A minoxidil nanocrystal suspension and its preparation method

Abstract

The present invention belongs to the technical field of pharmaceutical preparations, and specifically discloses a minoxidil nanocrystal suspension and a preparation method thereof. The preparation method includes the following steps: S1. Add a stabilizer to water, and after stirring evenly, obtain a stabilizer mixture; S2. Add minoxidil to the stabilizer mixture, and place it on a high-speed shearing machine for pre-shearing until the stabilizer and minoxidil are fully pre-mixed to obtain a crude suspension; S3. Grind the crude suspension to obtain a minoxidil nanocrystal suspension. The present invention uses a non-ionic polymer and an ionic surfactant compounded to form a stabilizer, and synergistically uses a high-speed pre-shearing method before ball milling. Only through ball milling and a small amount of stabilizer compounding dosage, the preparation of a minoxidil nanocrystal suspension with small size, uniform dispersion, stable suspension, good solubility, and safe and energy-saving can be completed.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a minoxidil nanocrystal suspension and a preparation method thereof. Background Art

[0002] Minoxidil was initially an oral drug for treating hypertension. Hair regrowth and systemic hirsutism were found in patients, and subsequently it has become a first-line product for treating androgenetic alopecia. Minoxidil has extremely poor solubility in water, and a large amount of propylene glycol is mostly used to improve its solubility and promote transdermal absorption. Although the solubility of the active ingredient is improved by using 50% propylene glycol, it is prone to cause problems such as dermatitis and dandruff, with poor irritation and compliance. In Chinese Patent Application CN102349913A, a high-concentration glycerol-based minoxidil tincture and its preparation method mentioned that no matter how the proportions of water, ethanol, and glycerol are adjusted in the mixed solvent of minoxidil, the minoxidil concentration cannot reach more than 2%. It can be seen that the problem of difficult dissolution of minoxidil has always been the main problem faced in the preparation process. How to improve the dissolution performance of minoxidil and increase the content of minoxidil in the preparation has also become a key point in subsequent research.

[0003] Drug nanonization refers to preparing drugs into nanoparticles at the nanoscale. For some poorly soluble drugs, nanonization can significantly increase their surface area to volume ratio, thereby enhancing the dissolution rate and solubility of the drugs. However, the content of stabilizers in most of the current commercially available nanocrystal suspensions is relatively large, and even the content of stabilizers is greater than the content of the drug itself. These high contents of stabilizers may, to a certain extent, affect the drug delivery effect or preparation efficiency. Taking the minoxidil nanocrystal suspension as an example, Chinese Patent Application CN116919898A, a minoxidil nanocrystal suspension composition, a minoxidil nanocrystal suspension and its preparation method and application, discloses the use of wet media milling and vitamin E polyethylene glycol succinate as a stabilizer to prepare a minoxidil nanocrystal suspension with a particle size of 300 nm and PDI = 0.4. Its particle size distribution is not uniform enough, and large particles can be seen in the characterization test. Moreover, the content of the stabilizer and auxiliary agent used in this technology is more than the drug content, which may affect the further use of minoxidil.

[0004] Due to the unique physical and chemical properties of minoxidil, it is very difficult to process it into nanoparticles at the nanoscale and maintain stability. At the same time, due to the characteristics of the application field of minoxidil itself, it further increases the difficulty of preparing the minoxidil nanocrystal suspension. Therefore, there is an urgent need for a minoxidil nanocrystal suspension with small size, uniform dispersion, stable suspension, safe to use, and suitable for large-scale industrial production, as well as a preparation method thereof. Summary of the Invention

[0005] To solve the problems existing in the prior art, the present invention provides a minoxidil nanocrystal suspension and a preparation method thereof, which can achieve precise control of the small average particle size and narrow distribution of the minoxidil nanocrystal suspension, solve the problem that the minoxidil nanocrystal suspension is prone to aggregation and precipitation, and have high storage stability. The method of the present invention has low cost and is convenient for industrialization.

[0006] To achieve the above-mentioned invention purpose, the present invention provides the following technical solutions: A preparation method of a minoxidil nanocrystal suspension, comprising the following steps:

[0007] S1. Add a stabilizer to water under stirring conditions, and after stirring evenly, obtain a stabilizer mixture; the stabilizer includes a non-ionic surfactant;

[0008] S2. Add minoxidil to the stabilizer mixture to obtain a minoxidil mixture. After stirring the minoxidil mixture to room temperature, put it into a high-speed shearing machine for pre-shearing until it is evenly mixed, and then prepare a coarse suspension;

[0009] S3. Grind the coarse suspension, and after the grinding is completed, filter it to obtain a minoxidil nanocrystal suspension.

[0010] By combining the method of mixing a stabilizer including a non-ionic surfactant with minoxidil and then performing pre-shearing, the present invention can achieve precise control of the small average particle size and narrow distribution of the nanocrystal suspension without adding other redundant components.

[0011] Further, the non-ionic surfactant includes hydroxypropyl cellulose.

[0012] Further, the non-ionic surfactant also includes one or more of hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, Tween, and polyvinylpyrrolidone.

[0013] Further, the stabilizer also includes an ionic surfactant.

[0014] Further, the ionic surfactant is selected from one or more of stearic acid, sodium cholate, sodium deoxycholate, cetyltrimethylammonium bromide, and lecithin.

[0015] The minoxidil nanocrystal suspension of the present invention can prepare a stable nano-suspension by using a non-ionic polymer as a stabilizer. When the stabilizer is hydroxypropyl cellulose (HPC), and combined with various parameters in the grinding process, precisely controlling the dissolution conditions of HPC and the degree of wetting and binding with minoxidil can reduce the particle size and monodispersity coefficient of the prepared nanocrystal suspension, improve the stability of the nanocrystal suspension, including particle size stability and suspension stability of the suspension, and then prepare a minoxidil nanocrystal suspension with small size, uniform dispersion and stable suspension. Under this condition, the drug particles can be effectively wetted, and sufficient steric hindrance and / or electrostatic barrier can be provided for the drug particles to prevent aggregation over time.

[0016] Furthermore, the mass percentage content of the stabilizer in the stabilizer mixture is 0.1 - 1.0%.

[0017] More specifically, the stabilizer is a compound of hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP) and sodium cholate with a mass ratio of (0.1 - 1.0):(0.2 - 0.6):(0.1 - 0.7).

[0018] The minoxidil nanocrystal suspension prepared by using a single non-ionic polymer or a charged ionic surfactant alone shows an unstable trend in terms of particle size, monodispersity coefficient or suspension stabilizer (presence or absence of precipitation), and particle aggregation occurs, that is, the particle size and PDI increase or the suspension shows unstable sedimentation. In order to further obtain a minoxidil nanocrystal suspension with smaller particle size and stability, the present invention can further improve the particle size and stability of the minoxidil nanocrystal suspension stored at different temperatures by using a compound of hydroxypropyl cellulose (HPC), PVP and sodium cholate with a specific ratio. The compounding of different surfactants can achieve an effect of 1 + 1 > 2. The analysis shows that when using HPC or other stabilizers alone, the steric hindrance or electrostatic repulsion provided is not sufficient to stabilize the minoxidil nanocrystal suspension. At the same time, because minoxidil is a highly hydrophobic drug, under the hydrophobic effect, there is a balance between the repulsive potential energy and attractive potential energy of minoxidil particles. At this time, when adding a stabilizer, it must be able to overcome the van der Waals force or the attractive interaction between particles to disperse the particles, which means that the repulsive interaction provided by the stabilizer in the system must be greater than the attractive interaction between drugs. The compound stabilizer can simultaneously provide steric hindrance and electrostatic repulsion for the drug, thereby obtaining a minoxidil nanocrystal suspension with smaller particle size and stability, and improving the storage stability at the same time.

[0019] Furthermore, the mass percentage content of minoxidil in the mixture in step S2 is 0.5 - 15%.

[0020] Further, the conditions for pre-shearing in step S2 are as follows: the shearing speed is 3500 - 7000 rpm / min, the shearing time is 5 - 20 min, and the shearing temperature is 20 - 35 °C.

[0021] In the present invention, after the stabilizer and minoxidil are mixed and dissolved, pre-shearing is carried out by a high-speed shearing machine and then grinding is carried out, which can improve the particle size and dispersion uniformity of the minoxidil nanocrystal suspension. It is found during the experiment that under specific pre-shearing conditions, the pre-shearing method can produce a synergistic effect with the stabilizer to prepare a minoxidil nanocrystal suspension with good storage stability under different temperature conditions.

[0022] Further, the stirring speed in both step S1 and step S2 is 200 - 1000 rpm / min.

[0023] Further, the coarse suspension is mixed with zirconia beads for grinding; the volume ratio of the coarse suspension to the zirconia beads is 1:0.5 - 5, and the diameter of the zirconia beads is 0.2 - 1.0 mm.

[0024] Further, the grinding parameters in step S3 are as follows: the rotation speed is 200 - 2000 rpm, the grinding temperature is 4 - 40 °C, and the grinding time is 0.5 - 4 h.

[0025] Further, filtration is carried out under a standard sieve, and the specification of the standard sieve is 50 - 100 mesh.

[0026] The second aspect of the present invention provides the minoxidil nanocrystal suspension prepared by the above preparation method.

[0027] Further, the minoxidil nanocrystal suspension is used for preparing drugs for treating androgenetic alopecia, alopecia areata, chemotherapy-induced alopecia, and intractable hypertension.

[0028] A lyoprotectant is added to the minoxidil nanocrystal suspension prepared in the present invention. After complete pre-freezing, it is placed in a vacuum freeze dryer for vacuum drying overnight to obtain minoxidil nanocrystal lyophilized powder.

[0029] The lyoprotectant is selected from at least one of trehalose, mannitol, sucrose, glucose, lactose, sorbitol, and fructose.

[0030] The mass percentage of the lyoprotectant in the minoxidil nanocrystal suspension is 0.05 - 5.0%.

[0031] The pre-freezing conditions are pre-freezing completely for 0.5 - 4 h under one of the conditions of liquid nitrogen, -80 °C, or a cold trap.

[0032] Compared with the prior art, the present invention has achieved beneficial technical effects:

[0033] 1. A minoxidil nanocrystal suspension with small size, uniform dispersion and stable suspension was prepared. A wet media ball milling method was provided, which can nanonize drugs without using carriers or organic solvents, and avoid the problems of subsequent formulation use and safety caused by high-concentration stabilizers. Through the synergistic effect of using a specific stabilizer prescription ratio, pre-shearing process adjustment and operation parameter optimization, a minimal amount of stabilizer (<1.0 wt.%) can fully infiltrate drug particles and stabilize the nanocrystal suspension, realizing the preparation of small-size minoxidil nanocrystals;

[0034] 2. The present invention provides a method for preparing a minoxidil nanocrystal suspension. By using a stable wet media ball milling technology, the energy utilization efficiency is greatly improved, and the preparation of minoxidil nanocrystals can be completed only through ball milling and a small amount of stabilizer compounding dosage;

[0035] 3. In the process of converting the preparation of minoxidil nanocrystal suspension from small-scale to large-scale production, maintaining the consistency of product quality is an important challenge. During scale-up production, new problems may occur, such as uneven mixing and particle morphology changes. Traditional ultrasound is difficult to scale up, and the centrifugation treatment step is long. Through the synergistic effect of pre-shearing and stabilizers, ultrasound and centrifugation are not required, and the prepared particles are smaller and more uniform without bimodality. The preparation conditions of the present invention are mild, and do not change the crystal structure of minoxidil nanocrystals, which can be applied to large-scale production and has extremely high economic value and market prospects;

[0036] 4. Through the synergistic effect of stabilizers and pre-shearing treatment, the prepared minoxidil nanocrystal suspension has excellent long-term storage stability under different temperature conditions;

[0037] 5. In the present invention, the affinity between HPC and minoxidil is the best. By compounding HPC with other non-ionic polymers and charged ionic surfactants, better steric hindrance and electrostatic repulsion can be provided for the nanocrystal suspension. At the same time, the use of compounded stability can make the stability and release degree of the minoxidil nanocrystal suspension better;

[0038] 6. By adjusting the type and dosage of stabilizers, using non-ionic polymers and charged ionic surfactants to provide steric hindrance and electrostatic repulsion simultaneously to reduce the particle size of drugs and stabilize the nanocrystal suspension, and by using the method of high-speed pre-shearing to fully infiltrate drug particles with stabilizers before ball milling, the drugs can be nanonized without using carriers or organic solvents, improving the water solubility of drugs, and avoiding the influence of high-concentration stabilizers on subsequent formulations and the drugs themselves. By optimizing the operation parameters of the ball milling machine and the content of stabilizers in the suspension, the preparation of a minoxidil nanocrystal suspension with small size, uniform dispersion, stable suspension, good solubility and safe energy-saving is realized. Brief Description of the Drawings

[0039] Figure 1 It is a process schematic diagram of the preparation method of the minoxidil nanocrystal suspension of the present invention;

[0040] Figure 2 It is a schematic diagram of the minoxidil nanocrystal suspension prepared in Example 3;

[0041] Figure 3 It is a schematic diagram of the dynamic light scattering particle size distribution in Example 3;

[0042] Figure 4 It is a schematic diagram of the dynamic light scattering particle size distribution in Comparative Example 1;

[0043] Figure 5 It is a schematic diagram of the Zeta potential in Example 3;

[0044] Figure 6 It is a SEM scanning schematic diagram of the minoxidil raw material drug;

[0045] Figure 7 It is a SEM scanning schematic diagram of the minoxidil nanocrystal suspension in Example 3;

[0046] Figure 8 It is the XRD pattern of the minoxidil nanocrystal suspension and the minoxidil raw material drug in Example 3;

[0047] Figure 9 It is the FTIR spectrum of the minoxidil nanocrystal suspension and the minoxidil raw material drug in Example 3;

[0048] Figure 10 It is the UV-Vis scanning spectrum of the minoxidil nanocrystal suspension and the minoxidil raw material drug in Example 3;

[0049] Figure 11 It is the in vitro release curve of the minoxidil nanocrystal suspension and the minoxidil raw material drug in Example 3;

[0050] Figure 12 It is the in vitro release curve of the minoxidil nanocrystal suspension in Example 3, Example 6, Comparative Example 1 and Comparative Example 2. Detailed Description of the Embodiments

[0051] In order to enable those skilled in the art to better understand this solution, the following further elaborates on this solution in conjunction with specific embodiments. The process methods used in the embodiments are all conventional methods unless otherwise specified; the materials used, unless otherwise specified, can all be obtained from commercial channels.

[0052] The influence of different HPC dosages in Examples 1-4 on the preparation of the minoxidil nanocrystal suspension.

[0053] As Figure 1 shown, this embodiment provides a minoxidil nanocrystal suspension, and its preparation method includes the following steps:

[0054] S1. Slowly add hydroxypropyl cellulose (the addition dosage is shown in Table 1) to 100 mL of water. After stirring until it is completely dissolved, then add 0.25 g of polyvinylpyrrolidone (PVP-K30, average molecular weight 58000) and 0.25 g of sodium cholate, and stir at 500 rpm / min until completely dissolved to obtain a stabilizer mixture for later use;

[0055] S2. Add 10 g of minoxidil to every 100 mL of the stabilizer mixture to obtain a minoxidil mixture. Stir at a speed of 1000 rpm for 10 min. After the minoxidil mixture returns to room temperature, place it on a high-speed shearer for shearing at a temperature of 25°C and a speed of 5000 rpm for pre-shearing for 10 min to obtain a coarse suspension;

[0056] S3. Use a centrifugal ball mill to transfer the coarse suspension to a grinding tank. With the set grinding parameters: the diameter of the grinding beads (zirconia beads) is 0.4 - 0.5 mm, the speed is 450 rpm, and the ratio of the coarse suspension to the grinding beads is 1:1.5 (volume ratio). After grinding for 3 h, pass through a 100-mesh standard sieve to obtain the minoxidil nanocrystal suspension.

[0057] The steps to prepare the minoxidil nanocrystal suspension into a freeze-dried powder are as follows: Add 2 g of mannitol (freeze-drying protectant) to every 100 mL of the suspension. After pre-freezing completely at -80°C, place it in a vacuum freeze-dryer for vacuum drying overnight to obtain the minoxidil nanocrystal freeze-dried powder.

[0058] According to the above operations of S1 - S3, the minoxidil nanocrystal suspension is subjected to dynamic light scattering (DLS) testing, and the results are recorded in Table 1.

[0059]

[0060] From the data in Table 1, it can be seen that when the content of other stabilizers is fixed and the dosage in the HPC system is changed, it has a certain influence on the particle size of the suspension, showing that the particle size first decreases and then increases with the addition amount of HPC. Figure 2 It is a schematic diagram of the minoxidil nanocrystal suspension prepared in Example 3.

[0061] Example 5

[0062] The difference between this embodiment and Example 3 is that in step S1, PVP is not added, and 0.65 g of HPC and 0.25 g of sodium cholate are compounded to obtain a stabilizer mixture. Then, follow the subsequent steps of Example 3 to prepare the minoxidil nanocrystal suspension and characterize its results.

[0063] Example 6

[0064] The difference between this example and Example 3 is that in step S1, only 0.9 g of HPC is added to prepare a stabilizer mixture. Then, follow the subsequent steps of Example 3 to prepare a minoxidil nanocrystal suspension and characterize its results.

[0065] Example 7

[0066] The difference between this example and Example 3 is that in step S1, only 0.9 g of polyvinylpyrrolidone (PVP) is used as the stabilizer to prepare a stabilizer mixture. Then, follow the subsequent steps of Example 3 to prepare a minoxidil nanocrystal suspension and characterize its results.

[0067] Example 8

[0068] The difference between this example and Example 3 is that in step S1, only 0.9 g of sodium cholate is used as the stabilizer to prepare a stabilizer mixture. Then, follow the subsequent steps of Example 3 to prepare a minoxidil nanocrystal suspension and characterize its results.

[0069] Example 9

[0070] The difference between this example and Example 3 is that in step S1, only 0.9 g of sodium carboxymethyl cellulose is used as the stabilizer to prepare a stabilizer mixture. Then, follow the subsequent steps of Example 3 to prepare a minoxidil nanocrystal suspension and characterize its results.

[0071] Comparative Example 1

[0072] The difference between this comparative example and Example 3 is that in step S1, only 0.9 g of vitamin E polyethylene glycol succinate (ViE-TPGS) is used as the stabilizer, and then follow the subsequent steps of Example 3 to prepare a minoxidil nanocrystal suspension and characterize its results.

[0073] Comparative Example 2

[0074] The difference between this comparative example and Example 3 is that in step S1, only 0.9 g of hydroxypropyl methyl cellulose (HPMC) is used as the stabilizer, and then follow the subsequent steps of Example 3 to prepare a minoxidil nanocrystal suspension and characterize its results.

[0075] Comparative Example 3

[0076] The difference between this comparative example and Example 3 is that in step S1, only 0.9 g of poloxamer 188 (Poloxamer188) is used as the stabilizer, and then follow the subsequent steps of Example 3 to prepare a minoxidil nanocrystal suspension and characterize its results.

[0077] Comparative Example 4

[0078] The difference between this comparative example and Example 3 is that in step S1, only 0.9 g of sodium dodecyl sulfate (SDS) is used as the stabilizer, and then the minoxidil nanocrystal suspension is prepared according to the subsequent steps of Example 1, and its results are characterized.

[0079] Examples 10 - 14 and Comparative Examples 5 - 8

[0080] The differences from Example 3 are as follows: the shearing conditions are different. In step S2, pre-shearing is not carried out, or the shearing speed is adjusted to 3500 rpm, 5000 rpm, 7000 rpm, 9000 rpm, or the shearing time is adjusted to 5 min, 10 min, 20 min, or the shearing temperature is increased to 25 °C, 35 °C, 50 °C, and then direct ball milling is carried out to prepare the minoxidil nanocrystal suspension, and its results are characterized. See Table 3 for details.

[0081] Performance Test

[0082] 1. Evaluate the influence of different types of single stabilizers on the suspension of minoxidil nanocrystals

[0083] The suspension states of the suspensions after standing for 12 h in Examples 6 - 9 and Comparative Examples 1 - 4 are respectively detected and recorded, and the results are recorded in Table 2.

[0084]

[0085] It can be seen from the data in Table 2 that under the same conditions, when using a single stabilizer, the minoxidil nanocrystal suspension prepared with hydroxypropyl cellulose has the highest stability, and only a small amount of precipitation occurs after standing for 12 hours; followed by polyvinylpyrrolidone, sodium cholate, and sodium carboxymethylcellulose, and a large amount of precipitation begins after standing for 12 hours; while the stabilities of vitamin E polyethylene glycol succinate, hydroxypropyl methylcellulose, poloxamer 188, sodium dodecyl sulfate, etc. are the worst, and all precipitate after standing for 12 hours. The chemical name of minoxidil is 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide, which contains two amino structures and a piperidine group. This molecule can provide unique 3 hydrogen bond donors and 3 hydrogen bond acceptors. It should be noted that both HPC and sodium cholate contain rich ether bonds or hydroxyl groups, and also have the functions of hydrogen bond donors and acceptors. They can be combined through intermolecular hydrogen bonds to form a surfactant layer with both steric hindrance and electrostatic barrier effects on the surface of minoxidil nanocrystals, thereby reducing the aggregation of nanocrystals and improving the stability.

[0086] 2. Evaluate the influence of the shearing conditions of HPC on the minoxidil nanocrystal suspension

[0087] The D90 and the suspension states after standing for 12 hours in Examples 6, 10 - 14 and Comparative Examples 5 - 8 are respectively detected and recorded, and the results are recorded in Table 3:

[0088]

[0089] As can be seen from the data in Table 3, the pre-shearing step after mixing HPC and minoxidil before ball milling has a great influence on the particle size and its stability. That is, under the same conditions, if the mixed solution of HPC and minoxidil is not pre-sheared before ball milling, there will be obvious large particles in the prepared nanocrystal suspension, and D90>4000nm. This may be because the mild pre-shearing method can make the stabilizer combine with minoxidil in advance, avoiding the destruction of the structure of a large amount of free stabilizer by the high-energy shearing force generated by the machine operation and the force generated when the medium collides with the drug during ball milling, resulting in the influence of its stability. At the same time, the comparison between Example 6 and Comparative Example 5 can illustrate the influence of the pre-shearing of HPC on the whole system. It shows that the present invention can prepare a nanocrystal suspension with good storage stability only under specific stabilizers and specific pre-shearing conditions.

[0090] Moreover, different HPC treatment conditions also have a certain influence on the particle size and stability of the nanocrystal suspension. As can be seen from the data in Table 2, when the shearing speed exceeds 9000rpm or the shearing temperature is greater than 50°C, the particle size of the nanocrystal suspension will increase sharply and a large amount of precipitation will occur in the suspension, while the shearing time has little effect on the result within 5-20min; when the shearing conditions of HPC are at a shearing speed of 3500-7000rpm, a shearing temperature below 35°C and a shearing time within 5-20min, the particle size and stabilizer of the minoxidil nanocrystal suspension with HPC as the stabilizer are the best.

[0091] The characteristic of the treatment method of HPC in Example 6 of the present invention is to pre-treat HPC mildly, that is, to pre-shear the mixed solution of HPC and minoxidil before ball milling, so that HPC is fully infiltrated and combined on the minoxidil particles, avoiding the destruction of the structure of free HPC by the high-energy shearing force during ball milling, resulting in the influence of its own performance. At the same time, being pre-combined on the drug particles can also provide sufficient steric hindrance and / or electrostatic barrier for the minoxidil particles to prevent aggregation over time.

[0092] 3. Evaluate the influence of the types of individual different stabilizers on the particle size and monodispersity of the minoxidil nanocrystal suspension

[0093] The particle sizes and their monodispersity coefficients at the time of preparation and 14 days later of Examples 6-9 and Comparative Examples 1-4 were detected and recorded respectively, and the results are recorded in Table 4:

[0094]

[0095] From the data in Table 4, it can be seen that under the same conditions, the average particle size of the minoxidil nanocrystal suspension prepared by using stabilizers such as hydroxypropyl cellulose, polyvinylpyrrolidone, sodium cholate, and sodium hydroxypropyl cellulose individually is in the range of 200 - 400 nm, the PDI is in the range of 0.2 - 0.3, the deviation between parallel samples is small, and the stability is high; the particle size is small and evenly dispersed; among them, hydroxypropyl cellulose and polyvinylpyrrolidone are the most stable, and the particle size and PDI hardly change after standing at room temperature for half a month; while the particle size or PDI of sodium cholate, sodium hydroxypropyl cellulose, etc. all show a tendency to increase to varying degrees, and the deviation between parallel samples is huge, and the reproducibility of batch preparation is small.

[0096] Based on the data in Table 3 and Table 4, it can be seen that the overall stability and particle size dispersibility of HPC are the best.

[0097] 4. Evaluate the effect of the compound of HPC and ionic surfactants on the suspension of minoxidil nanocrystals

[0098] The suspension states of the suspensions in Examples 3 and 5 - 6 after standing at room temperature for 12 h were detected and recorded respectively, and the results are recorded in Table 5:

[0099]

[0100] From the results in Table 5, it can be seen that after the compound of the non - ionic polymer HPC and other ionic surfactants, the stability of the minoxidil nanocrystal suspension is improved, and no sedimentation occurs after standing. It shows that the compound of HPC and other ionic surfactants can improve the stability of the minoxidil nanocrystal suspension.

[0101] 5. Evaluate the effect of the compound of HPC and ionic surfactants on the particle size and monodispersity of the minoxidil nanocrystal suspension

[0102] The changes in the particle size and its monodispersity coefficient within 30 days after the preparation of Examples 3 and 5 - 6 were detected and recorded respectively, and the results are recorded in Table 6:

[0103]

[0104] From the data in Table 6, it can be seen that after the compound of HPC and ionic surfactants, its particle size or monodispersity coefficient has decreased to varying degrees. Combining the data in Table 5, it can be known that the compound of HPC and ionic surfactants can provide a smaller particle size and higher suspension stability than those containing only HPC or ionic surfactants, that is, the simultaneous presence of steric hindrance and electrostatic repulsion in the suspension system can achieve better stability and reduce the particle size and monodispersity coefficient.

[0105] Detect the Zeta potential of the minoxidil nanocrystal suspension prepared in Example 3, as Figure 3 、 Figure 5 shown, compared with Figure 4Comparing shows that the absolute value of the Zeta potential in Example 3 is high (the Zeta potential is -33.54), indicating that the suspension is a stable system.

[0106] The SEM of the minoxidil nanocrystal suspension and minoxidil raw material prepared in Example 3 was tested, as Figures 6 - 7 shown. The particle size in Example 3 is much smaller than that of the raw material drug and is uniform respectively. It shows that the minoxidil nanocrystal suspension obtained in Example 3 is a nanoparticle with a small and uniform particle size.

[0107] The XRD of the minoxidil nanocrystal lyophilized powder and minoxidil raw material prepared in Example 3 was tested (the test angle 2θ is in the range of 5 - 80°, the test step size is 0.04, and the integration time is 0.5 s), as Figure 8 shown. The crystal structure of the minoxidil nanocrystal is similar to that of the minoxidil raw material drug, indicating that the structure of the minoxidil nanocrystal obtained in Example 3 has not changed during the preparation process.

[0108] The FTIR of the minoxidil nanocrystal lyophilized powder and minoxidil raw material prepared in Example 3 was tested (the scanning wavelength is 400 - 4000 cm-1), as Figure 9 shown. The spectrum of the minoxidil nanocrystal is basically the same as that of the raw material drug, indicating that the crystal form structure of the minoxidil nanocrystal obtained in Example 3 has not changed during the preparation process. It solves the problem in the prior art that ball milling in the preparation of some minoxidil suspensions may cause crystal transformation, which may have an adverse impact on the performance and efficacy of the drug. The technical solution of the present invention can avoid this problem.

[0109] The absorption wavelengths of the minoxidil nanocrystal suspension and minoxidil raw material prepared in Example 3 were scanned under ultraviolet light (the scanning wavelength is 200 - 400 nm), as Figure 10 shown. Both the minoxidil nanocrystal suspension and the minoxidil raw material drug have absorption peaks at 229 nm, 262 nm, and 287 nm, among which 229 nm is the maximum absorption wavelength, indicating that the structure of the minoxidil nanocrystal obtained in Example 3 has not changed during the preparation process.

[0110] 6. The nanocrystal suspensions prepared in Example 3, 5, 6 and Comparative Example 5 were respectively placed at 4°C, 25°C (room temperature), and 40°C for 9 months and then detected. The results are shown in Table 7.

[0111]

[0112] As can be seen from Table 7, after the minoxidil nanocrystal suspensions prepared in Examples 3, 5, and 6 were stored at different temperatures, the particle size, PDI, and D90nm had better stability, significantly superior to that of Comparative Example 5. Among them, the overall effect of Example 3 was better. This indicates that the compounded stabilizer and pre-shearing treatment have an important impact on the stability of the minoxidil nanocrystal suspension at different temperatures.

[0113] 7. In vitro release test

[0114] The in vitro release of the minoxidil nanocrystal suspensions and / or minoxidil raw material drug prepared in Example 3, Example 6, and Comparative Examples 1-2 was tested. The specific operation was as follows: The minoxidil nanocrystal suspensions of Example 3, Example 6, and Comparative Examples 1-2 and their minoxidil raw material drug solutions with the same concentration were loaded into a 30KDa dialysis bag and placed in 500 mL of PBS7.4 with a volume ratio of 1X of the coarse suspension to zirconia beads. Stirred in a water bath at 37°C. 5 mL of the dissolution medium (PBS) was taken for detection (UV, 230 nm) at 10 min, 20 min, 40 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 22 h respectively, and an equal volume of fresh PBS was taken to make up for it. The results are as Figure 11 shown. The in vitro release rate of the minoxidil raw material drug is not as good as that of the minoxidil nanocrystals. The dissolution of the minoxidil nanocrystals releases about 90% within 4 h, while the raw material drug is only about 50%. This shows that the minoxidil nanocrystal suspension prepared in Example 3 has better release and transdermal effects than the minoxidil raw material drug; Figures 11 - 12 shown. The release rule of the suspensions with different particle sizes in PBS7.4 as the dissolution medium is that the smaller the particle size, the faster the release rate, indicating that the minoxidil nanocrystal suspension with a smaller particle size may have a better penetration-enhancing effect. Through the synergistic effect of the compounded stabilizer and pre-shearing in the present invention, the minoxidil nanocrystals have better release effects and transdermal effects.

[0115] The above are only the embodiments of the present application. The protection scope of the present application is not limited by these specific embodiments, but is determined by the claims of the present application. For those skilled in the art, the protection scope of the present invention should be substitutions and modifications that do not deviate from the present invention and are covered by the rights of this patent application.

Claims

1. A method for preparing a minoxidil nanocrystal suspension, characterized in that: The following steps are involved: S1. Add a stabilizer to water under stirring conditions, and stir evenly to obtain a stabilizer mixture; the stabilizer is a compound of hydroxypropyl cellulose, polyvinyl pyrrolidone and sodium cholate in a mass ratio of (0.1-1.0): (0.2-0.6): (0.1-0.7); the mass percentage of the stabilizer in the stabilizer mixture is 0.1-1.0%; S2, adding minoxidil to the stabilizer mixture to obtain a minoxidil mixture, stirring the minoxidil mixture to room temperature, and then placing it in a high-speed shearing machine for pre-shearing, the pre-shearing conditions are: shearing speed of 3500-7000rpm / min, shearing time of 5-20min, shearing temperature of 20-35°C, until the mixture is uniformly mixed to obtain a coarse suspension; S3, grinding the coarse suspension, and filtering after grinding to obtain a minoxidil nanocrystal suspension.

2. The method for preparing a minoxidil nanocrystal suspension according to claim 1, wherein In step S2, the mass percentage of minoxidil in the mixed solution is 0.5-15%.

3. A minoxidil nanocrystal suspension prepared by the preparation method according to any one of claims 1 to 2.

4. The minoxidil nanocrystal suspension according to claim 3 is used to prepare a medicine for treating androgenic alopecia, alopecia areata, chemotherapy-induced alopecia, and refractory hypertension.

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