Local external medicine composition for treating alopecia as well as preparation method and application thereof

Abstract

The invention belongs to the field of medicine preparations, and particularly relates to a local external medicine composition for treating alopecia, the medicine composition comprises at least one active component, and the medicine composition comprises the following components in percentage by weight: 1-10% w / w of minoxidil or salt thereof, 0-50% w / w of propylene glycol, 1-50% w / w of ethanol and 10-50% w / w of C3-C10 ether solvent, the total dosage of the propylene glycol and the ethanol is less than or equal to 50% w / w, and the total dosage of the propylene glycol and the ethanol is less than or equal to 50% w / w. The pharmaceutical composition at least has the following excellent characteristics: good curative effect, high drug solubility, high patient efficiency, quick response, few adverse reactions, low scalp irritation, good stability, easy use, no greasy feeling after use, good drug permeability, high bioavailability, few use times, good patient compliance and the like.

Description

Technical Field

[0001] The present application belongs to the field of pharmaceutical preparations, and specifically relates to a pharmaceutical composition for treating hair loss, and a preparation method and use thereof. Technical Background

[0002] Among all types of hair loss, androgenetic alopecia (AGA) is the most common. AGA is a hair loss disease that begins in adolescence or late adolescence and is characterized by progressive miniaturization of hair follicles. AGA often occurs in young and middle-aged people with active sebaceous gland secretion, and can occur in both men and women.

[0003] At present, topical minoxidil is the first-line drug for the treatment of AGA. It is also the recommended drug for patients with alopecia areata (AA) in the stable stage and with a small area of ​​hair loss. It can also moderately or significantly improve hair loss caused by chemotherapy. The mechanism of action of minoxidil in promoting hair growth is still unclear. It is currently believed that there may be multiple mechanisms. One of them is that the sulfotransferase at the root of the hair follicle converts minoxidil into minoxidil sulfate, which stimulates hair growth. The topical dosage forms of minoxidil include solution, foam, and spray. Existing minoxidil topical products contain a large amount of propylene glycol or ethanol. For example, the currently available 5% minoxidil solution contains 50% propylene glycol, which not only has an irritating / sensitizing effect on the scalp, but also easily causes greasy hair, which is even more "worse" for patients with greasy scalp. The 5% minoxidil foam contains more than 50% ethanol, which evaporates quickly during use, easily causing the active ingredients of the drug to precipitate, resulting in low drug bioavailability; in addition, the local precipitation of active ingredients of the drug will also irritate the scalp. In addition, due to the low transdermal absorption rate and poor bioavailability of the active ingredients in the existing minoxidil topical preparations, less than 40% of patients respond to topical minoxidil treatment. Moreover, patients need to use it twice a day, and the treatment cycle is long (3-6 months), resulting in poor patient compliance.

[0004] Therefore, it is very necessary to develop a topical minoxidil preparation that has low irritation, high transdermal absorption rate, high response rate and is easy to use. Summary of the invention

[0005] The main purpose of the present application is to provide a topical external pharmaceutical composition for treating hair loss, which has at least one of the following excellent properties: good efficacy, high drug solubility, high patient efficacy, rapid onset, few adverse reactions, low scalp irritation, good stability, easy to use, non-greasy after use, good drug permeability, high bioavailability, few times of use, good patient compliance, etc.

[0006] This application intends to use C3-C with low skin irritation and low viscosity 10The use of ether solvents in combination with propylene glycol and ethanol, on the one hand, takes advantage of the unexpected synergistic solubilization effect between several solvents, reduces the dosage of propylene glycol and ethanol while ensuring sufficient drug solubility, and reduces scalp irritation and greasy feeling; on the other hand, using C3-C 10 Ether solvents have a good permeation-promoting effect, which increases the transdermal absorption of drugs, improves the patient's response rate and treatment effect, and reduces the frequency of use.

[0007] In one aspect of the present application, a topical pharmaceutical composition for treating hair loss is provided, the pharmaceutical composition comprising at least one active ingredient, and based on the total weight of the pharmaceutical composition, the pharmaceutical composition comprises:

[0008]

[0009] and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0010] In the preferred technical solution of the present application, the active ingredient comprises at least any one of minoxidil, minoxidil sulfate and minoxidil hydrochloride or a combination thereof; more preferably any one of minoxidil and minoxidil sulfate or a combination thereof.

[0011] In the preferred technical solution of this application, the C3-C 10 The ether solvent is selected from at least one of diethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether and diethylene glycol methyl ethyl ether; preferably, the C3-C 10 The ether solvent is selected from diethylene glycol monoethyl ether.

[0012] In the preferred technical solution of the present application, the propylene glycol accounts for 0-30% w / w of the total amount of the pharmaceutical composition; preferably 10-30% w / w, such as 15-25% w / w.

[0013] In some embodiments, the propylene glycol comprises 0% w / w, 5% w / w, 10% w / w, 15% w / w, 20% w / w, 25% w / w or 30% w / w of the total pharmaceutical composition.

[0014] In the preferred technical solution of the present application, the ethanol accounts for 10-50% w / w of the total amount of the pharmaceutical composition; preferably 10-40% w / w, such as 10-30% w / w.

[0015] In some embodiments, the ethanol accounts for 10% w / w, 15% w / w, 20% w / w, 25% w / w, 30% w / w, 35% w / w or 40% w / w of the total amount of the pharmaceutical composition. 10The ether solvent accounts for 15-50% w / w of the total amount of the pharmaceutical composition, more preferably 20-50% w / w.

[0016] In some embodiments, the C3-C 10 The ether solvent accounts for 15% w / w, 20% w / w, 25% w / w, 30% w / w, 35% w / w, 40% w / w, 45% w / w or 50% w / w of the total amount of the pharmaceutical composition.

[0017] In the preferred technical solution of the present application, the water accounts for 5-20% w / w of the total amount of the pharmaceutical composition, preferably 10-20% w / w.

[0018] In some embodiments, the water comprises 10% w / w, 11% w / w, 12% w / w, 13% w / w, 14% w / w, 15% w / w, 16% w / w, 17% w / w, 18% w / w, 19% w / w or 20% w / w of the total pharmaceutical composition.

[0019] In the preferred technical solution of the present application, the minoxidil or its salt accounts for 1-5% w / w of the total amount of the pharmaceutical composition, calculated as free minoxidil.

[0020] In the preferred technical solution of the present application, the pharmaceutical composition further contains 0.01-1% w / w finasteride or 0.01-1% w / w dutasteride. After local application, the pharmaceutical composition has a better therapeutic effect on androgenic alopecia, and is particularly suitable for the treatment of androgenic alopecia in young and middle-aged men.

[0021] In the preferred technical solution of the present application, the pharmaceutical composition may also contain water, propylene glycol, ethanol and C3-C 10 An organic solvent miscible with an ether solvent, wherein the organic solvent accounts for 1-20% w / w of the total amount of the pharmaceutical composition.

[0022] In the preferred technical solution of the present application, the water, propylene glycol, ethanol and C3-C 10 The organic solvent miscible with the ether solvent is selected from C2-C 10 At least one of an alcohol solvent and polyethylene glycol; preferably, the organic solvent is selected from at least one of glycerol, ethylene glycol, n-propanol, isopropanol, PEG200, PEG300, PEG400 and PEG600.

[0023] In some embodiments, the organic solvent is glycerol.

[0024] In the preferred technical solution of the present application, the pharmaceutical composition may also contain 0.05-20% w / w of water, propylene glycol, ethanol and C3-C 10 Surfactants that are miscible in ether solvents.

[0025] In the preferred technical scheme of the present application, the surfactant is selected from surfactants with an HLB value of 10-20; preferably, the surfactant is selected from at least one of polyoxyethylene (35) castor oil, polyoxyethylene (40) hydrogenated castor oil, 15-hydroxystearate polyethylene glycol, polyethylene glycol cetearyl alcohol ether, and polysorbate 80.

[0026] In some embodiments, the surfactant is polyoxyethylene (35) castor oil.

[0027] In the preferred technical solution of the present application, other pharmaceutically acceptable carriers mainly include at least one of preservatives, chelating agents, penetration enhancers, and moisturizers. The specific amount added is within the concentration range of excipients commonly used in pharmacy, cosmetics, or daily necessities.

[0028] In the preferred technical scheme of the present application, the preservative is selected from at least one of methyl parahydroxybenzoate (methylparaben), benzyl alcohol, sodium benzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, potassium sorbate, and phenoxyethanol; preferably methyl parahydroxybenzoate (methylparaben).

[0029] In the preferred technical scheme of the present application, the chelating agent is selected from at least one of ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), ethylenediamine-di(o-hydroxyphenyl)acetic acid (EDDHA), hydroxy-2-ethylenediaminetriacetic acid (HEDTA), ethylenediamine-di(o-hydroxy-p-methylphenyl)acetic acid (EDDHMA) and ethylenediamine-di(5-carboxy-2-hydroxyphenyl)acetic acid (EDDCHA); preferably ethylenediaminetetraacetic acid (EDTA).

[0030] In the preferred technical scheme of the present application, the penetration enhancer is selected from at least one of cocoyl capryloyl caprate, octyldodecanol, polyglycerol oleate, oleic acid, stearic acid, isostearic acid, lactic acid, lauric acid, polyethylene glycol, isopropyl myristate, isopropyl palmitate, dimethylacetamide, triglycerides, menthol, menthol, propylene glycol, borneol, cnidium monnieri oil, azone, sodium tetradecyl sulfate, geraniol, anethole and decyl methyl sulfoxide.

[0031] In the preferred technical solution of the present application, the moisturizing agent is selected from at least one of glycerin, paraffin oil, sorbitol, propylene glycol, isopropanol, ethanol, butylene glycol and hyaluronic acid.

[0032] In the preferred technical scheme of the present application, the pharmaceutical composition may also include at least one of water-soluble chitosan, polylactic acid-glycolic acid polyethylene glycol block copolymer (PLGA-PEG-PLGA), block copolymer of poly N-isopropylacrylamide and polyethylene glycol, and B vitamins; preferably, the pharmaceutical composition contains water-soluble chitosan and / or B vitamins; more preferably, the water-soluble chitosan is hydroxypropyl chitosan, and the B vitamins are vitamin B7.

[0033] In the preferred technical scheme of the present application, the content of minoxidil or its salt is 1.0%, 1.5%, 2%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0% of the total amount of the pharmaceutical composition; the content of finasteride is 0.1%, 0.2%, 0.5%, 0.75%, 1% of the total amount of the pharmaceutical composition; preferably, the contents of minoxidil or its salt and finasteride are 2% and 0.1%, 2% and 0.5%, 5% and 0.1%, 5% and 0.5% of the total amount of the pharmaceutical composition, respectively.

[0034] 1. Another aspect of the present application provides a topical pharmaceutical composition for treating hair loss, the pharmaceutical composition comprising:

[0035]

[0036] and other pharmaceutically acceptable carriers, and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0037] Preferably, the pharmaceutical composition comprises:

[0038]

[0039] and other pharmaceutically acceptable carriers, and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0040] More preferably, the pharmaceutical composition comprises:

[0041]

[0042] and other pharmaceutically acceptable carriers, and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0043] 2. Another aspect of the present application provides a topical pharmaceutical composition for treating hair loss, the pharmaceutical composition comprising:

[0044]

[0045] And other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0046] Preferably, the pharmaceutical composition comprises:

[0047]

[0048] and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0049] More preferably, the pharmaceutical composition comprises:

[0050]

[0051] And other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0052] 3. Another aspect of the present application provides a topical pharmaceutical composition for treating hair loss, the pharmaceutical composition comprising:

[0053]

[0054] and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0055] Preferably, the pharmaceutical composition comprises:

[0056]

[0057] and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0058] More preferably, the pharmaceutical composition comprises:

[0059]

[0060] and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0061] 4. Another aspect of the present application provides a topical hair growth pharmaceutical composition for treating hair loss, the pharmaceutical composition comprising:

[0062]

[0063] and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0064] Preferably, the pharmaceutical composition comprises:

[0065]

[0066] and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0067] More preferably, the pharmaceutical composition comprises:

[0068]

[0069]

[0070] and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0071] 5. Another aspect of the present application provides a topical hair growth pharmaceutical composition for treating hair loss, the pharmaceutical composition comprising:

[0072]

[0073] and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0074] Preferably, the pharmaceutical composition comprises:

[0075]

[0076] and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0077] More preferably, the pharmaceutical composition comprises:

[0078]

[0079]

[0080] and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0081] 6. Another aspect of the present application provides a topical hair growth pharmaceutical composition for treating hair loss, the pharmaceutical composition comprising:

[0082]

[0083] and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0084] Preferably, the pharmaceutical composition comprises:

[0085]

[0086] and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0087] More preferably, the pharmaceutical composition comprises:

[0088]

[0089] and other pharmaceutically acceptable carriers, wherein the total amount of propylene glycol and ethanol is ≤50% w / w.

[0090] Another aspect of the present application provides a use of the above-mentioned topical external pharmaceutical composition for treating hair loss in preparing a medicament for treating hair loss.

[0091] The hair loss refers to pathological hair loss, including but not limited to at least one of androgenic alopecia, alopecia areata, anagen effluvium, autoinduced alopecia, telogen effluvium and scarring alopecia, psychogenic alopecia, endocrine disorder alopecia, nutritional alopecia and chemical alopecia.

[0092] In the preferred technical solution of the present application, the hair loss is androgenic alopecia (AGA); more preferably, it is androgenic alopecia for young and middle-aged men.

[0093] Another aspect of the present application provides a use of the above-mentioned topical external pharmaceutical composition for treating hair loss in preparing a pharmaceutical preparation for topical application.

[0094] In the preferred technical solution of the present application, the drug preparation for local administration is a solution.

[0095] Furthermore, the solution is a completely dissolved type or a suspended type.

[0096] Another aspect of the present application provides a method for treating hair loss, comprising administering a therapeutically effective amount of the topical pharmaceutical composition of the present application to a subject in need thereof; preferably, the topical pharmaceutical composition is a solution. Further, the solution is a completely dissolved type or a suspension type.

[0097] Another aspect of the present application provides a method for preparing the above-mentioned pharmaceutical composition, the preparation method comprising the following steps:

[0098] (1) Dissolve the active ingredient in propylene glycol and / or ethanol, C3-C 10 In ether solvents, an organic phase is formed;

[0099] (2) dissolving other pharmaceutically acceptable carriers in water to form an aqueous phase;

[0100] (3) mixing the organic phase and the aqueous phase, stirring and emulsifying the organic phase and the aqueous phase to make the organic phase and the aqueous phase uniformly mixed to prepare the pharmaceutical composition.

[0101] In the preferred technical solution of the present application, a hydrophilic carrier component such as a solubilizer may be added in the step 2).

[0102] The pharmaceutical composition of the present application has the following beneficial effects:

[0103] (1) Good therapeutic effect. After topical use of the pharmaceutical composition of the present application, the patient has a high marked efficacy, and compared with the products on the market, it has a good therapeutic effect on hair loss, especially after combined topical use with finasteride, it has a faster onset of action, a higher marked efficacy, and a better therapeutic effect for AGA treatment.

[0104] (2) Low scalp irritation and few adverse reactions. Compared with the prior art which usually uses a large amount of propylene glycol (such as more than 50% W / W) or ethanol (such as more than 50% W / W) as a solvent to dissolve minoxidil and finasteride, which are poorly water-soluble, the propylene glycol, ethanol and diethylene glycol monoethyl ether in the pharmaceutical composition of the present application have a synergistic effect on increasing the solubility of minoxidil. While reducing the amount of propylene glycol and ethanol, it can also fully dissolve the active ingredients of the drug, meet the drug loading, reduce scalp irritation and allergy, and will not cause itching, dandruff, redness and swelling and other uncomfortable symptoms.

[0105] (3) The active ingredients of the drug are basically not precipitated or precipitated in small amounts. The prior art uses ethanol as a solvent, which is easy to volatilize, causing the drug to precipitate on the scalp before being absorbed, and the drug bioavailability is low. However, the present application uses diethylene glycol monoethyl ether as a solvent and a penetration enhancer to partially replace the sensitizing and irritating propylene glycol and ethanol. The solvent is not easy to volatilize during the application process, and can effectively control the active ingredients of the drug to be basically not precipitated or precipitated in small amounts during use, so that it can continue to penetrate the surface of the scalp into the hair follicles and other lesions, thereby improving the bioavailability of the drug and ensuring the efficacy of the drug.

[0106] (4) Good stability. The pharmaceutical composition of the present application uses propylene glycol, ethanol, C3-C 10 The ether solvent is used as a solvent and a permeation enhancer, and the prepared pharmaceutical composition exists in the form of a solution or a low-viscosity gel and has good stability.

[0107] (5) Patient compliance is good. The pharmaceutical composition described in this application is composed of propylene glycol, ethanol, C3-C 10 The ether solvent is used as the solvent, and the prepared pharmaceutical composition is a solution. The patient does not feel greasy when using it, and the experience is good. It can be sprayed or applied, which is easy to operate and improves the patient's comfort.

[0108] In the present application, "pharmaceutically acceptable carrier" refers to any pharmaceutically acceptable ingredient known to those skilled in the art, which is generally regarded as an inactive ingredient. DETAILED DESCRIPTION

[0109] Hereinafter, the present application will be explained in detail by the following examples in order to better understand the various aspects and advantages of the present application. However, it should be understood that the following examples are non-limiting and are only used to illustrate certain embodiments of the present application.

[0110] In this application, unless otherwise specified, various raw materials, reagents, instruments and equipment used in this application can be purchased from the market or prepared by existing methods.

[0111] Experimental Example 1 Investigation of the solubility of active ingredients in different solvents

[0112] Test method: Take 1mL of different solvents in a 5mL glass bottle, add excess minoxidil or finasteride, stir at room temperature for 24 hours, filter and measure the equilibrium solubility of minoxidil or finasteride by HPLC. The results are shown in Table 1:

[0113] Table 1 Equilibrium solubility of minoxidil and finasteride in different solvents

[0114]

[0115] The results showed that the solubility of minoxidil and finasteride in ethanol, propylene glycol and diethylene glycol monoethyl ether was higher than 15 mg / ml, which could better meet the medicinal needs.

[0116] Experimental Example 2 Investigation of the solubility and drug loading of minoxidil in aqueous solutions of propylene glycol, ethanol or diethylene glycol monoethyl ether at different concentrations

[0117] Test method: Take 1 mL of propylene glycol, ethanol and diethylene glycol monoethyl ether aqueous solution prepared in a certain proportion in a 5 mL glass bottle, add excess minoxidil and finasteride and stir, see Table 2.

[0118] Table 2 Drug loading of minoxidil in aqueous solution of different concentrations of propylene glycol ethanol or diethylene glycol monoethyl ether

[0119]

[0120] The results showed that when the proportions of ethanol, propylene glycol and diethylene glycol monoethyl ether in their respective aqueous solutions were lower than 30%, the solubility of minoxidil was no higher than 10 mg / ml, which could not meet the drug loading requirements of minoxidil (>20 mg / ml).

[0121] Experimental Example 3 Investigation of the solubility and drug loading of minoxidil in aqueous solutions of propylene glycol, ethanol and diethylene glycol monoethyl ether

[0122] Test method: According to the prescription in Table 3, take 1 mL of a mixed aqueous solution of propylene glycol, ethanol and diethylene glycol monoethyl ether in a good proportion into a 5 mL glass bottle, add an excess of minoxidil and stir, see Table 3.

[0123] Table 3 Drug loading of minoxidil in solution

[0124]

[0125] The results show:

[0126] 1) The solubility of minoxidil in solution samples numbered 3-1, 3-2, 3-3 and 3-8 was above 50 mg / ml, reaching the highest drug loading of currently available products on the market, and well meeting the medicinal needs. At the same time, the total content of ethanol and propylene glycol in the prescription was not higher than 50%, which could reduce the skin irritation and sensitization of the prescription;

[0127] 2) When 20% propylene glycol, 30% ethanol, and 30% diethylene glycol monoethyl ether were used as solvents, the corresponding solubility of minoxidil was 4.63 mg / ml, 10.77 mg / ml, and 10.70 mg / ml, respectively; when the solution samples used 20% propylene glycol + 30% ethanol (3-4), 20% propylene glycol + 30% diethylene glycol monoethyl ether (3-5), and 30% ethanol + 30% diethylene glycol monoethyl ether (3-6) as solvents, the corresponding solubility of minoxidil was 29.83 mg / ml, 20.91 mg / ml, and 36.72 mg / ml, respectively; when the three components (3-3) in the solution sample existed simultaneously as solvents (20% propylene glycol + 30% ethanol + 30% diethylene glycol monoethyl ether), the solubility of minoxidil reached 55.55 mg / ml.

[0128] visible:

[0129] When the three components (3-3) exist simultaneously as solvents, the corresponding solubility of minoxidil (55.55 mg / ml) is greater than the sum of the corresponding solubilities when 20% propylene glycol, 30% ethanol, and 30% diethylene glycol monoethyl ether exist separately as solvents (4.63+10.77+10.70=25.47 mg / ml).

[0130] When the three components (3-3) are present simultaneously as solvents, the solubility of minoxidil (55.55 mg / ml) is greater than the sum of the solubility when 20% propylene glycol is used as solvent and the solubility when 30% ethanol + 30% diethylene glycol monoethyl ether (3-6) is used as solvent (4.63 + 36.72 = 41.35 mg / ml).

[0131] When the three components (3-3) are present simultaneously as solvents, the corresponding minoxidil solubility (55.55 mg / ml) is greater than the solubility when 30% ethanol is used as solvent and the sum of the solubility when 20% propylene glycol + 30% diethylene glycol monoethyl ether (3-5) is used as solvent (10.77+20.91=31.68 mg / ml).

[0132] When the three components (3-3) are present as solvents at the same time, the corresponding minoxidil solubility (55.55 mg / ml) is greater than the solubility when 30% diethylene glycol monoethyl ether is used as solvent plus the sum of the solubilities when 20% propylene glycol + 30% ethanol (3-4) is used as solvent (10.70+29.83=40.53 mg / ml).

[0133] In summary, it is shown that using propylene glycol, ethanol and diethylene glycol monoethyl ether in a specific ratio as solvents at the same time has a synergistic effect in improving the solubility of minoxidil.

[0134] 3) For the solution sample No. 3-8, the solubility of minoxidil is above 50 mg / ml, which can meet the medicinal needs; for the solution samples No. 3-9, 3-10 and 3-11, the solubility of minoxidil is below 50 mg / ml, which cannot meet the medicinal needs. This is mainly because when the propylene glycol is less than 20%, for example, 10%, the weight ratio of ethanol and diethylene glycol monoethyl ether needs to be greater than 1 to make the solubility of minoxidil above 50 mg / ml.

[0135] Experimental Example 4 Investigation of the solubility and drug loading of minoxidil in aqueous solutions of propylene glycol, ethanol, diethylene glycol monoethyl ether and glycerol

[0136] Test method: Take 1 mL of a mixed aqueous solution of propylene glycol, ethanol, diethylene glycol monoethyl ether and glycerol in a good proportion in a 5 mL glass bottle, add an excess of minoxidil and stir, see Table 4.

[0137] Table 4 Drug loading of minoxidil

[0138]

[0139]

[0140] The results showed that when glycerol was added to the system and the content of propylene glycol was 5% or 0, the solubility of minoxidil in the system still exceeded 50 mg / ml, reaching the highest drug loading of currently available products on the market, which well met the medicinal needs and avoided the skin irritation and sensitization caused by high concentrations of propylene glycol.

[0141] Example 1 5% w / w minoxidil solution

[0142] prescription:

[0143]

[0144] Preparation method:

[0145] (1) dissolving a prescribed amount of minoxidil in a mixed solvent of diethylene glycol monoethyl ether, propylene glycol and ethanol to form an organic phase;

[0146] (2) Mixing the organic phase and the aqueous phase and uniformly dispersing them to obtain the solution.

[0147] Example 2 5% w / w minoxidil solution

[0148] prescription:

[0149]

[0150] Preparation method: Same as Example 1.

[0151] Example 3 5% w / w minoxidil solution

[0152] prescription:

[0153]

[0154] Preparation method: Same as Example 1.

[0155] Example 4 5% w / w minoxidil solution

[0156] prescription:

[0157]

[0158] Preparation method: Same as Example 1.

[0159] Example 5 5% w / w minoxidil solution

[0160] prescription:

[0161]

[0162] Preparation method:

[0163] (1) dissolving a prescribed amount of minoxidil in a mixed solvent of diethylene glycol monoethyl ether, propylene glycol, ethanol and glycerol to form an organic phase;

[0164] (2) Mixing the organic phase and the aqueous phase and uniformly dispersing them to obtain the solution.

[0165] Example 6 5% w / w minoxidil solution

[0166] prescription:

[0167]

[0168] Preparation method:

[0169] (1) dissolving a prescribed amount of minoxidil in a mixed solvent of diethylene glycol monoethyl ether, ethanol and glycerol to form an organic phase;

[0170] (2) Mixing the organic phase and the aqueous phase and uniformly dispersing them to obtain the solution.

[0171] Example 7 2% w / w minoxidil solution

[0172] prescription:

[0173]

[0174] Preparation method: Same as Example 1.

[0175] Example 8 1% w / w minoxidil solution

[0176] prescription:

[0177]

[0178] Preparation method: Same as Example 1.

[0179] Example 9 10% w / w minoxidil solution

[0180] prescription:

[0181]

[0182] Preparation method: Same as Example 1.

[0183] Example 10 Minoxidil finasteride solution

[0184] Prescription composition (unit dose):

[0185]

[0186] Preparation method:

[0187] (1) dissolving a prescribed amount of minoxidil and finasteride in a mixed solvent of diethylene glycol monoethyl ether, propylene glycol and ethanol to form an organic phase;

[0188] (2) Mixing the organic phase and the aqueous phase and uniformly dispersing them to obtain the pharmaceutical composition.

[0189] Example 11 Minoxidil Finasteride Solution

[0190] Prescription composition (unit dose):

[0191]

[0192]

[0193] Preparation method:

[0194] (1) dissolving the prescribed amount of minoxidil, finasteride, and methylparaben in a mixed solvent of ethanol, propylene glycol, diethylene glycol monoethyl ether, and glycerol to form an organic phase;

[0195] (2) dissolving other ingredients in water to form an aqueous phase;

[0196] (3) Mixing the organic phase and the aqueous phase and uniformly dispersing them to obtain the pharmaceutical composition.

[0197] It can be understood from the foregoing that although the specific embodiments of the present disclosure are described for the purpose of illustrative illustration, various modifications or improvements may be made by those skilled in the art without departing from the spirit and scope of the present disclosure. These modifications or improvements should all fall within the scope of the claims appended to the present disclosure.

Claims

1. A topical pharmaceutical composition for treating hair loss, the pharmaceutical composition comprising at least one active ingredient, based on the total weight of the composition, the pharmaceutical composition comprising: and other pharmaceutically acceptable carriers, wherein The total amount of propylene glycol and ethanol is ≤50% w / w.

2. The pharmaceutical composition according to claim 1, characterized in that The C3-C 10 The ether solvent is selected from at least one of diethylene glycol monoethyl ether, diethylene glycol diethyl ether, diethylene glycol monomethyl ether, diethylene glycol dimethyl ether and diethylene glycol methyl ethyl ether; preferably, the C3-C 10 The ether solvent is selected from diethylene glycol monoethyl ether.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that The propylene glycol accounts for 0-30% w / w of the total amount of the composition, preferably 10-30% w / w, more preferably 15-25% w / w; the ethanol accounts for 10-50% w / w of the total amount of the pharmaceutical composition, preferably 10-40% w / w, more preferably 10-30% w / w; the C3-C 10 The ether solvent accounts for 15-50% w / w of the total amount of the composition, more preferably 20-50% w / w; the water accounts for 5-20% w / w of the total amount of the composition, more preferably 10-20% w / w; the minoxidil or its salt accounts for 1-5% w / w of the total amount of the composition.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that The pharmaceutical composition further contains 0.01-1% w / w of finasteride or 0.01-1% w / w of dutasteride.

5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that The pharmaceutical composition may also contain water, propylene glycol, ethanol and C3-C 10 An organic solvent miscible with ether solvents, the organic solvent accounts for 1-20% w / w of the total amount of the pharmaceutical composition; preferably, the organic solvent is selected from C2-C 10 At least one of an alcohol solvent and polyethylene glycol; more preferably, the organic solvent is glycerol.

6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that The pharmaceutical composition may also contain water, propylene glycol, ethanol and C3-C 10 A surfactant miscible with ether solvents, wherein the surfactant accounts for 0.05-20% w / w of the total amount of the pharmaceutical composition; preferably, the surfactant is selected from surfactants with an HLB value of 10-20; more preferably, the surfactant is polyoxyethylene (35) castor oil.

7. The pharmaceutical composition according to any one of claims 1 to 6, characterized in that The pharmaceutical composition may also contain at least one of water-soluble chitosan, polylactic acid-glycolic acid polyethylene glycol block copolymer, block copolymer of poly N-isopropylacrylamide and polyethylene glycol, and B vitamins; preferably, the pharmaceutical composition contains water-soluble chitosan and / or B vitamins; more preferably, the water-soluble chitosan is hydroxypropyl chitosan, and the B vitamins are vitamin B7.

8. A method for preparing the pharmaceutical composition according to any one of claims 1 to 7, comprising the following steps: (1) Dissolve the active ingredient in propylene glycol and / or ethanol, C3-C 10 In ether solvents, an organic phase is formed; (2) dissolving other pharmaceutically acceptable carriers in water to form an aqueous phase; (3) mixing the organic phase and the aqueous phase, stirring and emulsifying to make the organic phase and the aqueous phase uniformly mixed to prepare the pharmaceutical composition; Preferably, a hydrophilic carrier component such as a solubilizer may be added in step 2).

9. Use of the pharmaceutical composition according to any one of claims 1 to 7 in the preparation of a medicament for treating hair loss; preferably, the hair loss refers to pathological hair loss, including but not limited to at least one of androgenic alopecia, alopecia areata, anagen effluvium, autoinduced alopecia, telogen effluvium and scarring alopecia, psychogenic alopecia, endocrine disorder alopecia, nutritional alopecia and chemical alopecia; more preferably, the hair loss is androgenic alopecia (AGA); more preferably, androgenic alopecia for young and middle-aged men.

10. Use of the pharmaceutical composition according to any one of claims 1 to 7 in the preparation of a pharmaceutical preparation for topical administration; preferably, the pharmaceutical preparation for topical administration is a solution; more preferably, the solution is a completely dissolved type or a suspension type.

Images