Preparation method of praziquantel soluble powder or liquid preparation

Abstract

The invention discloses a preparation method of praziquantel soluble powder, a liquid preparation and other dosage forms. According to the method, solid beverages or liquid beverages or raw materials thereof are used for preparing praziquantel soluble powder or liquid preparations and other dosage forms. According to the scheme, the praziquantel preparation which is low in cost, capable of being rapidly industrialized, easy and convenient to operate, high in solubility and good in stability is provided.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and specifically relates to a praziquantel preparation technology, which is mainly used for the preparation and application of low-cost, high-concentration and high-stability praziquantel liquid or soluble powder dosage forms. Background Art

[0002] As a new broad-spectrum antiparasitic drug, praziquantel has been widely used in clinical medicine. Praziquantel is effective against diseases such as Schistosoma japonicum, Schistosoma mansoni and Schistosoma haematobium, Clonorchis sinensis, Paragonimus, Fasciola zingiberensis, tapeworms and cysticercosis. Taking animal drugs as an example, at present (20230908), there are 433 approval numbers for praziquantel in Chinese veterinary drugs, including only three dosage forms: tablets (0.1g), premix 2% (for aquaculture) and powder (50%), with a single dosage form. Although in recent years, a variety of new dosage forms such as liposomes, microspheres, transdermal preparations, injections, suppositories, implants, etc. have appeared in patents and journals, using new technologies such as inclusion, emulsification, liposomes, nanoparticles, etc., but most preparations are still in the basic research or preclinical research stage.

[0003] At room temperature, the solubility of praziquantel raw material in water is about 0.26 mg / mL, and the dissolution rate is slow. Research results show that the release amount of raw praziquantel in the first hour of the release experiment is only equivalent to dissolving 1 mg in about 90 ml of aqueous release medium. After oral administration of ordinary preparations of praziquantel, the dissolution rate is slow, the absorption rate is high, and it has a significant first-pass effect in the liver. Therefore, after oral administration, the amount of praziquantel that enters the blood circulation and escapes liver metabolism is small, which seriously affects the efficacy. At the same time, limited by the solubility and dissolution rate of praziquantel, it cannot meet the needs of real users for fast, uniform, and high-concentration use of praziquantel preparations.

[0004] Making praziquantel into a high-concentration dosage form that is soluble or evenly dispersed in water has always been the unremitting pursuit of the majority of formulation personnel. At present, the use of solid dispersion technology, albumin, cyclodextrin, etc. in the literature can increase the solubility of praziquantel to 2-4 times that of its raw material. Among them, the highest solubilization effect is the use of hydroxypropyl-β-cyclodextrin to make an inclusion compound, and the solubility can reach 27mg / ml, which is 104 times that of the raw material. Although a high-solubility solution can also be obtained by using sodium dodecyl sulfate as a solubilizing agent, sodium dodecyl sulfate is a low to medium toxic compound that may harm water bodies and has a high toxicity to some organisms.

[0005] In general, the current technologies have defects such as complex processes, high raw material costs, high production costs, large amounts of auxiliary materials, and high toxicity. They cannot meet the clinical needs, especially the breeding industry's demand for solid or liquid preparations such as praziquantel water-soluble powder with high safety, good stability, and low cost. Summary of the invention

[0006] In view of the above situation, in order to overcome the defects of the prior art, one of the purposes of the present invention is to provide a low-cost, easy-to-operate and highly mature praziquantel solubilization method to solve the cost and industrialization difficulties of the current praziquantel solubilization technology.

[0007] One of the methods for achieving this purpose is to solubilize or suspend praziquantel by using ready-made foods or auxiliary materials that can be evenly dispersed in water and are rich in protein, fat, or lactose to form a stable dispersion. These materials include but are not limited to one or more mixtures of milk, yak milk or goat milk and their whole milk powder, skim milk powder or sugar-containing milk powder, or foods or drinks rich in protein and fat components, such as soy milk, soy milk powder, protein powder, and vegetable fat powder, and can be evenly dispersed in water. These solid particles that can be evenly dispersed in water and do not settle for a long time can be used as carriers to adsorb, solubilize or encapsulate praziquantel dissolved in water, and therefore can be used for the preparation of preparations such as poorly soluble aqueous liquids or water-soluble powders with good water dispersibility. Since these foods or auxiliary materials themselves are commodities that can be purchased in large quantities, simple operations such as mixing and sub-packaging are required when preparing soluble powders. Therefore, the manufacturer's investment in machinery, factory buildings, manpower, etc. is saved, greatly reducing costs.

[0008] Similarly, this purpose can also be achieved by simulating the main components of the above-mentioned products, semi-finished products or excipients, starting from the source, reorganizing the solid dispersion medium and mixing it with the API at appropriate steps to obtain a liquid or solid mixture. This will achieve the purpose of clarifying the components, improving the properties, and strengthening certain properties of the preparation. For example, in the process of preparing milk powder, praziquantel is added to raw milk, and it is dispersed and dissolved by heating and stirring, etc., and suitable preparation excipients can also be added. The subsequent steps are the same as the preparation of whole milk powder (spray drying, etc.) to obtain praziquantel milk powder.

[0009] The second purpose of the present invention is to provide a prescription and method of use of a highly soluble praziquantel preparation. The ratio of praziquantel to the above-mentioned solid excipient is 1:0.2 or more, and the preferred ratio is 1:0.8 or more. Among them, generally on the basis of ensuring good dispersibility of the solid excipient in the liquid, the greater the proportion of the solid excipient, the more the encapsulation effect and dissolution rate of the preparation can be ensured. When preparing an aqueous dispersion or using a water-soluble powder, in order to speed up the dissolution rate, the water can be heated first (50-100°C, preferably at 80-100°C), the mixed praziquantel mixture is added, and the praziquantel precipitate is stirred and dispersed until it completely disappears. The liquid is then placed at room temperature and gradually cooled to room temperature.

[0010] The third object of the present invention is to provide various suitable praziquantel preparations. The mixture prepared by the above technology and method can not only prepare praziquantel aqueous liquid, film, suppository, gel, water-soluble powder (such as uniform dispersion type), etc., but also can further prepare various solid and semi-solid dosage forms, such as capsules, powders, tablets, granules, pills, etc. The method is also applicable to the preparation of compound preparations containing praziquantel.

[0011] In summary, the advantages of the present invention are to provide a low-cost, rapidly industrializable, easy-to-operate praziquantel formulation with high solubility and high stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0012] Figure 1 This is the appearance diagram of Examples 1 and 2. DETAILED DESCRIPTION

[0013] The present invention is further described in detail below in conjunction with examples, but the embodiments of the present invention are not limited thereto.

[0014] Example 1 Weigh 25 mg of praziquantel and 25 mg of whole milk powder, mix them evenly, stir and disperse them in 50 mL of boiling water, and cool them to room temperature to obtain a uniformly dispersed praziquantel liquid. Figure 1 A.

[0015] Example 2 Weigh 25 mg of praziquantel and 25 mg of skimmed milk powder, mix them evenly, stir and disperse them in 50 mL of boiling water, and cool them to room temperature to obtain a uniformly dispersed praziquantel liquid. Figure 1 B.

[0016] Example 3 Weigh 25 mg of praziquantel and 25 mg of whole milk powder, mix them evenly, stir and disperse them in 50 mL of water at 90° C., and cool them to room temperature to obtain a uniformly dispersed praziquantel liquid with an approximate concentration of 0.5 mg / ml.

[0017] Example 4 Weigh 25 mg of praziquantel and 25 mg of skimmed milk powder, mix them evenly, stir and disperse and dissolve them in 50 mL of water at 90° C., and cool them to room temperature to obtain a uniformly dispersed praziquantel liquid.

[0018] Example 5 Weigh 25 mg of praziquantel, 20 mg of skimmed milk powder, and 5 mg of PVP-K30, mix them evenly, stir and disperse them in 50 mL of boiling water, and cool them to room temperature to obtain a uniformly dispersed praziquantel liquid.

[0019] Example 6 Weigh 25 mg of praziquantel, 20 mg of skimmed milk powder, and 5 mg of lactose, mix them evenly, stir and disperse and dissolve them in 50 mL of boiling water, and cool them to room temperature to obtain a uniformly dispersed praziquantel liquid.

[0020] Example 7 Weigh praziquantel and mix it evenly with an equal amount of whole milk powder to obtain a soluble powder with a praziquantel content of 50%.

[0021] Example 8 Weigh praziquantel and mix it evenly with an equal amount of skimmed milk powder to obtain a soluble powder with a praziquantel content of 50%.

[0022] Example 9 Weigh 25 mg of praziquantel and add it to 50 mL of raw milk at 80° C., stir and disperse it, and then cool it to room temperature to obtain a milk solution containing praziquantel.

[0023] Example 10 Weigh 25 mg of praziquantel and 25 mg of lactose, mix them evenly, stir and disperse and dissolve them in 50 mL of boiling water, and cool them to room temperature to obtain a uniformly dispersed praziquantel solution.

[0024] The representative embodiments mentioned above will be selected below to conduct relevant experiments to illustrate the characteristics and advantages of this technology.

[0025] Experimental Example 1 Comparison of physical stability of preparations

[0026] First, prepare the following control preparations, and place them at room temperature away from light together with Examples 1, 2, 3, and 4, and observe the appearance stability of the preparations. If additional suspensions or precipitations visible to the naked eye appear, it is determined to be unstable. The results are shown in Table 1. As can be seen from the table, the 1-4 preparations prepared using our preparation scheme are not only more stable than the praziquantel aqueous solution of the control preparation 1 at the same concentration, but also better than the solution prepared using the same dose of surfactants or polymer materials. The dissolution rate between the groups is not much different. Under this experimental condition, the concentration of the stable praziquantel solution can be increased to 0.5 mg / ml, and the stability time is more than 3 days, even more than 30 days. Therefore, using the formulation scheme of this patent, the resulting preparation has the characteristics of high concentration and good stability, and has good practicality. The preparation methods of several control preparations are:

[0027] Control preparation 1: Weigh 25 mg of praziquantel, stir and dissolve it in 50 mL of boiling water, and cool it to room temperature to obtain an aqueous solution of praziquantel with an approximate concentration of 0.5 mg / ml.

[0028] Control preparation 2: Weigh 25 mg of praziquantel and 25 mg of poloxamer 188, mix them well, stir and dissolve them in 50 mL of boiling water, cool to room temperature, and obtain an aqueous solution of praziquantel with an approximate concentration of 0.5 mg / ml.

[0029] Control preparation 3: Weigh 25 mg of praziquantel and 25 mg of PVA 1788, mix them well, stir and dissolve them in 50 mL of boiling water, and cool them to room temperature to obtain an aqueous solution of praziquantel with an approximate concentration of 0.5 mg / ml.

[0030] Table 1 Stability time of preparations (n=3)

[0031]

[0032] Experimental Example 2: Praziquantel heating stability test

[0033] Example 1-4 was boiled, maintained at 100°C, and samples were taken at regular intervals to determine the praziquantel content using the established ultraviolet spectrophotometry. The results showed that within 4 hours, the absorbance of Example 1-4 at 263 nm did not decrease compared to that at 0. This result shows that the prepared praziquantel preparation has good tolerance to heating.

[0034] Experimental Example 3 Dilution Experiment

[0035] The same volume of water was added to the experimental examples 1-4 for dilution, and the stability was good. The stability of the solution was not reduced after further dilution, indicating that the prepared solution had good dilution stability.

[0036] Example 4 Pancreatic enzyme experiment

[0037] Take 5 mg of whole milk powder / propylene glycol fatty acid ester / polyglycerol fatty acid ester, add 5 mg of praziquantel API and 5 ml of 0.25% pancreatic enzyme (5 ml of water for control), stir at 37°C for 20 minutes, and leave at room temperature for 1 day. Results Compared with the control, the addition of pancreatic enzyme had no significant effect on the dissolution of the three formulations investigated, and the solutions were all turbid with precipitation. Therefore, the addition of pancreatic enzyme could not increase the solubility to 1 mg / ml. This shows that the degradation products of the above materials under the action of pancreatic enzyme, such as fat, cannot promote the dissolution of praziquantel, which is different from the inference of the literature.

[0038] In short, this patent proposes a unique method that can be used to solve some problems in preparing praziquantel solution. The above-mentioned embodiments only express several embodiments of the present invention, and their descriptions are more specific and detailed, but they cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that for those of ordinary skill in the art, without departing from the concept of the present invention, some deformations and improvements can also be made, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention should be based on the attached claims.

Claims

1. A method for preparing a praziquantel preparation with high solubility and good stability, characterized in that: Praziquantel is mixed with a liquid beverage or a solid beverage or raw materials thereof and used for the preparation of various types of praziquantel preparations.

2. The use according to claim 1, characterized in that: The liquid beverage or solid beverage includes foods or auxiliary materials that can be uniformly dispersed in water and are rich in protein, fat or lactose, including but not limited to one or more mixtures of milk, yak milk or goat milk and whole milk powder, skimmed milk powder or sugar-containing milk powder, or soy milk, soy milk powder, protein powder, vegetable fat powder, etc.

3. The use according to claims 1-2, characterized in that: The raw materials or auxiliary materials mentioned above mainly refer to the main ingredients for preparing the above-mentioned products or semi-finished products or their similar properties.

4. The use according to claims 1-3, characterized in that: It is possible to start from the source of food or raw materials, reconstitute the solid dispersion medium and mix it with the API at appropriate steps to obtain a liquid or solid mixture, thereby achieving the purpose of clarifying the components, improving the properties, and strengthening certain properties of the preparation.

5. The use according to claims 1-4, characterized in that: In the process of preparing whole milk powder or skimmed milk powder, praziquantel is added to raw milk, and dispersed and dissolved by heating and stirring, and suitable preparation excipients are added at the same time. The subsequent steps are the same as the preparation of whole milk powder (freeze drying, spray drying, etc.) to obtain milk powder containing praziquantel.

6. The use according to claims 1-5, characterized in that: Other auxiliary materials can be added to the beverage as needed to further accelerate dissolution, improve solubility or drug stability.

7. The use according to claims 1-6, characterized in that: In order to quickly dissolve or evenly disperse praziquantel in a liquid, the liquid medium may be heated as required.

8. The use according to claims 1-7, characterized in that: The praziquantel liquid preparation prepared with skimmed milk powder has high solubility and good stability.

9. The use according to claims 1-8, characterized in that: By using the above technology and method, not only water-soluble powder and aqueous liquid of praziquantel can be prepared, but also film, suppository and gel can be prepared. It can also further prepare various solid, semi-solid dosage forms, gas preparations, etc., such as capsules, powders, tablets, granules, pills, etc.

10. The use according to claims 1-9, characterized in that: The above technology and method can also be used for the preparation of compound preparations of praziquantel and other drugs.

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