Rifaximin nanocrystal composition and preparation method thereof

Abstract

The invention relates to a rifaximin nanocrystal composition and a preparation method thereof. The rifaximin nanocrystal composition comprises rifaximin nanocrystals and a stabilizer. Rifaximin is a broad-spectrum intestinal antibiotic and achieves an antibacterial effect by inhibiting synthesis of bacterial protein. The nanocrystalline composition can increase the dissolution rate of the medicine in the intestinal tract, and the effect of improving the curative effect of the medicine is achieved. The preparation method is easy to operate, low in production cost and suitable for commercial production.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a rifaximin pharmaceutical composition and a preparation method thereof. Background Art

[0002] Rifaximin is an orally available broad-spectrum antibiotic with antimicrobial activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria. Its marketed dosage forms in China include tablets, capsules, dry suspensions, etc. Indications include intestinal infections caused by pathogens sensitive to rifaximin (including acute and chronic intestinal infections, diarrhea syndrome, summer diarrhea, traveler's diarrhea, and enterocolitis, etc.), prevention of infectious complications before and after gastrointestinal surgery, and adjuvant treatment of hyperammonemia (hepatic encephalopathy).

[0003] Rifaximin is almost insoluble in water, resulting in a slow dissolution rate. The drug exerts an antibacterial effect locally by killing pathogens in the intestine. By increasing the solubility and dissolution rate of rifaximin, on the one hand, the drug can effectively increase its entry into pathogen cells, increase cell permeability, accelerate and enhance the efficacy; on the other hand, it can increase the absorption of the drug in the intestine, improve bioavailability, and be used for systemic absorption and enable it to be used to treat systemic infections, especially Clostridium difficile infections, infections caused by Gram-positive and Gram-negative bacteria, and for the treatment of colon diseases. Considering the therapeutic value of rifaximin, as well as the continuous upgrading of liver diseases and alternative preparations, the discovery of alternative preparations and the use of rifaximin still exist.

[0004] CN 102665693 A discloses a preparation method of a rifaximin solid dispersion. In the patent, the solubility of rifaximin is improved by preparing it in the form of a solid dispersion. The methods adopted are a melting method and a spray drying method. The melting method requires melting and combining rifaximin and excipients. The melting point of rifaximin is 200-205°C. Drug impurities are easily generated at high temperatures, thereby affecting stability. The spray drying method requires the use of an organic solvent to dissolve rifaximin. The residual organic solvent will affect human safety.

[0005] CN 101623273 A discloses a rifaximin pharmaceutical composition dispersible tablet and a preparation method thereof. The preparation method improves the dissolution rate by adjusting the co-solvent, but there is no absorption data of the drug in vivo.

[0006] With the development of pharmaceutical preparations, nanocrystal technology provides a feasible technical method for improving the administration of poorly soluble drugs. This technology reduces the particle size of the drug to the nanoscale. When the drug exists in nanometer size, the properties of the drug can also undergo "earth-shaking" changes. It can effectively improve the solubility and dissolution rate of poorly soluble drugs, reduce the administration volume, reduce toxic side effects, and thus improve bioavailability and clinical efficacy. Considering the physical and chemical properties of rifaximin, providing a stable and effective rifaximin pharmaceutical composition to improve the solubility and bioavailability of the drug has become a technical problem that needs to be solved urgently. Summary of the invention

[0007] The purpose of the invention is to overcome the deficiencies of the above-mentioned prior art and provide a stable and effective rifaximin pharmaceutical composition and a preparation method thereof, so as to improve the solubility and bioavailability of the drug.

[0008] To achieve the above object, the technical solution adopted by the present invention is:

[0009] A pharmaceutical composition of rifaximin comprises rifaximin and a stabilizer, wherein the rifaximin is nanoscale, preferably crystalline.

[0010] Among them, nanocrystal technology is a novel pharmaceutical technology for increasing the solubility of poorly soluble drugs. Nano crystal-drugs refer to drug raw materials that are directly micronized to nanoscale drug particles. They are carrier-free submicron colloidal dispersion systems with particle sizes generally ranging from 100 to 1000 nm. They can effectively improve the solubility and dissolution rate of poorly soluble drugs, reduce the volume of administration, and reduce toxic side effects, thereby improving bioavailability and clinical efficacy.

[0011] Nanocrystal technology only contains active pharmaceutical ingredients (APIs) and stabilizers. The mechanism of action of the stabilizer is mainly to maintain the stability of the nanosystem through electrostatic repulsion or spatial barrier between ions, which can effectively reduce the aggregation of drug crystals and improve the stability of the product.

[0012] Rifaximin is the active ingredient and can be made at home or purchased from outside.

[0013] The present invention relates to a nanocrystalline pharmaceutical composition of rifaximin. The weight percentage of rifaximin in the pharmaceutical composition is 45-95%, preferably 55-90%, and more preferably 60-85%, based on the total weight (excluding solvent).

[0014] In one embodiment of the present invention, the weight percentage of the components calculated by the total weight of the prescription is calculated based on the pharmaceutical composition without solvent, wherein the weight percentage of the stabilizer is 5-55%, preferably 10-45%, and more preferably 15-40%.

[0015] The stabilizer is selected from one or more of cellulose, high molecular polymer, natural stabilizer and surfactant.

[0016] The cellulose is selected from one or more of hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose and hypromellose, among which hydroxypropyl cellulose, hypromellose and sodium carboxymethyl cellulose are preferred.

[0017] The high molecular polymer is selected from one or more of polyoxyethylene polyoxypropylene block copolymer, povidone, polyvinyl alcohol, and cross-linked polyvinyl alcohol, preferably polyoxyethylene polyoxypropylene block copolymer and povidone.

[0018] The surfactant is selected from one or more of sodium dodecylbenzene sulfonate, Span, Tween, sodium docusate, and sodium lauryl sulfate, preferably sodium docusate and sodium docusate.

[0019] The natural stabilizer is selected from one or more of sodium alginate, lecithin, gum arabic, mannitol, dextran and chitosan, preferably lecithin.

[0020] Wherein when the stability is selected from the combination of hydroxypropyl cellulose, docusate sodium and lecithin, wherein the weight percentage of hydroxypropyl cellulose in the nanocrystalline composition is selected from 5 to 30%, the weight percentage of docusate sodium is selected from 0.1 to 5%, and the weight percentage of lecithin is selected from 0.1 to 20%;

[0021] When the stability is selected from a combination of hypromellose, sodium lauryl sulfate and lecithin, the weight percentage of hypromellose in the nanocrystalline composition is selected from 5 to 35%, the weight percentage of sodium lauryl sulfate is selected from 0.1 to 5%, and the weight percentage of lecithin is selected from 0.1 to 15%;

[0022] When the stability is selected from a combination of sodium carboxymethylcellulose, sodium docusate and lecithin, the weight percentage of sodium carboxymethylcellulose in the nanocrystalline composition is selected from 5 to 25%, the weight percentage of sodium docusate is selected from 0.1 to 10%, and the weight percentage of lecithin is selected from 0.1 to 20%;

[0023] Cellulose is the main structural component of plant cell walls, usually combined with hemicellulose, pectin and lignin. The way and degree of combination have a great influence on the texture of plant-based foods. The viscosity range of cellulose varies at different concentrations and degrees of polymerization, which also leads to its application in different fields. Generally, the larger the molecular weight, the greater the viscosity.

[0024] In the present invention, the concentration of cellulose is controlled at 1-400 mPa.s, wherein the cellulose is preferably hydroxypropyl cellulose or hydroxypropyl methyl cellulose.

[0025] The cellulose viscosity refers to the apparent viscosity of a 2% cellulose aqueous solution at 20°C.

[0026] Among them, hydroxypropyl cellulose and hydroxypropyl methyl cellulose are selected from one or a combination of several viscosity ranges, preferably the viscosity range is 1 to 400 mPa.s; more preferably the viscosity range is 1 to 100 mPa.s, further preferably the viscosity range is 3 to 50 mPa.s, and most preferably 3 to 15 mPa.s.

[0027] In one embodiment of the present invention, rifaximin is selected from nanoscale, preferably crystalline.

[0028] In one embodiment of the present invention, in the particle size distribution of rifaximin nanocrystals, when the cumulative distribution percentage from small to large reaches 90%, the particle size value corresponding to dv(90) is one or a combination of several particle size ranges of dv(90)<2000nm, dv(90)<1000nm, dv(90)<600nm, dv(90)<300nm, dv(90)<100nm and dv(90)<50nm. The smaller the particle size, the higher the degree of increasing the saturated solubility and dissolution rate of the drug, so that the drug can be quickly absorbed and take effect quickly, thereby significantly improving the bioavailability of the drug.

[0029] The present invention also provides a method for preparing a nanocrystalline suspension. The drug nanocrystal technology is a preparation technology that reduces the particle size to nanometer level by grinding, dispersing or precipitating drug particles, and stabilizes the particles under the action of a stabilizer. The preparation technology can be divided into a top-down method (such as high-pressure homogenization or medium grinding method) and a bottom-up method (such as good solvent-antisolvent addition method, supercritical fluid method).

[0030] Wherein, the preparation method of nanocrystals in the present invention is selected from the Top-Down method.

[0031] The Top-Down method refers to a method of directly micronizing the drug itself into a product, and reducing large drug particles to nanometer-sized particles through mechanical force, which mainly includes media grinding method, high-pressure homogenization method, etc. The use of mechanical grinding to grind the drug particle size to nanometer level can significantly increase the solubility and dissolution rate of the drug, improve the absorption rate of the drug, and significantly improve the cell permeability and bioavailability of the drug.

[0032] The media grinding method is divided into dry grinding and wet grinding. Wet media grinding (WMM) is mainly used in industry.

[0033] The particle size of the grinding media in the grinding chamber is in the range of 0.1 to 2.0 mm, and is usually a bead coated with ceramic (yttrium stabilized zirconia), zirconia, stainless steel, glass, chromium, agate, glass or polystyrene resin. After the drug, stabilizer and water are mixed in a certain proportion, they are put into a closed grinding chamber containing grinding media. The drug particles, grinding media and the wall of the device collide with each other under high-speed rotation, generating continuous and strong impact force and shear force to provide the energy required for the micronization of drug particles, thereby producing nanocrystals. The grinding time during preparation depends on the required particle size, and is closely related to the hardness, batch size, number of grinding beads, grinding speed, grinding temperature, etc. of the drug. The grinding time is inversely proportional to the grinding speed, and low-speed long-time grinding or high-speed short-time grinding is usually selected. However, too high a grinding speed, too large a batch size, and too long a grinding time are the main reasons for the aggregation of small particles into large particles, and the longer the time, the more difficult it is to control the microbial load.

[0034] The present invention also provides a method for preparing a nanocrystalline suspension, wherein the method can be selected from wet medium grinding according to the physicochemical properties of rifaximin. The specific steps are as follows:

[0035] Step 1—dissolve one or more stabilizers in purified water to prepare a stabilizer solution, add rifaximin, and stir evenly to obtain a rifaximin suspension;

[0036] Step 2—adding grinding beads to a wet grinder, setting the grinding production speed, and wet grinding the suspension obtained in step (1) to obtain a rifaximin nanocrystal suspension;

[0037] The stabilizer solution contains purified water in an amount of 70 to 98% by weight, based on the total weight.

[0038] The grinding beads can be glass beads, stainless steel beads, zirconium oxide beads, polystyrene resin beads, preferably zirconium oxide beads;

[0039] The diameter of the grinding beads is one of 0.1mm, 0.3mm, 0.5mm, 0.8mm, 1.0mm, 1.2mm, and 2mm, preferably 0.3mm to 1mm;

[0040] The grinding production speed is 2m / s to 20m / s, preferably 6m / s to 16m / s, more preferably 8m / s to 12m / s;

[0041] The present invention also provides a method for solidifying a nanocrystalline suspension, wherein since the nanocrystalline suspension has poor stability during storage and transportation, the rifaximin nanocrystals will gradually aggregate and settle over time, and the nanocrystals are solidified onto a soluble excipient, so that rifaximin can maintain a nanocrystalline form for a long time, and at the same time, it is convenient for subsequent preparation into tablets, capsules, granules, etc., and is convenient for transportation and storage.

[0042] The excipients used for solidification are soluble excipients, preferably mannitol, sorbitol, xylitol, lactose, sucrose, glucose, fructose, powdered sugar, erythrose, xylitol and the like and their derivatives; further preferably mannitol, sucrose, lactose and the like and their derivatives.

[0043] The solidification method is selected from one or more of fluidized bed technology, spray drying technology, and freeze drying. In the present invention, the fluidized bed technology is preferably used to solidify the nanocrystalline suspension.

[0044] Beneficial effects:

[0045] 1. The present invention is the first to prepare a rifaximin nanocrystal composition. Compared with raw materials that have not been treated with nanocrystals, the dissolution rate is higher, the absorption in the body is faster, the bioavailability is higher, and the efficacy of the drug in the human body is effectively improved. The efficacy problem caused by the low solubility of rifaximin is solved, and the antibacterial effect is more effective.

[0046] 2. The nanocrystalline composition prepared by the present invention uses one or more stabilizers to make the nanocrystalline particle size smaller, which is convenient for absorption in the body; the solution is also more stable, which is convenient for industrial production, and solves the problem of unstable particle size during commercial production of nanocrystalline suspensions.

[0047] 3. The nanocrystalline composition prepared by the present invention can be solidified onto a soluble excipient, has good stability, can maintain the nano state after re-dissolution, and can be prepared into a variety of solid preparations, which greatly improves the portability and compliance of the drug, facilitates clinical use, and solves clinical problems such as the inconvenience of transportation, carrying and taking of nanocrystalline suspensions. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 Figure 2 is the particle size diagram of the rifaximin nanocrystal drug composition DETAILED DESCRIPTION

[0049] The present invention is further described in detail below in conjunction with the embodiments, but is not limited to the following embodiments. Equivalent substitutions or changes made by those skilled in the art based on the present invention without departing from the essential content of the present invention are also within the protection scope of the present invention.

[0050] In the embodiment, the particle size distribution is measured by a Malvern 3000 laser particle size analyzer, and Dv(90) is selected as the measurement parameter. The Dv(90) of the nanocrystals is detected immediately after grinding and recorded as T0. After 1 day (24h), the weight is 1:1, and the score (S) is calculated according to the following formula. With the score as an indicator, the stabilizer composition with a higher score is better: score (S) = 1 / T0+1 / T1.

[0051] Wherein, T0 represents the Dv(90) particle size of the nanocrystals obtained after grinding, and T1 represents the Dv(90) particle size of the nanocrystals after 1 day (24h).

[0052] Example 1 - Stabilizer Screening

[0053] The present invention uses wet grinding technology to prepare the nanocrystalline composition (equipment: Walburg DYNO-MILL MULTI LAB), and in order to reduce the particle size, a stabilizer is added for grinding.

[0054] In this experiment, a stabilizer was selected and tested under the same wet mill parameters (zirconia beads 0.5 mm, production speed 10 m / s, peristaltic pump speed 30 rpm, grinding time 1 h) to determine the best type of composition, and the nanocrystal particle size Dv(90) was detected on day 0 and recorded as T0; the particle size Dv(90) was detected again after being placed in a 4°C refrigerator for 24 h and recorded as T1. The score (S) = 1 / T0+1 / T1, and the one with a higher score is the better prescription.

[0055] The experimental design is as follows:

[0056]

[0057] As shown in the above data, rifaximin can reduce the drug Dv (90) from 56.75 μm to 1.10 μm by nanocrystal grinding technology, but the drug particle size cannot be further reduced; after adding stabilizers to the prescriptions, the particle size of rifaximin can be reduced, but after 1 day (24 hours), the nanocrystals agglomerate and the nanocrystal particle size Dv (90) increases significantly. In the examples, the scores of prescriptions 3-6 are all greater than 2.0, indicating that the use of a single stabilizer can either obtain nanocrystals with smaller particle sizes at 0 days, or the particle size stability is better after 24 hours. Therefore, in the present invention, cellulose stabilizers hydroxypropyl cellulose, hydroxypropyl methylcellulose and sodium carboxymethyl cellulose, surfactants sodium docusate, sodium lauryl sulfate, and natural stabilizer lecithin are selected as priority screening, and surfactant Tween is selected, and natural stabilizer mannitol is also selected as a stabilizer for further screening.

[0058] Example 2 - Stabilizer Screening 2:

[0059] The present invention uses wet grinding technology to prepare the nanocrystalline composition (equipment: Walburg DYNO-MILL MULTI LAB), and in order to reduce the particle size, a variety of stabilizers are added for grinding.

[0060] In this experiment, a variety of stabilizers were selected and tested under the same wet mill parameters (zirconia beads 0.5 mm, production speed 10 m / s, peristaltic pump speed 30 rpm, grinding time 1 h) to determine the best type of composition. The nanocrystal particle size Dv(90) was detected on day 0 and recorded as T0. The particle size Dv(90) was detected again after 24 h and recorded as T1. The score (S) = 1 / T0+1 / T1, and the one with a higher score is the better prescription.

[0061] The experimental design is as follows:

[0062]

[0063] The research results show that after adding multiple stabilizers, the stability of nanocrystals after 24 hours is greatly improved, and the particle size can be kept less than 2000nm after 24 hours, especially the combination of three stabilizers. Prescription 11 involves the combination of hydroxypropyl cellulose, lecithin, and docusate sodium, prescription 13 involves the combination of hydroxypropyl methylcellulose, lecithin, and sodium lauryl sulfate, and prescription 14 involves the combination of sodium carboxymethyl cellulose, lecithin, and docusate sodium. The scores are all greater than 4, which are significantly greater than other stabilizer combinations, indicating better stability.

[0064] Example 3 - Process Screening:

[0065] The present invention uses wet grinding technology to prepare the nanocrystalline composition (equipment: Walburg DYNO-MILL MULTI LAB), and the grinding process is screened to reduce the particle size.

[0066] 19.0 g of sodium carboxymethylcellulose (15 mPa.s), 1.0 g of sodium docusate and 10.0 g of lecithin were dissolved in 500.0 g of purified water, and 70.0 g of rifaximin was added after dissolution. The process parameters were studied according to the following prescription, and the design was as follows:

[0067]

[0068]

[0069] The results show that when the grinding bead size is 0.3mm-2.0mm, the nanocrystal size Dv(90) can be made less than 2000nm. Among them, prescriptions 15-18 show that the smaller the grinding bead size, the smaller the nanocrystal size obtained, but conversely, the smaller the particle size, the higher the multiple of particle size growth after 24 hours. Prescriptions 17, 20 and 21 show that grinding beads of different materials have different grinding effects on nanocrystals. Among them, the scores of zirconium oxide and stainless steel beads are both greater than 4, but zirconium oxide is safer in the process of producing drugs.

[0070] Example 4 - Curing of Nanocrystalline Composition:

[0071] The nanocrystalline suspension prepared according to the formula and process of prescription 18 in Example 3 was solidified on the excipients within 3 hours using fluidized bed top spraying technology. The excipients included soluble excipients mannitol, lactose, sucrose, and insoluble excipients microcrystalline cellulose and starch. The specific implementation process is as follows:

[0072] 1) Select a 150um filter bag, install it with a 1.0mm diameter spray gun, and use a B-type airflow distribution plate. Add the excipient to the multifunctional fluidized bed (equipment model: FLZB-1.5), set the filter bag oscillation interval to 5 minutes, the inlet air temperature to 50-70°C, and control the air volume to 20-120m 3 / h, so that the excipient is in a fluidized state and preheated to an excipient temperature of 30-45°C;

[0073] 2) Connect the infusion pipeline, place the nanocrystal suspension on the electronic scale, keep stirring, and deliver the nanocrystal suspension to the spray gun port to peel;

[0074] 3) After the material temperature reaches the requirement, control the inlet air temperature to 55-70°C, keep the excipient temperature at 25-40°C for drug application, and record other parameters as shown in the following table:

[0075] 4) When the nanocrystal suspension reaches the theoretical amount, stop spraying, maintain the original parameters, dry for 10 minutes, and stop.

[0076] 5) The prescription table is as follows:

[0077]

[0078]

[0079] Note: Water is removed during the process

[0080] The composition prepared by formula 24-28 was added to purified water and then ultrasonically dissolved. After filtering with a 1.0 μm filter membrane, the particle size of rifaximin was measured by a Malvern 3000 laser particle size analyzer. Dv(50) and Dv(90) were recorded and compared. The comparison results are shown in the table below:

[0081]

[0082] The results showed that compared with prescription 18 (score 4.95), prescriptions 24-27 used soluble excipients as curing agents, and found that the particle size of the cured nanocrystalline composition did not change significantly after redissolution, but the particle size increased significantly when insoluble excipients were used, and the score dropped to 2. This shows that in the process of curing agent screening, soluble excipients are significantly better than insoluble excipients.

[0083] Example 5 - Dissolution Study

[0084] The rifaximin raw material (not processed by nanocrystal process), the prescription 18 in Example 3 (nanocrystalline suspension), the prescription 26 in Example 4 (sucrose solidification), the marketed product (Rifaximin tablets, specification 0.2g) were used to conduct dissolution study in a simulated intestinal fluid pH environment.

[0085] The implementation plan is as follows: Weigh an appropriate amount of rifaximin composition (containing 0.2 g of rifaximin), and according to the dissolution and release determination method of Part IV of the 2020 edition of the "Chinese Pharmacopoeia" (General Rule 0931 Method 2), use 1000 ml of pH 7.4 phosphate buffer (and add 0.25% sodium dodecyl sulfate, v / v) aqueous solution as the dissolution medium, the rotation speed is 75 rpm per minute, the temperature is 37°C, the sampling time is 5min, 15min, 30min, 45min and 60min, and the dissolution solution is filtered with a PES filter membrane to detect the in vitro dissolution curve.

[0086]

[0087]

[0088] The results of the study showed that the dissolution endpoint of rifaximin raw materials in the medium was only 68%, and prescription 18 was a nanocrystalline suspension, which could dissolve about 90% immediately after being added to the dissolution medium. Prescription 26 showed that after solidification with the soluble excipient sucrose, the dissolution at 5 minutes would decrease slightly, but the dissolution endpoint could reach more than 90%. Compared with the marketed product Xifushen, the dissolution rate and dissolution rate of the nanocrystalline composition at 5 minutes and 60 minutes of the dissolution endpoint were significantly improved. In summary, after rifaximin was prepared into nanocrystals, the dissolution rate and dissolution rate were significantly improved, and there was no difference in dissolution after solidification on sucrose, which was significantly better than the rifaximin raw materials without nanocrystal treatment and the marketed product Xifushen.

[0089] Example 6 - In vivo bioavailability

[0090] Twelve female beagle dogs weighing 4.5-5.5 kg were randomly divided into 4 groups. They were fasted for 24 hours before taking the medicine and had free access to water. Rifaximin raw material (untreated with nanocrystals, 0.2 g), prescription 18 in Example 3 (containing 0.2 g of rifaximin in nanocrystal suspension), prescription 26 in Example 4 (solidified with sucrose, containing 0.2 g of rifaximin) and marketed product (Rifaximin tablets, specification 0.2g) were administered orally. Heparinized blood samples (about 2ml) were collected from the jugular vein at 1, 2, 4, 6, 8 and 24 hours after each administration and centrifuged at 2000rpm for 10 minutes. The concentration of rifaximin in plasma was determined by LC-MS / MS method with a sensitivity of 1.0ng / ml. The following bioavailability parameters were calculated according to the standard non-compartmental analysis method: C max , T max , AUC 0-24h (area under the concentration-time curve in a 24-h interval), calculated by the linear trapezoidal rule; AUC 0-inf (The area under the concentration-time curve is calculated by the logarithmic trapezoidal rule and extrapolated to infinity). The experimental data are shown in the table below.

[0091]

[0092] In vivo pharmacokinetic experimental data showed that the peak time of the drug in vivo was C 0. max The increase was 5.6 times and 4.8 times compared with the listed varieties. In comparison, C maxThe increases were 4.1 times and 3.5 respectively, indicating that the present invention can effectively improve the absorption rate of the drug; at the same time, the absorption degree of the drug in the body (AUC) of prescriptions 18 and 20 were significantly improved compared with the rifaximin raw material and the marketed product, indicating that the nanocrystalline composition of the present invention can effectively improve the bioavailability of the drug and has great advantages in clinical application.

Claims

1. A nanocrystalline pharmaceutical composition of rifaximin, characterized in that: The pharmaceutical composition comprises rifaximin and a stabilizer, wherein the rifaximin is nanometer-sized, the weight percentage of the rifaximin in the pharmaceutical composition is 45-95%, and the weight percentage of the stabilizer is 5-55%.

2. The nanocrystalline pharmaceutical composition according to claim 1, characterized in that The stabilizer is selected from one or more of cellulose, high molecular polymer, natural stabilizer, and surfactant; The cellulose is selected from one or more of hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, and hypromellose; The high molecular polymer is selected from one or more of polyoxyethylene-polyoxypropylene block copolymer, polyvinyl alcohol, and cross-linked polyvinyl alcohol; The surfactant is selected from one or more of sodium dodecylbenzene sulfonate, Span, Tween, sodium dodecyl sulfate, and docusate sodium; The natural stabilizer is selected from one or more of sodium alginate, lecithin, gum arabic, mannitol, sucrose, dextran and chitosan.

3. The nanocrystalline pharmaceutical composition according to claim 1, characterized in that When the stability is selected from a combination of hydroxypropyl cellulose, docusate sodium and lecithin, the weight percentage of hydroxypropyl cellulose in the nanocrystalline composition is selected from 5 to 30%, the weight percentage of docusate sodium is selected from 0.1 to 5%, and the weight percentage of lecithin is selected from 0.1 to 20%; When the stability is selected from a combination of hypromellose, sodium lauryl sulfate and lecithin, the weight percentage of hypromellose in the nanocrystalline composition is selected from 5 to 35%, the weight percentage of sodium lauryl sulfate is selected from 0.1 to 5%, and the weight percentage of lecithin is selected from 0.1 to 15%; When the stability is selected from a combination of sodium carboxymethylcellulose, sodium docusate and lecithin, the weight percentage of sodium carboxymethylcellulose in the nanocrystalline composition is selected from 5 to 25%, the weight percentage of sodium docusate is selected from 0.1 to 10%, and the weight percentage of lecithin is selected from 0.1 to 20%.

4. The nanocrystalline pharmaceutical composition according to claim 1, characterized in that The viscosity of the cellulose is selected from 1 to 400 mPa.s.

5. The nanocrystalline pharmaceutical composition according to claim 1, characterized in that: In the particle size distribution of rifaximin nanocrystals, when the cumulative distribution percentage from small to large reaches 90%, the particle size value corresponding to dv(90) is dv(90)<2000nm, dv(90)<1000nm, dv(90)<600nm, dv(90)<300nm, dv(90)<100nm and dv(90)<50nm, or a combination of several particle size ranges.

6. A method for preparing a nanocrystalline suspension of rifaximin, characterized in that: The steps include: Step 1—dissolve one or more stabilizers in purified water to prepare a stabilizer solution, add rifaximin, and stir evenly to obtain a rifaximin suspension; Step 2—Add grinding beads to a wet grinder, set the grinding production speed, and wet grind the suspension obtained in step (1) to obtain a rifaximin nanocrystal suspension.

7. The method for preparing the nanocrystalline suspension of rifaximin according to claim 6, characterized in that: The stabilizer solution contains purified water in an amount of 70 to 98% by weight based on the total weight.

8. The method for preparing the nanocrystalline suspension of rifaximin according to claim 6, characterized in that: The grinding beads can be glass beads, stainless steel beads, zirconium oxide beads, polystyrene resin balls, and the diameter of the grinding beads is one of 0.1mm, 0.3mm, 0.5mm, 0.8mm, 1.0mm, 1.2mm, and 2mm.

9. The method for preparing the nanocrystalline suspension of Fuximin according to claim 6, characterized in that: The grinding production speed of the wet grinder is 2m / s to 20m / s.

10. The method for preparing the nanocrystalline suspension of Fuximin according to claim 6, characterized in that: The rifaximin nanocrystal suspension can be solidified onto a soluble excipient, and the soluble excipient is selected from mannitol, sorbitol, xylitol, lactose, sucrose, glucose, fructose, powdered sugar, erythritol, xylitol, etc. and their derivatives.

11. The method for preparing the nanocrystalline suspension of Fuximin according to claim 6, characterized in that: After the rifaximin nanocrystal suspension is dried, it is re-dissolved in water, and the particle size value dv(90) is less than 1000 nm.

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