Nano calculus bovis gel and preparation method thereof

Abstract

The invention discloses nanometer calculus bovis gel and a preparation method thereof. The nanometer calculus bovis gel is prepared from calculus bovis and a gel material in a weight ratio of 1: (1000-4000), the calculus bovis is one of natural calculus bovis, calculus bovis cultured in vitro, calculus bovis cultured in vivo and artificial calculus bovis; the gel material is prepared from a gel matrix, a humectant, a pH regulator, a preservative and purified water in a weight ratio of 1: (1-10): (0-3): (0-0.2): (20-50). The preparation method comprises the following steps: S1, dissolving bezoar in a dimethyl sulfoxide solution as an organic phase, dropwise adding the organic phase into an emulsifier-containing water phase under a stirring condition, mixing, continuously stirring, and aging for a certain time to obtain a bezoar nanocrystal solution; and S2, performing high-speed centrifugation and washing on the calculus bovis nanocrystal solution for purification, adding a gel material, and uniformly stirring to obtain the nanometer calculus bovis gel. The chemical composition of the obtained nanometer calculus bovis is not changed in the preparation process, the particle size is uniform, the chemical property is stable, the nanometer calculus bovis is uniformly dispersed in a gel matrix, and the stability is good.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, and particularly relates to a nano-bezoar gel and its preparation method. Background Technology

[0002] Bezoar is a gallstone from cattle and a traditional and precious Chinese medicinal material. It has the effects of clearing the mind, opening the orifices, cooling the liver, calming wind, and detoxifying. It is used to treat symptoms such as delirium due to fever, phlegm coma due to stroke, convulsions, epilepsy, sore throat, mouth and tongue sores, carbuncles and boils.

[0003] Calculus gallus domesticus (ox gallstone) exhibits poor stability in solution; heating or pH changes can affect the stability of its active ingredients. Nanotechnology can not only improve the bioavailability of drugs but also enhance their stability, and has been widely used in pharmaceutical formulations in recent years. Common preparation methods for nanosuspensions fall into three main categories: dispersion methods (media grinding, high-pressure homogenization), coagulation methods (supercritical fluid technology, solvent-antisolvent method, nanospray drying), and emulsification methods.

[0004] Chinese Patent Application No. 2023115238929 discloses a method for preparing an artificial bezoar nanosuspension, comprising 50-400 mg of artificial bezoar, 100-200 mg of stabilizer, and 100 ml of water. The preparation method includes the following steps: weighing 100-200 mg of stabilizer and 100 ml of water, dissolving the stabilizer in the water to obtain a stabilizer solution; weighing 50-400 mg of artificial bezoar and 200 mg of stabilizer, mixing the artificial bezoar with the stabilizer solution, pouring the mixed solution into the feed cup of a homogenizer, and homogenizing under a certain pressure to obtain the artificial bezoar nanosuspension. This method uses high-pressure homogenization to prepare the artificial bezoar nanosuspension to improve the stability of artificial bezoar, but it has the following drawbacks:

[0005] (1) High-pressure homogenization is not suitable for drug solutions with high concentration and viscosity, and the number of homogenization cycles is relatively large, resulting in uncontrollable nanocrystal particle size. The equipment is easily clogged during the homogenization process, making large-scale preparation difficult.

[0006] (2) Before homogenizing with a high-pressure homogenizer, the drug powder should be pre-micronized into particles with a particle size of no more than 25 μm.

[0007] (3) The temperature of the medicine solution will rise during the high-pressure homogenization process, which may destroy the active substances in bezoar.

[0008] (4) This method requires special equipment, has high energy consumption, and requires operating experience.

[0009] Therefore, there is an urgent need to develop a new method for preparing bezoar nanocrystals that is simple to operate, requires inexpensive equipment, and is easy to industrialize. Summary of the Invention

[0010] To overcome the shortcomings of the prior art, this invention provides a nano-bezoar gel and its preparation method. The method uses a simple and easily industrialized solvent-antisolvent method to prepare bezoar nanocrystals. Bezoar is dissolved in dimethyl sulfoxide, and then the bezoar solution is added dropwise to an antisolvent (purified water). When the bezoar concentration reaches supersaturation, bezoar nanocrystals precipitate. The bezoar nanocrystals are then further processed into nano-bezoar gel, which is convenient for clinical application.

[0011] To achieve the above objectives, this application adopts the following technical solution:

[0012] In a first aspect, the present invention provides a nano-bezoar gel, which is composed of bezoar and gel material in a weight ratio of 1:(1000-4000);

[0013] The bezoar mentioned is one of the following: natural bezoar, in vitro cultured bezoar, in vivo cultured bezoar, and artificial bezoar;

[0014] The gel material is composed of a gel matrix, a humectant, a pH adjuster, a preservative, and purified water in a weight ratio of 1:(1-10):(0-3):(0-0.2):(20-50).

[0015] The gel matrix is ​​one of sodium alginate, carbomer, sodium carboxymethyl cellulose, chitosan, and polyvinylpyrrolidone.

[0016] In the above technical solution, the moisturizer is one of glycerin and propylene glycol.

[0017] In the above technical solution, the pH adjuster is one of triethanolamine, lactic acid, and acetic acid.

[0018] In the above technical solutions, the preservative is one of ethylparaben, methylparaben, benzoic acid, sodium benzoate, and benzalkonium bromide.

[0019] Secondly, the present invention provides a method for preparing nano-bezoar gel, comprising the following steps:

[0020] S1. Dissolve bezoar in dimethyl sulfoxide solution as the organic phase. Under stirring conditions, control the dropping rate and add it dropwise to the aqueous phase containing emulsifier. After mixing, continue stirring and aging for a certain time to obtain bezoar nanocrystal solution.

[0021] S2. The bezoar nanocrystal solution was purified by high-speed centrifugation and washing to remove organic solvents and emulsifiers. The gel material was added and stirred evenly to obtain nano bezoar gel.

[0022] The bezoar mentioned therein is one of the following: natural bezoar, in vitro cultured bezoar, in vivo cultured bezoar, and artificial bezoar;

[0023] The gel material is composed of a gel matrix, a humectant, a pH adjuster, a preservative, and purified water in a weight ratio of 1:(1-10):(0-3):(0-0.2):(20-50).

[0024] The weight ratio of bezoar to gel material is 1:(1000-4000);

[0025] The gel matrix is ​​one of sodium alginate, carbomer, sodium carboxymethyl cellulose, chitosan, and polyvinylpyrrolidone.

[0026] In the above technical solution, in S1, the concentration of the bezoar-dimethyl sulfoxide solution is 6-10 mg / mL. The emulsifier is one of polyvinyl alcohol, poloxamer 407, and poloxamer 188. The volume ratio of the organic phase to the aqueous phase is 1:(15-25). The stirring speed is 500-900 rpm. The aging time is 0.5-5 hours.

[0027] In the above technical solutions, in S2, the high-speed centrifugation speed is 10000-15000 r / min, and the centrifugation time is 10-30 min.

[0028] The beneficial effects of this invention are as follows:

[0029] This invention prepares bezoar nanocrystals at room temperature without altering the solution pH using a solvent-antisolvent method. This preparation method is simple to operate, requires inexpensive equipment, and is easier for industrial production. Furthermore, the bezoar nanocrystals are further prepared into nano-bezoar gel, which shows no discoloration or deterioration after one year of storage. Moreover, the prepared nano-bezoar gel can effectively treat acne with minimal skin irritation. Attached Figure Description

[0030] Figure 1 This is a scanning electron microscope image of bezoar nanoparticles;

[0031] Figure 2 The energy spectrum of free bezoar;

[0032] Figure 3 The energy spectrum of bezoar nanocrystals;

[0033] Figure 4 Image of the appearance of nano-bezoar gel;

[0034] Figure 5 This is a picture of the appearance of nano-bezoar gel after being placed at 4°C for 1 year. Detailed Implementation

[0035] To better illustrate the objectives, technical solutions, and advantages of this invention, the invention will be further described below in conjunction with specific embodiments. This invention can be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the inventive concept to those skilled in the art. This invention will be defined only by the claims.

[0036] Example 1

[0037] Accurately weigh 20 mg of cultured bezoar and dissolve it in 2 mL of dimethyl sulfoxide. Add the cultured bezoar solution dropwise to 40 mL of 0.2% poloxamer 407 solution at 700 rpm, mix, and continue stirring for 1 hour to obtain a nanocrystalline solution. Centrifuge the nanocrystals at 11500 rpm for 20 min, discard the supernatant, and wash and purify with deionized water to obtain the bezoar nanocrystalline solution. Take 1.2 g of sodium alginate, add an appropriate amount of purified water and stir well. Add 6 g of glycerol and 0.1 g of sodium benzoate, stir well, add the bezoar nanocrystalline solution, add water to 40 g, stir well, and dispense into containers to obtain nano-bezoar gel.

[0038] Example 2

[0039] Accurately weigh 20 mg of natural bezoar and dissolve it in 2 mL of dimethyl sulfoxide. Add the in vitro cultured bezoar solution dropwise to 35 mL of 0.2% poloxamer 407 solution at 700 rpm, mix, and continue stirring for 1 hour to obtain a nanocrystalline solution. Centrifuge the nanocrystals at 11500 rpm for 20 min, discard the supernatant, and wash and purify with deionized water to obtain the bezoar nanocrystalline solution. Weigh 0.6 g of carbomer and swell it overnight in an appropriate amount of water. Add the bezoar nanocrystalline solution to the swollen carbomer, then add 6 g of glycerol and 0.1 g of sodium benzoate. Slowly add triethanolamine to adjust the pH to 7 while stirring to form a gel. Add purified water to a final volume of 40 g and stir until homogeneous. Dispense the gel to obtain the nano-bezoar gel.

[0040] Example 3

[0041] Accurately weigh 15 mg of cultured bezoar and dissolve it in 2 mL of dimethyl sulfoxide. Add the cultured bezoar solution dropwise to 40 mL of 0.5% poloxamer 407 solution at 700 rpm, mix, and continue stirring for 1 hour to obtain a nanocrystalline solution. Centrifuge the nanocrystals at 11500 rpm for 20 min, discard the supernatant, and wash and purify with deionized water to obtain the bezoar nanocrystalline solution. Take 1.2 g of sodium alginate, add an appropriate amount of purified water and stir well. Add 6 g of glycerol and 0.1 g of sodium benzoate, stir well, add the bezoar nanocrystalline solution, add water to 40 g, stir well, and dispense into containers to obtain nano-bezoar gel.

[0042] Example 4

[0043] Accurately weigh 20 mg of artificial bezoar, add 2 mL of dimethyl sulfoxide to dissolve it, and add the above in vitro cultured bezoar solution dropwise to 30 mL of 0.2% poloxamer 407 solution at 700 rpm. Mix and continue stirring for 1 hour to obtain a nanocrystalline solution. Centrifuge the nanocrystals at 11500 rpm for 20 min, discard the supernatant, and wash and purify with deionized water to obtain the bezoar nanocrystalline solution. Mix 3 g of sodium carboxymethyl cellulose, 0.05 g of chlorhexidine acetate, and 7 g of glycerol. Add the bezoar nanocrystalline solution to the sodium carboxymethyl cellulose gel, stir to form a gel, add purified water to 45 g, and dispense to obtain the nano-bezoar gel.

[0044] Comparative Example 1

[0045] The difference compared to Example 1 is that the mass of the in vitro cultured bezoar is 30 mg.

[0046] Comparative Example 2

[0047] The difference from Example 1 is that dimethyl sulfoxide is replaced with ethanol.

[0048] Comparative Example 3

[0049] The difference compared to Example 1 is that the volume of the poloxamer 407 solution is 25 mL.

[0050] Comparative Example 4

[0051] The difference compared to Example 1 is that the volume of dimethyl sulfoxide is 4 mL.

[0052] Performance testing

[0053] 1. Particle size determination of bezoar nanocrystal solution

[0054] The particle size of the bezoar nanocrystal solutions in the examples and comparative examples was determined using a dynamic light scattering nanoparticle size analyzer. An appropriate amount of bezoar nanocrystal solution emulsion was diluted with purified water to a transmittance of approximately 100 kcps, and the particle size of the bezoar nanocrystal solution was measured. The results are as follows:

[0055] Particle size (nm) Example 1 423.21±8.34 Example 2 543.23±7.19 Example 3 478.69±8.29 Example 4 496.13±5.92 Comparative Example 1 1438.63±34.87 Comparative Example 2 1618.47±37.48 Comparative Example 3 1842.63±32.59 Comparative Example 4 1643.52±41.39

[0056] The above results indicate that the particle size of the bezoar nanocrystal solutions in Examples 1-4 is better than that in Comparative Examples 1-4. The bezoar nanocrystal solution in Example 1 was added to the gel matrix to prepare bezoar nanogels, and the performance was further measured.

[0057] 2. Observation of the surface morphology of bezoar nanocrystals in Example 1

[0058] The microstructure of bezoar nanocrystals was observed using transmission electron microscopy. Before observation, a solution of bezoar nanocrystals was dropped onto a copper grid and allowed to dry naturally. After drying, it was observed under a transmission electron microscope. Figure 1 It can be seen that the bezoar nanocrystals appear as mica under an electron microscope, and no obvious aggregation was observed.

[0059] 3. Energy spectroscopy observation of free bezoar and bezoar nanocrystals from Example 1

[0060] Trace elemental analysis of free bezoar and bezoar nanocrystals was performed using transmission electron microscopy. Before observation, solutions of free bezoar and bezoar nanocrystals were dropped onto a copper grid and allowed to dry naturally. After drying, they were scanned and observed under a transmission electron microscope. Figure 2 The energy spectrum of free bezoar. Figure 3 The image shows the energy dispersive spectroscopy (EDS) spectrum of bezoar nanocrystals. The EDS spectrum reveals that the elemental composition and proportions of free bezoar and bezoar nanocrystals are essentially the same, indicating that this invention successfully prepared bezoar nanocrystals without altering their elemental structure.

[0061] 4. Observation of the appearance and morphology of nano-bezoar gel in Example 1

[0062] Nano-bezoar gel was prepared using the method described in Example 1. Figure 4 It can be seen that the prepared nano-bezoar gel is yellow in appearance, has good gel fluidity, is easy to apply, has a pH value of 6-7, and has no obvious skin irritation.

[0063] 5. Stability of bezoar nanogel in Example 1

[0064] The nano-bezoar gel prepared in Example 1 was placed at 4°C for one year, and its appearance and properties were observed. Figure 5 It can be seen that when the nano-bezoar gel is refrigerated at 4°C, it still appears yellow and has not deteriorated, and it has good spreadability.

[0065] Obviously, the above embodiments are merely illustrative examples for clear explanation and are not intended to limit the implementation. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations here. However, obvious variations or modifications derived therefrom are still within the scope of protection of this invention.

Claims

1. A nano-bezoar gel, characterized in that: It is composed of bezoar and gel material in a weight ratio of 1:(1000~4000); The bezoar mentioned is one of the following: natural bezoar, in vitro cultured bezoar, in vivo cultured bezoar, and artificial bezoar; The gel material is composed of a gel matrix, a humectant, a pH adjuster, a preservative, and purified water in a weight ratio of 1:(1-10):(0-3):(0-0.2):(20-50). The gel matrix is ​​one of sodium alginate, carbomer, sodium carboxymethyl cellulose, chitosan, and polyvinylpyrrolidone.

2. The nano-bezoar gel according to claim 1, characterized in that: The moisturizer is one of glycerin and propylene glycol.

3. The nano-bezoar gel according to claim 1, characterized in that: The pH adjuster is one of triethanolamine, lactic acid, and acetic acid.

4. The nano-bezoar gel according to claim 1, characterized in that: The preservative is one of ethylparaben, methylparaben, benzoic acid, sodium benzoate, and benzalkonium bromide.

5. A method for preparing nano-bezoar gel, characterized in that: Includes the following steps: S1. Dissolve bezoar in dimethyl sulfoxide solution as the organic phase, and add it dropwise to the aqueous phase containing emulsifier under stirring conditions. After mixing, continue stirring and aging for a certain period of time to obtain bezoar nanocrystal solution. S2. The bezoar nanocrystal solution is purified by high-speed centrifugation and washing to remove organic solvents and emulsifiers. Gel material is added and stirred evenly to obtain the nano bezoar gel. The bezoar mentioned therein is one of the following: natural bezoar, in vitro cultured bezoar, in vivo cultured bezoar, and artificial bezoar; The gel material is composed of a gel matrix, a humectant, a pH adjuster, a preservative, and purified water in a weight ratio of 1:(1-10):(0-3):(0-0.2):(20-50). The weight ratio of bezoar to gel material is 1:(1000-4000); The gel matrix is ​​one of sodium alginate, carbomer, sodium carboxymethyl cellulose, chitosan, and polyvinylpyrrolidone.

6. The preparation method according to claim 5, characterized in that: In S1, the concentration of bezoar-dimethyl sulfoxide solution is 6–10 mg / mL.

7. The preparation method according to claim 5, characterized in that: In S1, the emulsifier is one of polyvinyl alcohol, poloxamer 407, and poloxamer 188.

8. The preparation method according to claim 5, characterized in that: In S1, the volume ratio of the organic phase to the aqueous phase is 1:(15-25).

9. The preparation method according to claim 5, characterized in that: In S1, the aging time is 0.5 to 5 hours.

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