Pharmaceutical composition containing minoxidil, preparation method therefor and use thereof

Abstract

A pharmaceutical composition containing minoxidil, which is composed of minoxidil, a filler, a sustained-release material, a glidant and a lubricant, wherein the specification of minoxidil is 1.25-5.0 mg, and the sustained-release material is selected from hypromellose. The minoxidil composition has a sustained-release effect of 8-12 hours in vitro, has an ideal in-vivo plasma concentration and bioavailability, and ensures the safety and effectiveness of the use of minoxidil.

Description

A pharmaceutical composition containing minoxidil, preparation method and application thereof Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a pharmaceutical composition containing minoxidil, a preparation method and an application thereof. Background Art

[0002] Androgenetic alopecia (AGA), previously known as seborrheic alopecia or premature balding, is a progressive hair loss disorder that occurs during and after puberty. In men, it primarily manifests as a receding hairline on the forehead and / or progressive thinning and thinning of hair on the top of the head, also known as male pattern alopecia. In women, it primarily manifests as progressive thinning and thinning of hair on the top of the head. A smaller percentage of women experience diffuse thinning without a receding hairline, known as female pattern alopecia. The prevalence of AGA varies significantly across different ethnic groups, with a higher incidence in Caucasians and a lower incidence in Blacks and Asians. The latest epidemiological survey in my country shows that the prevalence of AGA in Chinese men is 21.3% and in women is 6.0%. This disease significantly impacts patients' mental health and quality of life. Early diagnosis and appropriate treatment can improve the condition in most patients.

[0003] Minoxidil is a potassium channel opener. Potassium channel opening is an important step in regulating hair growth. In vitro and in vivo experiments on animal models have shown that minoxidil is a potassium channel activator that can increase the permeability of potassium ions and prevent calcium ions from flowing into cells, resulting in a decrease in the concentration of free calcium ions in cells. In the presence of calcium ions, epidermal growth factor inhibits hair growth.

[0004] Minoxidil was first developed by Pfizer and launched in the United States in October 1979. It was marketed as a 2.5mg and 10mg tablet for the treatment of refractory hypertension in adults, with hirsutism being its primary side effect. Based on this discovery, Johnson & Johnson developed a topical minoxidil solution for the treatment of hair loss in both men and women. The 2% solution was launched in the United States in August 1988. In November 1997, Johnson & Johnson developed a 5% topical solution for the treatment of male pattern baldness. In 2006, Johnson & Johnson refined the solution and developed a 5% minoxidil foam. Currently, all approved minoxidil formulations for the treatment of hair loss in China and abroad are topical formulations. This suggests that, although studies have shown that oral administration of 1.25mg / day of LDOM can effectively improve hair loss, there are currently no oral formulations of minoxidil for the treatment of hair loss on the market.

[0005] After searching, the inventors discovered that the original manufacturer conducted a test on the serum minoxidil concentration and systemic safety of the tablets. The results demonstrated that when the serum minoxidil concentration was below 20 ng / mL, no systemic safety issues arose. The development target for the topical minoxidil solution was also based on this limit. However, when the 2.5 mg / tablet oral tablet of minoxidil is used to treat refractory hypertension, the serum minoxidil concentration is above 20 ng / mL. Oral tablets below 2.5 mg are considered low-dose tablets, posing a higher risk of drug uniformity during the manufacturing process.

[0006] Tablets offer many advantages over topical scalp administration. For example, oral formulations typically contain no solvents, are more convenient to use, allow for precise dosage control, and eliminate the need to consider scalp absorption. However, the development of minoxidil tablets still presents significant technical challenges: ensuring optimal systemic exposure while reducing minoxidil concentration. To achieve this goal, sustained-release minoxidil formulations are preferred.

[0007] In order to develop an oral sustained-release formulation containing milodinil that is safe, effective, and stable and improves patient compliance, it has become a product and technology gap in this field. Summary of the Invention

[0008] In response to the above technology, the inventors have provided a pharmaceutical composition containing minoxidil, preferably a sustained-release pharmaceutical composition. Compared to immediate-release tablets, sustained-release tablets can reduce the serum minoxidil concentration (Cmax), which is related to systemic safety. The US Food and Drug Administration (FDA) considers a Cmax below 20 ng / mL to be free of hypertensive effects. To further improve safety, the inventors set a development target for sustained-release minoxidil tablets of no more than 10 ng / mL, while maintaining similar bioavailability to conventional tablets. This presents additional challenges for the development of oral medications.

[0009] At the same time, it is reported that more than 90% of minoxidil is absorbed through the gastrointestinal tract, so it can be inferred that minoxidil is better absorbed in the upper small intestine. Therefore, the development of a specific sustained-release dosage form may require further exploration. Since there is no sustained-release tablet formulation of minoxidil on the market, the absorption of minoxidil in the entire gastrointestinal tract is unclear, especially whether the drug is absorbed in the colon. Therefore, how to adjust the release pattern of sustained-release tablets and related issues of bioavailability need to be urgently addressed.

[0010] In order to achieve the above technical objectives, namely, to develop an ideal pharmaceutical composition containing minoxidil that is safe and has good bioavailability, the present invention provides a pharmaceutical composition containing minoxidil, comprising minoxidil, a filler, a sustained-release material, a glidant, and a lubricant. Specifically, the pharmaceutical composition containing minoxidil comprises a combination of 0.1-5% minoxidil, 30-50% sustained-release material, 0.1-2% glidant, 0.1-2% lubricant, and the balance being filler, wherein the filler comprises a hydrophobic component and a hydrophilic component, wherein the hydrophobic component is selected from one or a combination of microcrystalline cellulose and calcium hydrogen phosphate; and the hydrophilic component is selected from one or a combination of lactose and xylitol.

[0011] The sustained-release material is selected from one or a combination of hypromellose and hydroxypropyl cellulose;

[0012] The glidant is selected from colloidal silicon dioxide, talc, or a combination thereof;

[0013] The lubricant is selected from one or more combinations of magnesium stearate and sodium stearyl fumarate.

[0014] Furthermore, in the above pharmaceutical composition, the pharmaceutical composition is composed of a combination of 0.5-2.5% minoxidil, 30-50% sustained-release material, 0.1-2% glidant and 0.1-2% lubricant, and the balance being filler in weight percentage.

[0015] Furthermore, in the above pharmaceutical composition, the pharmaceutical composition is composed of a combination of 0.5-2.5% minoxidil, 35-45% sustained-release material, 0.1-1% glidant and 0.1-1% lubricant, and the balance being filler in weight percentage.

[0016] Furthermore, in the above pharmaceutical composition, the sustained-release material is hypromellose, preferably K100.

[0017] Furthermore, in the above pharmaceutical composition, the filler is a combination of microcrystalline cellulose and lactose, with a weight ratio of 2-5:1, more preferably 2-4.81:1.

[0018] The present invention further provides a preparation containing the above pharmaceutical composition, wherein the preparation is a sustained-release tablet.

[0019] Furthermore, the above preparation is a sustained-release oral preparation, preferably with a dosage of 1.0-5.0 mg.

[0020] The present invention further provides a method for preparing the above-mentioned pharmaceutical composition, which comprises the following steps:

[0021] 1) mixing the prescribed amount of minoxidil and the hydrophobic component of the filler at a volume ratio of 1:2-1:5 to obtain material 1;

[0022] 2) mixing the remaining filler with the material 1 obtained in step 1), and then sieving the material 2 through comil screening;

[0023] 3) sieving the prescribed amount of glidant and sustained-release material comil and mixing with material 2 from step 2) to obtain material 3;

[0024] 4) Adding the prescribed amount of lubricant to the material 3 obtained in step 3) and mixing them to obtain the pharmaceutical composition.

[0025] The present invention further provides the above-mentioned pharmaceutical composition, which is prepared by the following steps:

[0026] 1) mixing the prescribed amount of minoxidil and the hydrophobic component of the filler at a volume ratio of 1:2-1:5 to obtain material 1;

[0027] 2) mixing the remaining filler with the material 1 obtained in step 1), and then sieving the material 2 through comil screening;

[0028] 3) sieving the prescribed amount of glidant and sustained-release material comil and mixing with material 2 from step 2) to obtain material 3;

[0029] 4) Adding the prescribed amount of lubricant to the material 3 obtained in step 3) and mixing them to obtain the pharmaceutical composition.

[0030] Furthermore, in the above preparation method, the pore size of the comil is in the range of 700 to 1300 μm, and the rotation speed is in the range of 1300 to 2000 rpm.

[0031] Furthermore, in the above preparation method, the mixing speed of step 1, step 2, step 3 and step 4 is in the range of 10 to 25 rpm, and the mixing time is in the range of 5 to 15 min.

[0032] Furthermore, the present invention provides a use of the above-mentioned pharmaceutical composition or the above-mentioned preparation or the pharmaceutical composition prepared by the above-mentioned preparation method in the preparation of a drug for preventing and treating hair loss.

[0033] Technical purpose:

[0034] 1. The average maximum blood drug concentration is less than 10 ng / mL, which is twice the safe concentration limit of 20 ng / mL.

[0035] Compared with the same dose of immediate-release tablets, it maximizes the relative bioavailability, reduces the dosage and improves safety.

[0036] 2. Compared with minoxidil solution, it has similar systemic exposure (AUC), improving the safety and efficacy of minoxidil sustained-release tablets.

[0037] Technical advantages:

[0038] 1. Sustained-release tablets can greatly reduce the maximum blood drug concentration in the body (below 10 ng / ml) and improve the safety of oral use.

[0039] 2. Sustained-release tablets can provide patients with another option for scalp administration.

[0040] 3. The 8-hour sustained-release effect in vitro can not only reduce the maximum blood drug concentration, but also slowly release the drug to ensure sustained therapeutic effect.

[0041] 4. The tablets prepared by the present invention have stable quality, small difference in in vitro release and good safety.

[0042] 5. The tablets prepared by the present invention have good stability and can meet the long-term validity period of at least 2 years.

[0043] The minoxidil sustained-release tablets adopt the second method of the Chinese Pharmacopoeia dissolution and release determination method, the paddle method, with a rotation speed of 75 rpm, a volume of 900 mL, and a medium of pH 7.2 phosphate buffer, and can achieve an 8-hour sustained-release effect, wherein the 1-hour release is 15% to 35%, the 4-hour release is 50% to 70%, and the 8-hour release is not less than 80%.

[0044] In in vivo experiments, it was found that the sustained-release material and sustained-release time were studied separately, and it was found that they had a significant impact on bioavailability, which is rarely addressed in other studies. For example, the inventors found that even if different sustained-release materials had the same in vitro release, the in vivo exposure was inconsistent; the bioavailability of 8-hour sustained-release tablets was higher than that of 12-hour sustained-release tablets; at the same time, the inventors found that the formulation containing mannitol reduced the release rate in accelerated and long-term stability tests. The inventors conducted a compatibility study on minoxidil and different fillers, and finally concluded that the incompatibility between mannitol and minoxidil was the cause. Lactose was determined to be an alternative excipient because lactose and mannitol have similar solubility and similar hydrophilicity.

[0045] The present invention solves the specification problem of low-dose drugs. Note: Since minoxidil accounts for less than 2.5% of the prescription and is a "highly active" drug, tablet content uniformity is a key internal control parameter. The inventors investigated the effects of different processes on tablet content uniformity and ultimately determined the preparation method of minoxidil sustained-release tablets. This is a topic not covered in previous studies on minoxidil and is encountered for the first time. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] Figure 1. Dissolution curves of different sustained-release materials;

[0047] Figure 2. Dissolution curves of different sustained-release behaviors;

[0048] Figure 3. Dissolution profiles of Formulation 6 under different conditions;

[0049] Figure 4. Dissolution curves of different HPMC levels;

[0050] Figure 5. Formulation composition of different microcrystal / lactose ratios;

[0051] Figure 6. Dissolution profiles of different doses. DETAILED DESCRIPTION

[0052] The following examples are used to further illustrate the present invention but are not intended to limit the present invention.

[0053] In the following examples, minoxidil was supplied by KUMAR, India; lactose was supplied by Meggle; hypromellose was supplied by Colorcon; mannitol was supplied by Roquette; microcrystalline cellulose was supplied by FMC; calcium hydrogen phosphate was supplied by Sprague-Dawley; hydroxypropyl cellulose was supplied by Ashland; cross-linked sodium carboxymethyl cellulose was supplied by JRS; colloidal silicon dioxide was supplied by EVONIK, and polyoxyethylene (PEO) was supplied by Danisco; and magnesium stearate was supplied by FACI.

[0054] Example 1 - Investigation of different sustained-release materials

[0055] Different sustained-release materials can achieve the same in vitro dissolution behavior, but due to their varying hydrophilicity and the influence of gastrointestinal motility, they may exhibit different in vivo performance. The present inventors selected three sustained-release materials to develop minoxidil sustained-release tablets and 2.5 mg immediate-release tablets to compare the relative bioavailability of different sustained-release matrices relative to immediate-release tablets. The formulation compositions of the sustained-release tablets are shown in Table 1, and the formulation compositions of the immediate-release tablets are shown in Table 2.

[0056] The inventors' formulation structure consists of a filler, a sustained-release material, a glidant, and a lubricant. The glidant and lubricant are colloidal silicon dioxide and magnesium stearate, respectively. Microcrystalline cellulose is insoluble in water and a plastic material with excellent compressibility. Mannitol is soluble in water and a brittle material with excellent flowability. In tablet formulation development, these two are often combined as fillers to improve the compressibility and flowability of drug powders. Therefore, this combination of the two is selected as the filler in this product.

[0057] Table 1. Composition of different sustained-release materials

[0058] Table 2. Prescription composition of immediate-release tablets (2.5 mg)

[0059] The tablets produced by the immediate-release formulation disintegrate rapidly within 60 seconds, with a dissolution rate of 100% in 5 minutes. The immediate-release tablets are prepared by conventional mixed tableting.

[0060] The preparation method of the prescription in Table 1 is as follows: (1) the minoxidil and microcrystals in the prescription amount are in a volume ratio of 1:2, the rotation speed is 14 rpm, and the mixing time is 7 min.

[0061] (2) The prescribed amount of mannitol and the remaining microcrystalline cellulose were passed through a 35-mesh sieve and mixed with the material in step 1 at a speed of 14 rpm for 7 minutes.

[0062] (3) The material of step 2 was sieved through a comil with a mesh size of 1016 μm and a rotation speed of 1750 rpm.

[0063] (4) The prescribed amount of sustained-release material and colloidal silicon dioxide were sieved through the comil of step 3, with a sieve aperture of 1016 μm and a rotation speed of 1750 rpm.

[0064] (5) The mixture obtained in step 3 and step 4 was mixed at a speed of 14 rpm and a mixing time of 7 min.

[0065] (6) Add magnesium stearate with a mesh size of 60 into the hopper in step 5 and mix at a speed of 14 rpm for 7 min.

[0066] (7) Finally, the desired tablets are obtained by tableting.

[0067] Release Determination Test Method: Take the test sample and dissolve it in 900 mL of pH 7.2 phosphate as the dissolution medium according to the 2020 edition of the Chinese Pharmacopoeia. The dissolution medium is maintained at 75 rpm. Samples are taken at different time points and filtered through a 0.45 μm filter membrane. The filtrate is used as the test solution. An appropriate amount of minoxidil reference substance is dissolved in methanol / dissolution medium (80:20) and diluted to approximately 0.002 mg / mL for later use. The UV absorbance of the test solution is measured at 231 nm to calculate the sample solubility.

[0068] The in vitro cumulative dissolution rates of Formulation 1, Formulation 2, and Formulation 3 are shown in Table 3.

[0069] Table 3. Cumulative dissolution data for Formulation 1, Formulation 2, and Formulation 3

[0070] The cumulative dissolution curves of Prescription 1, Prescription 2, and Prescription 3 are shown in Figure 1 below.

[0071] Conclusion: The above data show that the different sustained-release materials of Formulations 1, 2, and 3 have similar in vitro dissolution, all achieving a 12-hour sustained-release effect. The inventors then investigated the PK behavior of the three formulations in dogs relative to the relative bioavailability of the same-dose immediate-release tablet.

[0072] Study objective: To investigate the pharmacokinetic (PK) characteristics of minoxidil sustained-release tablets and their relative bioavailability compared with immediate-release tablets after single oral administration of different doses in beagle dogs.

[0073] Experimental design: Single-center, open-label, single-dose parallel controlled trial

[0074] Test drugs: Tablets compressed using prescription 1, prescription 2, prescription 3 and prescription 4 respectively

[0075] Number of subjects: 20 in total, 5 in each group

[0076] Research methods: All dogs were fasted for at least 10 hours the day before administration. Minoxidil sustained-release tablets were orally administered once on a fasting stomach on D1. The administration time was fixed at 8:30±0.5h in the morning.

[0077] Detection method: LC-MS / MS method was used to determine the concentration of minoxidil in serum

[0078] The test results are as follows:

[0079] Table 4. Pharmacokinetic parameters of different doses

[0080] Pharmacokinetic results revealed an unexpected finding: While the three sustained-release materials exhibited similar performance in vitro, they exhibited significant differences in vivo. Polyethylene oxide (PEO) exhibited the highest relative bioavailability, at 81.2%, but the maximum plasma concentration exceeded the target concentration by 10 ng / mL. Hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) exhibited relative bioavailability of 65.7% and 56.6%, respectively. Therefore, Formulation 1, with its relatively high bioavailability, was selected for further study.

[0081] Example 2- Investigation of different sustained-release behaviors

[0082] Example 1 demonstrates that HPMC exhibits good in vivo performance in animals, but its relative bioavailability is low at 65.7%. This may be due to slow release and poor colonic absorption. To verify this conclusion, the inventors simultaneously developed a formulation using HPMC as a sustained-release matrix, resulting in a faster in vitro release (8-hour sustained-release), and compared the relative bioavailability of the two formulations. The formulation compositions are shown in Table 5.

[0083] Table 5. Composition of different sustained-release formulations

[0084] After tableting, the cumulative dissolution of the tablets obtained for each prescription is shown in Table 6.

[0085] Table 6. Cumulative dissolution data for Formulations 1, 5, and 6

[0086] The cumulative dissolution curves of Prescription 1, Prescription 5 and Prescription 6 are shown in Figure 2 below.

[0087] Conclusion: In Figure 2, Formulation 5 achieves 8-hour in vitro sustained release by reducing the proportion of HPMC K4M. However, dissolution variability is significant, with a relative standard deviation exceeding 5% (Formulation 5). This variability can easily lead to large fluctuations in plasma drug concentrations in vivo, compromising safety. A formulation using the relatively low-viscosity HPMC K100 not only achieves 8-hour in vitro sustained release but also exhibits minimal dissolution variability (Formulation 6). To compare the relative bioavailability of a faster-release formulation (8-hour sustained release) versus a slower-release formulation (12-hour sustained release), the following human studies were conducted.

[0088] Study objective: To investigate the relative bioavailability of low-viscosity minoxidil sustained-release tablets and high-viscosity minoxidil immediate-release tablets after a single oral dose in healthy male subjects on an empty stomach.

[0089] Trial design: Single-center, open-label, single-dose, double-crossover trial

[0090] Test drug: Tablets compressed using prescription 1 and prescription 6

[0091] Number of subjects: 6 in total

[0092] Research Methods: Subjects fasted for at least 10 hours the night before each dosing cycle and took one minoxidil sustained-release tablet (1.8 mg) or one minoxidil immediate-release tablet (2.5 mg) with 240 mL of warm water while fasting. The dosing schedule was as follows:

[0093] Table 7. Dosage route

[0094] The test results are as follows.

[0095] Table 8. PK parameters

[0096] Conclusion: The relative bioavailability of low-viscosity minoxidil sustained-release tablets (Formulation 6) was 14% higher than that of high-viscosity minoxidil sustained-release tablets (Formulation 1), and the blood concentration was below the target limit of 10 ng / mL, indicating that the bioavailability of Formulation 6 was approximately 80% compared with the same dose of immediate-release tablets.

[0097] Example 3 - Stability Study of Formulation 6

[0098] Formula 6 is an optimized formula that not only has good bioavailability but also has a blood concentration of less than 10 ng / mL. The inventors investigated the accelerated and long-term stability studies of Formula 6.

[0099] The dissolution data of Formulation 6 at accelerated doses for 6 months and long-term doses for 6 months are shown in the table below.

[0100] Table 9. Cumulative dissolution data of Formulation 6 under different conditions

[0101] The dissolution curve is shown in Figure 3 below.

[0102] Conclusion: The dissolution of Formulation 6 was significantly reduced after 6 months of accelerated treatment and 12 months of long-term treatment, and the relative standard deviation (RSD) of the dissolution rate was greater than 5%. The change in dissolution rate may lead to changes in in vivo behavior, which is extremely high risk.

[0103] Based on experience, the presence of hypromellose in the formulation does not cause changes in the dissolution profile due to its sufficient sustained-release capacity. It is speculated that the interaction between the filler and the drug causes changes in the crystal form or particle size of minoxidil, leading to changes in dissolution rate. Based on this speculation, the inventors investigated the compatibility of minoxidil with different fillers.

[0104] The samples were divided into four parallel groups and placed under frozen sealed (-20°C), high temperature 60°C sealed, light sealed, and high humidity 92.5% RH open conditions, with test periods of 15 days and 30 days. The frozen sealed (-20°C) group served as the control group to facilitate the identification of factors affecting degradation. Minoxidil and excipients were weighed and placed in brown bottles under high temperature and humidity conditions, and in transparent glass bottles under light conditions. After thorough mixing, they were placed separately according to the four designed conditions. The specific types of excipients involved, mixing ratios, test conditions, and their results are shown in the table below.

[0105] Table 10. Excipient Compatibility (Binary Mixtures)

[0106] Compatibility tests showed that minoxidil and mannitol produced impurities at high temperatures, but remained stable under high humidity and light conditions. Minoxidil and calcium hydrogen phosphate, microcrystalline cellulose, xylitol, and lactose were also stable under high temperature, high humidity, and light conditions.

[0107] It can be inferred that the decrease in the content of minoxidil sustained-release tablets during the stability process is caused by mannitol. Therefore, the present inventors replaced the filler mannitol with lactose to investigate the in vitro dissolution and storage stability.

[0108] Formula 6 has been screened and found to meet the development goals of this patent. However, due to poor stability, only the filler mannitol was replaced with lactose, which has similar properties. This is presumably unaffected by in vivo absorption. Literature indicates that the systemic exposure of minoxidil topical solution is 18.71 ng / hr / mL, while the systemic exposure of 2.5 mg is 26.77 ng / hr / mL. Based on dose correction, to achieve a systemic exposure of 18.71 ng / hr / mL in vivo, the dose needs to be reduced: 18.71 ng / hr / mL x 2.5 mg / 26.77 ng / hr / mL = 1.75 mg. Therefore, it can be inferred that a 1.8 mg sustained-release tablet can achieve the same systemic exposure as minoxidil topical solution, while further reducing the maximum blood concentration and significantly improving safety.

[0109] The next step is to verify the above speculation.

[0110] Example 4 - Relative Bioavailability of 1.8 mg Sustained-Release Tablets and Commercial Minoxidil Topical Solution

[0111] Prescription 7 containing lactose was designed based on Prescription 6, and the prescription composition is shown in Table 11.

[0112] Table 11. Composition of 1.8 mg sustained-release tablets

[0113] The pharmacokinetic characteristics of formulation 7 and commercial minoxidil topical solution were investigated.

[0114] Study objective: To investigate the pharmacokinetic (PK) characteristics of a single oral dose of 1.8 mg minoxidil sustained-release tablets in healthy male subjects and the effect of multiple topical administrations of 5% Minoxidil Topical Solution. bioavailability.

[0115] Trial Design: Single-center, open-label, single-dose and multiple-dose studies

[0116] Test drug: Test formulation: Tablets compressed using Formula 7

[0117] Reference preparation: Minoxidil solution (trade name: ); Specification: 5%; Batch Number: 3432CP; Valid until: November 2025; Packaging: 60 mL / bottle; Storage: Store at room temperature below 20°C to 25°C. Manufacturer: JOHNSON & JOHNSON CONSUMER INC.

[0118] Number of subjects: 6 in total

[0119] Research method: Single oral administration: The subjects fasted for at least 10 hours the day before administration. All subjects were given a single oral administration of 1.25 mg of minoxidil sustained-release tablets on an empty stomach on D1. The administration time was fixed at 8:30±0.5 hours in the morning. The subjects were required to keep their upper body upright within 4 hours after administration on D1.

[0120] Multiple topical administration: D4 to D8 are multiple topical administrations, twice a day (12 hours apart) using a dropper to draw up 1 mL of 5% Minoxidil Topical Solution. Apply the solution to the scalp and massage until absorbed. The administration time is fixed every day, 8:30±0.5h in the morning and 20:30±0.5h. Administer once on the morning of D9 by using a dropper to absorb 1mL of 5% Minoxidil Topical Solution. Apply the solution to the scalp and massage until absorbed. The administration time is 8:30 ± 0.5 hours in the morning. Avoid any contact with the head within 4 hours after administration on Days 4-9.

[0121] Washout period: 3 days

[0122] Detection method: LC-MS / MS method was used to determine the concentration of minoxidil in serum

[0123] The test results are as follows:

[0124] Table 12. Pharmacokinetic parameters of 1.8 mg sustained-release tablets and minoxidil solution

[0125] Conclusion: The results demonstrate that minoxidil sustained-release tablets (Formulation 7) and the reference formulation have similar systemic exposure. Relative bioavailability was 102%, and the maximum plasma concentration was below the target limit of 10 ng / mL. Therefore, Formulation 7 is the target formulation for this invention.

[0126] Example 5 - Study of Different Hydroxypropyl Methylcellulose K100 Levels

[0127] Hydroxypropyl methylcellulose as a sustained-release matrix directly affects the dissolution behavior of minoxidil sustained-release tablets. In order to determine the appropriate level of hydropropyl methylcellulose, the present inventors studied the level of hydropropyl methylcellulose. The formulation composition is shown in the table below.

[0128] Table 13. Composition of different HPMC formulations

[0129] Tablets obtained from Prescription 7, Prescription 8, and Prescription 9 were compressed and subjected to dissolution studies. The data are shown in the table below.

[0130] Table 14. Cumulative dissolution data of different HPMC levels

[0131] The higher the F2, the more similar the curves are. Generally, when it is greater than 50, the curves can be considered similar.

[0132] The dissolution curve is shown in Figure 4 below.

[0133] Conclusion: As shown in Figure 4, relative to the target prescription (prescription 7), when the prescription ratio of hypromellose is 35% to 45%, the similarity factor f2 is greater than 60. Therefore, the prescription ratio of hypromellose is selected to be 35% to 45%.

[0134] Example 6 - Study of the Microcrystalline Cellulose / Lactose Ratio

[0135] Microcrystalline cellulose is a poorly soluble excipient, while lactose is a readily soluble excipient. Different ratios of the two may affect tablet dissolution. To screen for the optimal microcrystalline cellulose / lactose ratio, the inventors designed four microcrystalline cellulose / lactose ratios: 4.81:1, 3:1, 2:1, and 1:1. The formulation composition is shown in the table below.

[0136] Table 15. Microcrystal / lactose ratio formula composition

[0137] Prepared using preparation process 2

[0138] Tableting situation: Prescription 11 can be compressed to a maximum of 120N, but cannot be compressed to the target hardness of 150N. This may be due to the reduction of microcrystals and poor compressibility.

[0139] Table 16. Cumulative dissolution data for Formulation 7 and Formulations 9-11

[0140] The higher the F2, the more similar the curves are. Generally, if it is greater than 50, the curves can be considered similar.

[0141] The dissolution curve is shown in Figure 5 below.

[0142] Conclusion: In Figure 5, formulations 7, 9, 10, and 11 were examined respectively. It was found that when the ratio of microcrystals to lactose was 4.81:1 to 1:1, the dissolution of minoxidil sustained-release tablets was similar. However, as the microcrystals decreased, the compressibility decreased. Therefore, the optimal ratio of microcrystals to lactose was 4.81:1 to 2:1.

[0143] Example 7 - Effect of different processes on tablet content uniformity

[0144] Since minoxidil accounts for a low proportion in the prescription, the risk of the content uniformity of the tablets affecting the tablet quality is high. In order to screen a suitable process, the effects of the following processes on the content uniformity of the tablets were investigated with prescription 7 as the target prescription.

[0145] Process 1:

[0146] (1) Premix the prescribed amount of minoxidil, lactose, microcrystalline cellulose, hypromellose and colloidal silicon dioxide at a speed of 14 rpm for 14 min.

[0147] (2) Add magnesium stearate with a 60-mesh filter and mix at a speed of 14 rpm for 7 min.

[0148] (3) Tablet compression, target tablet weight is 200 mg, hardness is 150N.

[0149] Process 2:

[0150] (1) The prescribed amount of minoxidil and microcrystals were premixed in a volume ratio of 1:2, with a rotation speed of 14 rpm and a mixing time of 7 min.

[0151] (2) Pass the prescribed amount of lactose and the remaining microcrystals through a 35-mesh sieve and mix with the material from step ① at a speed of 14 rpm for 7 min.

[0152] (3) The material from step ② was sieved through a comil with a mesh size of 1016 μm and a rotation speed of 1750 rpm.

[0153] (4) The prescribed amount of hydroxypropyl methylcellulose and colloidal silicon dioxide were sieved through the comil of step ③, with a sieve mesh size of 1016 μm and a rotation speed of 1750 rpm.

[0154] (5) The mixture obtained in step ③ and step ④ was mixed at a speed of 14 rpm and a mixing time of 7 min.

[0155] (6) Add magnesium stearate with a mesh size of 60 into the hopper in step ⑤ and mix at a speed of 14 rpm for 7 min.

[0156] (7) Tablet compression, target tablet weight is 200 mg, hardness is 150N.

[0157] Process 3:

[0158] (1) The prescribed amount of minoxidil and microcrystals were premixed in a volume ratio of 1:5, with a rotation speed of 14 rpm and a mixing time of 7 min.

[0159] (2) Pass the prescribed amount of lactose and the remaining microcrystals through a 35-mesh sieve and mix with the material from step ① at a speed of 14 rpm for 7 min.

[0160] (3) The material from step ② was sieved through a comil with a mesh size of 1016 μm and a rotation speed of 1750 rpm.

[0161] (4) The prescribed amount of hydroxypropyl methylcellulose and colloidal silicon dioxide were sieved through the comil of step ③, with a sieve mesh size of 1016 μm and a rotation speed of 1750 rpm.

[0162] (5) The mixture obtained in step ③ and step ④ was mixed at a speed of 14 rpm and a mixing time of 7 min.

[0163] (6) Add magnesium stearate with a mesh size of 60 into the hopper in step ⑤ and mix at a speed of 14 rpm for 7 min.

[0164] (7) Tablet compression, target tablet weight is 200 mg, hardness is 150N.

[0165] Process 4:

[0166] (1) The prescribed amount of minoxidil and microcrystals were premixed in a volume ratio of 1:10, with a rotation speed of 14 rpm and a mixing time of 7 min.

[0167] (2) Pass the prescribed amount of lactose and the remaining microcrystals through a 35-mesh sieve and mix with the material from step ① at a speed of 14 rpm for 7 min.

[0168] (3) The material from step ② was sieved through a comil with a mesh size of 1016 μm and a rotation speed of 1750 rpm.

[0169] (4) The prescribed amount of hydroxypropyl methylcellulose and colloidal silicon dioxide were sieved through the comil of step ③, with a sieve mesh size of 1016 μm and a rotation speed of 1750 rpm.

[0170] (5) The mixture obtained in step ③ and step ④ was mixed at a speed of 14 rpm and a mixing time of 7 min.

[0171] (6) Add magnesium stearate with a mesh size of 60 into the hopper in step ⑤ and mix at a speed of 14 rpm for 7 min.

[0172] (7) Tablet compression, target tablet weight is 200 mg, hardness is 150N.

[0173] Tablets were prepared by process 1, process 2, process 3 and process 4, and the content uniformity is shown in the table below.

[0174] Table 17. Summary of content uniformity of tablets produced by different processes

[0175] The data above show that using process 1, the tablets had a large deviation in content uniformity, with an AV value of 14.77, almost failing the standard. When minoxidil and microcrystalline cellulose were premixed, the tablets all met the content uniformity requirements. However, when the minoxidil and microcrystalline cellulose premix ratio was 1:10, the content uniformity met the limit requirements, but the content uniformity deviation was large. Therefore, a minoxidil:microcrystalline cellulose ratio of 1:2 to 1:5 was selected.

[0176] Example 8 - Stability Study

[0177] Results of stability tests: Tablets made from prescription 7 were packaged in commercial packaging and placed under accelerated conditions of 40°C / 75% RH for 1 month, 3 months, and 6 months. The properties, content, related substances, and release rates were measured. The results are shown in the table below.

[0178] Table 18. Accelerated (40°C / 75% RH) stability results for target formulations

[0179] Conclusion: The above stability results show that the target formulation has basically no changes in properties, content, related substances and release rate after being placed under accelerated conditions for 6 months, and the formulation is stable.

[0180] Example 9 - Different dosage formulation compositions and in vitro dissolution curves

[0181] Table 19. Composition of different dosage prescriptions

[0182] The preparation method is the same as preparation process 2.

[0183] The dissolution results of the above different doses are shown in Figure 6 below. It is found that the in vitro dissolution of each formulation in Figure 6 has a similar dissolution curve. According to the same formulation principle, their in vivo bioavailability is similar.

Claims

1. A pharmaceutical composition containing minoxidil, characterized in that The invention comprises a combination of 0.1-5% minoxidil, 30-50% sustained-release material, 0.1-2% glidant, 0.1-2% lubricant, and the balance being a filler, wherein the filler contains a hydrophobic component and a hydrophilic component, wherein the hydrophobic component is selected from one or a combination of microcrystalline cellulose and calcium hydrogen phosphate; and the hydrophilic component is selected from one or a combination of lactose and xylitol. The sustained-release material is selected from one or a combination of hypromellose and hydroxypropyl cellulose; The glidant is selected from colloidal silicon dioxide, talc, or a combination thereof; The lubricant is selected from one or a combination of magnesium stearate and sodium stearyl fumarate.

2. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition consists of 0.5-2.5% minoxidil, 30-50% sustained-release material, 0.1-2% glidant, 0.1-2% lubricant, and the balance being filler.

3. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition consists of 0.5-2.5% minoxidil, 35-45% sustained-release material, 0.1-1% glidant, 0.1-1% lubricant, and the balance being filler.

4. The pharmaceutical composition according to claim 1, characterized in that The sustained-release material is hypromellose, preferably K100.

5. The pharmaceutical composition according to claim 1, characterized in that The filler is a combination of microcrystalline cellulose and lactose, with a weight ratio of 1-5:1, more preferably 2-4.81:

1.

6. A preparation, characterized in that Comprising the pharmaceutical composition according to claim 1.

7. The preparation according to claim 6, characterized in that The preparation is an oral sustained-release preparation.

8. A method for preparing the pharmaceutical composition according to claim 1, characterized in that: It consists of the following steps: 1) mixing the prescribed amount of minoxidil and the hydrophobic component of the filler at a volume ratio of 1:2-1:5 to obtain material 1; 2) mixing the remaining filler with the material 1 obtained in step 1), and then sieving the material 2 through comil screening; 3) sieving the prescribed amount of glidant and sustained-release material comil and mixing with material 2 from step 2) to obtain material 3; 4) Adding the prescribed amount of lubricant to the material 3 obtained in step 3) and mixing them to obtain the pharmaceutical composition.

9. The preparation method according to claim 8, characterized in that: The pore size of the comil is in the range of 700 to 1300 μm, and the rotation speed is in the range of 1300 to 2000 rpm.

10. Use of the pharmaceutical composition according to any one of claims 1 to 5, the preparation according to any one of claims 6 to 7, or the pharmaceutical composition prepared by the preparation method according to any one of claims 8 to 9 in preparing a drug for preventing and treating hair loss.

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