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride is 2.8-3.2 g:146-155 mL:8.6-8.8 g:1.18-1.23 g; The pH of the phosphate buffer is 4.8-5.2; The mass concentration of the hydrochloric acid solution is 15-18wt%; The amino compound is a mixture of 1,6-hexanediamine and diethylenetriamine, and the mass ratio of the 1,6-hexanediamine to diethylenetriamine is 1:2.2-2.

5.

4. The method for preparing a sustained-release erythromycin thiocyanate soluble powder according to claim 1, characterized in that: In the chitosan carboxymethylation step, the mass concentration of the sodium hydroxide solution is 42-45%; The mass volume ratio of the chitosan, isopropanol, sodium hydroxide solution, sodium castor oil sulfonate, chloroacetic acid, and coconut oil diethanolamide is 3.2-3.8 g: 36-43 mL: 9.6-10.3 mL: 0.5-0.7 g: 66-72 mL: 0.6-1.0 g; The ultrasonic treatment has an ultrasonic power of 136-145W and an ultrasonic frequency of 20-25kHz; The stirring temperature is 43-47°C and the stirring time is 1.6-1.8h; The secondary stirring has a stirring temperature of 43-47° C. and a stirring time of 2.4-2.6 h.

5. The method for preparing a sustained-release erythromycin thiocyanate soluble powder according to claim 1, characterized in that: In the step of preparing modified chitosan, the mass volume ratio of the carboxymethyl chitosan, deionized water, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N-hydroxysuccinimide, and amino gelatin is 8.7-9.3 g: 900-1050 mL: 2.5-2.7 g: 1.8-2.2 g: 10.1-10.3 g.

6. The method for preparing a sustained-release erythromycin thiocyanate soluble powder according to claim 1, characterized in that: In the coating step, in the mixed solution 1, the mass ratio of erythromycin thiocyanate, glycerol, and deionized water is 9.7-10.3:0.8-1.2:116-125; In the second mixed solution, the mass ratio of modified chitosan to acetic acid solution is 1.0-1.4:28-32; The mass concentration of the acetic acid solution is 18-22%; The mass ratio of the mixed solution 2, the mixed solution 1, sucrose stearate and the functional agent is 34.5-35.5:130-134:1.1-1.3:1.6-1.

8.

7. The method for preparing a sustained-release erythromycin thiocyanate soluble powder according to claim 1, characterized in that: In the coating step, the ultrasonic treatment is performed once, with an ultrasonic time of 27-33 min, an ultrasonic power of 226-233 W, and an ultrasonic frequency of 40-45 kHz; The secondary ultrasonic treatment has an ultrasonic time of 17-22 min, an ultrasonic power of 226-233 W, and an ultrasonic frequency of 40-45 kHz.

8. The method for preparing a sustained-release erythromycin thiocyanate soluble powder according to claim 1, characterized in that: In the preparation method of the functional agent, the mass ratio of the β-cyclodextrin, deionized water and sodium periodate is 4.8-5.2:105-116:9.4-9.

8.

9. The method for preparing a sustained-release erythromycin thiocyanate soluble powder according to claim 1, characterized in that: In the mixing step, the mass ratio of the sustained-release erythromycin thiocyanate particles, deionized water, Tween 20, PVP K30, anhydrous glucose and xanthan gum is 15.3-15.8:63-66:2.3-2.7:0.8-1.2:78-82:0.7-1.

3.

10. The sustained-release erythromycin thiocyanate soluble powder prepared according to the preparation method according to any one of claims 1 to 9.

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