Minoxidil film coating agent as well as preparation method and application thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and provides a minoxidil film coating agent as well as a preparation method and application thereof. The minoxidil film coating agent provided by the invention comprises 40-60% of propylene glycol, 3-7% of polyvinyl alcohol, 20-30% of ethanol, 1-7% of minoxidil and the balance of water. According to the invention, propylene glycol is taken as a solvent, a plasticizer and a transdermal absorption enhancer, polyvinyl alcohol is taken as a film-forming material, and ethanol is taken as a volatile agent, after administration, ethanol is volatilized to promote film formation of polyvinyl alcohol, and propylene glycol enhances the plasticity of the formed film, so that the effect of reducing liquid medicine loss is achieved, the local medicine concentration is increased, and the bioavailability is improved. The minoxidil liniment disclosed by the invention has excellent skin permeability, can effectively convey a medicine to a required part, and can ensure that the medicine is released at a fixed position of the skin and is accurately administered in a medicine release process, so that the stimulation of liquid medicine flow to other parts is reduced, and a good treatment effect is achieved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to a minoxidil coating agent, its preparation method, and its application. Background Technology

[0002] Hair loss and alopecia areata, as common hair diseases, not only affect the patient's appearance but also negatively impact their mental health and quality of life. From a physiological perspective, hair plays important roles such as protecting the scalp and regulating body temperature. Extensive hair loss or alopecia areata can expose the scalp to the external environment, increasing the risk of scalp damage from ultraviolet rays and bacterial infections.

[0003] Minoxidil is a commonly used drug on the market for treating hair loss and alopecia areata. Its mechanism of action is mainly to open potassium channels, reduce the concentration of intracellular calcium ions, stimulate the proliferation and differentiation of hair follicle epithelial cells, prolong the hair growth phase, and at the same time dilate scalp blood vessels, improve blood circulation around hair follicles, and provide sufficient nutrition to hair, thereby promoting hair growth and improving hair loss symptoms.

[0004] However, the commonly used minoxidil dosage form on the market is currently a liniment. As a topical preparation, it has certain drawbacks in terms of administration. Because the liquid in the liniment is thin, it can easily flow to other normal body parts after being administered using a dropper, resulting in an excessively low drug concentration at the administration site, reduced efficacy, and the liquid flowing to other normal body parts may irritate or damage the skin in those areas, causing unnecessary adverse reactions. Summary of the Invention

[0005] In view of this, the present invention provides a minoxidil film-forming agent, its preparation method, and its application. The minoxidil film-forming agent provided by the present invention can rapidly form a film after administration, reducing drug flow, increasing local drug concentration, and improving bioavailability.

[0006] To achieve the above-mentioned objectives, the present invention provides the following technical solution: A minoxidil coating agent comprising the following components by mass fraction: 40-60% propylene glycol, 3-7% polyvinyl alcohol, 20-30% ethanol, 1-7% minoxidil, and the balance being water.

[0007] Preferably, the minoxidil coating agent comprises the following components by mass fraction: 45-55% propylene glycol, 4-6% polyvinyl alcohol, 22-25% ethanol, 4-6% minoxidil, and the balance being water.

[0008] Preferably, the minoxidil coating agent comprises the following components by mass fraction: 51.8% propylene glycol, 5% polyvinyl alcohol, 23.76% ethanol, 5% minoxidil, and 14.44% water.

[0009] Preferably, the ethanol is anhydrous ethanol.

[0010] The present invention also provides a method for preparing the minoxidil coating agent described above, comprising the following steps: Polyvinyl alcohol is dissolved in a portion of water to obtain a polyvinyl alcohol solution; Minoxidil was dissolved in propylene glycol to obtain a minoxidil solution; The polyvinyl alcohol solution, minoxidil solution, the remaining water and ethanol are mixed to obtain the minoxidil coating agent.

[0011] Preferably, the polyvinyl alcohol is dissolved at a temperature of 70~80°C.

[0012] Preferably, the dissolution temperature of minoxidil is 70~80℃.

[0013] Preferably, the mixing temperature of the polyvinyl alcohol solution, minoxidil solution, the remaining water and ethanol is below 35°C.

[0014] Preferably, the method for mixing the polyvinyl alcohol solution, minoxidil solution, remaining water and ethanol is as follows: add minoxidil solution to polyvinyl alcohol solution, then add remaining water and ethanol in sequence, and then stir for 5 to 10 minutes.

[0015] The present invention also provides the use of the minoxidil film-forming agent described in the above-described scheme or the minoxidil film-forming agent prepared by the preparation method described in the above-described scheme in the preparation of a drug for treating hair loss and / or alopecia areata.

[0016] This invention provides a minoxidil film-forming agent comprising the following components by mass fraction: 40-60% propylene glycol, 3-7% polyvinyl alcohol, 20-30% ethanol, 1-7% minoxidil, and the balance being water. This invention uses propylene glycol as a solvent, plasticizer, and transdermal absorption enhancer; polyvinyl alcohol as the film-forming material; and ethanol as a volatile agent. After administration, ethanol evaporation promotes polyvinyl alcohol film formation, and propylene glycol enhances the plasticity of the film, thereby reducing drug loss, increasing local drug concentration, and improving bioavailability, thus improving patient compliance. The minoxidil film-forming agent of this invention has excellent skin permeability, effectively delivering the drug to the desired site. Furthermore, during drug release, the excipients in the film-forming agent ensure that the drug is released at a fixed location on the skin, ensuring precise drug delivery and reducing irritation to other areas caused by drug flow, thereby achieving a good therapeutic effect. Detailed Implementation

[0017] The present invention provides a minoxidil coating agent comprising the following components by mass fraction: 40-60% propylene glycol, 3-7% polyvinyl alcohol, 20-30% ethanol, 1-7% minoxidil, and the balance being water.

[0018] The minoxidil coating agent provided by this invention comprises 40-60% propylene glycol, preferably 45-55%, and specifically 51.8% by mass fraction. This invention uses propylene glycol as a solvent, plasticizer, and transdermal absorbent, which can dissolve minoxidil, promote drug absorption, and simultaneously increase the flexibility and extensibility of the film after formation.

[0019] The minoxidil film-forming agent provided by this invention comprises 3-7% polyvinyl alcohol, preferably 4-6%, and specifically 5% by mass fraction; the polyvinyl alcohol is polyvinyl alcohol powder, specifically polyvinyl alcohol 05-88. This invention uses polyvinyl alcohol as a film-forming material for film formation after drug administration.

[0020] The minoxidil coating agent provided by the present invention comprises 20-30% ethanol, preferably 22-25%, and specifically 23.76% by mass fraction; the ethanol is preferably anhydrous ethanol; the present invention uses ethanol as a volatile agent to accelerate the film formation of polyvinyl alcohol and shorten the film formation time through ethanol evaporation.

[0021] The minoxidil coating agent provided by the present invention comprises 1-7% minoxidil, preferably 4-6%, and specifically 5%, by mass fraction.

[0022] The minoxidil coating agent provided by the present invention comprises, by mass fraction, the balance being water, preferably purified water.

[0023] The present invention also provides a method for preparing the minoxidil coating agent described above, comprising the following steps: Polyvinyl alcohol is dissolved in a portion of water to obtain a polyvinyl alcohol solution; Minoxidil was dissolved in propylene glycol to obtain a minoxidil solution; The polyvinyl alcohol solution, minoxidil solution, the remaining water and ethanol are mixed to obtain the minoxidil coating agent.

[0024] This invention dissolves polyvinyl alcohol (PVA) in a portion of water to obtain a PVA solution. In this invention, the preferred dissolution temperature of the PVA is 70-80°C; in a specific embodiment of this invention, it is preferable to first heat the water to 70-80°C, and then add the PVA to dissolve it; after dissolution, it is preferable to lower the temperature of the resulting PVA solution to below 35°C.

[0025] This invention dissolves minoxidil in propylene glycol to obtain a minoxidil solution. In this invention, the preferred dissolution temperature of minoxidil is 70-80°C; in a specific embodiment of this invention, it is preferable to first heat the propylene glycol to 70-80°C, and then add minoxidil to dissolve it; after dissolution, it is preferable to lower the temperature of the resulting minoxidil solution to below 35°C.

[0026] After obtaining the polyvinyl alcohol solution and minoxidil solution, the present invention mixes the polyvinyl alcohol solution, minoxidil solution, remaining water, and ethanol to obtain the minoxidil coating agent. In the present invention, the mixing temperature of the polyvinyl alcohol solution, minoxidil solution, remaining water, and ethanol is preferably below 35°C; the mixing method is preferably as follows: adding the minoxidil solution to the polyvinyl alcohol solution, then sequentially adding the remaining water and ethanol, followed by stirring for 5-10 minutes; in a specific embodiment of the present invention, it is preferable to rinse the container used to prepare the minoxidil solution with the remaining water before adding it to the system for mixing.

[0027] The present invention also provides the use of the minoxidil film-forming agent described in the above-described scheme or the minoxidil film-forming agent prepared by the preparation method described in the above-described scheme in the preparation of a drug for treating hair loss and / or alopecia areata.

[0028] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0029] Example 1 The formulation of minoxidil film-forming agents is shown in Table 1: Table 1. Minoxidil film-forming formulation

[0030] The preparation method is as follows: (1) Weigh 130g of purified water into a container, heat it to 70℃, add 50g of polyvinyl alcohol 05-88 to dissolve it, and cool it down to below 35℃; (2) Weigh 518g of propylene glycol into a suitable container, heat to 70°C, add 50g of minoxidil raw material, stir until completely dissolved, and cool to below 35°C; (3) Add the minoxidil solution prepared in (2) to the polyvinyl alcohol solution prepared in (1), rinse the container in (2) with the remaining 14.4g of purified water and add it to the polyvinyl alcohol solution prepared in (1), then add 237.6g of anhydrous ethanol, stir and mix for 5min to obtain minoxidil coating agent.

[0031] Example 2 The formulation of minoxidil film-forming agents is shown in Table 2: Table 2 Minoxidil Film Formulation Formula

[0032] The preparation method is as follows: (1) Weigh 140g of purified water into a container, heat it to 70℃, add 40g of polyvinyl alcohol 05-88 to dissolve it, and cool it down to below 35℃; (2) Weigh 518g of propylene glycol into a suitable container, heat to 70°C, add 50g of minoxidil raw material, stir until completely dissolved, and cool to below 35°C; (3) Add the minoxidil solution prepared in (2) to the polyvinyl alcohol solution prepared in (1), rinse the container in (2) with the remaining 14.4g of purified water and add it to the polyvinyl alcohol solution prepared in (1), then add 237.6g of anhydrous ethanol, stir and mix for 5min to obtain minoxidil coating agent.

[0033] Example 3 The formulation of minoxidil film-forming agents is shown in Table 3: Table 3 Minoxidil film-forming formulation

[0034] The preparation method is as follows: (1) Weigh 120g of purified water into a container, heat it to 70℃, add 60g of polyvinyl alcohol 05-88 to dissolve it, and cool it down to below 35℃; (2) Weigh 518g of propylene glycol into a suitable container, heat to 70°C, add 50g of minoxidil raw material, stir until completely dissolved, and cool to below 35°C; (3) Add the minoxidil solution prepared in (2) to the polyvinyl alcohol solution prepared in (1), rinse the container in (2) with the remaining 14.4g of purified water and add it to the polyvinyl alcohol solution prepared in (1), then add 237.6g of anhydrous ethanol, stir and mix for 5min to obtain minoxidil coating agent.

[0035] Comparative Example 1 The formulation of minoxidil film-forming agents is shown in Table 4: Table 4 Minoxidil Film Formulation Formula

[0036] The preparation method is as follows: (1) Weigh 100g of purified water into a container, heat it to 70℃, add 80g of polyvinyl alcohol 05-88 to dissolve it, and cool it down to below 35℃; (2) Weigh 518g of propylene glycol into a suitable container, heat to 70°C, add 50g of minoxidil raw material, stir until completely dissolved, and cool to below 35°C; (3) Add the minoxidil solution prepared in (2) to the polyvinyl alcohol solution prepared in (1), rinse the container in (2) with the remaining 14.4g of purified water and add it to the polyvinyl alcohol solution prepared in (1), then add 237.6g of anhydrous ethanol, stir and mix for 5min to obtain minoxidil coating agent.

[0037] Comparative Example 2 The formulation of minoxidil film-forming agents is shown in Table 5: Table 5 Minoxidil Film Formulation Formula

[0038] The preparation method is as follows: (1) Weigh 130g of purified water into a container, heat it to 70℃, add 50g of povidone K30 to dissolve it, and cool it down to below 35℃; (2) Weigh 518g of propylene glycol into a suitable container, heat to 70°C, add 50g of minoxidil raw material, stir until completely dissolved, and cool to below 35°C; (3) Add the minoxidil solution prepared in (2) to the povidone K30 solution prepared in (1), rinse the container in (2) with the remaining 14.4g of purified water and add it to the povidone K30 solution prepared in (1), then add 237.6g of anhydrous ethanol, stir and mix for 5min to obtain minoxidil coating agent.

[0039] Comparative Example 3 The specific steps for preparing a common minoxidil solution are as follows: Weigh 518g of propylene glycol into a suitable container, heat to 70℃, add 50g of minoxidil raw material, stir until completely dissolved, cool to below 35℃, then add 237.6g of anhydrous ethanol and 194.4g of purified water, stir and mix for 5min to obtain a minoxidil solution.

[0040] Test case The preparations of Examples 1-3 and Comparative Examples 1-3 were subjected to tests for skin irritation, transdermal absorption, and stability, wherein: Skin irritation tests were performed using a rabbit skin erythema / edema model (OECD 404), and the results are shown in Table 4.

[0041] The transdermal absorption test method is as follows: Test solution: Take pigskin and fix it between the two halves of the diffusion cell with clamps. Apply 20 μL of minoxidil lotion evenly to the skin membrane. Add 12 mL of receiving solution to the receiving cell, ensuring the skin is just in contact with the liquid surface. Stir the receiving solution continuously at 600 rpm to allow the drug to be released naturally, and maintain a constant temperature of 32 ± 1℃. Take 12 mL of receiving solution at 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 12 h after application (replenish the receiving cell with 12 mL of receiving solution immediately after sampling) and test the minoxidil concentration in the receiving solution.

[0042] Minoxidil concentration was determined by chromatography, and the specific steps are as follows: Reference stock solution: Accurately weigh about 2.0 mg of minoxidil reference standard into a 20 mL volumetric flask, dissolve and dilute to the mark with the mobile phase, and shake well.

[0043] 1% linear solution: Accurately measure 0.1 mL of the reference stock solution, place it in a 100 mL volumetric flask, dilute to the mark with the mobile phase, and shake well; 5% linear solution: Accurately measure 0.5 mL of the reference stock solution, place it in a 100 mL volumetric flask, dilute to the mark with the mobile phase, and shake well; 10% linear solution: Accurately measure 0.1 mL of the reference stock solution, place it in a 10 mL volumetric flask, dilute to the mark with the mobile phase, and shake well; 50% linear solution: Accurately measure 0.5 mL of the reference stock solution, place it in a 10 mL volumetric flask, dilute to the mark with the mobile phase, and shake well; 100% linear solution: Accurately measure 1 mL of the reference stock solution and place it in a 10 mL volumetric flask. Dilute to the mark with the mobile phase and shake well.

[0044] Chromatographic conditions: Octadecylsilane-bonded silica gel (4.6 × 250 mm, 5 μm) was used as the stationary phase; methanol-water-trifluoroacetic acid (methanol, water and trifluoroacetic acid volume ratio of 700:300:1) (containing 2 g of sodium heptanesulfonate per 1000 mL) was used as the mobile phase; the flow rate was 1.0 mL per minute; the column temperature was 30 °C; the detection wavelength was 230 nm; and the injection volume was 10 μL.

[0045] Assay method: Accurately inject 10 μL of the test solution into the high-performance liquid chromatograph and record the chromatogram. For a series of reference solutions, plot a standard curve with minoxidil peak area as the ordinate and minoxidil concentration as the abscissa. Substitute the minoxidil peak area into the standard curve for the test solution and calculate the minoxidil concentration. Then, calculate the transdermal absorption and transdermal rate based on the measured minoxidil concentration. The test results are shown in Table 6.

[0046] Stability testing included accelerated and long-term stability tests. Accelerated testing conditions were: 40℃ / 25% RH, stored for 6 months, followed by testing of drug retention rate and pH value, and observation of drug properties. Long-term stability testing conditions were: 25℃ / 40% RH, stored for 12 months, followed by testing of drug retention rate and pH value, and observation of drug properties (the initial pH value of the coatings prepared in Examples 1-3 was 8.2 ± 0.3, and the initial pH value of the ordinary solution in Comparative Example 3 was 8.0). The test results are shown in Table 6.

[0047] Table 6 Test Results

[0048] The test results in Table 1 show that: (1) Skin safety: The erythema and edema scores of the coating agent of this invention were significantly lower than those of the ordinary solution in Comparative Example 3, demonstrating that film formation after administration reduced drug flow and effectively decreased irritation to other sites. In Comparative Example 1, the reduced amount of polyvinyl alcohol resulted in poorer film-forming properties and a higher erythema score.

[0049] (2) Transdermal synergistic effect: Compared to ordinary solutions, the film-forming agent of this invention forms a film after drug administration, which reduces drug flow, increases local drug concentration, and significantly increases cumulative penetration and transdermal rate, demonstrating that this invention can improve efficacy and achieve therapeutic effects. In Comparative Example 1, the amount of polyvinyl alcohol was increased; in Comparative Example 2, polyvinyl alcohol was replaced with povidone K30, and the transdermal absorption and transdermal rate of the resulting film-forming agents were significantly reduced.

[0050] (3) Stability advantage: In accelerated and long-term tests, the drug retention rate, pH value changes, and property changes of the coating agent of this invention are far superior to those of ordinary solution-type products, proving that the product has good stability.

[0051] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A minoxidil coating agent, characterized in that, It includes the following components by mass fraction: propylene glycol 40-60%, polyvinyl alcohol 3-7%, ethanol 20-30%, minoxidil 1-7%, and the balance being water.

2. The minoxidil coating agent according to claim 1, characterized in that, It includes the following components by mass fraction: propylene glycol 45-55%, polyvinyl alcohol 4-6%, ethanol 22-25%, minoxidil 4-6%, and the balance being water.

3. The minoxidil coating agent according to claim 1 or 2, characterized in that, The components include the following components by mass fraction: propylene glycol 51.8%, polyvinyl alcohol 5%, ethanol 23.76%, minoxidil 5%, and water 14.44%.

4. The minoxidil coating agent according to claim 1, characterized in that, The ethanol is anhydrous ethanol.

5. The method for preparing the minoxidil coating agent according to any one of claims 1 to 4, characterized in that, Includes the following steps: Polyvinyl alcohol is dissolved in a portion of water to obtain a polyvinyl alcohol solution; Minoxidil was dissolved in propylene glycol to obtain a minoxidil solution; The polyvinyl alcohol solution, minoxidil solution, the remaining water and ethanol are mixed to obtain the minoxidil coating agent.

6. The preparation method according to claim 5, characterized in that, The polyvinyl alcohol is dissolved at a temperature of 70~80℃.

7. The preparation method according to claim 5, characterized in that, The dissolution temperature of minoxidil is 70~80℃.

8. The preparation method according to claim 5, characterized in that, The mixing temperature of the polyvinyl alcohol solution, minoxidil solution, the remaining water and ethanol is below 35°C.

9. The preparation method according to claim 5, characterized in that, The polyvinyl alcohol solution, minoxidil solution, remaining water and ethanol are mixed as follows: minoxidil solution is added to polyvinyl alcohol solution, then the remaining water and ethanol are added sequentially, and then stirred for 5-10 minutes.

10. The use of the minoxidil film-forming agent according to any one of claims 1 to 4 or the minoxidil film-forming agent prepared by the preparation method according to any one of claims 5 to 9 in the preparation of a medicament for treating hair loss and / or alopecia areata.

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