Compound preparation for treating alopecia and preparation technology thereof

Abstract

The invention relates to the related field of treatment of alopecia, in particular to a compound preparation for treating alopecia and a preparation technology of the compound preparation for treating alopecia. The first active component accounts for 1-10% by mass of the compound preparation, the second active component accounts for 0.1-5% by mass of the compound preparation, the first active component is minoxidil, and the second active component is finasteride. The compound preparation is a gel, plays a local role and is free of irritation, and the medicine can be better reserved to act on the scalp, so that the effect of treating alopecia is achieved.

Description

Technical Field

[0001] The present invention relates to the field related to the treatment of hair loss, and specifically relates to a compound preparation for treating hair loss and its preparation technology. Background Art

[0002] With the development of society, people's life rhythm is getting faster and faster, bringing problems such as irregular work and rest, high mental stress, insomnia, anxiety and so on. The phenomenon of hair loss and hair shedding is becoming more and more serious. In recent years, the number of hair loss people in our country has increased linearly. On average, 1 out of every 6 people has hair loss, and those between 20 and 40 years old account for a relatively large proportion. There are many reasons for hair loss, including seborrheic alopecia, blood-heat alopecia, male pattern alopecia and hereditary factor alopecia. Although hair loss and alopecia areata do not endanger life, they can damage the appearance of patients to varying degrees, affect physical and mental health and quality of life, and often bring serious impacts on the psychology, work and social activities of patients.

[0003] Currently, finasteride, minoxidil, spironolactone, dutasteride, corticosteroids, ketoconazole, copper peptides, etc. are used for the treatment of hair loss and hair growth.

[0004] The currently common minoxidil solution on the market is a minoxidil hair growth liquid containing a large amount of propylene glycol. During the use process, it has a relatively large irritation to the skin. Some users are allergic to propylene glycol, resulting in increased dandruff, itchy skin, strong greasy feeling, and in severe cases, it will cause a rapid increase in hair loss. Minoxidil needs to be used for a long time to achieve obvious hair growth, and there will be a withdrawal reaction after stopping the drug, so there are potential safety hazards.

[0005] Finasteride is a synthetic steroid compound. It is a specific inhibitor of type II 5α-reductase, an intracellular enzyme in the process of androgen testosterone being metabolized into dihydrotestosterone. By inhibiting the generation of local dihydrotestosterone (DHT) in the scalp, it promotes hair growth and prevents continued hair loss. Common adverse reactions of using finasteride include occasionally affecting sexual function (such as erectile dysfunction, decreased libido and ejaculatory dysfunction, etc.), and there may also be a phenomenon of decreased sperm count during the treatment period. Other rare adverse reactions include gynecomastia and testicular pain in men. Long-term high-dose use will also weaken muscle strength and cause osteoporosis, and it is contraindicated for lactating and pregnant women.

[0006] Most of the usage routes of finasteride are oral administration, and the systemic blood drug concentration absorption is affected by the first-pass metabolism, with more adverse reactions. Summary of the Invention

[0007] According to the defects of the prior art, the purpose of the present invention is to provide a compound preparation, which is a gel preparation. This preparation exerts its effect locally and has no irritation, and can make the drug better retain its effect on the scalp.

[0008] For the above purposes, the present invention discloses a compound preparation comprising a first active ingredient and a second active ingredient, wherein the first active ingredient accounts for 1-10% by mass of the compound preparation and the second active ingredient accounts for 0.1-5% by mass of the compound preparation.

[0009] In an embodiment of the present invention, the first active ingredient is minoxidil.

[0010] In an embodiment of the present invention, the first active ingredient minoxidil has formulations with different concentrations, usually 2% and 5%. Male patients are generally recommended to use 5% minoxidil, and this specification is mainly applied in the market. The concentration of minoxidil in the embodiment of the present invention is preferably 5%.

[0011] In an embodiment of the present invention, the second active ingredient is one or more of finasteride, spironolactone, dutasteride, corticosteroid, ketoconazole, copper peptide, etc.

[0012] In an embodiment of the present invention, the second active ingredient is preferably finasteride.

[0013] In an embodiment of the present invention, the dosage of the second active ingredient finasteride varies depending on the treatment purpose and the patient's condition. The dosage for treating male androgenetic alopecia is 0.1% (1 mg). Therefore, the concentration of finasteride in the embodiment of the present invention is preferably 0.1%.

[0014] Propylene glycol has strong fat solubility, can dissolve many drugs, and has the ability to make the skin better absorb moisture. It has a good moisturizing effect on the skin. In addition, it can dissolve drugs well, promote the permeability of drugs, and make the skin better absorb. However, propylene glycol has certain side effects. It may stimulate the local skin and cause skin allergies, such as erythema or itching discomfort, and may also cause side effects such as local burning pain.

[0015] In the present invention, propylene glycol can dissolve minoxidil well. However, when the dosage of propylene glycol is greater than 20%, it will cause certain skin irritation. If the dosage of propylene glycol is too low, an excessive amount of ethanol needs to be added to dissolve minoxidil, which will lead to too fast drying rate of the sample and reduced permeability. Otherwise, minoxidil is likely to precipitate and produce white precipitate. Therefore, the concentration of propylene glycol in the embodiment of the present invention is preferably 10%.

[0016] The present invention provides the following technical solutions: A preparation method of a stable gelling agent, comprising: preparing a minoxidil solution: heating solvent 1 to 40°C - 60°C, adding the minoxidil active ingredient thereto, and obtaining a minoxidil-containing solution after complete dissolution; preparing a finasteride solution, dissolving finasteride in a certain amount of solvent 2, and stirring to dissolve to obtain a finasteride solution; mixing the solutions containing two active ingredients to prepare a compound preparation, and the raw and auxiliary materials of the compound preparation are calculated by mass percentage, including 0.01% - 1% of an antioxidant, 0.01% - 1% of a metal ion chelating agent, 0.5% - 10% of a surfactant, 0.1% - 10% of a penetration enhancer, 0.1% - 10% of a thickening agent, and 1% - 30% of a humectant. Adding the auxiliary materials to the mixed solution containing two active ingredients and stirring to obtain a compound preparation.

[0017] In the present invention, for the preparation of the minoxidil solution, solvent 1 is heated to 40°C - 60°C, the minoxidil active ingredient is added thereto, and a minoxidil-containing solution is obtained after complete dissolution.

[0018] .. Solvent 1 of the present invention includes but is not limited to ethanol, propylene glycol, glycerol, water, isopropanol or a mixed solvent of the above solvents.

[0019] In the present invention, the percentage range of solvent 1 is between 10% and 80%, preferably between 20% and 70%, and more preferably between 30% and 60%.

[0020] In the present invention, for the preparation of the finasteride solution, finasteride is dissolved in a certain amount of solvent 2, and stirred to dissolve to obtain a finasteride solution; Solvent 2 of the present invention includes but is not limited to ethanol, propylene glycol, glycerol, water and isopropanol.

[0021] In the present invention, the percentage range of solvent 2 is between 10% and 80%, preferably between 20% and 70%, and more preferably between 30% and 60%.

[0022] The antioxidant in the present invention includes but is not limited to butylated hydroxyanisole, dibutylhydroxytoluene, propyl gallate, tert-butylhydroquinone.

[0023] The metal ion chelating agent in the present invention includes but is not limited to citric acid, EDTA-2Na and phosphate derivatives.

[0024] The surfactant in the present invention includes but is not limited to Tween 80, sodium dodecyl sulfate, lecithin, etc.

[0025] The thickening agent in the present invention includes but is not limited to carbomer, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, xanthan gum, etc.

[0026] The penetration enhancer in the present invention includes but is not limited to dimethyl sulfoxide, azone, propylene glycol, menthol, etc.

[0027] In the present invention, the moisturizer includes, but is not limited to, propylene glycol and glycerol. Detailed implementation manners

[0028] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0029] A compound preparation for treating hair loss, the active ingredients of the compound preparation include a first active ingredient minoxidil, and a second active ingredient being one or more of finasteride, spironolactone, dutasteride, corticosteroid, ketoconazole, exosome or copper peptide, preferably finasteride.

[0030] As a technical optimization scheme of the present invention, the mass percentage ratio of minoxidil to finasteride is (1 - 10) to (0.1 - 5).

[0031] As a technical optimization scheme of the present invention, minoxidil has poor solubility in water and needs to be dissolved in other solvents. The commonly used solvent in the market is propylene glycol. A certain amount of propylene glycol has good moisture retention, but when the dosage is greater than 20%, it will cause certain skin irritation, especially for long-term use. Therefore, the dosage of propylene glycol in the solvent for dissolving minoxidil is 1 - 20%.

[0032] As a technical optimization scheme of the present invention, the solvent for dissolving minoxidil is a mixture of propylene glycol, glycerol and ethanol.

[0033] As a technical optimization scheme of the present invention, the mass percentage content of propylene glycol in the solvent for dissolving minoxidil is less than 20%.

[0034] As a technical optimization scheme of the present invention, the ratio of propylene glycol, glycerol and ethanol is (1 - 20), (5 - 30), (5 - 30).

[0035] A preparation process of a compound preparation for treating hair loss, including the following steps:

[0036] Step 1: Add minoxidil into a mixed solvent of propylene glycol, glycerol and absolute ethanol, heat to 40 - 60 °C, heat and stir until dissolved to obtain a minoxidil solution;

[0037] Step 2: Dissolve finasteride in ethanol, stir until dissolved, add dibutylhydroxytoluene and stir evenly, then add a penetration enhancer and stir evenly, and then add menthol and stir evenly to obtain a solution containing finasteride;

[0038] Step 3: Dissolve EDTA-2Na in purified water and stir evenly to obtain a solution containing EDTA-2Na;

[0039] Step 4: Mix and stir evenly the solution containing minoxidil and finasteride, then add the EDTA-2Na solution, stir, then add Tween, stir, add glycerol, stir, and add peppermint oil and stir;

[0040] Step 5: Neutralize the pre-swollen carbomer solution with triethanolamine, add a certain amount to the above solution, and stir evenly;

[0041] Step 6: Finally, add ethanol or water to the full volume and stir evenly.

[0042] A preparation process of a compound preparation for treating alopecia areata, comprising the following steps:

[0043] Step 1: Add minoxidil to a mixed solvent with a preferred ratio of propylene glycol, glycerol and absolute ethanol (10:15:20), heat to 40-60 °C, heat and stir to dissolve to obtain a minoxidil solution;

[0044] Step 2: Dissolve finasteride in ethanol, stir to dissolve, add 0.1% dibutylhydroxytoluene and stir evenly, then add 1% penetration enhancer and stir evenly, then add menthol and stir evenly to obtain a solution containing finasteride;

[0045] Step 3: Dissolve EDTA-2Na in purified water and stir evenly to obtain a solution containing EDTA-2Na;

[0046] Step 4: Mix and stir evenly the solution containing minoxidil and finasteride, then add the EDTA-2Na solution, stir, then add 3% Tween, stir, add glycerol, stir, and add peppermint oil and stir.

[0047] Step 5: Neutralize the pre-swollen carbomer solution with triethanolamine, add a certain amount to the above solution, and stir evenly;

[0048] Step 6: Finally, add ethanol or water to the full volume and stir evenly.

[0049] A preparation process of a compound preparation for treating alopecia areata, the penetration enhancer includes but is not limited to azone, isopropyl myristate, propylene glycol, menthol, etc., and azone is preferred.

[0050] A preparation process of a compound preparation for treating alopecia areata, the amount of water for dissolving EDTA-2Na ranges from 1% to 10%.

[0051] Example 1:

[0052] Dissolve minoxidil in ethanol, with a mass ratio of 1:15;

[0053] Example 2:

[0054] Dissolve minoxidil in a mixed solvent of propylene glycol, absolute ethanol and water, and the mass ratio is minoxidil:propylene glycol:absolute ethanol:water = 1:5:2:1;

[0055] Example 3:

[0056] Dissolve minoxidil in propylene glycol, and the mass ratio of minoxidil to propylene glycol is 1:8;

[0057] Example 4:

[0058] Dissolve minoxidil in propylene glycol and heat it at 40°C to 60°C, and the mass ratio of minoxidil to propylene glycol is 1:8;

[0059] Example 5:

[0060] Dissolve minoxidil in a mixed solution of propylene glycol and Tween, and heat it at 40°C to 60°C. The mass ratio of minoxidil, propylene glycol and Tween is 1:8:0.3;

[0061] Example 6:

[0062] Dissolve minoxidil in a mixed solution of propylene glycol and sodium dodecyl sulfate, and heat it at 40°C to 60°C. The mass ratio of minoxidil, propylene glycol and sodium dodecyl sulfate is 1:10:0.3;

[0063] Example 7:

[0064] Dissolve minoxidil in glycerol and heat it at 40°C to 60°C, and the mass ratio of minoxidil to glycerol is 1:20;

[0065] Example 8:

[0066] Dissolve minoxidil in a mixture of ethanol and glycerol, and heat it at 40°C to 60°C. The mass ratio of minoxidil to ethanol and glycerol is 1:6:2;

[0067] Example 9:

[0068] Dissolve minoxidil in polyethylene glycol 400 and heat it at 40°C to 60°C, and the mass ratio of minoxidil to polyethylene glycol is 1:10;

[0069] Example 10:

[0070] Dissolve minoxidil in a mixture of ethanol, glycerol and propylene glycol, and heat it at 40°C to 60°C. The mass ratio of minoxidil to ethanol, glycerol and propylene glycol is 1:6:2:2;

[0071] Example 11:

[0072] Finasteride was dissolved in absolute ethanol, and the mass ratio of finasteride to absolute ethanol was 1:50;

[0073] Since minoxidil has low solubility in water and ethanol, propylene glycol is generally used for dissolution in the currently marketed formulations, and some surfactants such as Tween and sodium dodecyl sulfate can be added to increase the solubility of minoxidil.

[0074] Finasteride is readily soluble in ethanol.

[0075] The dissolution states of the above Examples 1 - 11 are shown in Table 1.

[0076] Table 1

[0077]

[0078] Among them, some of the dissolution states are as follows:

[0079]

[0080] Example 12:

[0081] Propylene glycol, absolute ethanol and water were mixed in a ratio of 5:2:1, the mixed solvent was heated to 50 °C, minoxidil was added thereto, and then Tween, finasteride and dibutylhydroxytoluene were added in sequence, and stirred until dissolved to obtain Solution A;

[0082] Disodium ethylenediaminetetraacetate was dissolved in water to obtain Solution B;

[0083] Solution A and Solution B were mixed, glycerol and menthol oil were added and stirred for 5 min, and a certain amount of carbomer solution was added to the solution and stirred evenly.

[0084] In the compound preparation prepared by the present invention, propylene glycol is 25%, absolute ethanol is 10%, Tween is 5%, finasteride is 0.1%, and dibutylhydroxytoluene is 0.1%.

[0085] Example 13:

[0086] Propylene glycol and Tween were mixed and heated to 50 °C, and minoxidil was added thereto to obtain Solution A;

[0087] Finasteride was dissolved in an ethanol solution and stirred until dissolved to obtain Solution B;

[0088] Solution A and Solution B were mixed, and a certain amount of carbomer solution was added to the solution and stirred evenly.

[0089] Example 14:

[0090] Mix propylene glycol and Tween, heat to 50 °C, and add minoxidil thereto to obtain Solution A;

[0091] Dissolve finasteride in an ethanol solution and stir to dissolve to obtain Solution B;

[0092] Mix Solution A and Solution B, add a certain amount of hydroxyethyl cellulose solution to the solution, and stir evenly.

[0093] Example 15:

[0094] Mix propylene glycol and Tween, heat to 50 °C, and add minoxidil thereto to obtain Solution A;

[0095] Dissolve finasteride in an ethanol solution and stir to dissolve to obtain Solution B;

[0096] Mix Solution A and Solution B, add a certain amount of hypromellose solution to the solution, and stir evenly.

[0097] Example 16:

[0098] Heat propylene glycol to 50 °C, and add minoxidil thereto to obtain Solution A;

[0099] Dissolve finasteride in an ethanol solution and stir to dissolve to obtain Solution B;

[0100] Mix Solution A and Solution B, add a certain amount of carbomer solution to the solution, and stir evenly.

[0101] Example 17:

[0102] Heat propylene glycol to 50 °C, and add minoxidil thereto to obtain Solution A;

[0103] Dissolve finasteride in an ethanol solution and stir to dissolve to obtain Solution B;

[0104] Dissolve dibutylhydroxytoluene in absolute ethanol and stir to dissolve to obtain Solution C;

[0105] Dissolve disodium ethylenediaminetetraacetate in water and stir to dissolve to obtain Solution D;

[0106] Add Solution B, C, and D to Solution A in sequence and stir evenly.

[0107] Example 18:

[0108] Heat propylene glycol to 50 °C, and add minoxidil thereto to obtain Solution A;

[0109] Dissolve finasteride in an ethanol solution and stir to dissolve to obtain Solution B;

[0110] Mix solution A and solution B, add a certain amount of hydroxyethyl cellulose solution to the solution, and stir evenly.

[0111] Example 19:

[0112] Heat the mixture of propylene glycol, glycerin and ethanol to 50 °C, and add minoxidil to it to obtain solution A;

[0113] Dissolve finasteride in ethanol solution, stir until dissolved, then add dibutylhydroxytoluene, laurocapram and menthol to it, and stir until dissolved to obtain solution B;

[0114] Dissolve disodium ethylenediaminetetraacetate in water and stir until dissolved to obtain solution C;

[0115] Add solution B and C to solution A in sequence, stir evenly, then add glycerin, tween and peppermint oil in sequence, stir evenly, and add an appropriate amount of carbomer solution, and stir evenly.

[0116] Example 20:

[0117] Heat the mixture of propylene glycol, glycerin and ethanol to 50 °C, and add minoxidil to it to obtain solution A;

[0118] Dissolve finasteride in ethanol solution, stir until dissolved, then add dibutylhydroxytoluene, laurocapram and menthol to it, and stir until dissolved to obtain solution B;

[0119] Dissolve disodium ethylenediaminetetraacetate in water and stir until dissolved to obtain solution C;

[0120] Add solution B and C to solution A in sequence, stir evenly, then add glycerin, tween and peppermint oil in sequence, stir evenly, and add an appropriate amount of carbomer solution, and stir evenly.

[0121] The formulations of the above compound preparations 10 - 18 are listed in Table 2 after sorting.

[0122] Table 2

[0123]

[0124]

[0125] The appearance characteristics of the above compound preparations 12 - 20 are listed in Table 3 after sorting.

[0126] Table 3

[0127]

[0128] The above is a description of the embodiments of the present invention. Through the above description of the disclosed embodiments, those skilled in the art can implement or use the present invention. Various modifications to these embodiments will be obvious to those skilled in the art in the field of agricultural technology. The general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to these embodiments shown herein, but rather will conform to the widest scope consistent with the principles and novel points disclosed herein.

[0129] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific embodiments described. Obviously, many modifications and variations can be made according to the content of this specification. These embodiments are selected and specifically described in this specification to better explain the principles and practical applications of the present invention, so that those skilled in the art in the relevant technical field can well understand and utilize the present invention. The present invention is only subject to the claims and their full scope and equivalents.

Claims

1. A compound preparation for treating hair loss, characterized in that, The active ingredients of the compound preparation include minoxidil as the first active ingredient, and one or more of finasteride, spironolactone, dutasteride, corticosteroid, ketoconazole, exosomes or copper peptides as the second active ingredient, preferably finasteride.

2. The compound preparation for treating alopecia according to claim 1, characterized in that, The mass percentage ratio of minoxidil to finasteride is (1-10) to (0.1-5).

3. The compound preparation for treating alopecia according to claim 1, wherein, Minoxidil has poor solubility in water and needs to be dissolved in other solvents. The commonly used solvent on the market is propylene glycol. A certain amount of propylene glycol has good moisturizing properties, but when the dosage is greater than 20%, it will cause certain skin irritation, especially for long-term use. Therefore, the dosage of propylene glycol in the solvent for dissolving minoxidil is 1-20%.

4. A compound preparation for treating hair loss according to claim 3, wherein the solvent for dissolving minoxidil is a mixture of propylene glycol, glycerol and ethanol.

5. A compound preparation for treating hair loss according to claim 4, wherein the mass percentage content of propylene glycol in the solvent for dissolving minoxidil is less than 20%.

6. A compound preparation for treating hair loss according to claim 3, wherein the ratio of propylene glycol, glycerol and ethanol is (1-20), (5-30), (5-30).

7. The preparation process of a compound preparation for treating hair loss, characterized in that, It includes the following steps: Step 1: Add minoxidil to a mixed solvent of propylene glycol, glycerol and absolute ethanol, heat to 40-60°C, heat and stir to dissolve to obtain a minoxidil solution; Step 2: Dissolve finasteride in ethanol, stir to dissolve, add dibutylhydroxytoluene and stir evenly, then add a penetration enhancer and stir evenly, and then add menthol and stir evenly to obtain a solution containing finasteride; Step 3: Dissolve EDTA-2Na in purified water and stir evenly to obtain a solution containing EDTA-2Na; Step 4: Mix and stir the solutions containing minoxidil and finasteride, then add the EDTA-2Na solution, stir, then add Tween, stir, add glycerol, stir, and add peppermint oil and stir; Step 5: Neutralize the pre-swollen carbomer solution with triethanolamine, add a certain amount to the above solution, and stir evenly; Step 6: Finally, add ethanol or water to the full volume and stir evenly.

8. The preparation process of a compound preparation for treating hair loss according to claim 7, characterized in that, It includes the following steps: Step 1: Add minoxidil to a mixed solvent of propylene glycol, glycerol and absolute ethanol with a preferred ratio of (10:15:20), heat to 40-60°C, heat and stir to dissolve to obtain a minoxidil solution; Step 2: Dissolve finasteride in ethanol, stir to dissolve, add 0.1% dibutylhydroxytoluene and stir evenly, then add 1% penetration enhancer and stir evenly, and then add menthol and stir evenly to obtain a solution containing finasteride; Step 3: Dissolve EDTA-2Na in purified water and stir evenly to obtain a solution containing EDTA-2Na; Step 4: Mix and stir the solutions containing minoxidil and finasteride, then add the EDTA-2Na solution, stir, then add 3% Tween, stir, add glycerol, stir, and add peppermint oil and stir. Step 5: Neutralize the pre-swollen carbomer solution with triethanolamine, add a certain amount to the above solution, and stir evenly; Step 6. Finally, add ethanol or water to the full volume and stir evenly.

9. The preparation process of a compound preparation for treating hair loss according to claim 8, characterized in that, The penetration enhancer includes but is not limited to azone, isopropyl myristate, propylene glycol, menthol, etc., and azone is preferred.

10. The preparation process of a compound preparation for treating alopecia according to claim 8, characterized in that, The amount of water for dissolving EDTA-2Na ranges from 1% to 10%.

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