High-water-solubility calculus bovis factitius composition and preparation method thereof

Abstract

According to the high-water-solubility calculus bovis factitius composition and the preparation method thereof, under the combined action of a surfactant, a water-soluble auxiliary material and a cosolvent, the solubility of bilirubin and cholic acid which are effective components of calculus bovis factitius in water is greatly improved, and the solubility of the bilirubin and the solubility of cholic acid reach 3.05 mu g / mL and 110.1 mu g / mL respectively. Meanwhile, the stability of the medicine can be effectively enhanced. The aqueous solution of the high-water-solubility calculus bovis factitius composition is prepared into an oral liquid type liquid preparation. The preparation method is simple and safe in process and suitable for industrialization.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a highly water-soluble artificial bezoar composition and a preparation method thereof. Background Art

[0002] Artificial bezoar, also known as bezoar or bezoar powder, is a loose yellow powder. It has the effects of clearing away heat and detoxifying, resolving phlegm and calming the nerves. Artificial bezoar has a wide range of medical applications and is often used to treat phlegm-heat delirium, coma and aphasia, acute convulsions in children, sore throat, mouth sores, carbuncles and furuncles. At present, artificial bezoar is made from ox bile powder, bile acid, hyodeoxycholic acid, taurine, bilirubin, cholesterol, trace elements, etc. Among them, bilirubin is a bile pigment extracted from bile. It is an orange to reddish brown crystalline powder. It is the main component of artificial bezoar and the basis for evaluating the quality of artificial bezoar. Bilirubin is a poorly soluble substance with poor chemical stability. It will degrade in its light, humidity and heat environment. These properties limit the bioavailability of the drug. The 2020 edition of the <<Chinese Pharmacopoeia>> stipulates that the bilirubin content in artificial bezoar shall not be less than 0.63%. In summary, it is of great significance to improve the solubility and stability of bilirubin in water.

[0003] In the disclosed method of increasing the water solubility of artificial bezoar, although the taste and bad smell of artificial bezoar can be improved to a certain extent, the water solubility of the artificial bezoar solution prepared by the above-mentioned existing preparation method is low, and the bilirubin in the artificial bezoar aqueous solution prepared by the prior art method is only 15% of the bilirubin content in the raw material sample and the state is unstable, thereby affecting the stability of the artificial bezoar biological liquid preparation, and also causing a great waste of materials. Therefore, the current artificial bezoar aqueous solution obtained by solubilizing artificial bezoar with an organic solvent has problems such as low drug content and poor solution stability, which is difficult to meet the preparation requirements. Based on this, the inventor innovatively proposes a highly water-soluble artificial bezoar composition and a preparation method thereof. Summary of the invention

[0004] The purpose of the present invention is to provide a highly water-soluble artificial bezoar composition and a preparation method thereof, which effectively solves the problems of low bilirubin and bile acid drug content and poor solution stability in an artificial bezoar aqueous solution under weak acid or weak alkaline conditions through the combined action of a surfactant, a water-soluble auxiliary material and a cosolvent, thereby greatly improving the solubility of artificial bezoar in water and maintaining drug stability.

[0005] In order to solve the above technical problems, the present invention is achieved through the following technical solutions: The present invention provides a highly water-soluble artificial bezoar composition, the raw materials for preparing the composition comprise the following components by weight: 0.1-8 parts of artificial bezoar, 20-80 parts of surfactant, 1-10 parts of water-soluble auxiliary materials, and 20-90 parts of cosolvent.

[0006] Preferably, a highly water-soluble artificial bezoar composition is prepared from raw materials comprising the following components by weight: 5 parts of artificial bezoar, 40 parts of surfactant, 1.5 parts of water-soluble auxiliary materials, and 90 parts of cosolvent.

[0007] Preferably, the water-soluble excipient is mixed by vitamin C, sodium benzoate, and EDTA-2Na. Under weak acid or weak base conditions, the solubility of bilirubin and bile acid in artificial bezoar in water will increase. Vitamin C promotes the ionization of sodium benzoate and EDTA-2Na in aqueous solution on the one hand, and enhances the dissolution and release of artificial bezoar when playing a drug effect on the other hand; the pH of the mixed solution is adjusted to be weak acid or weak base by three reagents of vitamin C, sodium benzoate, and EDTA-2Na, which can promote the solubility of bilirubin and bile acid in water to prevent the activity of the drug from being destroyed in a strong acid and strong base environment.

[0008] Preferably, the surfactant is at least one of polysorbate 80, polyoxyethylene hydrogenated castor oil (RH40), polyoxyethylene purified castor oil (EL35), glutamic acid, and aspartic acid. The surfactants are all highly efficient solubilizers, and the artificial bezoar is efficiently solubilized by the surfactant and evenly dispersed in the co-solvent to form a stable solution.

[0009] Preferably, the cosolvent is at least one of polyethylene glycol 400, anhydrous ethanol, glycerol and propylene glycol; at 40-50°C, the medicinal ingredients in the artificial bezoar are effectively dissolved in the cosolvent.

[0010] Another object of the present invention is to improve the water solubility of artificial bezoar, and to provide a method for preparing a highly water-soluble artificial bezoar composition, which comprises the following steps: (1) placing the raw materials of artificial bezoar and surfactant at a certain temperature and stirring them evenly for 8-12 hours to fully dissolve them; (2) Fully dissolve the water-soluble excipients and co-solvents in water; (3) slowly adding the solution obtained in step (1) dropwise to the solution obtained in step (2) while stirring until the mixture is fully mixed; (4) Adjust the pH value, let it stand and filter.

[0011] Preferably, in step (1), the temperature control temperature is 40-50° C. In step (3), the stirring time is 30-60 min. In step (4), the pH value is 4.5-8.5.

[0012] Preferably, the aqueous solution of the highly water-soluble artificial bezoar composition is prepared into a liquid preparation in the form of an oral liquid.

[0013] Compared with the prior art, the present invention has the following beneficial effects: 1. The present invention uses vitamin C, sodium benzoate and EDTA-2Na as water-soluble excipients. Vitamin C promotes the ionization of sodium benzoate and EDTA-2Na in aqueous solution, and enhances the dissolution and release of artificial bezoar when exerting its medicinal effect; the pH of the mixed solution is adjusted to be weak acid or weak base by using vitamin C, sodium benzoate and EDTA-2Na, which can promote the solubility of bilirubin in water, so as to prevent the activity of the drug from being destroyed in a strong acid or strong base environment.

[0014] 2. The surfactants used in the present invention are all highly effective solubilizers, and the artificial bezoar is efficiently solubilized by the surfactants, and evenly dispersed into the cosolvent to form a stable solution. At the same time, the cosolvent used is at least one of polyethylene glycol 400, anhydrous ethanol, glycerol, and propylene glycol; at 40-50°C, the drug components in the artificial bezoar are effectively promoted to dissolve in the cosolvent.

[0015] 3. In the preparation method of the present invention, the solubility of bilirubin and bile acid, the effective components of artificial bezoar, in water is greatly promoted by the combined action of surfactants, water-soluble excipients and cosolvents, and the solubility reaches 3.05 μg / mL and 110.1 μg / mL respectively. At the same time, the stability of the drug can be effectively enhanced. The preparation method of the present invention is simple and safe, and is suitable for industrialization. The aqueous solution of the highly water-soluble artificial bezoar composition is made into an oral liquid preparation. DETAILED DESCRIPTION

[0016] The technical solution of the present invention is further described below in conjunction with various embodiments. The embodiments are only examples of the technical solution of the present invention and its effects. Any technical solution formed by equivalent exchange or equivalent replacement falls within the scope of protection of the patent rights of the present invention. The following embodiments demonstrate the technical effects of the solution described in the present invention. Example 1

[0017] The water-soluble artificial bezoar solution is prepared as follows: (1) Add 0.1 g of artificial bezoar to a mixed solution of 10 g of polyoxyethylene hydrogenated castor oil and 10 g of polysorbate 80, and stir thoroughly at 45 °C for 8 h; (2) Dissolve 1.0 g sodium benzoate, 0.1 g vitamin C, 0.5 g EDTA-2Na and 40 g polyethylene glycol 400 in 5 g water; (3) Slowly add solution (1) into solution (2) and continue stirring for 60 min, then cool to room temperature; (4) Adjust the pH to 4.5, then make up the volume and filter to obtain the artificial bezoar aqueous solution. Example 2

[0018] The water-soluble artificial bezoar solution is prepared as follows: (1) Add 0.25 g of artificial bezoar to a mixed solution of 20 g of polyoxyethylene hydrogenated castor oil (RH40) and 20 g of polyoxyethylene purified castor oil (EL35), and stir thoroughly at 40 °C for 12 h. (2) Dissolve 1.5 g sodium benzoate, 0.1 g vitamin C, 1 g EDTA-2Na, 60 g polyethylene glycol 400, and 5 g propylene glycol in 5 g water; (3) Slowly add solution (1) into solution (2) and continue stirring for 30 min, then cool to room temperature; (4) Adjust the pH to 5.3, then make up the volume and filter to obtain the artificial bezoar aqueous solution. Example 3 The water-soluble artificial bezoar solution is prepared as follows:

[0019] (1) Add 3 g of artificial bezoar to a mixed solution of 30 g of polysorbate 80, 30 g of polyoxyethylene hydrogenated castor oil (RH40), and 20 g of polyoxyethylene purified castor oil (EL35), and stir thoroughly at 50 °C for 10 h; (2) Dissolve 1.5 g sodium benzoate, 0.2 g vitamin C, 1 g EDTA-2Na, 5 g anhydrous ethanol, and 90 g polyethylene glycol 400 in 5 g water; (3) Slowly add solution (1) into solution (2) and continue stirring for 30 min, then cool to room temperature; (4) Adjust the pH to 8.0, then make up the volume and filter to obtain the artificial bezoar aqueous solution. Example 4

[0020] The water-soluble artificial bezoar solution is prepared as follows: (1) Add 0.5 g artificial bezoar to a mixed solution of 10 g polyoxyethylene hydrogenated castor oil-RH40 and 1 g glutamic acid, and stir thoroughly at 40 °C for 11 h; (2) Dissolve 0.1 g vitamin C, 1.0 g sodium benzoate, 1 g EDTA-2Na, 50 g polyethylene glycol 400, and 5 g glycerol in 5 g water; (3) Slowly add solution (1) into solution (2) and continue stirring for 60 min, then cool to room temperature; (4) Adjust the pH to 6.0, then make up the volume and filter to obtain the artificial bezoar aqueous solution. Example 5

[0021] The water-soluble artificial bezoar solution is prepared as follows: (1) Add 0.5 g artificial bezoar to a mixed solution of 10 g polysorbate 80 and 1 g aspartic acid and stir thoroughly at 43 °C for 9 h. (2) Dissolve 0.1 g vitamin C, 1.5 g sodium benzoate, 1 g EDTA-2Na, 5 g anhydrous ethanol, and 5 g glycerol in 5 g water; (3) Slowly add solution (1) into solution (2) and continue stirring for 60 min, then cool to room temperature; (4) Adjust the pH to 8.5, then make up the volume and filter to obtain the artificial bezoar aqueous solution. Comparative Example 1

[0022] The water-soluble artificial bezoar solution is prepared as follows: (1) Dissolve 0.2 g artificial bezoar, 0.1 g vitamin C, 1.0 g sodium benzoate, 1 g EDTA-2Na, and 5 g ethanol in 500 mL water; continue stirring for 60 min and then cool to room temperature; (2) Adjust the pH to 6.0, then make up the volume and filter to obtain the artificial bezoar aqueous solution. Comparative Example 2

[0023] The preparation method of water-soluble artificial bezoar solution is as follows: place 0.04 g of artificial bezoar and 40 mL of chloroform in a 50 mL brown volumetric flask, treat with ultrasound for 30 min to fully dissolve, filter, and dilute to the scale with chloroform to obtain the artificial bezoar chloroform solution. Comparative Example 2

[0024] Take 4g of ox bile powder, 2.5g of bovine nitrate, 0.5g of bilirubin, 1.5g of cholesterol, 7.5g of bile acid, 9g of hyodeoxycholic acid, 3.5g of inorganic salt, 1.5g of magnesium sulfate, 0.4g of ferrous sulfate, 2.5g of tricalcium phosphate, 15g of polyethylene glycol 3000, 25g of cyclodextrin, and 15g of lactose.

[0025] The water-soluble artificial bezoar solution is prepared as follows: (1) taking the ox bile powder, bovine nitric acid, bilirubin, cholesterol, bile acid, hyodeoxycholic acid, inorganic salts, magnesium sulfate, ferrous sulfate, and tricalcium phosphate according to the selected weight, mixing them, and then crushing them into nano powder; (2) taking the polyethylene glycol 3000 according to the selected weight, heating it at 65° C. to melt it, then adding the nano powder obtained in step (1) and mixing them evenly, cooling and crushing them into 80 mesh fine powder; (3) Mixing a selected weight of cyclodextrin with the fine powder obtained in step (2) and ball milling for 1 hour, then adding a selected weight of the water-soluble auxiliary material lactose and continuing to ball mill for 2 hours, and finally crushing to obtain the water-soluble artificial bezoar.

[0026] The bilirubin and bile acid contents of the water-soluble artificial bezoar solutions obtained in Experimental Examples 1-5 and Comparative Examples 1-3 were respectively determined, and the determination method and steps are as follows: UV-spectrophotometric determination of bilirubin:

[0027] (1) Preparation of bilirubin reference solution: Take 10 mg of bilirubin reference, weigh accurately, place in a 100 mL brown volumetric flask, add 80 mL of chloroform, sonicate to fully dissolve, dilute to scale with chloroform, and shake well. Accurately measure 10 mL, place in a 50 mL brown volumetric flask, dilute to scale with chloroform, and shake well to obtain the bilirubin reference solution.

[0028] (2) Preparation of standard curve: Accurately measure 4 mL, 5 mL, 6 mL, 7 mL, and 8 mL of the reference solution and place them in 25 mL brown volumetric flasks respectively. Dilute to the mark with chloroform and shake well.

[0029] (3) Sample preparation and testing: Accurately measure 100 mL of this product and place it in a separatory funnel. Add 1 M hydrochloric acid and extract with chloroform 4 times, 15 mL, 15 mL, 10 mL, and 5 mL each time. Place the extract in a 50 mL brown volumetric flask, dilute to the mark with chloroform, shake well, and filter thoroughly. Take the filtrate and measure the absorbance at 450 nm-460 nm, with the absorbance as the ordinate and the concentration as the abscissa. Determine the absorbance according to the method, read the weight of bilirubin in the sample solution from the standard curve, and calculate. Stability test:

[0030] The samples were subjected to preliminary stability test according to the method of the 2010 edition of the Chinese Pharmacopoeia. The specific steps are as follows: The samples were placed in brown vials and sealed. They were placed at a temperature of 40°C ± 2 and a humidity of 75% ± 5% for 6 months. The samples were taken in the first, second, third and sixth months to test the bilirubin and bile acid contents.

[0031] The artificial bezoar solutions prepared by the method of the present invention in the above-mentioned Examples 1-5 are numbered AE in sequence, and the artificial bezoar solutions prepared by the prior art in the above-mentioned Comparative Examples 1-3 are numbered FH in sequence, and then samples AH are compared.

[0032] The solubility (μg / mL) of the above two drug components is compared as follows: Samples AH were weighed 80 mg and dissolved in 100 mL of water, and the bilirubin and bile acid content was determined according to the above-mentioned method for determining the bilirubin and bile acid content.

[0033] Table 1 Comparison of solubility (μg / mL) of artificial bezoar active ingredients in the examples and comparative examples Table 2 Comparison of stability and solubility of artificial bezoar in the embodiments and comparative examples (μg / mL) The results show that: AE of the present invention has greatly increased its water solubility by adding solubilizing agent and cosolvent, and improved its stability by adding water-soluble excipients. F is directly dissolved with organic solvent, and the solubility of bilirubin and bile acid in the obtained solution is low. G is an artificial bezoar solution directly dissolved with chloroform, which has good solubility but poor stability; H is an artificial bezoar made of cyclodextrin inclusion compound, and its solubility and stability are still not as significant as the method of the present invention.

[0034] In addition, practice shows that the present invention shows that the aqueous solution can be used to prepare an oral liquid preparation, which greatly improves the bioavailability of artificial bezoar.

Claims

1. A highly water-soluble artificial bezoar composition and a preparation method thereof, characterized in that: The raw materials for its preparation comprise the following components by weight: 0.1-8 parts of artificial bezoar, 20-80 parts of surfactant, 1-10 parts of water-soluble auxiliary material and 20-90 parts of cosolvent.

2. A highly water-soluble artificial bezoar composition and preparation method thereof according to claim 1, characterized in that: The prepared raw materials comprise the following components by weight: 5 parts of artificial bezoar, 40 parts of surfactant, 1.5 parts of water-soluble auxiliary materials, and 90 parts of cosolvent.

3. A highly water-soluble artificial bezoar composition and preparation method thereof according to claim 1, characterized in that: The water-soluble auxiliary material is prepared by mixing vitamin C, sodium benzoate and EDTA-2Na.

4. A highly water-soluble artificial bezoar composition and preparation method thereof according to claim 1, characterized in that: The surfactant is at least one of polysorbate 80, polyoxyethylene hydrogenated castor oil (RH40), polyoxyethylene purified castor oil (EL35), glutamic acid and aspartic acid.

5. A highly water-soluble artificial bezoar composition and preparation method thereof according to claim 1, characterized in that: The cosolvent is at least one of polyethylene glycol 400, anhydrous ethanol, glycerol and propylene glycol.

6. A highly water-soluble artificial bezoar composition and preparation method thereof according to claim 1, characterized in that: It includes the following steps: (1) placing the raw materials of artificial bezoar and surfactant at a certain temperature and stirring them evenly for 8-12 hours to fully dissolve them; (2) Fully dissolve the water-soluble excipients and co-solvents in water; (3) slowly adding the solution obtained in step (1) dropwise to the solution obtained in step (2) while stirring until the mixture is fully mixed; (4) Adjust the pH value, let it stand and filter.

7. A highly water-soluble artificial bezoar composition and preparation method thereof according to claim 6, characterized in that: In the step (1), the temperature is 40-50° C.; in the step (3), the stirring time is 30-60 min; and in the step (4), the pH value is 4.5-8.

5.

8. An oral liquid preparation prepared from an aqueous solution of the highly water-soluble artificial bezoar composition prepared by the preparation method according to any one of claims 1 to 7.