Application of carbohydrate, pharmaceutical composition containing carbohydrate and preparation

Abstract

The invention discloses a pharmaceutical composition for treating alopecia, which contains minoxidil, optionally finasteride and / or dutasteride, and a specific kind of carbohydrates. The specific type of carbohydrates can effectively improve the stability of the pharmaceutical composition, including reducing the generation of impurities in the pharmaceutical composition and prolonging the stable storage period of the pharmaceutical composition at low temperature or high temperature. The invention further discloses a preparation for treating alopecia, and the preparation can be widely applied clinically.

Description

[0001] This invention claims the priority of a prior application titled "Application of a Carbohydrate, and Pharmaceutical Composition and Preparation Comprising a Carbohydrate", with an application number of 202410031870.9, filed on January 9, 2024. The content of the above prior application is incorporated herein by reference. Technical Field

[0002] This invention relates to the field of biomedicine, and particularly to a pharmaceutical composition for treating hair loss. Background Art

[0003] Hair loss can be divided into irreversible cicatricial alopecia and reversible non-cicatricial alopecia. Non-cicatricial alopecia is the most common, including androgenetic alopecia, alopecia areata, and telogen effluvium.

[0004] Minoxidil, chemically named 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide, is a clinically known drug for treating hair loss. Finasteride, chemically named N-tert-butyl-3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, is a specific inhibitor of intracellular enzyme type II 5α-reductase in the process of testosterone metabolism to dihydrotestosterone, and can be used to treat androgenetic alopecia.

[0005] However, Minoxidil has poor stability, and the external liquid preparation will turn yellow and gradually deepen over time. Some studies have explored adding antioxidants, metal ion chelators (such as EDTA), pigments, buffer regulators, etc. to the pharmaceutical composition of Minoxidil to improve the discoloration problem, but still fail to improve the stability of the drug active ingredient well, especially the stability under long-term or high-temperature environments.

[0006] Therefore, providing a stable pharmaceutical composition or preparation of Minoxidil is an urgent problem to be solved. Summary of the Invention

[0007] Through a large number of experimental studies, the inventors unexpectedly found that certain carbohydrates are particularly suitable as stabilizers for Minoxidil pharmaceutical compositions, enabling the properties of the pharmaceutical compositions to remain stable for a long time.

[0008] Thus, the present invention provides the following technical solutions:

[0009] In a first aspect, the present invention provides a pharmaceutical composition for treating hair loss, which contains the following components:

[0010] (A) Minoxidil 0.1 - 10 (w / v)%, preferably 1 - 6 (w / v)%;

[0011] (B) Stabilizer 0.5 - 2.5 (w / v)%, preferably 1 - 2 (w / v)%;

[0012] (C) Alcohol solvent 10 - 90 (w / v)%; and,

[0013] (D) Optionally, other pharmaceutically acceptable carriers.

[0014] Wherein, the stabilizer is a carbohydrate; the carbohydrate is selected from at least one of sucrose, sucralose, trehalose, mannitol or meglumine, preferably at least one of sucrose, sucralose or trehalose, and most preferably trehalose.

[0015] As described above, the pharmaceutical composition of the present invention contains the first active ingredient minoxidil.

[0016] Preferably, the pharmaceutical composition of the present invention further contains a second active ingredient. For example, the second active ingredient is selected from finasteride, dutasteride, spironolactone or nilutamide, etc.

[0017] Preferably, the pharmaceutical composition of the present invention further contains ingredient (E), and the ingredient (E) is selected from at least one of the following (e1) or (e2):

[0018] (e1) Finasteride 0.01 - 1 (w / v)%; the content of finasteride is preferably 0.05 - 0.5 (w / v)%;

[0019] (e2) Dutasteride 0.001 - 0.5 (w / v)%; the content of dutasteride is preferably 0.01 - 0.4 (w / v)%; more preferably 0.05 - 0.4 (w / v)%.

[0020] Preferably, the ingredient (E) is (e1).

[0021] Preferably, the ingredient (E) is (e2).

[0022] Preferably, the ingredient (E) is (e1) and (e2).

[0023] Preferably, the pharmaceutical composition of the present invention may further contain ingredient (F): (F) Amino acid 0.1 - 5 (w / v)%; the amino acid is preferably selected from at least one of L - proline, L - arginine or L - serine, and more preferably L - proline.

[0024] Preferably, the alcohol solvent in the pharmaceutical composition of the present invention can be selected from at least one of propylene glycol, isopropyl alcohol or ethanol.

[0025] Preferably, the alcohol solvent is a mixture of propylene glycol and ethanol.

[0026] Preferably, the content of the alcohol solvent is preferably 20 - 85 (w / v)%.

[0027] Preferably, the alcohol solvent is a mixture of 25 - 40 (w / v)% propylene glycol and 35 - 45 (w / v)% ethanol.

[0028] In the pharmaceutical composition of the present invention, other pharmaceutically acceptable carriers may include water.

[0029] Preferably, the pharmaceutical composition of the present invention basically does not contain antioxidants and / or pigments;

[0030] Specifically, the content of the antioxidant in the pharmaceutical composition can be 0.1 (w / v)% or less, or 0.01 (w / v)% or less;

[0031] Specifically, the content of the pigment in the pharmaceutical composition is 0.1 (w / v)% or less, or 0.01 (w / v)% or less.

[0032] In a second aspect, the present invention provides a preparation for treating hair loss, comprising the pharmaceutical composition of the present invention.

[0033] Preferably, the preparation can be a liquid preparation, such as a solution, suspension, liniment, paint, tincture or spray, etc.

[0034] In a third aspect, the present invention provides an application of a carbohydrate in improving the stability of a pharmaceutical composition containing minoxidil, wherein:

[0035] The carbohydrate is selected from at least one of sucrose, sucralose, trehalose, mannitol or meglumine.

[0036] Preferably, the carbohydrate is selected from at least one of sucrose, sucralose or trehalose.

[0037] Particularly preferably, the carbohydrate is trehalose.

[0038] The carbohydrate of the present invention can be applied in the following pharmaceutical composition, and the pharmaceutical composition contains the following components:

[0039] (A) Minoxidil 0.1 - 10 (w / v)%, preferably 1 - 6 (w / v)%;

[0040] (B) Stabilizer 0.5 - 2.5 (w / v)%, preferably 1 - 2 (w / v)%;

[0041] (C) Alcohol solvent 50 - 90 (w / v)%;

[0042] (D) Optionally, other pharmaceutically acceptable carriers;

[0043] (E) Optionally, (e1) finasteride 0.01 - 1 (w / v)%, preferably 0.05 - 0.5 (w / v)%, and / or, (e2) dutasteride 0.001 - 0.5 (w / v)%, preferably 0.01 - 0.4 (w / v)%, more preferably 0.05 - 0.4 (w / v)%; and,

[0044] (F) Optionally, amino acid 0.1 - 5 (w / v)%; the amino acid is preferably at least one selected from L - proline, L - arginine, L - serine, and more preferably L - proline.

[0045] Preferably, the component (E) is (e1).

[0046] Preferably, the component (E) is (e2).

[0047] Preferably, the component (E) is (e1) and (e2).

[0048] Preferably, the carbohydrate is the only stabilizer active ingredient in the pharmaceutical composition containing minoxidil.

[0049] Preferably, the pharmaceutical composition applied with the carbohydrate basically does not contain antioxidants and / or pigments.

[0050] Preferably, the content of the antioxidant in the pharmaceutical composition applied with the carbohydrate is 0.1 (w / v)% or below 0.01 (w / v)%.

[0051] Preferably, the content of the pigment in the pharmaceutical composition applied with the carbohydrate is 0.1 (w / v)% or below 0.01 (w / v)%.

[0052] Fourth aspect, the present invention provides an application of any one of the foregoing pharmaceutical compositions of the present invention in the preparation of a drug for treating hair loss - related diseases. For example, the hair loss - related diseases include at least one of androgenetic alopecia, alopecia areata, or telogen effluvium. Description of the Drawings

[0053] Figure 1 : Appearance photos of the pharmaceutical compositions of Examples 1 - 6 after being placed at 60°C for 1 month on the 0th day.

[0054] Figure 2 : Appearance photos of the pharmaceutical composition added with a stabilizer not of the present invention after being placed at 60°C for 1 month on the 0th day.

[0055] Figure 3 : Results of in vitro transdermal tests after applying the pharmaceutical compositions of Examples 7 and 9 of the present invention and commercial products, where A is the cumulative permeation curve of minoxidil and B is the cumulative permeation curve of finasteride. Detailed Embodiments

[0056] In the following description, numerous specific details are set forth in order to provide a more thorough understanding of the present invention. However, it will be apparent to one of ordinary skill in the art that the present invention may be practiced without one or more of these specific details. In other instances, well-known features have not been described in order to avoid obscuring the present invention.

[0057] The following describes the implementation of the present invention in detail in conjunction with the term definitions:

[0058] I Drug active ingredient

[0059] In the pharmaceutical composition of the present invention, minoxidil is the first active ingredient.

[0060] In some embodiments, minoxidil is the sole active ingredient.

[0061] In other embodiments, in addition to minoxidil, the pharmaceutical composition of the present invention may further contain other active ingredients, such as a second active ingredient.

[0062] The aforementioned active ingredients all refer to drugs having therapeutic effects on hair loss-related diseases. The second active ingredient is a drug known in the art for treating hair loss-related diseases, such as finasteride, dutasteride, spironolactone, nilutamide, etc.

[0063] (1) Minoxidil

[0064] In one embodiment of the present invention, the structural formula of minoxidil is shown as Formula I:

[0065]

[0066] Generally, during storage or use, minoxidil will change color, such as turning yellow. As the time of use or storage extends, the color of the pharmaceutical composition containing minoxidil will show a tendency to deepen.

[0067] On the other hand, during long-term storage, impurities will be generated in minoxidil. The known impurities are ImpA, ImpB, and ImpC, and their structures are shown as follows:

[0068]

[0069] In one embodiment of the present invention, minoxidil can be crystalline minoxidil or powdered minoxidil.

[0070] (2) Finasteride

[0071] In some embodiments of the present invention, the pharmaceutical composition of the present invention contains finasteride as the second active ingredient.

[0072] In one embodiment of the present invention, the structural formula of finasteride is as shown in Formula II:

[0073]

[0074] Similarly, during storage or use, impurities may also be generated in finasteride, and the known impurities are ImpD and ImpE, and the structures are as shown below:

[0075]

[0076] In one embodiment of the present invention, the pharmaceutically active ingredient of the present invention may be minoxidil and / or finasteride. In some embodiments, the pharmaceutically active ingredient of the present invention is minoxidil and finasteride.

[0077] According to the requirements of the therapeutic effect of the drug, the content of minoxidil in the pharmaceutical composition of the present invention may be 0.1-10 (w / v)%, 0.5-6 (w / v)%, 1-5 (w / v)%, 2-4 (w / v)% or 3 (w / v)%.

[0078] According to the requirements of the therapeutic effect of the drug, the content of finasteride in the pharmaceutical composition of the present invention may be 0.01-1 (w / v)%, 0.02-0.5 (w / v)%, 0.05-0.4 (w / v)%, 0.08-0.3 (w / v)% or 0.1-0.2 (w / v)%.

[0079] (3) Dutasteride

[0080] In some embodiments of the present invention, the pharmaceutical composition of the present invention contains dutasteride as the second active ingredient.

[0081] In one embodiment of the present invention, the structural formula of dutasteride is as shown in Formula III:

[0082]

[0083] Similarly, during storage or use, impurities may also be generated in dutasteride, and the known impurities are ImpF and ImpG, and the structures are as shown below:

[0084]

[0085] In one embodiment of the present invention, the pharmaceutically active ingredient of the present invention may be minoxidil and dutasteride.

[0086] In some embodiments, the pharmaceutically active ingredient of the present invention is minoxidil, finasteride and dutasteride.

[0087] According to the requirements of the therapeutic effect of the drug, the content of finasteride in the pharmaceutical composition of the present invention can be 0.001-1 (w / v)%, 0.005-0.5 (w / v)%, 0.01-0.4 (w / v)%, 0.02-0.4 (w / v)%, or 0.05-0.4 (w / v)%.

[0088] II Stabilizer

[0089] In one embodiment of the present invention, a specific type of carbohydrate is selected as the stabilizer of the pharmaceutical composition, such as sucrose, sucralose, trehalose, mannitol, or meglumine. Preferably, the carbohydrate is sucrose, sucralose, or trehalose. Particularly preferably, the carbohydrate is trehalose.

[0090] In order to make the pharmaceutical composition have good long-term stability and temperature resistance, the addition amount of the stabilizer is preferably 0.5-2.5 (w / v)%, 0.8-2.2 (w / v)%, 1-2 (w / v)%, or 1.2-1.5 (w / v)%.

[0091] In a preferred embodiment of the present invention, the above-mentioned specific type of carbohydrate of the present invention is the only active ingredient of the stabilizer in the pharmaceutical composition, that is, the pharmaceutical composition basically does not contain other stabilizers.

[0092] The above "basically does not contain" means that the content of the corresponding substance in the pharmaceutical composition is below 0.1 (w / v)%, or below 0.01 (w / v)%, or below 0.001 (w / v)%, or below 0.0001 (w / v)%.

[0093] In another embodiment of the present invention, the pharmaceutical composition of the present invention basically does not contain antioxidants. Such as tocopherol, etc.

[0094] Preferably, the content of the antioxidant in the pharmaceutical composition of the present invention is below 0.1 (w / v)%, or below 0.01 (w / v)%, or below 0.001 (w / v)%, or below 0.0001 (w / v)%.

[0095] In another embodiment of the present invention, the pharmaceutical composition of the present invention basically does not contain pigments. Such as yellow pigment, azo red pigment, orange pigment, etc.

[0096] Preferably, the content of the pigment in the pharmaceutical composition of the present invention is below 0.1 (w / v)%, or below 0.01 (w / v)%, or below 0.001 (w / v)%, or below 0.0001 (w / v)%.

[0097] III Other pharmaceutical excipients

[0098] According to requirements, the pharmaceutical composition of the present invention may optionally contain at least one of the following substances:

[0099] (1) Amino acid

[0100] In one embodiment of the present invention, the pharmaceutical composition of the present invention further contains an amino acid. The addition of the amino acid can reduce the irritation of the drug to the skin and improve the repair function of the skin at the administration site.

[0101] Preferably, the amino acid is selected from at least one of L-proline, L-arginine or L-serine. More preferably, the amino acid is selected from L-proline.

[0102] In one embodiment of the present invention, the content of the amino acid is 0.1 - 5 (w / v)%, 0.5 - 2.5 (w / v)% or 1 - 2 (w / v)%.

[0103] (2) Solvent

[0104] In one embodiment of the present invention, the pharmaceutical composition of the present invention contains a solvent.

[0105] The solvent can be an organic solvent or an aqueous solvent. Preferably, it contains a mixture of an organic solvent and an aqueous solvent.

[0106] In one embodiment of the present invention, the pharmaceutical composition of the present invention contains an alcohol solvent.

[0107] Preferably, the alcohol solvent is a monohydric alcohol or a dihydric alcohol of C 2-8 Preferably, it is propylene glycol, isopropyl alcohol or ethanol.

[0108] The content of the alcohol solvent is 10 - 90 (w / v)%, 20 - 85 (w / v)%, 50 - 80 (w / v)% or 60 - 70 (w / v)%.

[0109] Preferably, the alcohol solvent is a mixture of propylene glycol and ethanol. For example, the content of propylene glycol can be 25 - 40 (w / v)% or 30 - 35 (w / v)%. For example, the content of ethanol can be 35 - 45 (w / v)% or 35 - 40 (w / v)%.

[0110] In another embodiment of the present invention, the pharmaceutical composition of the present invention contains water.

[0111] The content of water is 1 - 99.9 (w / v)%, 5 - 80 (w / v)%, 10 - 70 (w / v)%, 15 - 60 (w / v)%, 20 - 50 (w / v)% or 25 - 45 (w / v)%.

[0112] IV Pharmaceutical Compositions and Preparations

[0113] Unless otherwise specified, the materials or reagents used in the embodiments of the present invention are all ordinary commercially available products. Unless otherwise specified, the experimental methods used are conventional methods known in the art. Unless otherwise specified, the percentage content of each component in the present invention refers to mass / volume percentage (% w / v, g / mL). For example, 5% means that 5 g of the substance is contained in every 100 mL of the composition. For example, adding water to 100% means adding water to make the volume of the composition reach 100 mL. In the examples, " / " indicates not carried out or not applicable.

[0114] In a specific embodiment, the pharmaceutical composition of the present invention comprises:

[0115] Minoxidil 2.0 - 5.0%, Finasteride 0.05 - 0.5%, Propylene Glycol 25 - 40%, Ethanol 35 - 45%, Stabilizer 0.5 - 2.5%, Amino Acid 0 - 2.5%, Water added to 100%.

[0116] In a specific embodiment, the pharmaceutical composition of the present invention comprises:

[0117] Minoxidil 2.0 - 5.0%, Finasteride 0.1 - 0.3%, Propylene Glycol 25 - 40%, Ethanol 35 - 45%, Stabilizer 1.0 - 2.0%, Amino Acid 0.5 - 2.5%, Water added to 100%.

[0118] In a specific embodiment, the pharmaceutical composition of the present invention comprises:

[0119] Minoxidil 2.0 - 5.0%, Finasteride 0.1 - 0.3%, Propylene Glycol 30 - 35%, Ethanol 35 - 40%, Stabilizer 1.0 - 2.0%, Amino Acid 1.0 - 2.0%, Water added to 100%.

[0120] In a specific embodiment, the pharmaceutical composition of the present invention comprises:

[0121] Minoxidil 5.0%, Finasteride 0.1%, Sucrose 1.0 - 2.0%, Propylene Glycol 30 - 35%, Ethanol 35 - 40%, Water added to 100%.

[0122] In a specific embodiment, the pharmaceutical composition of the present invention comprises:

[0123] Minoxidil 2.0 - 5.0%, Finasteride 0.1 - 0.3%, Sucralose 1.0 - 2.0%, Propylene Glycol 30 - 35%, Ethanol 35 - 40%, Water added to 100%.

[0124] In a specific embodiment, the pharmaceutical composition of the present invention comprises:

[0125] Minoxidil 2.0 - 5.0%, Finasteride 0.1 - 0.3%, Trehalose 1.0 - 2.0%, Propylene Glycol 30 - 35%, Ethanol 35 - 40%, Water q.s. 100%.

[0126] In a specific embodiment, the pharmaceutical composition of the present invention comprises:

[0127] Minoxidil 2.0 - 5.0%, Finasteride 0.1 - 0.3%, Trehalose 1.0 - 2.0%, Propylene Glycol 30 - 35%, Ethanol 35 - 40%, L - Proline 1.0 - 2.0%, Water q.s. 100%.

[0128] In a specific embodiment, the pharmaceutical composition of the present invention comprises:

[0129] Minoxidil 2.0 - 5.0%, Dutasteride 0.001 - 0.5%, Propylene Glycol 25 - 40%, Ethanol 35 - 45%, Stabilizer 0.5 - 2.5%, Amino Acid 0 - 2.5%, Water q.s. 100%.

[0130] In a specific embodiment, the pharmaceutical composition of the present invention comprises:

[0131] Minoxidil 2.0 - 5.0%, Dutasteride 0.01 - 0.4%, Propylene Glycol 25 - 40%, Ethanol 35 - 45%, Stabilizer 1.0 - 2.0%, Amino Acid 0.5 - 2.5%, Water q.s. 100%.

[0132] In a specific embodiment, the pharmaceutical composition of the present invention comprises:

[0133] Minoxidil 2.0 - 5.0%, Dutasteride 0.05 - 0.4%, Propylene Glycol 30 - 35%, Ethanol 35 - 40%, Stabilizer 1.0 - 2.0%, Amino Acid 1.0 - 2.0%, Water q.s. 100%.

[0134] In a specific embodiment, the pharmaceutical composition of the present invention comprises:

[0135] Minoxidil 2.0 - 5.0%, Dutasteride 0.05 - 0.4%, Sucralose 1.0 - 2.0%, Propylene Glycol 30 - 35%, Ethanol 35 - 40%, Water q.s. 100%.

[0136] In a specific embodiment, the pharmaceutical composition of the present invention comprises:

[0137] Minoxidil 2.0 - 5.0%, Dutasteride 0.05 - 0.4%, Trehalose 1.0 - 2.0%, Propylene Glycol 30 - 35%, Ethanol 35 - 40%, Water q.s. 100%.

[0138] In a specific embodiment, the pharmaceutical composition of the present invention comprises:

[0139] Minoxidil 2.0 - 5.0%, dutasteride 0.05 - 0.4%, trehalose 1.0 - 2.0%, propylene glycol 30 - 35%, ethanol 35 - 40%, L-proline 1.0 - 2.0%, and water is added to 100%.

[0140] The pharmaceutical composition of the present invention is suitable for being formulated into external preparations, such as liquid external preparations.

[0141] Preferably, it can be formulated into common liquid preparations in the art with conventional pharmaceutical excipients in the art, such as solutions, suspensions, liniments, paints, tinctures, sprays, etc.

[0142] The preparation of the present invention can be used for treating alopecia, and has a certain hair growth effect after being administered to patients. By locally administering the composition to people in need, it can promote hair growth and is used for treating alopecia including androgenetic alopecia, alopecia areata, telogen effluvium and other diseases.

[0143] The pharmaceutical composition and its preparation of the present invention have good stability and have at least one of the following performance parameters (1) to (5):

[0144] (1) No crystal precipitation occurs after being placed at a low temperature of 2 - 8°C for more than 1 month.

[0145] (2) After being placed at 60°C under dry conditions for more than 1 month, according to the first method of the solution color inspection method in Part IV of the Chinese Pharmacopoeia 2020 Edition, its color depth is less than the color comparison solution of Standard Yellow No. 1, and more preferably less than the color comparison solution of Standard Yellow No. 0.5.

[0146] (3) After being placed at 40°C under dry conditions for more than 3 months, according to the first method of the solution color inspection method in Part IV of the Chinese Pharmacopoeia 2020 Edition, its color depth is less than the color comparison solution of Standard Yellow No. 1, and more preferably less than the color comparison solution of Standard Yellow No. 0.5.

[0147] (4) After being placed at 60°C under dry conditions for more than 1 month, the mass content of minoxidil impurities is 0.2% or less of the total mass content of minoxidil, preferably 0.15% or 0.12% or less.

[0148] (5) After being placed at 60°C under dry conditions for more than 1 month, the mass content of finasteride impurities is 0.13% or less of the total mass content of finasteride, preferably 0.11% or less.

[0149] The present invention is further illustrated by the following specific examples.

[0150] Examples

[0151] Drug source: The minoxidil compound was purchased from Changzhou Jinsheng Pharmaceutical Factory. The finasteride compound was purchased from Hubei Gedian Humanwell Pharmaceutical Co., Ltd. The dutasteride compound was purchased from Sichuan Guowei Pharmaceutical Co., Ltd.

[0152] Preparation of the composition: According to the formulation dosage, the drug active ingredients (minoxidil, optional finasteride and / or dutasteride), propylene glycol and ethanol were mixed, stirred and dissolved at about 40 - 60 °C to obtain a clear solution, an aqueous solution of the stabilizer was added, stirred evenly, made up to 100 mL with water, and dispensed into small packaging bottles to obtain the product.

[0153] Stability investigation: The composition samples were placed in an oven at 60 °C under dry conditions for 1 month (1M), sampled at 0 day, observed for appearance, and the color change of the samples was examined according to Method 1 of the Color Inspection of Solutions in Part IV of the Chinese Pharmacopoeia 2020 Edition, with reference to the Yellow Hue Standard Colorimetric Solution (purchased from Shanghai Orient Pharmaceutical Technology Industry Co., Ltd.).

[0154] Examples 1 - 3: Compositions containing minoxidil

[0155] The composition formulations and stability investigation results are shown in Table 1.

[0156] Table 1

[0157]

[0158] Examples 4 - 12: Compositions containing minoxidil and finasteride. The composition formulations and stability investigation results are shown in Tables 2 to 4.

[0159] Table 2

[0160]

[0161] Table 3

[0162]

[0163]

[0164] Table 4

[0165]

[0166] Figure 1 Exemplarily shown are the appearance diagrams of the pharmaceutical compositions of Examples 1 - 6 at 0 day and after being placed at high temperature of 60 °C for 1 month. From Figure 1 and Tables 1 - 4, it can be seen that the pharmaceutical compositions of the present invention still have long-term stability in a high-temperature environment.

[0167] Examples 13 - 18: Compositions containing minoxidil and dutasteride

[0168] The composition formulations and stability investigation results are shown in Tables 5 to 6 as follows.

[0169] Table 5

[0170]

[0171]

[0172] Table 6

[0173]

[0174] It can be seen from the results in Tables 5 - 6 that the pharmaceutical composition containing minoxidil and dutasteride of the present invention also has good stability.

[0175] Comparative Example 1:

[0176] The following shows some of the experiments and results during the research process of the present invention for comparison to facilitate understanding of the characteristics of the present invention.

[0177] Mix 5.0 g of minoxidil, 0.1 g of finasteride, 30 g of propylene glycol and 40 g of absolute ethanol, heat and stir to dissolve until clear at 50 ± 10 °C, add different stabilizers shown in the following table respectively, make up the volume to 100 mL with water, stir evenly to obtain the pharmaceutical composition. Dispense the composition samples into small packaging bottles, and investigate the stability of each group of samples by the same method as in the examples. The results are shown in Table 7.

[0178] Table 7

[0179]

[0180]

[0181] Figure 2 Exemplarily shown are the appearance diagrams of the pharmaceutical compositions containing different stabilizers at 0 day and after being placed at 60 °C for 1 month. It can be seen from Table 7 that only specific types of carbohydrates of the present invention can effectively improve the stability of the pharmaceutical composition of the present invention.

[0182] Comparative Example 2:

[0183] Mix 5.0 g of minoxidil, 0.1 g of finasteride, 30 g of propylene glycol and 40 g of absolute ethanol, heat and stir to dissolve until clear at 50 ± 10 °C, add different components shown in Table 6 below respectively, make up the volume to 100 mL with water, stir evenly to obtain the pharmaceutical composition. Dispense the composition samples into small packaging bottles, place them at 2 - 8 °C for 1 month, and investigate the stability of the samples. The results are shown in Table 8. It can be seen that when the content of the stabilizer is too high, a small amount of crystals will be produced after the composition of the present invention is placed.

[0184] Table 8

[0185]

[0186]

[0187] Stability Test of the Composition of Test Example 1

[0188] In this test example, the stability of some representative compositions of the present invention was investigated. In addition, the chemical stability tests of two marketed products were carried out as references.

[0189] Test Samples:

[0190] The compositions of Example 5, Example 7, Example 9 and Example 12 of the present invention;

[0191] Commercially available product 1: MorrF 5% (produced by INTAS PHARMACEUTICALS LTD., India, batch number M2308702, containing 5% minoxidil + 0.1% finasteride);

[0192] Commercially available product 2: (produced by JOHNSON AND JOHNSON GROUP CONSUMER COMPANIES, USA, batch number 0593CP, containing 5% minoxidil)

[0193] Test Method:

[0194] The samples were placed in an oven at 40 °C under dry conditions for 3 months and at 60 °C under dry conditions for 1 month respectively, and samples were taken at 0 day to detect the impurity contents of minoxidil and finasteride respectively to investigate the stability of the samples. When detecting finasteride, the sample solution can be directly injected (the finasteride concentration is about 1 mg / ml), and the chromatogram at a wavelength of 210 nm was recorded. The finasteride and impurity peaks are within the range of retention time of 20 - 35 min; when detecting minoxidil, the sample solution was diluted with a diluent to a minoxidil concentration of about 0.25 mg / ml and then injected, and the chromatogram at a wavelength of 230 nm was recorded. The minoxidil and impurity peaks are within the range of retention time of 0 - 18 min. The area normalization method was used, and the solvent peak was deducted to calculate the impurity contents of finasteride and minoxidil respectively.

[0195] Detection Method: The HPLC detection conditions are as follows:

[0196] Chromatographic column: Waters XBridge C18 (4.6×150 mm, 3.5 μm)

[0197] Flow rate: 1.0 ml / min

[0198] Column temperature: 40 °C

[0199] Mobile phase A: Methanol - water - phosphoric acid (350:650:1) (containing 2 g of sodium heptanesulfonate per 1000 ml)

[0200] Mobile phase B: Methanol

[0201] Gradient elution program:

[0202]

[0203] Injection volume: 10 μL

[0204] Detection wavelength (DAD): Minoxidil: 230 nm; Finasteride: 210 nm

[0205] Needle washing solution: 80% methanol

[0206] Diluent: Methanol - water - phosphoric acid (350:650:1)

[0207] The experimental results are shown in Table 9.

[0208] Table 9

[0209]

[0210] As can be seen from the above table, the composition of the present invention has excellent physical and chemical stabilities compared with the existing products.

[0211] Test Example 2 Stability test of the composition

[0212] In this test example, the stabilities of some representative compositions were investigated.

[0213] Samples: Example 13, Example 15, Example 16 and Example 18;

[0214] Test method: The samples were taken after being placed in a drying condition at 40 °C (oven) for 3 months and at 60 °C (oven) for 1 month on the 0th day, and the impurity contents of minoxidil (diluted to a concentration of about 0.25 mg / ml with the diluent) and dutasteride (injected directly) were detected respectively to investigate the stability of the samples. The area normalization method was used. When calculating the impurities of minoxidil, the solvent peak and the dutasteride peak were deducted; when calculating the impurities of dutasteride, the solvent peak and the minoxidil and its impurity peaks were deducted.

[0215] HPLC detection conditions for minoxidil (these conditions are also applicable to any composition of the present invention):

[0216] Chromatographic column: Waters XBridge C18 (4.6 × 150 mm, 3.5 μm)

[0217] Flow rate: 1.0 ml / min

[0218] Column temperature: 40 °C

[0219] Mobile phase A: Methanol - water - phosphoric acid (350:650:1) (containing 2 g of sodium heptanesulfonate per 1000 ml)

[0220] Mobile phase B: Methanol

[0221] Gradient elution program:

[0222]

[0223] Injection volume: 15 μL

[0224] Detection wavelength: 230 nm

[0225] Needle wash solution: 50% methanol

[0226] Diluent: Methanol - water (350:650)

[0227] HPLC detection method for dutasteride:

[0228] Chromatographic column: GL Sciences Inertsil ODS - 3V (4.6×150 mm, 5 μm)

[0229] Flow rate: 1.0 ml / min

[0230] Column temperature: 40 °C

[0231] Mobile phase A: 0.1% phosphoric acid aqueous solution; Mobile phase B: Acetonitrile

[0232] Gradient elution program:

[0233]

[0234]

[0235] Injection volume: 20 μL

[0236] Detection wavelength: 220 nm

[0237] Needle wash solution: 50% acetonitrile

[0238] Diluent: Acetonitrile - water (600:400)

[0239] The experimental results are shown in Table 10.

[0240] Table 10

[0241]

[0242] As can be seen from the above table, the composition of the present invention has excellent physical and chemical stabilities.

[0243] Test Example 3 In Vitro Transdermal Test

[0244] Test Samples:

[0245] The compositions of Example 7 and Example 9 of the present invention;

[0246] Commercially available product 1: MorrF 5%, Commercially available product 2: Same as above;

[0247] Commercially available product 3: (Produced by Difa Cooper S.p.A, batch number 302371, containing 2.275 mg / ml finasteride)

[0248] Test Method:

[0249] Place the skin of 1-month-old male miniature pigs on the diffusion cell. Take 40 μL of each composition sample and spread it evenly on the pig skin. The receiving cell contains PBS 7.2 medium. Samples are taken at 1, 2, 4, 6, 12, and 24 hours respectively. Using a liquid chromatography-mass spectrometry instrument (Waters SQDetector2 quadrupole liquid chromatography-mass spectrometry instrument), the contents of minoxidil and finasteride are calculated by the standard curve method. Among them, minoxidil is determined using an ultraviolet detector, and finasteride is determined using a mass spectrometry detector. Calculate the cumulative permeation amounts of minoxidil and finasteride at each time point and the cumulative permeation rate in 24 hours, and conduct a t-test statistical analysis on the 24-hour cumulative permeation amount of the samples of each example and the 24-hour cumulative permeation amount of the commercially available products (p < 0.05 indicates a statistically significant difference).

[0250] HPLC Detection Conditions: Chromatographic column: Agilent XDB-C18 (2.1 mm × 50 mm, 3.5 μm); Flow rate: 0.6 ml / min; Column temperature: 35°C; Diluent: PBS, pH 7.2; Mobile phase A: 0.1% formic acid solution; Mobile phase B: Acetonitrile; Gradient elution program:

[0251] Injection volume: 10 μL; Detector (UV + MS): Minoxidil: 280 nm, Finasteride: m / z 373.30 (mass-to-charge ratio, selected ion detection).

[0252]

[0253] Figure 3The in vitro transdermal test results after applying the compositions of Examples 7 and 9 of the present invention and commercial products are shown. The experimental results show that the cumulative permeation amounts of minoxidil and finasteride in the composition solution of the present invention through in vitro transdermal absorption are close to the in vitro transdermal absorption effects of commercial products, and there is no significant difference in the cumulative permeation amounts among the groups (P>0.05).

[0254] According to the requirements of the "Technical Guidelines for the Study of Drug Irritation, Hypersensitivity and Hemolysis", irritation, hypersensitivity and hemolysis refer to the toxicity (such as irritation and local hypersensitivity, etc.) produced on the local part of drug administration and / or the toxicity produced on the whole body (such as systemic hypersensitivity and hemolysis, etc.) after the drug preparation is administered through non-oral routes such as skin, mucosa, cavity, blood vessel, etc., and it is a component of preclinical safety evaluation.

[0255] The following Test Examples 4 and 5 conduct the skin irritation test on damaged skin and the eye irritation test on rabbits for different compositions to investigate the irritation of the compositions of the present invention and commercial preparations to the damaged skin and eyes of rabbits.

[0256] Test Example 4: Skin Irritation Test on Damaged Skin

[0257] Test samples: Compositions of Examples 7 and 9 of the present invention; Commercial Product 1: MorrF 5%, Commercial Product 2: Same as above.

[0258] Test method: Referring to the test method in the "Technical Guidelines for the Study of Drug Irritation, Hypersensitivity and Hemolysis", New Zealand rabbits (4 in each group) are adaptively raised for 3-4 days, and then hair removal is carried out. On both sides of the spine of the animal's back, a piece of body hair is symmetrically shaved off (the hair removal area on each side is 4 cm×4 cm; during the test period, if it is found that hair growth has hindered the observation of skin appearance, hair removal must be carried out again; 24 hours after hair removal, drug application is carried out); after hair removal, a "well" shape is made on the damaged skin with a sterile syringe needle, and the degree of skin damage is limited to the damaged epidermal layer, and the damaged skin is continuously damaged every week during drug administration. The ipsilateral left and right self-contrast method is used, and the test substance is directly applied to the hair-removed area. For the multiple-dose skin irritation test, the drug is continuously administered at the same site, 2 times a day, with an interval of 6 hours, and the drug is administered for 4 weeks.

[0259] Evaluation index: Before each drug administration every day, and 30-60 minutes, 24, 48 and 72 hours after removing the drug at the last application on the last day, the skin reaction is observed with the naked eye under natural light or full-spectrum light (if there is a persistent injury, it is necessary to extend the observation period to evaluate the recovery situation and time, and the extension period is generally not more than 2 weeks). Calculate the average integral value of each group at each observation time point, and then calculate the average integral value of skin irritation of each animal every day during the observation period, and evaluate the irritation intensity in the following way.

[0260] Table 11 Scoring Criteria for Skin Irritation Reaction

[0261]

[0262] Table 12 Evaluation Criteria for Skin Irritation Intensity

[0263] Score Evaluation 0～0.49 Non-irritating 0.5～2.99 Mild irritation 3.0～5.99 Moderate irritation 6.0～8.00 Severe irritation

[0264] The test results are shown in Table 13 below.

[0265] Table 13 Results of Skin Irritation Test on Damaged Skin

[0266] Group Mean score Stimulus intensity evaluation Example 7 0 None Example 9 0 None Commercially available product 1 0 None Commercially available product 2 0.75 Mild

[0267] As can be seen from the above table, the topical compositions of Examples 7 and 9 of the present invention are substantially non-irritating to damaged skin.

[0268] Test Example 5: Ocular Irritation Test on Rabbits

[0269] Test Samples: Compositions of Examples 7 and 9 of the present invention; Commercial Product 1: MorrF 5% (same as above); Commercial Product 4: MINORGA 5% (produced by Laboratoires Bailleul S.A., batch number H0182, containing 5% minoxidil).

[0270] Test Method: Referring to the test method in the "Technical Guidelines for the Study of Drug Irritation, Allergic Reaction and Hemolysis", New Zealand rabbits were used, 4 in each group. The rabbits were fixed, one eyelid was gently pulled down, and the test sample was dropped into the conjunctival sac, 1 - 2 drops of the liquid medicine were dropped. To prevent the liquid medicine from overflowing and ensure sufficient exposure of the drug, the eyelid was immediately gently closed for about 1 min. At 1, 2, 4, 24, 48 and 72 hours after administration, the irritation reaction was examined using a slit lamp, and the time required for the eye to recover to the normal state after being stimulated was recorded. The mean integral of each group was calculated according to Table 14 below and the degree of irritation was judged according to Table 15.

[0271] Table 14 Score Criteria for Ocular Irritation Reaction

[0272]

[0273]

[0274] Table 15 Evaluation Criteria for Ocular Irritation

[0275] Score Evaluation 0-3 Non-irritating 4-8 Mild irritation 9-12 Moderate irritation 13-16 Severe irritation

[0276] The test results are shown in Table 16 below.

[0277] Table 16 Results of Ocular Irritation Experiment

[0278] Group Mean maximum stimulus score Maximum stimulus intensity Recovery time Example 7 4.88 Mild 24 hours Example 9 3.25 Mild 24 hours Commercially available product 1 7.36 Mild 72 hours Commercially available product 4 6.63 Mild 48 hours

[0279] As can be seen from the above table, the pharmaceutical composition of the present invention has low eye irritation.

[0280] For the above embodiments, all technical solutions falling within the concept of the present invention are within the protection scope of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications should also be regarded as within the protection scope of the present invention.

Claims

1. A pharmaceutical composition for treating hair loss, which contains the following components: (A) Minoxidil 0.1 - 10 (w / v)%, preferably 1 - 6 (w / v)%; (B) Stabilizer 0.5 - 2.5 (w / v)%, preferably 1 - 2 (w / v)%; (C) Alcohol solvent 10 - 90 (w / v)%; and, (D) Optionally, other pharmaceutically acceptable carriers. Among them, The stabilizer is a carbohydrate; the carbohydrate is selected from at least one of sucrose, sucralose, trehalose, mannitol or meglumine, preferably from at least one of sucrose, sucralose or trehalose, and most preferably trehalose.

2. The pharmaceutical composition according to claim 1, which further contains component (E), and the component (E) is selected from at least one of the following (e1) or (e2): (e1) Finasteride 0.01 - 1 (w / v)%; the content of finasteride is preferably 0.05 - 0.5 (w / v)%; (e2) Dutasteride 0.001 - 0.5 (w / v)%; the content of dutasteride is preferably 0.01 - 0.4 (w / v)%; Preferably, the component (E) is (e1); or, preferably, the component (E) is (e2); or, preferably, the component (E) is (e1) and (e2).

3. The pharmaceutical composition according to claim 1, which further contains component (F): (F) Amino acid 0.1 - 5 (w / v)%; the amino acid is preferably selected from at least one of L - proline, L - arginine or L - serine, and more preferably L - proline.

4. The pharmaceutical composition according to claim 1, wherein: The alcohol solvent is selected from at least one of propylene glycol, isopropyl alcohol or ethanol, preferably a mixture of propylene glycol and ethanol; the content of the alcohol solvent is preferably 20 - 85 (w / v)%, and more preferably the alcohol solvent is a mixture of 25 - 40 (w / v)% of propylene glycol and 35 - 45 (w / v)% of ethanol; The other pharmaceutically acceptable carriers contain water.

5. The pharmaceutical composition according to any one of claims 1 - 4, and the pharmaceutical composition basically does not contain antioxidants and / or pigments; Preferably, the content of antioxidants in the pharmaceutical composition is below 0.1 (w / v)%, or below 0.01 (w / v)%; Preferably, the content of pigments in the pharmaceutical composition is below 0.1 (w / v)%, or below 0.01 (w / v)%.

6. A preparation for treating hair loss, which contains the pharmaceutical composition according to any one of claims 1 - 5, and preferably, the preparation is a liquid preparation, such as a solution, suspension, liniment, paint, tincture or spray.

7. An application of a carbohydrate in improving the stability of a pharmaceutical composition containing minoxidil, wherein: The carbohydrate is selected from at least one of sucrose, sucralose, trehalose, mannitol or meglumine, preferably from at least one of sucrose, sucralose or trehalose, and most preferably trehalose.

8. The application according to claim 7, and the pharmaceutical composition contains the following components: (A) Minoxidil 0.1 - 10 (w / v)%, preferably 1 - 6 (w / v)%; (B) Stabilizer 0.5 - 2.5 (w / v)%, preferably 1 - 2 (w / v)%; (C) Alcohol solvent 50 - 90 (w / v)%; (D) Optionally, other pharmaceutically acceptable carriers; (E) Optionally, (e1) Finasteride 0.01 - 1 (w / v)%, preferably 0.05 - 0.5 (w / v)%, and / or, (e2) Dutasteride 0.001 - 0.5 (w / v)%, preferably 0.01 - 0.4 (w / v)%; and, (F) Optionally, amino acid 0.1 - 5 (w / v)%; the amino acid is preferably at least one selected from L - proline, L - arginine or L - serine, more preferably L - proline; Preferably, the component (E) is (e1); or, preferably, the component (E) is (e2); or, preferably, the component (E) is (e1) and (e2).

9. The application according to any one of claims 7 - 8, wherein the carbohydrate is the only stabilizer active ingredient in the pharmaceutical composition containing minoxidil; Preferably, the pharmaceutical composition basically does not contain antioxidants and / or pigments; Preferably, the content of the antioxidant in the pharmaceutical composition is 0.1 (w / v)% or less than 0.01 (w / v)%; Preferably, the content of the pigment in the pharmaceutical composition is 0.1 (w / v)% or less than 0.01 (w / v)%.

10. The application of the pharmaceutical composition according to any one of claims 1 - 5 in the preparation of a drug for treating hair loss - related diseases, preferably, the hair loss - related diseases include at least one of androgenetic alopecia, alopecia areata or telogen effluvium.

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