Veterinary albendazole tablet and preparation method thereof

Abstract

The invention belongs to the technical field of veterinary drugs, relates to a veterinary albendazole tablet, and provides a preparation method of the preparation. The tablet consists of albendazole, trehalose, sodium taurocholate and other pharmaceutically acceptable adhesives, disintegrating agents and lubricating agents. The albendazole is fully dispersed by spray-drying a mixed solution of albendazole, trehalose and sodium taurocholate, and the dosage of trehalose and sodium taurocholate is controlled, so that the dissolution and stability of the product are improved.

Description

Technical Field

[0001] The invention belongs to the technical field of veterinary drugs, and particularly relates to an albendazole tablet for animals and a preparation method thereof. Background Art

[0002] Albendazole, also known as albendazole, has a chemical name of 5-propylthiobenzimidazole-2-carbamic acid methyl ester. It belongs to the benzimidazole class of drugs. It is a broad-spectrum, highly effective, low-toxic anthelmintic drug launched by Smith Kline in the United States in 1977. It is widely used to treat parasitic infections such as pinworms, roundworms, tapeworms, and hydatids. It is the first choice anthelmintic recommended by the World Health Organization (WHO). Its chemical structure is as follows:

[0003]

[0004] Albendazole is a white or off-white powder; odorless. It is slightly soluble in acetone or chloroform, almost insoluble in ethanol, insoluble in water; it dissolves in glacial acetic acid. It is rapidly metabolized into sulfoxides, sulfone alcohols and 2-amine sulfone alcohols in the body. However, due to the low solubility of this drug, its absorption and utilization in animals are limited. Traditional drug preparation technologies such as micronization, preparation of suspensions or suspensions, etc., can improve the solubility and bioavailability of drugs to a certain extent, but the effect is limited. The dosage forms used clinically include tablets, powders, premixes, suspensions, solutions, injections and other dosage forms.

[0005] CN87108271.3 discloses a method for preparing a soluble synergistic albendazole powder, which is prepared by grinding, drying and pulverizing albendazole with bile powder, water and gelatin solution.

[0006] CN95100206.6 discloses a hydrophilic formulation of albendazole. The process is as follows: (1) dissolving albendazole in an organic solvent. If it is dissolved at low temperature, hydrochloric acid must be added to acidify it into a solution state; (2) adding deionized water and a surfactant (dispersant), a penetrant, etc. to mix and form a water-soluble suspension; or adding a carrier to form a soluble ultrafine powder. The present invention can be used to prepare two hydrophilic formulations for the production of agricultural fungicides, medicines, etc.

[0007] CN200510098951.8 discloses a new albendazole preparation, which solves the problems of poor physical stability and large volume of albendazole emulsion. The composition of the new albendazole preparation comprises, by weight percentage, 1-35 albendazole, 3-85 edible oil or fatty acid, 1-40 emulsifier, 0-45 organic acid or amide, 0-40 auxiliary emulsifier, 0-10 pH regulator, 0-0.05 antioxidant, and 0-84 curing agent. The preparation method is simple and easy, and the operation and industrial production are easy. The new albendazole preparation has the characteristics of good solubility and high bioavailability, can improve the therapeutic effect, and is convenient for storage and transportation.

[0008] CN200610129699.7 discloses an albendazole chewable tablet for dogs and cats, which breaks through the disadvantage of poor palatability of existing tablets, can promote dogs and cats to fully chew and absorb, effectively ensure the dosage, improve the cure rate of dog and cat diseases, and reduce the waste of medicine. The tablet of the present invention comprises: aspartame 1-5%, oral glucose and skim milk powder mixture 20-30%, oral glucose and skim milk powder in the mixture The ratio of 1:1-1:4; excipient 40%-60%, glidant 0.5-1%, albendazole 30-50%.

[0009] CN201210317207.2 relates to an albendazole dispersible tablet and a preparation method thereof, wherein the dispersible tablet is composed of the following raw materials in weight proportion: 200g of albendazole, 50-160g of a disintegrant, 18-118g of a diluent, 2-12g of a surfactant, 6-16g of a sweetener, 3-12g of a glidant, and 1-4g of a lubricant. The present invention adopts suitable auxiliary materials to prepare the albendazole dispersible tablet, which significantly improves the bioavailability of the drug and improves the efficacy of the drug.

[0010] CN201310455521.1 discloses a compound ivermectin solid dispersion, which is made of the following raw materials in parts by weight: 0.1-5 parts of ivermectin, 1-20 parts of albendazole, 10-80 parts of organic solvent, 5-90 parts of polymer carrier, and 2-15 parts of surfactant. The present invention utilizes solid dispersion technology to improve the solubility of ivermectin and albendazole in water, improve their oral bioavailability, reduce the amount of drugs used, reduce toxic side effects, and the product of the present invention has good stability and good application prospects.

[0011] CN201310482959.9 provides a veterinary dispersible tablet, which is prepared from raw and auxiliary materials in the following weight ratio: 7-13 parts of albendazole, 70-90 parts of hawthorn, 15-25 parts of tangerine peel, 40-50 parts of microcrystalline cellulose, 6-10 parts of sodium carboxymethyl cellulose, 8-12 parts of cross-linked polyvinyl pyrrolidone, 12-18 parts of sucrose powder, and an appropriate amount of lubricant.

[0012] CN201510666691.3 discloses a veterinary albendazole dispersible tablet, which is composed of a main ingredient, a disintegrant, a binder and an auxiliary material in a weight ratio of 40-85:3-10:5-15:5-25; the following steps are performed: (1) weighing; (2) grinding: micronizing the weighed main ingredient for later use; (3) mixing: mixing the micronized main ingredient with the disintegrant, the binder and the auxiliary material, and then tableting to obtain an albendazole dispersible tablet.

[0013] CN202410759878.7 provides an albendazole ivermectin microcrystalline dispersion and a preparation method thereof. By reasonably proportioning auxiliary ingredients such as polyethylene glycol 4000, colloidal silicon dioxide and sodium alginate and the proportion thereof, an albendazole ivermectin microcrystalline dispersion with good dispersibility and high stability in water is obtained. The microcrystalline dispersion can have good solubility under low pH conditions, significantly improving the bioavailability of albendazole and ivermectin in the body, and providing convenient conditions for the administration of albendazole and ivermectin in drinking water.

[0014] CN202411028690.1 discloses a highly bioavailable albendazole nanocrystal and a preparation method thereof. The nanocrystal of the present invention is prepared by mixing albendazole, a natural glycoside stabilizer and water to form a suspension, and the suspension is ground by wet media; the average particle size is 100 to 500 nm. The nanocrystal of the present invention is obtained by dispersing albendazole in a natural glycoside solution and subjecting it to nano-treatment, and has a high drug loading, which can greatly improve the solubility and dissolution of albendazole, thereby improving its absorption and bioavailability.

[0015] In order to improve the dissolution performance of albendazole, Xie Yinghua et al. used sodium dodecyl sulfate and polysorbate 80 in combination to increase the solubility of albendazole in water; different batches of albendazole dispersible tablets prepared completely disintegrated within 122 seconds, and the cumulative dissolution rate of the drug was greater than 80% at 45 minutes. (Xie Yinghua, Zhang Dongmei, Han Yu, et al. Study on albendazole dispersible tablets based on solubilization [J]. Journal of Hebei University of Science and Technology, 2021, 42(6): 619-626.)

[0016] Luo Binghua studied the effect of API particle size distribution on the dissolution of albendazole tablets. The API was pre-treated by airflow milling process. When the particle size characteristic value d(0.5) was controlled to be 5-10 μm and d(0.9) to be 10-20 μm, the dissolution behavior of the tablets showed a high degree of similarity with the reference tablets. (Luo Binghua. Effect of API particle size on in vitro dissolution of albendazole tablets [J]. Today's Pharmacy, 2021, 31(10): 753-755.)

[0017] Whether in the field of veterinary preparations or in the field of human medicines, in order to improve the solubility of albendazole, researchers have successively developed and studied different preparations such as solid dispersions, inclusion compounds and liposomes, nanocrystals, and controlled particle size. The above preparations have problems such as limited ability to improve the bioavailability of albendazole, excessive excipient load, and difficulty in industrialization. Summary of the invention

[0018] In view of the problems existing in the prior art, the present invention provides an albendazole tablet and provides a preparation method of the preparation. The tablet of the present invention has the advantages of simple preparation process, stable quality, high dissolution, high bioavailability, and convenience for industrial production.

[0019] Specifically, the purpose of the present invention is achieved through the following technical solutions:

[0020] An albendazole tablet is composed of albendazole, trehalose, sodium taurocholate and other pharmaceutically acceptable binders, disintegrants and lubricants.

[0021] In a preferred embodiment, the mass ratio of albendazole to trehalose and sodium taurocholate is: 1:1.0-3.0:0.2-0.6; preferably 1:2:0.4.

[0022] In a preferred embodiment, the binder is selected from one or more of hydroxypropyl methylcellulose, povidone K30, and pregelatinized starch. More preferably, the binder is povidone K30.

[0023] In a preferred embodiment, the disintegrant is selected from one or more of sodium carboxymethyl starch, sodium hydroxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, and crospovidone, and is further preferably cross-linked sodium carboxymethyl cellulose.

[0024] In a preferred embodiment, the lubricant is selected from one or more of talc and magnesium stearate; more preferably magnesium stearate.

[0025] In a preferred embodiment, the albendazole tablets consist of the following ingredients:

[0026]

[0027] In a preferred embodiment, the albendazole tablets consist of the following ingredients:

[0028]

[0029]

[0030] Another object of the present invention is to provide a method for preparing the above-mentioned albendazole tablets, which mainly comprises the following steps:

[0031] 1) Add the prescribed amount of sodium taurocholate and trehalose to hot ethanol in sequence, stir and dissolve; then add albendazole and stir evenly, add to a spray dryer, adjust the spray conditions, spray dry, and obtain a mixed powder;

[0032] 2) Add appropriate amount of water to the prescribed amount of adhesive to prepare an adhesive solution for later use;

[0033] 3) adding the prescribed amount of disintegrant and the mixed powder obtained in step 1 to a wet granulator, preparing wet granules with the binder solution obtained in step 2, and drying and granulating the wet granules with a pulverizing granulator;

[0034] 4) lubricating and blending the particles obtained in step 3 with a lubricant to produce a final blend;

[0035] 5) The final blend is tableted to obtain albendazole tablets.

[0036] In a preferred embodiment, the hot ethanol is temperature controlled at 40-50°C.

[0037] In a preferred embodiment, the binder is added with an appropriate amount of water to prepare a binder solution with a concentration of 2 to 5%, and more preferably 3%.

[0038] In a preferred embodiment, the spray drying conditions are: inlet temperature of 80-120°C, outlet temperature of about 50-70°C, spray flow rate of 5-12ml / min, compressed air flow rate of 8-15L / min; further preferably, the inlet temperature is 90°C, the outlet temperature is 60°C, the spray flow rate is 8ml / min, and the compressed air flow rate is 10L / min.

[0039] Compared with the prior art, in the albendazole tablet of the present invention, trehalose can effectively disperse albendazole, make albendazole microcrystallized, and reduce the hygroscopicity of the albendazole tablet, thereby preferably improving the stability of the tablet. The addition of sodium taurocholate effectively improves the dissolution of the tablet. By controlling the dosage of trehalose and sodium taurocholate, the rapid dissolution of the product is guaranteed, the preparation is smooth, the quality is stable, and the product is safe and effective. DETAILED DESCRIPTION

[0040] The present invention is further described below by way of examples. It should be correctly understood that the examples of the present invention are provided only for illustrating the present invention, rather than limiting the present invention, and therefore, simple modifications of the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0041] Example 1

[0042]

[0043]

[0044] Preparation process:

[0045] 1) Add the prescribed amount of sodium taurocholate and trehalose to an appropriate amount of ethanol at 40-50°C in sequence and stir until dissolved; then add albendazole and stir evenly, add to a spray dryer, adjust the spray conditions: inlet temperature is 90°C, outlet temperature is 60°C, spray flow rate is 8ml / min, compressed air flow rate is 10L / min, spray dry to obtain a mixed powder;

[0046] 2) Add appropriate amount of water to the prescribed amount of adhesive Povidone K30 to prepare a Povidone K30 solution with a concentration of 3%; set aside;

[0047] 3) adding the prescribed amount of disintegrant croscarmellose sodium and the mixed powder obtained in step 1 to a wet granulator, using the povidone K30 solution obtained in step 2 to prepare wet granules, and drying and granulating the wet granules with a pulverizing and granulating machine;

[0048] 4) lubricating and blending the granules obtained in step 3 and lubricant magnesium stearate to produce a final blend;

[0049] 5) The final blend is tableted to obtain albendazole tablets.

[0050] Example 2

[0051]

[0052] Preparation process: Same as Example 1.

[0053] Example 3

[0054]

[0055]

[0056] Preparation process: Same as Example 1.

[0057] Example 4

[0058]

[0059] Preparation process: Same as Example 1.

[0060] Example 5

[0061]

[0062] Preparation process: Same as Example 1.

[0063] Example 6

[0064]

[0065]

[0066] Preparation process: Same as Example 1.

[0067] Example 7

[0068]

[0069] Preparation process: Same as Example 1.

[0070] Example 8

[0071]

[0072] Preparation process: Same as Example 1.

[0073] Comparative Example 1

[0074]

[0075]

[0076] Preparation process:

[0077] 1) Add the prescribed amount of trehalose to an appropriate amount of ethanol at 40-50°C and stir until dissolved; then add albendazole and stir evenly, add to the spray dryer, adjust the spray conditions: inlet temperature is 90°C, outlet temperature is 60°C, spray flow rate is 8ml / min, compressed air flow rate is 10L / min, spray dry to obtain mixed powder;

[0078] 2) Add appropriate amount of water to the prescribed amount of adhesive Povidone K30 to prepare a Povidone K30 solution with a concentration of 3%; set aside;

[0079] 3) adding the prescribed amount of disintegrant croscarmellose sodium and the mixed powder obtained in step 1 to a wet granulator, using the povidone K30 solution obtained in step 2 to prepare wet granules, and drying and granulating the wet granules with a pulverizing and granulating machine;

[0080] 4) lubricating and blending the granules obtained in step 3 and lubricant magnesium stearate to produce a final blend;

[0081] 5) The final blend is tableted to obtain albendazole tablets.

[0082] Comparative Example 2

[0083]

[0084] Preparation process:

[0085] 1) Add the prescribed amount of sodium taurocholate to an appropriate amount of ethanol at 40-50°C and stir until dissolved; then add albendazole and stir evenly, add to a spray dryer, adjust the spray conditions: inlet temperature is 90°C, outlet temperature is 60°C, spray flow rate is 8ml / min, compressed air flow rate is 10L / min, spray dry to obtain a mixed powder;

[0086] 2) Add appropriate amount of water to the prescribed amount of adhesive Povidone K30 to prepare a Povidone K30 solution with a concentration of 3%; set aside;

[0087] 3) adding the prescribed amount of disintegrant croscarmellose sodium and the mixed powder obtained in step 1 to a wet granulator, using the povidone K30 solution obtained in step 2 to prepare wet granules, and drying and granulating the wet granules with a pulverizing and granulating machine;

[0088] 4) lubricating and blending the granules obtained in step 3 and lubricant magnesium stearate to produce a final blend;

[0089] 5) The final blend is tableted to obtain albendazole tablets.

[0090] Verification example:

[0091] Test Example 1: Dissolution test (in accordance with the relevant provisions of the Veterinary Pharmacopoeia of the People's Republic of China)

[0092] Take the tablets obtained in the above examples and comparative examples, and follow the dissolution method (Appendix 0931 Method 2), with 900 ml of 0.1 mol / L hydrochloric acid solution as the dissolution medium, the speed is 75 revolutions per minute, and operate according to the method. After 5 min, 10 min, 15 min, 20 min, 30 min, and 45 min, take the solution for filtration, accurately measure an appropriate amount of the filtrate, and dilute it with 0.1 mol / L sodium hydroxide solution to prepare a solution containing about 10 μg per 1 ml, as the test sample solution. Liquid; take about 20 mg of albendazole reference substance, accurately weigh it, put it in a 100 ml volumetric flask, add 5 ml of 2% hydrochloric acid methanol solution, shake to dissolve, dilute to the scale with 0.1 mol / L hydrochloric acid solution, shake well, accurately measure 5 ml, put it in a 100 ml volumetric flask, dilute to the scale with 0.1 mol / L sodium hydroxide solution, shake well, as the reference substance solution, measure the absorbance at a wavelength of 308 nm according to the UV-Vis spectrophotometry (Appendix 0401), and calculate the dissolution amount of each tablet.

[0093] Table 1 Dissolution of tablets in various embodiments

[0094]

[0095] Test Example 2: Stability Test

[0096] In accordance with the relevant provisions of the Veterinary Pharmacopoeia of the People's Republic of China, the accelerated stability of this product was investigated.

[0097] Content determination: Take 20 tablets, accurately weigh them, grind them into powder, accurately weigh an appropriate amount (equivalent to 20 mg of albendazole), place them in a 100 ml volumetric flask, add 10 ml of glacial acetic acid, shake to dissolve the albendazole, dilute to the mark with ethanol, shake well, filter, accurately measure 5 ml of the filtrate, place it in a 100 ml volumetric flask, dilute to the mark with ethanol, shake well, and measure the absorbance at a wavelength of 295 nm according to the UV-Vis spectrophotometry (Appendix 0401). Press C 12 H 15 The absorption coefficient of N3O2S (E 1cm 1％ ) is calculated as 444, and the test results are as follows:

[0098] Table 2 Stability test results

[0099] Stability test conditions: 30℃±2℃, 75%RH±5℃, accelerated 6 months.

[0100]

[0101] As can be seen from Table 1, Examples 1-8 have a good dissolution effect, but it can also be seen that in Example 6, the amount of trehalose is relatively large, and the dissolution is poor compared to that of Example 1. The possible reason is that the amount of trehalose is large. Although albendazole is fully dispersed after spray drying, the actual trehalose content is high, and its preparation has poor water absorption, which will greatly limit the effect of disintegrant water absorption and disintegration, and the dissolution is slow. In Example 7, the amount of trehalose is less, so that albendazole cannot be fully dispersed. Albendazole only dissolves under the solubilization of sodium taurocholate, and the dissolution is also relatively slow. As can be seen from Table 2, after stability investigation, the dissolution of Examples 6 and 7 is worse at 20min. The amount of sodium taurocholate was investigated in Examples 4 and 5. It can be seen from Table 1 that the amount of sodium taurocholate in Example 5 is large at 20min, and its dissolution is relatively good, but it can be seen from Table 2 that after stability investigation, the dissolution of Example 5 changes greatly, which affects the stability of the tablet. The above data show that trehalose can effectively disperse albendazole and at the same time, trehalose can effectively reduce the hygroscopicity of albendazole tablets. The uniformity and stability of the tablets are guaranteed. The effect of sodium taurocholate in promoting dissolution adjusts the problem of poor water absorption and slow dissolution of trehalose. Trehalose and sodium taurocholate effectively solve the dissolution and stability problems of albendazole tablets through spray drying.

Claims

1. An albendazole tablet for veterinary use, characterized in that: The composition is composed of albendazole, trehalose, sodium taurocholate and other pharmaceutically acceptable binders, disintegrants and lubricants.

2. The veterinary albendazole tablet according to claim 1, characterized in that: The mass ratio of albendazole to trehalose and sodium taurocholate is 1:1.0-3.0:0.2-0.6, preferably 1:2:0.

4.

3. The veterinary albendazole tablet according to claim 1, characterized in that: The binder is selected from one or more of hydroxypropyl methylcellulose, povidone K30, and pregelatinized starch; and the binder is preferably povidone K30.

4. The veterinary albendazole tablet according to claim 1, characterized in that: The disintegrant is selected from one or more of sodium carboxymethyl starch, sodium hydroxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, and crospovidone; more preferably, cross-linked sodium carboxymethyl cellulose.

5. The veterinary albendazole tablet according to claim 1, characterized in that The lubricant is selected from one or more of talc and magnesium stearate; more preferably magnesium stearate.

6. The veterinary albendazole tablet according to claim 1, characterized in that: The veterinary albendazole tablets are composed of the following ingredients:

7. The veterinary albendazole tablet according to claim 6, characterized in that: The veterinary albendazole tablets are composed of the following ingredients:

8. A method for preparing the veterinary albendazole tablets according to claim 1, characterized in that: The main steps include: 1) Add the prescribed amount of sodium taurocholate and trehalose to hot ethanol in sequence, stir and dissolve; then add albendazole and stir evenly, add to a spray dryer, adjust the spray conditions, spray dry, and obtain a mixed powder; 2) Add appropriate amount of water to the prescribed amount of adhesive to prepare an adhesive solution for later use; 3) adding the prescribed amount of disintegrant and the mixed powder obtained in step 1 to a wet granulator, preparing wet granules with the binder solution obtained in step 2, and drying and granulating the wet granules with a pulverizer; 4) lubricating and blending the particles obtained in step 3 with a lubricant to produce a final blend; 5) The final blend is tableted to obtain albendazole tablets.

9. The method for preparing the veterinary albendazole tablets according to claim 8, characterized in that: The spray drying conditions are as follows: inlet temperature of 80-120°C, outlet temperature of about 50-70°C, spray flow rate of 5-12ml / min, compressed air flow rate of 8-15L / min; further preferably, the inlet temperature is 90°C, the outlet temperature is 60°C, the spray flow rate is 8ml / min, and the compressed air flow rate is 10L / min.

Images