Veterinary albendazole tablet and method for preparing the same

Abstract

The present application belongs to the technical field of veterinary medicine, and relates to a kind of veterinary albendazole tablets, and the preparation method of the preparation is provided.The tablet is composed of albendazole, trehalose, sodium taurocholate and other pharmaceutically acceptable binders, disintegrants and lubricants.By spray drying the mixed solution of albendazole, trehalose and sodium taurocholate, the albendazole is fully dispersed, and the amount of trehalose and sodium taurocholate is controlled, which improves the dissolution and stability of the product.

Description

Technical Field

[0001] This invention belongs to the field of veterinary drug technology, specifically relating to an albendazole tablet for veterinary use and its preparation method. Background Technology

[0002] Albendazole, also known as albendazole, chemically named methyl 5-propylthiobenzimidazole-2-carbamate, belongs to the benzimidazole class of drugs. It is a broad-spectrum, highly effective, and low-toxicity anthelmintic drug launched by SmithKline in 1977. It is widely used to treat infections caused by parasites such as pinworms, roundworms, tapeworms, and echinococcosis, and is the first-line 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, practically insoluble in ethanol, and insoluble in water; it is soluble in glacial acetic acid. It is rapidly metabolized in vivo to sulfoxide, sulfone alcohol, and 2-aminosulfone alcohol. However, the low solubility of this drug limits its absorption and utilization in animals. Traditional pharmaceutical formulation techniques, such as micronization and preparation as suspensions or precipitates, can improve drug solubility and bioavailability to some extent, but the effects are limited. Clinically used dosage forms include tablets, powders, premixes, suspensions, solutions, and injections.

[0005] CN87108271.3 discloses a method for preparing 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 processing technology for a hydrophilic formulation of thiamethoxam. The process is as follows: (1) Dissolve thiamethoxam in an organic solvent. If dissolving at low temperature, hydrochloric acid must be added to acidify it into a solution; (2) Add deionized water and surfactants (dispersants), penetrants, etc., and mix well to prepare a water-soluble suspension; or add a carrier to prepare a soluble ultrafine powder. Using this invention, two hydrophilic formulations can be prepared for use in the production of agricultural fungicides, pharmaceuticals, etc.

[0007] CN200510098951.8 discloses a novel albendazole formulation that solves the problems of poor physical stability and large volume of albendazole emulsions. Its composition, by weight percentage, contains: albendazole 1-35, edible oils or fatty acids 3-85, emulsifier 1-40, organic acid or amide 0-45, co-emulsifier 0-40, pH adjuster 0-10, antioxidant 0-0.05, and curing agent 0-84. The preparation method is simple and easy to implement, easy to operate and industrialize, and has the characteristics of good solubility and high bioavailability, which can improve the efficacy and facilitate storage and transportation.

[0008] CN200610129699.7 discloses an albendazole chewable tablet for dogs and cats, overcoming the shortcomings of poor palatability in existing tablets. This tablet promotes thorough chewing and absorption by dogs and cats, effectively ensuring the dosage, improving the cure rate of diseases in dogs and cats, and reducing drug waste. The tablet composition of this invention includes: 1-5% aspartame (by weight percentage), 20-30% a mixture of oral glucose and skim milk powder (the ratio of oral glucose to skim milk powder in the mixture is 1:1-1:4), 40%-60% excipients, 0.5-1% glidin, and 30-50% albendazole.

[0009] CN201210317207.2 relates to an albendazole dispersible tablet and its preparation method. The dispersible tablet is composed of the following raw materials in the indicated weight ratios: 200g albendazole, 50-160g disintegrant, 18-118g diluent, 2-12g surfactant, 6-16g sweetener, 3-12g glidant, and 1-4g lubricant. This invention uses suitable excipients to prepare albendazole dispersible tablets, significantly improving the bioavailability and efficacy of the drug.

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

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

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

[0013] CN202410759878.7 provides an albendazole-ivermectin microcrystalline dispersion and its preparation method. By rationally proportioning and mixing excipients such as polyethylene glycol 4000, colloidal silica, and sodium alginate, an albendazole-ivermectin microcrystalline dispersion with good dispersibility and high stability in water is obtained. The microcrystalline dispersion exhibits good dissolution under low pH conditions, significantly improving the bioavailability of albendazole and ivermectin in vivo, and providing convenient conditions for the administration of albendazole and ivermectin through drinking water.

[0014] CN202411028690.1 discloses a highly bioavailable albendazole nanocrystals and its preparation method. The nanocrystals of this invention are prepared by mixing albendazole, a naturally derived glycoside stabilizer, and water to form a suspension, which is then prepared by wet grinding. The average particle size is 100–500 nm. These nanocrystals are obtained by dispersing albendazole in a naturally derived glycoside solution and then nano-sizing it. They have a high drug loading capacity, significantly improving the solubility and dissolution rate of albendazole, thereby improving its absorption and bioavailability.

[0015] Xie Yinghua et al. used sodium dodecyl sulfate and polysorbate 80 in combination to improve the dissolution performance of albendazole, which increased the solubility of albendazole in water. Different batches of albendazole dispersible tablets prepared completely disintegrated within 122s, and the cumulative dissolution rate of the drug was greater than 80% at 45min. (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 active pharmaceutical ingredient (API) particle size distribution on the dissolution of albendazole tablets. By pretreating the API using an air jet milling process, and controlling the particle size characteristic value d(0.5) 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 to the reference tablets. (Luo Binghua. The effect of albendazole API particle size on the in vitro dissolution of its tablets [J]. Today's Pharmacy, 2021, 31(10): 753-755.)

[0017] In both the veterinary and human pharmaceutical fields, researchers have successively developed and studied various formulations to improve the solubility of albendazole, including solid dispersions, inclusion compounds and liposomes, nanocrystals, and particle size control. However, these formulations have problems such as limited ability to improve the bioavailability of albendazole, excessive excipient loading, and difficulties 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 a method for preparing the formulation. The tablet of the present invention has the advantages of simple formulation process, stable quality, high dissolution, high bioavailability, and ease of industrial production.

[0019] Specifically, the objective of this invention is achieved through the following technical solution:

[0020] An albendazole tablet comprising 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 to 3.0:0.2 to 0.6; preferably 1:2:0.4.

[0022] In a preferred embodiment, the adhesive is selected from one or more of hydroxypropyl methylcellulose, povidone K30, and pregelatinized starch. Povidone K30 is further preferred as the adhesive.

[0023] In a preferred embodiment, the disintegrant is selected from one or more of sodium carboxymethyl starch, sodium carboxymethyl cellulose, croscarmellose sodium, and crospovidone. Croscarmellose sodium is further preferred.

[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 components:

[0026]

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

[0028]

[0029]

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

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

[0032] 2) Prepare an adhesive solution by adding an appropriate amount of water to the prescribed amount of adhesive; set aside.

[0033] 3) Add the prescribed amount of disintegrant and the powder obtained in step 1 to a wet granulator, and use the binder solution obtained in step 2 to prepare wet granules. The wet granules are then dried and granulated by a pulverizer.

[0034] 4) The particles obtained in step 3 and the lubricant are lubricated and blended to produce the final blend;

[0035] 5) Compress the final blend into tablets to obtain albendazole tablets.

[0036] In a preferred embodiment, the hot ethanol is heated to 40-50°C.

[0037] In a preferred embodiment, the adhesive is mixed with an appropriate amount of water to prepare an adhesive solution with a concentration of 2-5%; more preferably 3%.

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

[0039] Compared with existing technologies, in the albendazole tablets of this invention, trehalose effectively disperses albendazole, causing it to microcrystalize and reducing the hygroscopicity of the tablets, thus significantly improving tablet stability. The addition of sodium taurocholate effectively improves the tablet's dissolution rate. By controlling the amounts of trehalose and sodium taurocholate, rapid dissolution, smooth preparation, stable quality, and safety and efficacy of the product are ensured. Detailed Implementation

[0040] The present invention will be further illustrated below through embodiments. It should be understood that the embodiments of the present invention are merely provided for illustrative purposes and are not intended to limit the present invention. Therefore, any simple modifications to the present invention based on 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℃ and stir until dissolved; then add albendazole and stir evenly, add to a spray dryer, and adjust the spray conditions: inlet temperature 90℃, outlet temperature 60℃, spray flow rate 8ml / min, compressed air flow rate 10L / min, spray dry to obtain mixed powder.

[0046] 2) Prepare a 3% povidone K30 solution by adding an appropriate amount of water to the prescribed amount of adhesive; set aside.

[0047] 3) The prescribed amount of disintegrant croscarmellose sodium and the powder obtained in step 1 are added to a wet granulator. The povidone K30 solution obtained in step 2 is used to prepare wet granules. The wet granules are dried and granulated by a pulverizer.

[0048] 4) The particles obtained in step 3 and the lubricant magnesium stearate are lubricated and blended to produce the final blend;

[0049] 5) Compress the final blend into tablets to obtain albendazole tablets.

[0050] Example 2

[0051]

[0052] Preparation process: Same as in Example 1.

[0053] Example 3

[0054]

[0055]

[0056] Preparation process: Same as in Example 1.

[0057] Example 4

[0058]

[0059] Preparation process: Same as in Example 1.

[0060] Example 5

[0061]

[0062] Preparation process: Same as in Example 1.

[0063] Example 6

[0064]

[0065]

[0066] Preparation process: Same as in Example 1.

[0067] Example 7

[0068]

[0069] Preparation process: Same as in Example 1.

[0070] Example 8

[0071]

[0072] Preparation process: Same as in 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℃ and stir until dissolved; then add albendazole and stir evenly, add to a spray dryer, and adjust the spray conditions: inlet temperature 90℃, outlet temperature 60℃, spray flow rate 8ml / min, compressed air flow rate 10L / min, spray dry to obtain mixed powder.

[0078] 2) Prepare a 3% povidone K30 solution by adding an appropriate amount of water to the prescribed amount of adhesive; set aside.

[0079] 3) The prescribed amount of disintegrant croscarmellose sodium and the powder obtained in step 1 are added to a wet granulator. The povidone K30 solution obtained in step 2 is used to prepare wet granules. The wet granules are dried and granulated by a pulverizer.

[0080] 4) The particles obtained in step 3 and the lubricant magnesium stearate are lubricated and blended to produce the final blend;

[0081] 5) Compress the final blend into tablets 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℃ and stir until dissolved; then add albendazole and stir evenly, add to a spray dryer, and adjust the spray conditions: inlet temperature 90℃, outlet temperature 60℃, spray flow rate 8ml / min, compressed air flow rate 10L / min, spray dry to obtain mixed powder.

[0086] 2) Prepare a 3% povidone K30 solution by adding an appropriate amount of water to the prescribed amount of adhesive; set aside.

[0087] 3) The prescribed amount of disintegrant croscarmellose sodium and the powder obtained in step 1 are added to a wet granulator. The povidone K30 solution obtained in step 2 is used to prepare wet granules. The wet granules are dried and granulated by a pulverizer.

[0088] 4) The particles obtained in step 3 and the lubricant magnesium stearate are lubricated and blended to produce the final blend;

[0089] 5) Compress the final blend into tablets to obtain albendazole tablets.

[0090] Verification Example:

[0091] Example 1: Dissolution Test (in accordance with 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 perform the dissolution test (Appendix 0931, Method II) using 900 ml of 0.1 mol / L hydrochloric acid solution as the dissolution medium and a rotation speed of 75 rpm. After 5 min, 10 min, 15 min, 20 min, 30 min, and 45 min, filter the solution. Accurately measure an appropriate amount of the filtrate and dilute it with 0.1 mol / L sodium hydroxide solution to prepare a solution containing approximately 10 μg per ml, which is used as the test sample solution. Separately, take approximately 20 mg of albendazole reference standard, accurately weigh it, place it in a 100 ml volumetric flask, add 5 ml of 2% hydrochloric acid methanol solution, shake to dissolve, dilute to the mark with 0.1 mol / L hydrochloric acid solution, shake well, accurately measure 5 ml, place it in a 100 ml volumetric flask, dilute to the mark with 0.1 mol / L sodium hydroxide solution, shake well, and use this as the reference solution. Measure the absorbance at a wavelength of 308 nm using ultraviolet-visible spectrophotometry (Appendix 0401), and calculate the dissolution amount per tablet.

[0093] Table 1 Dissolution rate of tablets in each example

[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: Accurately weigh 20 tablets obtained, grind them into a fine powder, accurately weigh an appropriate amount (approximately equivalent to 20 mg of albendazole), place it 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 using ultraviolet-visible spectrophotometry (Appendix 0401), according to C. 12 H 15 The absorption coefficient of N3O2S (E) 1cm 1％ The result is calculated as 444. The experimental results are shown in the table below:

[0098] Table 2. Stability test results

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

[0100]

[0101] Table 1 shows that Examples 1-8 have good dissolution effects. However, it also shows that in Example 6, the amount of trehalose used was relatively high, resulting in poorer dissolution compared to Example 1. This may be because the high amount of trehalose, although spray drying ensured sufficient dispersion of albendazole, resulted in a high actual trehalose content. The poor water absorption of the formulation significantly limited the disintegrant's role in water absorption and disintegration, leading to slow dissolution. In Example 7, the amount of trehalose was low, preventing sufficient dispersion of albendazole. Albendazole dissolved only with the aid of sodium taurocholate, resulting in relatively slow dissolution. Table 2 shows that, after stability testing, Examples 6 and 7 showed even worse dissolution at 20 minutes. The amount of sodium taurocholate used in Examples 4 and 5 was investigated. Table 1 shows that in Example 5, the higher amount of sodium taurocholate resulted in relatively better dissolution at 20 minutes. However, Table 2 shows that, after stability testing, the dissolution of Example 5 varied significantly, affecting the stability of the tablets. The data above shows that trehalose effectively disperses albendazole and reduces the hygroscopicity of albendazole tablets, ensuring tablet uniformity and stability. Sodium taurocholate promotes dissolution, addressing the issues of poor water absorption and slow dissolution associated with trehalose. Spray drying of trehalose and sodium taurocholate effectively solves the dissolution and stability problems of albendazole tablets.

Claims

1. A veterinary albendazole tablet, characterized in that, It consists of albendazole, trehalose, sodium taurocholate, and other pharmaceutically acceptable binders, disintegrants, and lubricants; The mass ratio of albendazole to trehalose and sodium taurocholate is 1:1.0-3.0:0.2-0.

6. The adhesive is selected from one or more of hydroxypropyl methylcellulose, polyvinyl ketone K30, and pregelatinized starch; The disintegrant is selected from one or more of sodium carboxymethyl starch, sodium carboxymethyl cellulose, croscarmellose sodium, and crospovidone; The lubricant is selected from one or more of talc and magnesium stearate; The veterinary albendazole tablets are composed of the following ingredients: 200 portions of albendazole Trehalose 200-600 parts Sodium taurocholate 40-120 parts 30-50 parts adhesive 80-100 parts of disintegrant 10-20 parts of lubricant.

2. The albendazole tablets for veterinary use according to claim 1, characterized in that, The mass ratio of albendazole to trehalose and sodium taurocholate is 1:2:0.

4.

3. The albendazole tablets for veterinary use according to claim 1, characterized in that, The adhesive is polyvinylpyrrolidone K30.

4. The albendazole tablets for veterinary use according to claim 1, characterized in that, The disintegrant is croscarmellose sodium.

5. The albendazole tablets for veterinary use according to claim 1, characterized in that, The lubricant is magnesium stearate.

6. The albendazole tablets for veterinary use according to claim 1, characterized in that, The veterinary albendazole tablets are composed of the following ingredients: 200 portions of albendazole 400 portions of trehalose 80 parts of sodium taurocholate Povidone K30 40 parts 90 parts of croscarmellose sodium cellulose 10 parts magnesium stearate.

7. A method for preparing veterinary albendazole tablets according to claim 1, characterized in that, The main steps include: 1) Add the prescribed amounts of sodium taurocholate and trehalose to hot ethanol in sequence and stir to dissolve; then add albendazole and stir evenly, add to a spray dryer, adjust the spray conditions, spray dry to obtain a mixed powder; 2) Prepare an adhesive solution by adding an appropriate amount of water to the prescribed amount of adhesive; set aside. 3) Add the prescribed amount of disintegrant and the powder obtained in step 1 to a wet granulator, and use the binder solution obtained in step 2 to prepare wet granules. The wet granules are then dried and granulated by a pulverizer. 4) The particles obtained in step 3 and the lubricant are lubricated and blended to produce the final blend; 5) Compress the final blend into tablets to obtain albendazole tablets.

8. The method for preparing veterinary albendazole tablets according to claim 7, characterized in that, The spray drying conditions are as follows: inlet temperature 80-120℃, outlet temperature 50-70℃, spray flow rate 5-12ml / min, and compressed air flow rate 8-15L / min.

9. The method for preparing veterinary albendazole tablets according to claim 7, characterized in that, The spray drying conditions are as follows: inlet temperature 90℃, outlet temperature 60℃, spray flow rate 8ml / min, and compressed air flow rate 10L / min.

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