External solution containing minoxidil and finasteride and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to an external solution containing minoxidil and finasteride and a preparation method of the external solution. According to the external solution containing minoxidil and finasteride provided by the invention, the solvent and the penetration enhancer are added, so that the active ingredients of minoxidil and finasteride have higher retention volume in the skin, and can play a better role, thereby generating a more excellent hair growth effect.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to an external-use solution containing minoxidil and finasteride and a preparation method thereof. Background Art

[0003] Minoxidil, chemical name is 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide, chemical formula is C9H 15 N5O, a white crystalline powder, is a peripheral vasodilator.

[0004] In the 1970s, minoxidil was first developed by Pfizer as an oral tablet (2.5 mg and 10 mg) for the treatment of severe and refractory hypertension. The drug can directly relax vascular smooth muscle and has a strong dilation effect on arterioles, but it also has the side effect of hirsutism. The original research company found through the test data of minoxidil concentration and safety that when the minoxidil in serum is less than 20 ng / mL, there will be no systemic safety problems. Based on this discovery, Johnson developed a 2% minoxidil topical solution (excipients are ethanol, propylene glycol and water), which was approved by the FDA in 1988 for the treatment of mild to moderate androgenic alopecia (AGA) in men. Since then, a 5% topical solution and a 5% minoxidil foam have gradually been launched on the market. Long-term local use of minoxidil can stimulate hair growth in patients with hair loss and alopecia areata, but its exact mechanism for treating hair loss is still unclear. Clinical studies have shown that when used topically in patients with normal blood pressure and untreated hypertension, no systemic effects caused by minoxidil absorption were shown.

[0005] Finasteride, chemical name is N-tert-butyl 3-oxo-4-aza-5α-androst-1-ene-17β-carboxamide, chemical formula is C 23 H 36 N2O2 is a specific competitive inhibitor of type II 5α-reductase.

[0006] Finasteride, as a specific type II 5α-reductase competitive inhibitor, inhibits the activity of 5α-reductase and inhibits the conversion of testosterone into dihydrotestosterone (DHT) in the scalp, thereby reducing the production of DHT and treating androgenic alopecia in male patients. According to a press release from the Cody Group, unlike oral finasteride, finasteride spray allows patients to apply the drug directly and accurately to the scalp surface, maintain a high concentration at the medication site, reduce systemic exposure to the drug, and thus reduce the side effects often caused by oral medications.

[0007] Minoxidil and finasteride have different mechanisms of action. The former directly promotes hair growth, while the latter indirectly slows down hair loss by changing hormone levels. When used together, the two can synergistically improve the therapeutic effect of AGA. However, most of the drugs currently available for the treatment of male pattern baldness are single topical liquid preparations of minoxidil and finasteride, and their penetration effect is poor. Most of them are difficult to be absorbed by the skin during use, which greatly reduces the therapeutic effect. The permeability of the drug determines the therapeutic effect of the topical drug. Therefore, improving the permeability of the drug is an urgent problem to be solved.

[0008] In view of the above problems, this paper invented a compound external solution of minoxidil and finasteride. By adding a penetration enhancer, the intradermal retention of the active ingredients of minoxidil and finasteride is increased to more than 1.7 times that of the solution without a penetration enhancer. Summary of the invention

[0009] In view of this, the technical problem to be solved by the present invention is to provide an external solution containing minoxidil and finasteride and a preparation method thereof.

[0010] The external solution containing minoxidil and finasteride provided by the invention comprises: minoxidil, finasteride, a solvent and a penetration enhancer.

[0011] In the present invention, the solvent is ethanol, propylene glycol and water. In a specific embodiment, in the solvent of the present invention, the volume ratio of ethanol, propylene glycol and water is 30: (30-50): (10-40). For example, in the solvent of the present invention, the volume ratio of ethanol to propylene glycol is preferably 30:30, or 30:50.

[0012] The external solution provided by the present invention contains the following components per liter of solution:

[0013]

[0014]

[0015] The balance is water.

[0016] In order to improve the permeability of the solution preparation, a penetration enhancer is added to the solution. The present invention screens the penetration enhancer, and experiments show that after adding DMA (N, N-dimethylacetamide), azone, dimethyl isosorbide, and menthol penetration enhancers to the prescription, the penetration effect can be increased, and the intradermal retention of the drug can be increased. Among them, the menthol penetration enhancement effect is relatively good, and the intradermal retention of minoxidil can be increased by 1.9 times, and the intradermal retention of finasteride can be increased by 1.7 times. Its penetration enhancement effect is much better than other penetration enhancers, and is much better than minoxidil and finasteride alone. In the present invention, the penetration enhancer is selected from at least one of DMA (N, N-dimethylacetamide), azone, dimethyl isosorbide or menthol.

[0017] In some embodiments, the penetration enhancer is menthol. In this embodiment, the content of menthol in the external solution is 5g to 10g; for example, the content of menthol is 5g, 7.5g or 10g.

[0018] In the embodiment, the topical solution consists of minoxidil, finasteride, propylene glycol, ethanol, menthol and water.

[0019] In this embodiment, each liter of solution contains the following components:

[0020]

[0021] The balance is water.

[0022] Preferably, the external solution contains the following components per liter of solution:

[0023]

[0024] The balance is water.

[0025] In a specific embodiment, taking 100 mL of the topical solution as an example, it contains: 5 g minoxidil, 0.025 g finasteride, 50 ml propylene glycol, 30 ml ethanol, 0.75 g menthol, and water to make up to 100 ml.

[0026] In other embodiments, the penetration enhancer is DMA, and the content of DMA in each liter of the external solution is 5g to 15g.

[0027] In this example, the topical solution consists of minoxidil, finasteride, propylene glycol, ethanol, DMA and water.

[0028] Specifically, the external solution contains the following components per liter of solution:

[0029]

[0030] The balance is water.

[0031] In other embodiments, the penetration enhancer is dimethyl isosorbide, and the content of dimethyl isosorbide in each liter of the external solution is 5 g to 15 g.

[0032] In this embodiment, the topical solution consists of minoxidil, finasteride, propylene glycol, ethanol, dimethyl isosorbide and water.

[0033] Specifically, the external solution contains the following components per liter of solution:

[0034]

[0035] The balance is water.

[0036] In other embodiments, the penetration enhancer is azone, and the content of azone in each liter of the external solution is 10g to 30g.

[0037] In this embodiment, the topical solution consists of minoxidil, finasteride, propylene glycol, ethanol, azone and water.

[0038] Specifically, the external solution contains the following components per liter of solution:

[0039]

[0040]

[0041] The balance is water.

[0042] The method for preparing the external solution as described above comprises:

[0043] Add minoxidil and finasteride to a mixture of ethanol and propylene glycol, stir at 50-60°C until the solid is completely dissolved, add a penetration enhancer after cooling to room temperature, stir to dissolve, and add water to make up to volume.

[0044] Or the preparation method of the external solution comprises:

[0045] Add minoxidil and finasteride to a mixture of ethanol and propylene glycol, mix at 50-60°C until the solid is completely dissolved, add a penetration enhancer after cooling to room temperature, mix well, and add water to make up to volume.

[0046] In the above method, the mixing and stirring are both carried out by commonly used mixing methods, including mechanical stirring, magnetic stirring, high-speed shearing, etc.

[0047] The present invention also provides the use of the external solution as mentioned above in preparing a product for preventing hair loss.

[0048] In the present invention, the dosage forms of the anti-hair loss product include tincture, liniment and spray.

[0049] The present invention also provides a method for preventing hair loss, which comprises applying the product as described above. In the present invention, the method of applying comprises external application.

[0050] The topical solution containing minoxidil and finasteride provided by the present invention:

[0051] 1. The external use solution provided by the present invention contains a solvent and a penetration enhancer, wherein:

[0052] 1) Choice of solvent:

[0053] Because propylene glycol turns yellow during use, the inventors have considered replacing propylene glycol with ethanol or a combination of ethanol and other ingredients. However, it was found that when a combination of ethanol and PEG400 excipients was used with a PEG content of more than 20%, minoxidil was not completely dissolved, and the samples showed crystallization after being refrigerated at 2 to 8°C. When a combination of ethanol and glycerol was used, the dosage range of glycerol was too narrow, and excessive or insufficient dosage could affect the dissolution rate and physical stability.

[0054] The inventors considered using ethanol, propylene glycol and water as solvents and found that: when ethanol and propylene glycol were in a ratio of 30-40:10, they could be dissolved at 50-60°C, but when placed at room temperature, they would immediately crystallize (the phenomenon was that solids were precipitated). Therefore, they finally selected a combination of ethanol, propylene glycol and water in a volume ratio of 30:(30-50) as a solvent;

[0055] 2) Selection of penetration enhancer:

[0056] The inventors selected 2% DGME (diethylene glycol monoethyl ether), 0.75% menthol, 0.8% DMA (N, N-dimethylacetamide), 2% azone and 0.8% isosorbide dimethyl ether to study the penetration enhancer and found that:

[0057] When preparing samples with 2% DGME as a penetration enhancer, it was found that the sample viscosity was too high, the fluidity was slightly poor, and there was a wall hanging phenomenon at room temperature. In addition, during the IVPT test, the amount retained on the skin was large while the amount retained in the skin was small. It was speculated that this might be related to the viscosity of the sample. Therefore, the amount of solvent was increased and the amount of DGME was reduced to 1%. It was found that when the viscosity was moderate, the IVPT data results were still not ideal and the penetration enhancement effect was poor. Therefore, it was shown that the penetration enhancement effect was related to the characteristics of the excipient itself.

[0058] The penetration-enhancing effect of menthol is significantly better than other excipients. In experiments using menthol at different concentrations as a penetration enhancer, it was found that the penetration-enhancing effect of the excipient is proportional to the amount added. Among them, 0.25% (w / v) menthol has a small penetration-enhancing effect, 0.5% to 1% menthol has a significant penetration-enhancing effect, and 0.75% and 1% (w / v) menthol have a better penetration-enhancing effect. In addition, the prescription containing DGME is sticky during actual use by patients, while the prescription containing menthol not only has good fluidity, but also has a special mint aroma, which brings a cool and comfortable feeling to patients during use and has good compliance.

[0059] The common dosage of azone as a penetration enhancer in preparations is 0.5% to 2.5%. When a high proportion of 2% azone was used as a penetration enhancer in the experiment, the intradermal retention was still lower than that of menthol. This penetration enhancer increased the intradermal retention of minoxidil to 1.4 times, while there was no significant change in finasteride, indicating that the penetration enhancer did not have a significant enough effect on the penetration of the active ingredient in this prescription system.

[0060] When 0.8% DMA (N,N-dimethylacetamide) and 0.8% isosorbide dimethyl ether were used as penetration enhancers, the samples were all colorless and transparent liquids with moderate viscosity, colorless and odorless. However, the IVPT experimental results found that the reagent did have a certain penetration-enhancing effect, the retention of minoxidil increased by 1.1 to 1.2 times, and the intradermal retention of finasteride did not increase significantly, which was far from the ideal effect.

[0061] 2. As the main treatment for hair loss, the topical solution provided by the present invention allows more active ingredients to remain in the skin, so that minoxidil and finasteride can better prevent hair loss. DETAILED DESCRIPTION

[0062] The present invention provides a topical solution containing minoxidil and finasteride and a preparation method thereof. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters to achieve it. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the method and application of this article without departing from the content, spirit and scope of the present invention to implement and apply the technology of the present invention.

[0063] Unless otherwise defined herein, scientific and technical terms related to the present invention shall have the meanings understood by those of ordinary skill in the art.

[0064] In the present invention, "and / or" describes the association relationship of associated objects, indicating that three relationships may exist. For example, A and / or B may represent: A exists alone, A and B exist at the same time, and B exists alone.

[0065] In the present invention, "at least one" means one or more, "more than one" means two or more. "At least one of the following" or similar expressions refers to any combination of these items, including any combination of single or plural items.

[0066] In the present invention, "include", "comprising" and "having" are used interchangeably, and are intended to indicate the inclusiveness of the scheme, meaning that the scheme may have other elements besides the listed elements. At the same time, it should be understood that the descriptions of "include", "comprising" and "having" used in this article also provide "consisting of..." or "as shown in..." schemes.

[0067] The numerical ranges and parameters involved in the present invention have been presented in the specific embodiments as accurately as possible. However, any numerical value inherently inevitably contains standard deviations due to individual testing methods. Therefore, unless otherwise explicitly stated, it should be understood that all numerical ranges or specific data used in this disclosure may have certain reasonable deviations within a certain range, such as: ±10%, ±5%, ±1% or ±0.5%.

[0068] Some cases are recorded in the examples and comparative examples of the present invention. The examples show some implementations of the present invention. However, this does not mean that the effects of the present invention can only be achieved in these cases. In fact, any concentration of each component near the proportion of the examples can achieve the effect of promoting penetration.

[0069] The inventors found that according to the IVPT (in vitro transdermal test) data, adding DMA, azone, dimethyl isosorbide and menthol penetration enhancers to the prescription can increase the penetration effect. Among them, menthol has a relatively good penetration enhancing effect, which can increase the average intradermal retention of minoxidil and finasteride to 1.9 times and 1.7 times, respectively. Its penetration enhancing effect is far better than other penetration enhancers.

[0070] The test materials used in the present invention are all common commercial products and can be purchased on the market. It should be understood that in various embodiments of the present application, the size of the sequence number of each process does not mean the order of execution, some or all of the steps can be executed in parallel or in sequence, and the execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application. The present invention is further described below in conjunction with the embodiments:

[0071] Example 1 to Example 2, Comparative Example 1 to Comparative Example 10:

[0072] The samples were prepared by designing the propylene glycol concentration to be 10%, 30%, and 50%, the glycerol content to be 10%, 20%, 30%, and 40%, and the PEG400 content to be 10%, 20%, 30%, and 40%.

[0073] 1. Composition: See Table 1

[0074] Table 1: Prescription composition of Example 1 to Example 2, Comparative Example 1 to Comparative Example 10

[0075] Components Minoxidil Finasteride Ethanol Propylene glycol glycerin PEG400 water Example 1 5g 0.025g 30ml 30ml / / Add to 100ml Example 2 5g 0.025g 30ml 50ml / / Add to 100ml Comparative Example 1 5g 0.025g 30ml 10ml / / Add to 100ml Comparative Example 2 5g 0.025g 40ml 10ml / / Add to 100ml Comparative Example 3 5g 0.025g 30ml / 10ml / Add to 100ml Comparative Example 4 5g 0.025g 30ml / 20ml / Add to 100ml Comparative Example 5 5g 0.025g 30ml / 30ml / Add to 100ml Comparative Example 6 5g 0.025g 30ml / 40ml / Add to 100ml Comparative Example 7 5g 0.025g 30ml / / 10ml Add to 100ml Comparative Example 8 5g 0.025g 30ml / / 20ml Add to 100ml Comparative Example 9 5g 0.025g 30ml / / 30ml Add to 100ml Comparative Example 10 5g 0.025g 30ml / / 40ml Add to 100ml

[0076] 2. Preparation method:

[0077] 1) Add minoxidil and finasteride to a mixture of solvent ethanol and propylene glycol / glycerol / polyethylene glycol 400, stir at 50-60° C. until the solid is completely dissolved, and stop heating;

[0078] 2) Add water to make up to volume.

[0079] Experimental Example 1: Investigation of physical stability

[0080] 1. Samples: Examples 1-2 and Comparative Examples 1-10.

[0081] 2. Experimental method: Observe and record the dissolution of minoxidil and finasteride during the preparation process. Store each prescription sample at 2-8°C for 24 hours and observe the physical stability of each sample.

[0082] 3. Experimental results:

[0083] 3.1 Dissolution: During the sample preparation process, the dissolution rate of minoxidil slowed down in the formulation containing 40% glycerol; it could not be completely dissolved in the formulation containing 20% ​​or more PEG400.

[0084] 3.2 Physical properties: see Table 2

[0085] Table 2: Physical properties of Examples 1 to 2 and Comparative Examples 1 to 10

[0086]

[0087]

[0088] The results showed that: Examples 1, 2 and Comparative Examples 4, 5 had good solubility and no solid precipitation at low temperature; the minoxidil in Comparative Examples 1 to 3 was unstable in the formulation of 10% propylene glycol and 10% glycerol, and the samples immediately crystallized after returning to room temperature. In the formulation containing more than 20% of PEG400 excipient, minoxidil was not completely dissolved, and the samples all crystallized after being refrigerated at 2-8°C, and all samples containing PEG400 showed discoloration and yellowing.

[0089] 4. Conclusion: 30%-50% propylene glycol and 20%-30% glycerol are suitable for the combination of minoxidil and finasteride.

[0090] Comparing propylene glycol and glycerol, the dosage range of glycerol is too narrow. Too much or too little dosage may affect the dissolution rate and physical stability. Therefore, propylene glycol is selected as the solvent for minoxidil and finasteride prescriptions.

[0091] Embodiment 3~embodiment 7:

[0092] The penetration enhancers of Design Example 3, Example 4, Example 5, Example 6 and Example 7 are 2% DGME, 0.75% menthol, 0.8% DMA, 0.8% isosorbide dimethyl ether and 2% azone (w / v), respectively.

[0093] 1. Composition: See Table 3

[0094] Table 3: Prescription composition of Examples 2 to 7

[0095]

[0096]

[0097] 2. Example 3, Example 5-7 Preparation method:

[0098] 1) Add minoxidil and finasteride to a mixture of solvents ethanol and propylene glycol, stir with magnetic force in a 50-60°C water bath until the solid is completely dissolved, stop heating, add a penetration enhancer after the solution cools to room temperature, and stir evenly;

[0099] 2) Add water to make up to volume.

[0100] 3. Preparation method of embodiment 4:

[0101] 1) Add minoxidil and finasteride to a mixture of solvents ethanol and propylene glycol, stir with a magnetic stirrer in a water bath at 50-60°C until the solid is completely dissolved, stop heating, wait for the solution to cool to room temperature, add a penetration enhancer, and stir with a magnetic stirrer in a water bath to dissolve;

[0102] 2) Add water to make up to volume.

[0103] Experimental Example 2: In vitro permeation test (IVPT) of different penetration enhancers

[0104] 1. Samples: Examples 2, 3, 4, 5, 6, and 7, minoxidil alone and finasteride alone.

[0105] Among them, the single minoxidil sample was purchased from the male minoxidil solution Rogaine of JOHNSON Company in the United States, with a specification of 5% and batch number 1373CP; the single finasteride sample was purchased from the finasteride spray Caretopic of Cantabria Labs, with a specification of 2.275 mg / ml and batch number 343163; the others were homemade example samples.

[0106] 2. Experimental method: Take samples for in vitro transdermal test.

[0107] Using a vertical osmotic diffusion instrument (Logan), the skin of Panamanian miniature pigs was selected for the test, and the skin diffusion area was 1.77cm 2, temperature 32±0.5℃. The loading volume of finasteride was 10μl, and the loading volume of other samples was 100μl, so that the minoxidil sample volume was 5mg, and the finasteride sample volume was 25μg. Each group of samples was added to the sample pool, 12ml of normal saline was used as the receiving solution, the speed was 600rpm / min, and samples were taken at 1, 2, 4, 6, 8, 10, 12, 16, and 24h respectively. Each prescription was tested 5 times in parallel, and the receiving solution, the sample solution of the residual amount on the skin, and the sample solution retained in the skin were taken to calculate the recovery rate.

[0108] Receiving liquid sample: Take the receiving liquid.

[0109] Residual sample solution on the skin: Remove the ex vivo skin after 24 hours. Use a disposable cotton swab to gently scrape the skin surface, scrape the remaining preparation on the skin surface as clean as possible and put it in a 50ml centrifuge tube, then take the eluate (50% methanol) to rinse and wipe the pig skin surface twice, 10ml each time, rinse the quantitative ring with an appropriate amount of eluate, rinse the preparation on the surface of the quantitative ring and collect it in the above centrifuge tube, add eluate to make up to 50ml, vortex for 2min, and then ultrasonicate for 30min.

[0110] Intradermal retention sample solution: cut the cleaned skin into rice-size pieces, place in a grinding jar, freeze in liquid nitrogen for 15 minutes, take out, grind into powder with a grinder, transfer the powder to a 20 ml volumetric flask with a diluent (50% methanol), make up to the scale, shake well, vortex for 2 minutes, centrifuge at 16000 rpm for 5 minutes, and take the supernatant.

[0111] 3. Detection method: The concentration of minoxidil and finasteride in each sample solution was determined by LC-MS method, and the cumulative permeation amount, skin retention amount, and average intradermal retention amount were calculated. The specific method is as follows:

[0112] 3.1 Minoxidil detection method:

[0113] Agilent Poroshell 120EC-C18 2.7um4.6*100mm chromatographic column was selected, and 0.1% phosphoric acid water (A)-acetonitrile (B) was used as the mobile phase for gradient elution, the flow rate was 1.0ml / min, the detection wavelength was 280nm, the column temperature was 35°C, and the injection volume was 10μl.

[0114] Table 4: Minoxidil elution method

[0115] Time (min) Mobile phase A% Mobile phase B% 0 75 25 7 15 85 10 15 85 10.1 75 25 15 75 25 0 75 25

[0116] 3.2 Finasteride detection method:

[0117] A Waters XBridge C18 5um, 4.6*150mm chromatographic column was selected, and 0.1% formic acid water (A)-acetonitrile (B) (1:1) was used as the mobile phase for isocratic elution. The flow rate was 1.0ml / min, the detection wavelength was 210nm, the column temperature was 30℃, and the injection volume was 10μl.

[0118] MS parameters: ion source API-ES, gas flow rate 12.0 L / min, signal acquisition time 2 min, capillary voltage 5500 V, SIM mode (positive ion) 373.50, ion source temperature 250 °C, nebulizer pressure 35 psig.

[0119] 4. Experimental results: see Table 5.

[0120] Table 5-1: IVPT mean results of different penetration enhancers

[0121]

[0122]

[0123] Table 5-2: IVPT mean results of different penetration enhancers

[0124]

[0125] (mean ± standard deviation, n = 5)

[0126] The results in Table 5 show that the recovery rates of each example are within the range of 80% to 120%, and the materials are basically balanced. The penetration effect of the self-developed sample is better than that of the commercially available product, which may be related to the fact that the propylene glycol and ethanol solvents in the prescription have a certain penetration-enhancing effect.

[0127] Comparing the six examples, when the penetration enhancer DGME was added, the intradermal retention of minoxidil and finasteride was reduced, and the retention on the skin was larger, which may be related to the large viscosity and poor fluidity of the prescription; the intradermal retention of the prescriptions with the addition of penetration enhancers azone, menthol, DMA and dimethyl isosorbide all tended to increase.

[0128] Among them, the most prominent is that when the penetration enhancer menthol is added, the intradermal retention of minoxidil is 1.9 times that of the group without the penetration enhancer, and the intradermal retention of finasteride is 1.7 times that of the group without the penetration enhancer. Therefore, menthol, azone, DMA and dimethyl isosorbide are selected as penetration enhancers, preferably menthol.

[0129] Embodiment 8~embodiment 9, comparative example 11:

[0130] According to the dosage range of menthol auxiliary material, the dosage of menthol was designed to be 0.50% and 1.00% respectively for IVPT experimental study, and compared with the 0.75% menthol IVPT data of Example 4 for analysis.

[0131] 1. Composition: See Table 6

[0132] Table 6: Examples 4, 8, 9 prescription composition

[0133] Components Comparative Example 11 Example 8 Example 4 Example 9 Minoxidil 50g 50g 50g 50g Finasteride 0.25g 0.25g 0.25g 0.25g Propylene glycol 500ml 500ml 500ml 500ml Ethanol 300ml 300ml 300ml 300ml Menthol 2.5g 5.0g 7.5g 10.0g water Add to 1L Add to 1L Add to 1L Add to 1L

[0134] 2. Preparation methods of Examples 8, 9 and Comparative Example 11:

[0135] Add minoxidil and finasteride to the mixture of ethanol and propylene glycol, stir with magnetic force in a water bath at 50-60℃ until the solid is completely dissolved, and stop heating. Cool the solution to room temperature, add the penetration enhancer, stir with magnetic force in a water bath to dissolve; add water to the fixed volume, mix well, and it is done.

[0136] Experimental Example 3: In vitro transdermal test (IVPT) of menthol at different concentrations

[0137] 1. Samples: Examples 8, 4, 9, and Comparative Example 11.

[0138] 2. Experimental method: See Experimental Example 2 for experimental method.

[0139] 3. Experimental results: see Table 7.

[0140] Table 7: Mean IVPT results for different concentrations of menthol prescriptions

[0141]

[0142] The results in Table 7 show that the greater the amount of penetration enhancer menthol used, the more obvious its penetration enhancing effect, and the amount retained in the skin increases with the increase in the proportion of the penetration enhancer. Among them, the penetration enhancing effects of Comparative Example 11 and Example 8 are relatively low, indicating that the penetration enhancing effect is too small when the menthol concentration is below 0.5%; the penetration enhancing effects of Example 4 and Example 9 are similar, far better than the penetration enhancing effects of other groups, indicating that when the menthol concentration exceeds 0.75%, the penetration enhancing effect no longer increases significantly. On the whole, 0.5-1.0% menthol can be selected as the penetration enhancer, preferably 0.75-1.0% menthol.

[0143] 4. Combined with the effect data analysis in the present invention:

[0144] According to the Technical Guidelines for In Vitro Release (IVRT) and In Vitro Transdermal (IVPT) Studies of Topically Acting Chemical Generic Drugs, "given that topically acting preparations with different indications work in different parts of the skin, preparations that only work in the stratum corneum and epidermis are not required to provide a complete IVPT flux curve." Based on the mechanism of action of minoxidil and finasteride, both mainly act on the hair follicles in the skin. Therefore, this experiment uses the amount of drug retained in the scalp as the evaluation indicator, namely the intradermal retention amount.

[0145] According to the results of the IVPT experiment, when menthol was added to the prescription as a penetration enhancer, the intradermal retention of minoxidil was 1.9 times that of the group without a penetration enhancer, and the intradermal retention of finasteride was 1.7 times that of the group without a penetration enhancer. It was also better than the single-ingredient preparation and had the best penetration-enhancing effect.

[0146] It can be seen from the above experiments that the minoxidil and finasteride compound external solution provided by the present invention not only has good permeability, but also has the advantages of simple process and convenient medication.

[0147] The above are only preferred embodiments of the present invention. It should be pointed out that, for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A topical solution containing minoxidil and finasteride, characterized in that: include: minoxidil, finasteride, solvents, and penetration enhancers; The penetration enhancer is selected from at least one of N,N-dimethylacetamide, azone, isosorbide dimethyl ether or menthol.

2. The external use solution according to claim 1, characterized in that The solvent is a mixture of ethanol, propylene glycol and water, wherein the volume ratio of ethanol, propylene glycol and water is 30: (30-50): (10-40).

3. The external use solution according to claim 1, characterized in that Each liter of solution contains the following components: The balance is water.

4. The external use solution according to any one of claims 1 to 3, characterized in that The penetration enhancer is isosorbide dimethyl ether, and the content of isosorbide dimethyl ether in each liter of the external solution is 5g to 15g.

5. The external use solution according to any one of claims 1 to 3, characterized in that The penetration enhancer is DMA, and the content of DMA in each liter of the external solution is 5g to 15g.

6. The external use solution according to any one of claims 1 to 3, characterized in that The penetration enhancer is azone, and the content of azone in each liter of the external solution is 10g to 30g.

7. The external use solution according to any one of claims 1 to 3, characterized in that: The penetration enhancer is menthol, and the content of menthol in each liter of the external solution is 5g-10g.

8. The external use solution according to claim 7, characterized in that Each liter of solution contains the following components: The balance is water.

9. The external use solution according to claim 7, characterized in that Each liter of solution contains the following components: The balance is water.

10. A method for preparing the external solution according to any one of claims 1 to 9, comprising: Add minoxidil and finasteride to a mixture of solvents ethanol and propylene glycol, mix at 50-60°C until the solid is completely dissolved, add a penetration enhancer after cooling to room temperature, stir to dissolve; add water to make up to volume.

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