Minoxidil nanocrystal freeze-dried powder as well as preparation method and application thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to minoxidil nanocrystal freeze-dried powder as well as a preparation method and application thereof. The freeze-dried powder comprises the following components in parts by weight: 0.1-2 parts of minoxidil, 1-5 parts of vitamin E polyethylene glycol succinate and 2-10 parts of an auxiliary agent. The freeze-dried powder is prepared through the steps of mixing, hydration, ultrasonic treatment, freeze-drying and the like. The minoxidil nanocrystal freeze-dried powder provided by the invention can solve the problem of indissolvability of minoxidil raw material medicines, improves the dissolution speed, stability and bioavailability, has no irritation and no anaphylaxis, has a remarkable treatment effect, is accurate in dosage control, is simple in preparation process operation, and can be used for treating various alopecia problems such as male alopecia, alopecia areata and the like.

Description

[0001] Cross-references

[0002] This application claims priority to the Chinese patent application filed on September 15, 2023, with application number 202311189296.1 and invention name “Minoxidil Nanocrystalline Lyophilized Powder, Preparation Method and Application Thereof”, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a minoxidil nanocrystalline freeze-dried powder and a preparation method and application thereof. Background Art

[0004] Hair loss is not only a physiological change, but also a physical and mental harm to people. It may affect personal image, self-esteem, emotional health and social interaction, thus affecting the overall quality of life. Therefore, it is particularly important to focus on mental health support and positive self-coping strategies for hair loss issues.

[0005] Hair loss is divided into normal hair loss and pathological hair loss. Male pattern baldness is a multi-gene recessive genetic disease with a genetic tendency, accounting for 95% of total hair loss. Male pattern baldness caused by genetics and hormonal imbalance mainly affects men. Hormonal imbalance, especially the effects of testosterone (male hormone), can cause hair follicles to become smaller and smaller, eventually resulting in the inability of fine hair to grow. As a result, male pattern baldness gradually reduces hair, especially at the hairline and top of the head, forming a typical "M" shape or bald head.

[0006] Currently, the FDA has only approved two drugs for the treatment of male pattern baldness, namely minoxidil and finasteride. Minoxidil is a topical medication that was originally used as a drug to treat high blood pressure. However, it was found that new hair may grow on the head when minoxidil is used. Therefore, minoxidil is approved for the treatment of male pattern baldness as a topical liquid or foam. It usually needs to be used every day, can help slow the rate of hair loss, and help promote some hair regrowth. However, its effects may vary from person to person, and may be less effective for some people. Oral minoxidil can cause systemic reactions, acts on the hair follicle area with less content, and is irritating to the cardiovascular system. Therefore, topical use is the best choice.

[0007] The main dosage forms for external use are mainly concentrated in aerosols, liniments, and tinctures. The concentrations of existing products are 2% and 5%. However, for common ordinary liquid preparations, due to the poor solubility of minoxidil raw materials, the current preparation technology is mostly to directly dissolve in solvents, and usually requires the addition of high-concentration organic reagents for dissolution, such as propylene glycol and ethanol. Among them, propylene glycol is used as a penetration enhancer and solubilizer, and the concentration is often as high as 30-50%. If propylene glycol is not included, the solubility of minoxidil is difficult to reach more than 2%. Therefore, most patients will cause local skin allergies and irritation after using solutions containing high concentrations of organic reagents, thereby affecting the growth of hair. At the same time, propylene glycol also has a sticky nature. After use, the hair will be greasy and have a peculiar smell, resulting in poor compliance of patients and difficulty in persisting in use. If the solvent is an ethanol solution, the residence time at the treatment site is short, it evaporates quickly, and the drug precipitates and adheres to the hair, and the therapeutic concentration is not reached, so the number of administrations needs to be increased. In addition, ethanol is also irritating, increasing the patient's discomfort.

[0008] Nanocrystal technology is a method of preparing drug micron-sized particles into nano-sized particles. It can increase the solubility and bioavailability of drugs, thereby improving drug absorption and distribution. Combining nanocrystal technology with the lyophilization (freeze drying) process to prepare nanocrystal lyophilized powder can bring significant advantages in drug stability and efficacy.

[0009] The prior art lacks a nanocrystalline lyophilized powder preparation with minoxidil as an active ingredient, and the preparation should have excellent dissolution rate, stability and bioavailability. Summary of the invention

[0010] The purpose of the present invention is to overcome the above-mentioned problems existing in the prior art and to provide a minoxidil nanocrystalline freeze-dried powder and a preparation method and application thereof.

[0011] In order to achieve the above-mentioned object, the first aspect of the present invention provides a minoxidil nanocrystalline freeze-dried powder, wherein the freeze-dried powder comprises the following components in parts by weight: 0.1-2 parts of minoxidil, 1-5 parts of vitamin E polyethylene glycol succinate and 2-10 parts of an auxiliary agent.

[0012] The second aspect of the present invention provides a method for preparing the minoxidil nanocrystalline freeze-dried powder according to the first aspect, comprising the following steps:

[0013] (1) mixing minoxidil and vitamin E polyethylene glycol succinate in an organic solvent, and then drying the organic solvent by spin drying;

[0014] (2) adding an inorganic solvent to the dried product for hydration;

[0015] (3) after vortexing the hydrated product, performing a first ultrasound in an ice water bath, and then performing a second ultrasound using a probe;

[0016] (4) centrifuging the second ultrasonic product and discarding the supernatant;

[0017] (5) adding an inorganic solvent to the lower precipitate, resuspending it, and then performing a third ultrasound with a probe to obtain a nanocrystal solution;

[0018] (6) Freezing the nanocrystal solution and then freeze-drying it to obtain freeze-dried powder.

[0019] The third aspect of the present invention provides the use of the minoxidil nanocrystalline freeze-dried powder described in the first aspect in an anti-hair loss and hair growth product.

[0020] Through the above technical solution, the beneficial technical effects achieved by the present invention are as follows:

[0021] The minoxidil nanocrystal freeze-dried powder provided by the present invention can solve the problem of poor solubility of the minoxidil raw material drug, improve the dissolution rate, stability and bioavailability, is non-irritating and non-allergenic, has significant therapeutic effect, precise dosage control, and a simple preparation process, and can be used to treat various hair loss problems such as male pattern baldness and alopecia areata. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 These are the experimental results of the permeability of minoxidil nanocrystalline freeze-dried powder prepared in Examples 1-3 of the present invention and Comparative Examples 1-3 in pig skin at different time points.

[0023] Figure 2 These are the experimental results of the dissolution rates of minoxidil nanocrystalline freeze-dried powders prepared in Examples 1-3 of the present invention and Comparative Examples 1-3 at different time points. DETAILED DESCRIPTION

[0024] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0025] The first aspect of the present invention provides a minoxidil nanocrystalline freeze-dried powder, which comprises the following components in parts by weight: 0.1-2 parts of minoxidil, 1-5 parts of vitamin E polyethylene glycol succinate and 2-10 parts of an auxiliary agent.

[0026] In the present invention, the minoxidil nanocrystalline freeze-dried powder includes a specific content of minoxidil, vitamin E polyethylene glycol succinate (TPGS) and an auxiliary agent. Its greatest feature is that it greatly improves the dissolution rate and stability of minoxidil, increases the bioavailability of the drug, does not contain an extremely low content of organic reagents, and avoids irritation to local skin.

[0027] The weight portion of the minoxidil can be selected from 0.1 part, 0.3 part, 0.5 part, 0.8 part, 1 part, 1.2 parts, 1.5 parts, 1.8 parts, 2 parts, and any value in the range consisting of any two of the above values.

[0028] The weight proportion of the vitamin E polyethylene glycol succinate can be 1 part, 2 parts, 3 parts, 4 parts, 5 parts, and any value in the range consisting of any two of the above values.

[0029] The weight proportion of the auxiliary agent can be 2 parts, 4 parts, 6 parts, 8 parts, 10 parts, or any value within the range of any two of the above values.

[0030] In some embodiments of the present invention, the weight average molecular weight of the vitamin E polyethylene glycol succinate is 1000-2000 g / mol, preferably 1513 g / mol.

[0031] In the present invention, the weight average molecular weight is measured by gel chromatography.

[0032] In some preferred embodiments of the present invention, the auxiliary agent further comprises at least one of mannitol and trehalose, preferably trehalose.

[0033] In some embodiments of the present invention, the lyophilized powder comprises the following components in parts by weight: 0.5 parts of minoxidil, 2.5 parts of vitamin E polyethylene glycol succinate and 4 parts of trehalose.

[0034] The invention prepares minoxidil into a nanocrystalline freeze-dried powder form, which can be stored for a long time. When used, a solvent is added to restore it to a solution form, which is convenient for use. After the minoxidil nanocrystalline freeze-dried powder is reconstituted, it is applied topically, the drug is absorbed through the skin, the adhesion to the surface is increased, and the saturation rate is increased, thereby improving the problem of low bioavailability of poorly soluble drugs.

[0035] The second aspect of the present invention provides a method for preparing the minoxidil nanocrystalline freeze-dried powder according to the first aspect, comprising the following steps:

[0036] (1) mixing minoxidil and vitamin E polyethylene glycol succinate in an organic solvent, and then drying the organic solvent by spin drying;

[0037] (2) adding an inorganic solvent to the dried product for hydration;

[0038] (3) after vortexing the hydrated product, performing a first ultrasound in an ice water bath, and then performing a second ultrasound using a probe;

[0039] (4) centrifuging the second ultrasonic product and discarding the supernatant;

[0040] (5) adding an inorganic solvent to the lower precipitate, resuspending it, and then performing a third ultrasound with a probe to obtain a nanocrystal solution;

[0041] (6) Freezing the nanocrystal solution and then freeze-drying it to obtain minoxidil nanocrystal freeze-dried powder.

[0042] In the present invention, minoxidil, vitamin E polyethylene glycol succinate and adjuvants are used as raw materials, and the minoxidil nanocrystalline freeze-dried powder obtained through specific operating steps can improve the dissolution rate and stability of minoxidil, thereby providing bioavailability, and is non-irritating to the skin, and has a significant effect in treating hair loss.

[0043] In some embodiments of the present invention, the organic solvent in step (1) is selected from at least one of methanol, acetonitrile and ethanol.

[0044] In some embodiments of the present invention, the organic solvent is spin-dried using a thin film dispersion method.

[0045] In some embodiments of the present invention, the drying conditions include: vacuum drying; a drying time of 60-120 min, for example, 60 min, 70 min, 80 min, 90 min, 100 min, 110 min, 120 min, and any value in the range composed of any two of the above values, or 90 min.

[0046] In some embodiments of the present invention, the hydration time in step (2) is 20-60 min, for example, 20 min, 30 min, 40 min, 50 min, 60 min, and any value in the range of any two of the above values, or 40 min.

[0047] In some embodiments of the present invention, the inorganic solvent is selected from at least one of pure water, physiological saline and PBS.

[0048] In some embodiments of the present invention, the vortexing time in step (3) is 4-14 minutes, such as 4 minutes, 6 minutes, 8 minutes, 10 minutes, 12 minutes, 14 minutes, and any value in the range of any two of the above values, or 10 minutes. The vortexing operation is to shake the thin film evaporated on the wall of the conical flask into the aqueous solution.

[0049] In some embodiments of the present invention, the first ultrasonic time is 4-14 minutes, such as 4 minutes, 6 minutes, 8 minutes, 10 minutes, 12 minutes, 14 minutes, and any value in the range of any two of the above values, or 10 minutes. The purpose of ultrasonication in an ice water bath is to initially shake down large particles.

[0050] In some embodiments of the present invention, the second ultrasound duration is 1-9 min, such as 1 min, 3 min, 5 min, 7 min, 9 min, and any value in the range of any two of the above values, or 5 min. The probe ultrasound is used to give greater energy to shake large particles into small particles.

[0051] In some embodiments of the present invention, the centrifugation conditions in step (4) include: a centrifugation rate of 10000-20000 rpm, for example, 10000 rpm, 12000 rpm, 14000 rpm, 16000 rpm, 18000 rpm, 20000 rpm, and any value in the range consisting of any two of the above values, or 14000 rpm; a centrifugation time of 0.5-2 h, for example, 0.5 h, 1 h, 1.5 h, 2 h, and any value in the range consisting of any two of the above values, or 1 h.

[0052] In some embodiments of the present invention, the time of the third ultrasound in step (5) is 1-9 min, for example, 1 min, 3 min, 5 min, 7 min, 9 min, and any value in the range consisting of any two of the above values, or 5 min.

[0053] In some embodiments of the present invention, the freezing temperature in step (6) is -100 to -20°C, for example, -100°C, -80°C, -60°C, -40°C, -20°C, any value in the range of any two of the above values, or -80°C.

[0054] In some embodiments of the present invention, the freeze-drying procedure in step (6) includes: freezing at -60 to -40°C for 5-7h, freezing at -40 to -20°C for 1-3h and starting to evacuate, freezing at -15 to -5°C for 1.5-2.5h, freezing at -4 to 4°C for 3-5h, heating to 5-15°C for 1-3h, heating to 15-25°C for 1-3h, heating to 25-35°C for 2-4h to obtain freeze-dried powder. The low temperature and vacuum conditions during the freeze-drying process can minimize the damage to the bioactive components in the nanocrystalline freeze-dried powder.

[0055] In some embodiments of the present invention, the freeze-drying procedure in step (6) includes: freezing at -50°C for 6 hours, freezing at -30°C for 2 hours and starting vacuuming, freezing at -10°C for 2 hours, freezing at 0°C for 4 hours, heating to 10°C and maintaining for 2 hours, heating to 20°C and maintaining for 2 hours, heating to 330°C and maintaining for 3 hours to obtain minoxidil nanocrystalline freeze-dried powder.

[0056] The third aspect of the present invention provides the use of the minoxidil nanocrystalline freeze-dried powder described in the first aspect in an anti-hair loss and hair growth product.

[0057] In the present invention, the minoxidil nanocrystalline freeze-dried powder can effectively prevent the aggregation and precipitation of particles, improve the stability of the preparation, and thus extend its shelf life. The freeze-dried powder can be conveniently prepared into different dosage forms, such as solid particles, tablets, capsules, etc., to adapt to different uses and routes.

[0058] The present invention will be described in detail below through examples.

[0059] In the following examples and comparative examples, if no specific conditions are specified, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used, if no manufacturer is specified, are all conventional products that can be obtained through commercial channels.

[0060] Sources:

[0061] Minoxidil: purchased from Shanghai McLean Biochemical Technology Co., Ltd.; catalog number: M831481-5g; Cas number: 38304-91-5;

[0062] Vitamin E polyethylene glycol succinate: purchased from Shanghai MacLean Biochemical Technology Co., Ltd.; catalog number: V819469-5g; Cas number: 9002-96-4;

[0063] D-Trehalose: purchased from Shanghai Aladdin Biochemical Technology Co., Ltd.; product number: D110019-5g; CAS number: 99-20-7.

[0064] Example 1

[0065] The minoxidil nanocrystalline freeze-dried powder comprises the following components in parts by weight: 0.5 parts of minoxidil, 2.5 parts of vitamin E polyethylene glycol succinate and 4 parts of trehalose.

[0066] (1) minoxidil and vitamin E polyethylene glycol succinate were first mixed in methanol, and then the organic solvent was dried by a thin film dispersion method and vacuum dried for 90 minutes;

[0067] (2) adding pure water to the dried product for hydration for 40 min;

[0068] (3) After vortexing the hydrated product for 10 min, the product was subjected to a first ultrasonic treatment in an ice water bath for 10 min, and then subjected to a second ultrasonic treatment using a probe for 5 min;

[0069] (4) centrifuging the second ultrasonic product at 14000 rpm for 1 h and discarding the supernatant;

[0070] (5) adding pure water to the lower precipitate, resuspending it, and then performing a third ultrasonic treatment for 5 min using a probe to obtain a nanocrystal solution;

[0071] (6) The nanocrystal solution was frozen at -80°C and then freeze-dried to obtain minoxidil nanocrystal freeze-dried powder. The freeze-drying procedure included: freezing at -50°C for 6 h, freezing at -30°C for 2 h and starting vacuuming, freezing at -10°C for 2 h, freezing at 0°C for 4 h, heating to 10°C and maintaining for 2 h, heating to 20°C and maintaining for 2 h, and heating to 30°C and maintaining for 3 h.

[0072] Example 2

[0073] The minoxidil nanocrystalline freeze-dried powder comprises the following components in parts by weight: 0.1 parts of minoxidil, 5 parts of vitamin E polyethylene glycol succinate and 2 parts of D-trehalose.

[0074] (1) minoxidil and vitamin E polyethylene glycol succinate were first mixed in methanol, and then the organic solvent was dried by a thin film dispersion method and vacuum dried for 60 minutes;

[0075] (2) adding pure water to the dried product for hydration for 20 min;

[0076] (3) After vortexing the hydrated product for 4 minutes, the first ultrasound was performed in an ice water bath for 4 minutes, and then the second ultrasound was performed using a probe for 1 minute;

[0077] (4) centrifuging the second ultrasonic product at 10,000 rpm for 0.5 h and discarding the supernatant;

[0078] (5) adding pure water to the lower precipitate, resuspending it, and then performing a third ultrasound for 1 min using a probe to obtain a nanocrystal solution;

[0079] (6) The nanocrystal solution was frozen at -100°C and then freeze-dried to obtain minoxidil nanocrystal freeze-dried powder. The freeze-drying procedure included: freezing at -60°C for 5 h, freezing at -40°C for 1 h and starting vacuuming, freezing at -15°C for 1.5 h, freezing at 4°C for 5 h, heating to 5°C and maintaining for 3 h, heating to 25°C and maintaining for 1 h, and heating to 25°C and maintaining for 4 h.

[0080] Example 3

[0081] The minoxidil nanocrystalline freeze-dried powder comprises the following components in parts by weight: 2 parts of minoxidil, 1 part of vitamin E polyethylene glycol succinate and 10 parts of D-trehalose.

[0082] (1) minoxidil and vitamin E polyethylene glycol succinate were first mixed in methanol, the organic solvent was dried by thin film dispersion method and vacuum dried for 120 minutes;

[0083] (2) adding pure water to the dried product for hydration for 60 min;

[0084] (3) After vortexing the hydrated product for 14 minutes, the first ultrasound was performed in an ice water bath for 14 minutes, and then the second ultrasound was performed using a probe for 9 minutes;

[0085] (4) centrifuging the second ultrasonic product at 20,000 rpm for 2 h and discarding the supernatant;

[0086] (5) adding pure water to the lower precipitate, resuspending it, and then performing a third ultrasonic treatment using a probe for 9 minutes to obtain a nanocrystal solution;

[0087] (6) The nanocrystal solution was frozen at -20°C and then freeze-dried to obtain minoxidil nanocrystal freeze-dried powder. The freeze-drying procedure included: freezing at -40°C for 7 h, freezing at -20°C for 3 h and starting vacuuming, freezing at -5°C for 2.5 h, freezing at -4°C for 3 h, heating to 15°C and maintaining for 1 h, heating to 15°C and maintaining for 3 h, and heating to 35°C and maintaining for 2 h.

[0088] Comparative Example 1

[0089] Minoxidil nanocrystalline lyophilized powder was prepared according to the method of Example 1, except that vitamin E polyethylene glycol succinate was replaced with an equal amount of poloxamer F127, and the other components remained unchanged.

[0090] Comparative Example 2

[0091] Minoxidil nanocrystalline freeze-dried powder was prepared according to the method of Example 1, except that trehalose was replaced with an equal amount of sucrose.

[0092] Comparative Example 3

[0093] Minoxidil nanocrystalline freeze-dried powder was prepared according to the method of Example 1, except that minoxidil was increased to 5 parts.

[0094] Test Example 1 Particle Size Detection

[0095] The minoxidil nanocrystalline freeze-dried powder obtained in Example 1-3 and Comparative Example 1-3 was added to pure water for re-dissolution to obtain a reconstituted solution, which was placed in a particle size cup and the particle size was measured using a Malvern particle size analyzer.

[0096] The results of dynamic light scattering showed that:

[0097] Example 1: The particle size after redissolution is 420.5 nm, the PDI is 0.699, the zeta potential is close to neutral, and the particle size distribution is uniform.

[0098] Comparative Example 2: The particle size after reconstitution was 732.1 nm, and the PDI was 1. From the particle size and PDI data, the effect was poor.

[0099] Comparative Example 3: The particle size after redissolution is 2409nm, and the PDI is 0.585. From the results, although the PDI has decreased, the particle size is still micron-level, which is inferior to nano-level nanocrystals.

[0100] Test Example 2: Penetration Verification

[0101] Fresh ex vivo pig skin was fixed in a Franz static vertical diffusion cell, with the stratum corneum layer facing the supply cell and the dermis layer facing the receiving cell. 30 parts of ethanol-normal saline were used as the receiving medium, a constant temperature water bath of 37±0.1℃, and constant stirring at 350rpm. After stabilization, the reconstituted solutions of minoxidil nanocrystal freeze-dried powder prepared in Examples 1-3 and Comparative Examples 1-3, the solutions of the above series of reconstituted solutions after being placed for 6 months through accelerated experiments, and the commercially available preparation-Dafeixin minoxidil lotion were applied respectively. The preparation of the reconstituted solution can refer to Test Example 1.

[0102] At different time points (0.5h, 2h, 4h, 8h, 12h, 24h), 1.0mL of transdermal receptor solution was drawn from the receptor pool and an equal volume of fresh receptor solution was added. The permeation amount of each experimental group was measured. After removing the skin and cutting it into pieces, it was immersed in methanol solution to fully dissolve the drug and the drug retention amount of each experimental group was measured (HPLC or fluorescence spectrophotometer). The results are shown in Figure 1 .

[0103] From the experimental results, the minoxidil release content of Example 1 is the highest, which shows that the drug release efficiency under this condition has been significantly improved. The second is Example 3, which also shows relatively good release characteristics although the release amount is not as good as Example 1. These results provide an important reference basis for subsequent optimization and also show the differences in release performance under different experimental conditions.

[0104] Test Example 3: Dissolution Rate Verification

[0105] Drawing of standard curve: accurately weigh 10mg of minoxidil, place it in a 10ml volumetric flask, add 0.1mol / L hydrochloric acid solution to dissolve to the scale, shake well, accurately pipette 1ml of the above stock solution, place it in a 10ml volumetric flask, continue to use 0.1mol / L hydrochloric acid solution to dissolve to the scale, shake well. Repeat the operation 4 times. Accurately pipette 0.1mol / L hydrochloric acid solution as the negative sample solution. Measure the absorbance of the above solution and the negative solution at 281nm respectively, and draw the absorbance and concentration into a standard curve.

[0106] The minoxidil nanocrystal freeze-dried powder obtained in Examples 1-3 and Comparative Examples 1-3 was reconstituted (refer to Test Example 1) to obtain a nanocrystal suspension, 1 mL was placed in a dialysis bag, both ends were tied and placed in a conical flask, the release medium was 0.1 mol / L hydrochloric acid solution, samples were taken at 0.5, 1, 3, 6, 12, and 24 hours, and the corresponding medium was supplemented at the same time. The solution drawn out was detected using an ultraviolet spectrophotometer and brought into the standard curve to calculate the dissolution rate of each group at each time point. Results are shown in Figure 2 .

[0107] The experimental results show that after being prepared into high-quality nanocrystals, the dissolution rate of minoxidil in Example 1 is significantly accelerated.

[0108] Minoxidil has poor water solubility, but by preparing it into nanocrystals, the particle size is greatly reduced, significantly increasing the surface area, thereby improving the solubility and dissolution rate of the drug and accelerating the absorption process. Due to the small particle size of nanocrystals, it can more easily penetrate the skin barrier, enhance local permeability, and increase the effective concentration of the drug in the skin or hair follicles, especially in topical preparations used to treat hair loss.

[0109] Test Example 4: Stability Verification

[0110] The minoxidil nanocrystalline freeze-dried powder obtained in Examples 1-3 and Comparative Examples 1-3 was placed in an environment of 40±2°C and RH75±5% for accelerated testing, and samples were taken at 0, 1, 2, 3, and 6 months for inspection. The inspection indicators included the content of related substances, particle size change, appearance, visible foreign matter, clarity and color of the solution, re-dissolution time, etc. It was found that the particle size of Example 1 maintained good stability and did not change much after being placed for 6 months.

[0111] Table 1 Basic characterization experimental results of minoxidil nanocrystalline freeze-dried powder at different time points in Examples 1-3 and Comparative Examples 1-3

[0112]

[0113]

[0114]

[0115] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A minoxidil nanocrystalline freeze-dried powder, characterized in that: The freeze-dried powder comprises the following components in parts by weight: 0.1-2 parts of minoxidil, 1-5 parts of vitamin E polyethylene glycol succinate and 2-10 parts of auxiliary agents.

2. The freeze-dried powder according to claim 1, wherein The weight average molecular weight of the vitamin E polyethylene glycol succinate is 1000-2000 g / mol, or 1513 g / mol; And / or, the auxiliary agent is selected from at least one of mannitol and trehalose.

3. The freeze-dried powder according to claim 1 or 2, wherein The freeze-dried powder comprises the following components in parts by weight: 0.5 parts of minoxidil, 2.5 parts of vitamin E polyethylene glycol succinate and 4 parts of trehalose.

4. A method for preparing minoxidil nanocrystalline freeze-dried powder according to any one of claims 1 to 3, characterized in that: The following steps are involved: (1) mixing minoxidil and vitamin E polyethylene glycol succinate in an organic solvent, and then drying the organic solvent by spin drying; (2) adding an inorganic solvent to the dried product for hydration; (3) after vortexing the hydrated product, performing a first ultrasound in an ice water bath, and then performing a second ultrasound using a probe; (4) centrifuging the second ultrasonic product and discarding the supernatant; (5) adding an inorganic solvent to the lower precipitate, resuspending it, and then performing a third ultrasound with a probe to obtain a nanocrystal solution; (6) Freezing the nanocrystal solution and then freeze-drying it to obtain minoxidil nanocrystal freeze-dried powder.

5. The preparation method according to claim 4, wherein: The organic solvent in step (1) is selected from at least one of methanol, acetonitrile and ethanol; and / or, spin-drying the organic solvent using a thin film dispersion method; And / or, the drying conditions include: vacuum drying; drying time is 60-120 min, or 90 min.

6. The preparation method according to claim 4, wherein The hydration time in step (2) is 20-60 min, or 40 min; And / or, the inorganic solvent is selected from at least one of pure water, physiological saline and PBS.

7. The preparation method according to claim 4, wherein The vortexing time in step (3) is 4-14 min, or 10 min; And / or, the first ultrasound duration is 4-14 min, or 10 min; And / or, the second ultrasound duration is 1-9 min, or 5 min.

8. The preparation method according to claim 4, wherein The centrifugal conditions in step (4) include: a centrifugal rate of 10000-20000 rpm, or 14000 rpm; a centrifugal time of 0.5-2 h, or 1 h; And / or, the duration of the third ultrasound in step (5) is 1-9 min, or 5 min.

9. The preparation method according to claim 4, wherein: The freezing temperature in step (6) is -100 to -20°C, or -80°C; And / or, the freeze-drying procedure of step (6) includes: freezing at -60 to -40°C for 5-7h, freezing at -40 to -20°C for 1-3h and starting vacuuming, freezing at -15 to -5°C for 1.5-2.5h, freezing at -4 to 4°C for 3-5h, heating to 5-15°C and keeping for 1-3h, heating to 15-25°C and keeping for 1-3h, heating to 25-35°C and keeping for 2-4h to obtain freeze-dried powder; Preferably, the freeze-drying procedure in step (6) includes: freezing at -50°C for 6 hours, freezing at -30°C for 2 hours and starting vacuuming, freezing at -10°C for 2 hours, freezing at 0°C for 4 hours, heating to 10°C and maintaining for 2 hours, heating to 20°C and maintaining for 2 hours, heating to 30°C and maintaining for 3 hours to obtain freeze-dried powder.

10. Use of the minoxidil nanocrystalline freeze-dried powder according to any one of claims 1 to 3 in anti-hair loss and hair growth products.

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