CN106821995B - Triclabendazole preparation and preparation method and application thereof - Google Patents

Abstract

The invention provides a triclabendazole preparation, and a preparation method and application thereof. In the preparation method, the used raw and auxiliary materials are low in price, the preparation process is simple, large-scale high-end equipment is not needed, the triclabendazole preparation can be conveniently and quickly prepared, and the prepared preparation has good dissolubility and dispersity. Meanwhile, in the preparation, the triclabendazole is matched with the wetting agent, the dispersing agent, the lipophilic surfactant, the soluble diluent and other components for use, so that the dissolubility and the dispersity of the triclabendazole can be effectively improved, the bioavailability of the triclabendazole is further improved, the triclabendazole can be further prepared into granules, tablets, dry suspensions or premixes in one step, and the requirements of different occasions are met; furthermore, the triclabendazole preparation can be further used for preparing a medicine for treating fasciolosis and can obtain a good treatment effect.

Description

Triclabendazole preparation and preparation method and application thereof

Technical Field

The invention relates to the field of insecticidal preparations, and particularly relates to a triclabendazole preparation as well as a preparation method and application thereof.

Background

The livestock and poultry parasitosis is various and often harms the health of animals in a concealed way. Parasites not only can influence the growth and development of young animals, but also can reduce the production performance and the product quality; meanwhile, the death of a large number of animals can be caused, and huge loss is caused to the animal husbandry; further, there are many livestock parasitic diseases which are diseases of both human and livestock, and the pathogens often infect humans, causing serious diseases in humans and causing death.

Fasciolosis is a global disease that primarily infects cattle and sheep, but also occurs in many other animals including horses, pigs, goats, rabbits, and in australia in local specialty animals such as kangaroos and bears; at the same time, people are also infected with liver flukes.

Liver flukes can cause severe economic losses. Worldwide annual losses due to fascioliasis are estimated to be more than $ 30 billion. Liver fluke infection reduces sheep production, including both wool growth and wool quality, as well as reducing the percentage of lambs and the rate of lambs growing, and sheep die from liver fluke infection. The prevention and cure principle of liver fluke disease is mainly to prevent, preferably to reduce the snail population (intermediate host) or to separate the livestock and the snail region, if the livestock and poultry have infection, the current mainly used therapeutic drugs are triclabendazole and biphenyl thiophenol.

Triclabendazole is a member of an anthelmintic benzimidazole family, is a drug with poor water solubility, belongs to a hydrophobic drug, is not easy to rapidly disperse in water, and has the phenomenon of adhesion and aggregation easily caused by tiny particles in the preparation process of a pharmaceutical preparation, so that other auxiliary materials or carriers are needed to improve the dissolution or the dispersibility of triclabendazole, and the bioavailability of triclabendazole is further improved.

Since triclabendazole is insoluble in water, the product preparation always takes suspension and solution as main components. For example, prior art patents: anthelmintic formulations (application No. CN200580051868.3) disclose a solution formulation prepared by dissolving triclabendazole in an organic solvent; meanwhile, the prior art patents: the benzimidazole anthelmintic composition (application number: CN200980139535.4) discloses a technical scheme for preparing benzimidazole anthelmintic, lactone solvent, volatile oil and surfactant into pour-on agent; also, prior art patents: oil suspension of benzimidazole drugs (application number: CN201110074200.8) discloses a technical proposal for preparing oily suspension from benzimidazole drugs, liquid grease, suspending agent and wetting agent; further, prior art patents: solvent systems for pour-on formulations for combating parasites (application No.: CN200880123259.8) disclose the preparation of pour-on formulations of benzimidazoles with glycol ethers and stability enhancers such as PEG200, tetraethylene glycol and propylene glycol.

Because the existing triclabendazole suspension and solvent have a lot of inconvenience in transportation and actual use, the research on triclabendazole solid preparation is always a hotspot.

At present, the triclabendazole preparation in China is mainly triclabendazole granules (10%), but the quality standard of the granules is to detect the dissolubility, so that the preparation prepared by enterprises is required to be a soluble preparation or a dry suspension preparation, and the preparation of the qualified triclabendazole preparation is difficult. Particularly, the problem that the triclabendazole soluble solid preparation needs to overcome the need of great strength is solved.

The more popular methods for preparing solid dispersions because of their use are spray drying techniques, vacuum drying techniques, freeze drying techniques, high speed milling ultra micronization, etc. The methods are reported to have good effects on solving the problems of solubility, dissolubility, dispersibility and the like of insoluble medicines, but the methods have high requirements on equipment or complex processes, are not suitable for the thin industry of veterinary medicines, and are particularly suitable for small and medium veterinary medicine production enterprises.

In view of the above, the present invention is particularly proposed.

Disclosure of Invention

The invention aims to provide a preparation method of a triclabendazole preparation, the method has the advantages of low price of raw and auxiliary materials, simple preparation process, no need of large-scale high-end equipment, convenient and rapid preparation of the triclabendazole preparation, and good dissolubility and dispersity of the prepared preparation.

The second objective of the present invention is to provide a triclabendazole preparation, wherein triclabendazole is used in combination with wetting agent, dispersant, lipophilic surfactant and soluble diluent, so as to effectively improve the dispersion degree of trichlorobenzene, and the triclabendazole can be further prepared into granules, tablets, dry suspensions or premixes in one step, and meet the requirements of different occasions.

The third purpose of the invention is to provide an application of the triclabendazole preparation. The triclabendazole preparation can effectively treat the fasciolosis hepatica, so that the triclabendazole preparation can be further used for preparing a medicine for treating the fasciolosis hepatica and can obtain a good treatment effect.

In order to achieve the above purpose of the present invention, the following technical solutions are adopted:

a method for preparing a triclabendazole formulation, said method comprising the steps of:

dissolving a dispersing agent in a wetting agent to obtain a mixed solution;

pulverizing the soluble diluent;

mixing triclabendazole, a lipophilic surfactant and a part of crushed soluble diluent to obtain a mixture A;

mixing the mixture A with the mixed solution, drying and crushing to obtain a mixture B;

and mixing the mixture B with the rest crushed soluble diluent to obtain the triclabendazole preparation.

Optionally, in the present invention, the wetting agent is water, ethanol or an ethanol aqueous solution.

Optionally, in the invention, the wetting agent is 1-5% by weight.

Optionally, in the present invention, the dispersant is one or a mixture of several of polyvinylpyrrolidone, sodium carboxymethyl cellulose, or crospovidone.

Optionally, in the present invention, the weight ratio of the wetting agent to the dispersing agent is greater than 1.

Optionally, in the present invention, the lipophilic surfactant is one or more of sorbitan monolaurate, sorbitan trilaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate, or lecithin derivatives.

Optionally, in the present invention, the lecithin derivative is one or a mixture of more of soybean lecithin, egg yolk lecithin, and rapeseed lecithin.

Optionally, in the present invention, the soluble diluent is one or a mixture of several of maltodextrin, anhydrous glucose, pregelatinized starch, soluble starch, lactose, sucrose and mannitol.

Meanwhile, the invention also provides a triclabendazole preparation prepared by the method.

Furthermore, the invention also provides application of the triclabendazole preparation in preparation of drugs for treating fascioliasis.

Compared with the prior art, the invention has the beneficial effects that:

(1) the raw and auxiliary materials of the invention are all pharmaceutical common auxiliary materials, and the price is low;

(2) the invention has simple process and does not need large-scale high-end equipment; the steps in the process are firstly mixed with part of soluble diluent and are dried in the last step, so that the wet granulation is relatively complete, the total amount of dried medicines is reduced, the time is saved, and the requirement on a drying box in large-scale production engineering is reduced;

(3) the triclabendazole preparation prepared by the invention has good dispersibility, dissolubility, dispersity and suspensibility; the compound premix can be further processed into granules, tablets, dry suspensions and premixes, and can be used for drinking water and mixing materials on the premise of meeting the quality standard.

Detailed Description

Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

In the invention, the triclabendazole preparation is prepared from the following components: triclabendazole, a wetting agent, a dispersing agent, a lipophilic surfactant, and a soluble diluent;

in one scheme of the invention, in the triclabendazole preparation, the raw material triclabendazole accounts for 5-20% of the total mass of the raw materials and the auxiliary materials; preferably, the triclabendazole accounts for 10-12% of the total mass of the raw and auxiliary materials;

and/or the mass of the dispersant is 0.1-3% of the total mass of the raw and auxiliary materials, for example, but not limited to, 0.5, 1 or 2% and the like;

and/or the mass of the wetting agent is 1-5% of the total mass of the raw and auxiliary materials, for example, but not limited to, 2, 3 or 4% and the like;

the mass of the lipophilic surface activity is 0.1-3% of the total mass of the raw and auxiliary materials, and can be, but is not limited to, 0.5, 1 or 2% and the like.

Wherein the wetting agent is water, ethanol or ethanol water solution; preferably, in the ethanol aqueous solution, the concentration of ethanol is lower than 60%;

meanwhile, the using amount of the wetting agent needs to be controlled, the waste of water and/or ethanol can be effectively avoided by controlling the using amount of the wetting agent, and the time required by later-period drying can be reduced;

wherein the dispersant is one or a mixture of several of polyvinylpyrrolidone (K12-K120), sodium carboxymethylcellulose or crospovidone;

similarly, the dosage of the dispersant is also controlled, and the mass gram ratio of the wetting agent to the dispersant is required to be more than 1, for example, the mass gram ratio of the wetting agent to the dispersant can be controlled to be (1.5-10): 1, etc.; this ensures that the dispersant is fully soluble in the wetting agent;

the lipophilic surfactant is one or a mixture of more of sorbitan monolaurate, sorbitan trilaurate, sorbitan monopalmitate, sorbitan monostearate, tristearyl sorbitan, sorbitan monooleate, sorbitan trioleate or lecithin derivatives, wherein the lecithin derivatives are one or a mixture of more of soybean lecithin, egg yolk lecithin or rapeseed lecithin; preferably, the lipophilic surfactant is a lecithin derivative; more preferably, the lipophilic surfactant is soybean phospholipid;

wherein the soluble diluent is one or a mixture of more of maltodextrin, anhydrous glucose, pregelatinized starch, soluble starch, lactose, sucrose and mannitol.

The preparation method has simple process, does not need large-scale high-end equipment, and is particularly suitable for small and medium enterprises, and the enterprises with relatively laggard production equipment; the preparation method comprises the following steps:

(a) dissolving a dispersing agent in a wetting agent to obtain a mixed solution of the dispersing agent and the wetting agent;

preferably, in this step, stirring is carried out so that the dispersing agent is completely dissolved in the wetting agent;

(b) pulverizing the soluble diluent;

preferably, in this step, the soluble diluent is pulverized until the particle size of the particles is less than or equal to 80 mesh;

(c) mixing triclabendazole, a lipophilic surfactant and a part of crushed soluble diluent to obtain a mixture A;

preferably, in the step, the crushed soluble diluent accounts for 10-30% of the total mass of the diluent;

(d) mixing the mixture A with the mixed solution, drying and crushing to obtain a mixture B;

preferably, in the step, the dried mixed system is crushed to the particle size of 24-80 meshes;

(e) and mixing the mixture B with the rest crushed soluble diluent to obtain the triclabendazole preparation.

Further, in the invention, the prepared clobendazole preparation can be prepared into granules, tablets, dry suspensions or premixes;

wherein, the granule can be prepared by dry granulation of triclabendazole preparation; the tablet can be prepared by tabletting the triclabendazole preparation.

Example 1

Respectively weighing or measuring 10% of triclabendazole, 1% of ethanol, 121% of polyvinylpyrrolidone K, 0.3% of soybean phospholipid, and a mixture of lactose and the balance of maltodextrin;

then, the triclabendazole formulation was prepared as follows:

(a) dissolving polyvinylpyrrolidone in ethanol to completely dissolve the polyvinylpyrrolidone to obtain a mixed solution;

(b) crushing lactose and maltodextrin to a particle size of less than or equal to 80 meshes to obtain a mixture of lactose and maltodextrin;

(c) mixing triclabendazole, soybean lecithin and a part of lactose and maltodextrin mixture to obtain a mixture A;

wherein the part of the mixture of lactose and maltodextrin accounts for 30 percent of the total mass of the mixture of lactose and maltodextrin;

(d) mixing the mixture A and the mixed solution, drying, and crushing to obtain a mixture B with the particle size of 24-80 meshes;

(e) the mixture B was mixed with the remaining lactose and maltodextrin mixture to obtain the triclabendazole formulation of example 1.

Example 2

Respectively weighing or measuring a proper amount of triclabendazole 20%, ethanol-water solution 5% (ethanol concentration is 50%), sodium carboxymethylcellulose 3%, sorbitan monostearate 2% and the balance of pregelatinized starch;

then, the triclabendazole formulation was prepared as follows:

(a) dissolving sodium carboxymethylcellulose in an ethanol-water solution to completely dissolve the sodium carboxymethylcellulose to obtain a mixed solution;

(b) pulverizing pregelatinized starch to a particle size of not more than 80 meshes to obtain pulverized pregelatinized starch;

(c) mixing triclabendazole, sorbitan monostearate and partially crushed pregelatinized starch to obtain a mixture A;

wherein the partially pulverized pregelatinized starch is 30% of the total mass of the pulverized pregelatinized starch;

(d) mixing the mixture A and the mixed solution, drying, and crushing to obtain particles with the particle size of 24-80 meshes to obtain a mixture B;

(e) and mixing the mixture B with the rest of the pregelatinized starch granules to obtain the triclabendazole preparation of example 2.

Example 3

Respectively weighing or measuring a proper amount of triclabendazole 5%, ethanol 3%, crospovidone 0.5%, sorbitan trioleate 1% and the balance of mannitol;

then, the triclabendazole formulation was prepared as follows:

(a) dissolving crospovidone in the ethanol-water solution, and completely dissolving the crospovidone to obtain a mixed solution;

(b) crushing mannitol to obtain mannitol powder, wherein the particle size of the mannitol powder is less than or equal to 80 meshes;

(c) mixing triclabendazole, sorbitan trioleate and part of mannitol powder to obtain a mixture A;

wherein, the part of mannitol powder accounts for 30 percent of the total mass of the mannitol powder;

(d) mixing the mixture A and the mixed solution, drying, and crushing to obtain particles with the particle size of 24-80 meshes to obtain a mixture B;

(e) and mixing the mixture B with the rest mannitol powder to obtain the triclabendazole preparation of the embodiment 3.

Experimental example 1

(1) Suspension demonstration test

1g of the triclabendazole preparations prepared in examples 1 to 3 were weighed out separately and dissolved in 100ml of water; the results show that all the solutions present a uniform dispersion system, no obvious foreign matters appear and the solution conforms to a drinking water system.

(2) Solubility test

Respectively carrying out dry granulation on the triclabendazole preparations prepared in examples 1-3 to respectively obtain granules, and then carrying out a solubility test;

the test method comprises the following steps: 10g of each group of granules are respectively taken, added into 200ml of hot water, stirred for 5min and observed.

As a result, it was found that the solutions of the respective groups exhibited uniform dispersion without any significant foreign matter.

(3) Test of drug efficacy

Selecting 20 sheep diagnosed with fasciolosis hepatica, and dividing the sheep into two groups, wherein each group comprises 10 sheep, one sheep is an example group, and the other sheep is a blank group;

in the example group, an appropriate amount of the triclabendazole preparation of example 1 was dissolved and dispersed in water in an amount of 10mg per kg of body weight of sheep in terms of triclabendazole, and each sheep in the example group was treated by drinking as daily drinking water; the blank group of sheep was drunk an equal amount of clear water and then subjected to control observation.

The result shows that after the sheep in the example group is treated by the medicine, the quantity of the worm eggs in the excrement is rapidly reduced, the worm eggs in the excrement completely disappear after 3 weeks, and no worm eggs are discharged again after 10 weeks; meanwhile, sheep death did not occur during treatment;

the worm egg amount in the feces of the sheep in the blank group is obviously increased along with the time, the sheep death also occurs in the period, and the further dissection shows that the worm egg amount is the death of the sheep caused by the fasciolosis.

The method has simple process, does not need large-scale high-end equipment, and can further simplify the preparation steps and improve the preparation efficiency by adjusting the mixing steps of the raw materials and the auxiliary materials; meanwhile, the triclabendazole preparation prepared by the method has dispersibility, dissolubility and suspensibility, can be further prepared into different formulations such as granules, tablets, dry suspensions or premixes, and can meet various environments and requirements.

While particular embodiments of the present invention have been illustrated and described, it would be obvious that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

Claims (8)

1. A preparation method of a triclabendazole preparation is characterized by comprising the following steps:

dissolving a dispersing agent in a wetting agent to obtain a mixed solution;

pulverizing the soluble diluent;

mixing triclabendazole, a lipophilic surfactant and a part of crushed soluble diluent to obtain a mixture A;

mixing the mixture A with the mixed solution, drying and crushing to obtain a mixture B;

mixing the mixture B with the rest crushed soluble diluent to obtain a triclabendazole preparation;

wherein the wetting agent is water, ethanol or ethanol water solution;

the weight percentage of the wetting agent is 1-5%.

2. The preparation method according to claim 1, wherein the dispersing agent is one or a mixture of polyvinylpyrrolidone, sodium carboxymethylcellulose, or crospovidone.

3. The process according to claim 2, wherein the weight ratio of the wetting agent to the dispersing agent is greater than 1.

4. The method according to claim 1, wherein the lipophilic surfactant is one or more selected from sorbitan monolaurate, sorbitan trilaurate, sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate, sorbitan monooleate, sorbitan trioleate, and lecithin derivatives.

5. The method according to claim 4, wherein the lecithin derivative is one or more of soybean lecithin, egg yolk lecithin, and rapeseed lecithin.

6. The preparation method according to claim 1, wherein the soluble diluent is one or more of maltodextrin, anhydrous glucose, pregelatinized starch, soluble starch, lactose, sucrose and mannitol.

7. A triclabendazole formulation made according to the method of any one of claims 1-6.

8. The use of the triclabendazole formulation according to claim 7 in the preparation of a medicament for the treatment of fasciola hepatica.