A pharmaceutical composition containing a 5α-reductase inhibitor

Abstract

The application provides a pharmaceutical composition containing a 5alpha-reductase inhibitor, which comprises a peripheral vasodilator, a 5alpha-reductase inhibitor, a non-volatile solvent, a volatile solvent and water. The inventors have unexpectedly found that by adjusting the solvent system, not only can the greasy feeling and irritation of the pharmaceutical composition of the peripheral vasodilator and the 5alpha-reductase inhibitor be effectively reduced, but also the optimal absorption effect of the compound drug can be achieved, the drug absorption utilization rate is further improved, and the patient compliance is greatly improved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a pharmaceutical composition containing a 5α-reductase inhibitor. Background Technology

[0002] Androgenetic alopecia (AGA) is the most common type of hair loss, formerly known as seborrheic alopecia or premature baldness. It is a progressive hair loss disorder that occurs during and after puberty. AGA is characterized by follicle miniaturization, resulting from increased sensitivity of localized scalp follicles to androgens, altering the hair growth cycle, causing follicle atrophy, and the gradual transformation and disappearance of terminal follicles into vellus hair. In men, it primarily manifests as a receding hairline and / or progressive thinning and thinning of hair on the crown, also known as male pattern alopecia. In women, it primarily manifests as progressive thinning and thinning of hair on the crown, with a smaller percentage experiencing diffuse hair thinning without a receding hairline, known as female pattern alopecia.

[0003] Currently, the most commonly used drugs for treating AGA include minoxidil and finasteride. Minoxidil (6-(1-piperidinyl)-2,4-pyrimidinediamine trioxide) is available in a topical solution form called Rogaine, which includes 2% and 5% concentrations. However, this topical minoxidil solution requires consistent application several times daily; irregular use or arbitrary discontinuation will lead to poor efficacy. This cumbersome procedure hinders user adherence.

[0004] Existing studies have shown that patients benefit more from the combined use of topical minoxidil and oral finasteride compared to using either drug alone, indicating a synergistic effect. However, the side effects and inconvenience of oral finasteride hinder patient adherence. Therefore, topical formulations of minoxidil and finasteride are currently one research direction. However, both commercially available minoxidil solutions and existing compound formulations (such as CN118384171A) suffer from issues such as greasy feel and irritation.

[0005] To improve user experience, the inventors studied the solvent system of the compound formulation and found that while propylene glycol has good moisturizing effects and plays a role in absorption, excessive amounts can easily lead to a greasy feeling and clog pores, thus reducing drug absorption. While reducing the propylene glycol content and increasing the ethanol content can reduce irritation, the rapid evaporation of ethanol causes the drug to dry quickly after application to the scalp, also reducing absorption. Therefore, it is essential to develop a compound drug formulation that can reduce greasiness and irritation while achieving optimal absorption. Summary of the Invention

[0006] The purpose of this invention is to provide a pharmaceutical composition containing a 5α-reductase inhibitor, which reduces the greasiness and irritation of topical preparations by adjusting the solvent system ratio, while also improving the absorption effect of compound drugs.

[0007] The present invention provides a pharmaceutical composition containing a 5α-reductase inhibitor, comprising, by weight percentage: 1.5%-6% peripheral vasodilator, 0.01%-0.5% 5α-reductase inhibitor, 15%-50% non-volatile solvent, 30%-70% volatile solvent, and 5%-20% water.

[0008] Further, the peripheral vasodilator is selected from one or more of minoxidil, buprodil, cetiridil, and their salts or derivatives, preferably minoxidil or its salts or derivatives; wherein the salt is an addition salt or onium salt formed by the reaction of the compound with an acid, wherein the acid includes, but is not limited to: formic acid, acetic acid, propionic acid, butyric acid, caprylic acid, adipic acid, oxalic acid, malonic acid, succinic acid, maleic acid, tartaric acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, phthalic acid, terephthalic acid, valeric acid, hexanoic acid, decanoic acid, stearic acid, palmitic acid, acrylic acid, citric acid, citric acid, sulfuric acid, phosphoric acid, nitric acid, hydrochloric acid; preferably minoxidil or minoxidil onium sulfate (2,6-diamino-4-(piperidin-1-yl)pyrimidin-1-onium-1-yl sulfate).

[0009] Furthermore, the 5α-reductase inhibitor is selected from finasteride, dutasteride, iridarone, or combinations thereof; preferably finasteride or dutasteride;

[0010] Furthermore, the non-volatile solvent is selected from propylene glycol, ethylene glycol, polyethylene glycol, glycerin or combinations thereof, preferably a combination of propylene glycol, propylene glycol and glycerin; the volatile solvent is selected from ethanol, isopropanol or combinations thereof, preferably ethanol.

[0011] Further, by weight percentage, the peripheral vasodilator is preferably 2%-5%; the 5α-reductase inhibitor is preferably 0.001%-0.5%, more preferably 0.005%-0.3%; the non-volatile solvent is preferably 20%-40%, more preferably 25%-35%; and the volatile solvent is preferably 40%-60%, more preferably 45%-55%.

[0012] Furthermore, by weight percentage, it also includes 0-20% moisturizer, preferably 0-15% moisturizer.

[0013] Furthermore, the moisturizer is selected from glycerin, urea, sorbitol, sodium hyaluronate, hydroxymethyl chitosan, or combinations thereof.

[0014] Furthermore, accelerators include solutions, sprays, and liniments.

[0015] The present invention also provides the use of a pharmaceutical composition containing a 5α-reductase inhibitor in the treatment or prevention of hair loss.

[0016] The present invention also provides the application of a pharmaceutical composition containing a 5α-reductase inhibitor in the treatment of alopecia areata and androgenetic alopecia.

[0017] Beneficial effects of the present invention: The inventors unexpectedly discovered that by adjusting the solvent system, not only can the skin greasiness and irritation of minoxidil compound preparations be effectively reduced, but the compound drugs can also achieve the best absorption effect, further improving the drug absorption and utilization rate and greatly improving patient compliance. Detailed Implementation

[0018] The present invention will be further described in detail below with reference to specific embodiments. The described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0019] Prescriptions of Examples 1-12 and Comparative Examples 1-9

[0020] Examples 1-12 and Comparative Examples 1-7 are formulations of solutions containing minoxidil + finasteride / dutasteride / iristaride + different solvent ratios, and the formulations of Comparative Example 8 (5% minoxidil Rogaine) and Comparative Example 9 (CN118384171A Example 1) are shown in Table 1.

[0021] Table 1. Prescriptions for Examples 1-12 and Comparative Examples 1-9

[0022]

[0023] Preparation methods of Examples 1-12 and Comparative Examples 1-7:

[0024] Take the prescribed amounts of propylene glycol + ethanol or propylene glycol + ethanol + glycerin according to Table 1, mix them evenly, add minoxidil and finasteride / dutasteride / iristaride according to the prescription amounts of each embodiment, stir and mix evenly, finally add purified water to dilute to the prescription amount, and fill into the container to obtain the solution.

[0025] Experimental Example 1: Transdermal Absorption Rate

[0026] 1. Experimental objective: To investigate the effect of different solvent ratios on drug absorption in formulation samples.

[0027] 2. Experimental Methods: Taking the 5% minoxidil + 0.02% dutasteride compound as an example, formulations 1-18 with different solvent ratios were prepared as experimental groups (preparation methods refer to Examples 1-12). Commercially available 5% minoxidil product (Rogaine) and CN118384171A Example 1 were used as control groups 1 and 2, respectively. The transdermal effects of the experimental and control groups were compared. The transdermal effect was evaluated by using isolated skin of miniature pigs to measure the cumulative permeation per unit area, cumulative permeation per 24 hours, and drug residue in the skin of each formulation.

[0028] 3. Experimental design: The experimental grouping and dosage design are shown in Table 2.

[0029] Table 2. Trial grouping and dosage design

[0030]

[0031] 4. Experimental results: The transdermal absorption effects of active ingredients in prescriptions 1-6 and control groups 1-2 are shown in Table 3.

[0032] Table 3 Transdermal effects of prescriptions 1-6 and control groups 1-2

[0033]

[0034]

[0035] As shown in Table 3, the transdermal drug penetration rate of formulations 3-5 of this invention is further improved compared with other formulations.

[0036] Experimental Example 2: Animal Stimulation Experiment

[0037] Experimental objective: To observe whether different solvent ratios in the formulations produced irritation at the application site by administering them to rabbit skin.

[0038] 1. Test samples: Formulas 1-6 shown in Table 2, and Comparative Examples 1 and 2.

[0039] 2. Experimental animals: Japanese white rabbits.

[0040] 3. Experimental Methods: Ten rabbits were used for irritation testing of each prescription. The prescribed medication was applied to the treated area after shaving. Dosage and administration: 0.5 mL / time, twice daily for 30 consecutive days. Before each administration, the presence of erythema, edema, or other irritants at the application site was observed and recorded to determine irritation. "None" indicates no erythema or edema in rabbits or mice within 30 days; "Mild irritation" indicates erythema in rabbits or mice within 30 days; "Moderate irritation" indicates erythema and edema in rabbits or mice within 30 days; " / " indicates no experiment was conducted.

[0041] 4. Experimental Design: The experimental group design is shown in Table 2.

[0042] 5. Experimental results: The experimental results of each prescription are shown in Table 4.

[0043] Table 4. Results of animal irritation tests for each prescription.

[0044]

[0045]

[0046] As shown in Table 4, no irritant reactions occurred with prescriptions 3-5 of the present invention within 30 days, while other prescriptions all showed irritant reactions to varying degrees.

[0047] Experiment 3: Oiliness Test

[0048] 1. Experimental objective: To compare the differences in oiliness of different samples by applying prescription samples with different solvent ratios to human skin.

[0049] 2. Test samples: prescriptions 3-6 shown in Table 2, and control group 1 and control group 2.

[0050] 3. Experimental population: 20 adult male subjects, with the sample applied to the back of the hand.

[0051] 4. Experimental Method: After washing and drying the backs of the hands of 20 subjects, 0.5 ml of Formula 3 sample was applied to the same area on the back of each hand. The greasiness of the sample was evaluated based on the application state (out of 5 points, with 1 point being the weakest greasiness and 5 points being the strongest greasiness). After scoring, the remaining sample on the back of the hands was washed and dried, and 0.5 ml of Formula 4 sample was applied to the same area on the back of the hands for evaluation. The above operation was repeated, and the greasiness scores of each group of samples were summarized.

[0052] 5. Experimental design: The experimental group design is shown in prescriptions 3-6 in Table 2, as well as control group 1 and control group 2.

[0053] 6. Experimental results: The experimental results of each prescription are shown in Table 5.

[0054] Table 5. Results of animal irritation tests for each prescription.

[0055]

[0056]

[0057] As shown in Table 5, the prescriptions of the present invention have a less greasy feel than those of the prior art, especially the solvent combinations of prescriptions 3 and 4, which provide a better user experience.

[0058] Experimental Example 4: Pharmacodynamic Experiment

[0059] 1. Experimental objective: To establish an androgenetic alopecia model by subcutaneous injection of testosterone propionate (5 mg / kg) into the back of male C57BL / 6J mice, and to compare the therapeutic effects of different prescription compound topical preparations on the androgenetic alopecia model.

[0060] 2. Test samples: Examples 1-12 and Comparative Examples 1-9 as shown in Table 1.

[0061] 3. Experimental animals: C57BL / 6J mice, weighing 18-22g.

[0062] 4. Experimental methods: 115 C57BL / 6J mice, weighing 18-22g, were used. Five mice were selected as the blank control group. The remaining mice were injected subcutaneously along the spine with testosterone propionate solution (5mg / kg, 10mL / kg) to induce the model. The injection was given once daily for 10 weeks. After the mice developed obvious hair loss areas on their backs, they were randomly divided into 22 groups: model control group, Example 1-12 groups, and Comparative Example 1-9 groups, with 5 mice in each group.

[0063] According to the prescriptions for each group, the bald areas of the mice after the modeling process were treated with topical medication, with an application area of ​​1 cm². 2 The dosage was 50 μL per mouse, administered twice daily at 6-hour intervals for 15 consecutive days. After the onset of the model, hair loss was observed and recorded weekly. Following administration, the skin and hair growth at the bald areas were observed weekly, and the hair growth score was recorded. The scoring criteria were: 0 points: no growth, pink skin in the bald area; 1 point: gray skin in the bald area (less than 20% hair growth); 2 points: black skin in the bald area (more than 20% but less than 40% hair growth); 3 points: black skin in the bald area with some hair growth (more than 40% but less than 60% hair growth); 4 points: black skin in the bald area with some hair growth (60%–80% hair growth); 5 points…

[0064] After the last administration, mice were euthanized by cervical dislocation. Skin around the administration site, along with the attached back muscle tissue and spine, was harvested and fixed from each group of mice. The skin tissue at the center of the administration site (the center of the spine and nearby skin tissue) was selected for HE staining. The morphological changes of hair follicles and skin irritation of each group of mice were observed under a microscope. The classification of hair growth stages at the center of the administration site under 100x magnification and the number of hair follicles at each stage under 200x magnification were observed and recorded. The ratio of terminal hair to vellus hair was calculated.

[0065] 5. Dosage design

[0066] The experimental grouping and dosage design are shown in Table 6.

[0067] Table 6. Trial grouping and dosage design

[0068]

[0069] 6. Experimental results: The statistical results of animal hair growth scores are shown in Table 7; the effects of the compound preparation on the average number of hair follicles and the ratio of terminal hair to vellus hair in mice with baldness after 2 weeks of administration are shown in Table 8.

[0070] Table 7 Statistical Results of Animal Hair Growth Scores

[0071]

[0072]

[0073] Note: Compared with the blank control group, "*" indicates P<0.05, and "**" indicates P<0.01.

[0074] Table 8. Effects of different formulations on the average number of hair follicles and the ratio of terminal hair to vellus hair in mice with induced baldness after 2 weeks of administration.

[0075]

[0076]

[0077]

[0078] Note: Compared with the blank control group, "*" indicates P<0.05, and "**" indicates P<0.01.

[0079] As shown in Tables 7 and 8, in different specifications of the topical combination of minoxidil + dutasteride / finasteride / iristaride, the solvent combination ratio of the present invention has a more significant therapeutic effect on mice with androgenetic alopecia induced by testosterone propionate compared with the prior art.

Claims

1. A pharmaceutical composition containing a 5α-reductase inhibitor, characterized in that, By weight percentage, it includes: 1.5%-6% peripheral vasodilator, 0.01%-0.5% 5α-reductase inhibitor, 15%-50% non-volatile solvent, 30%-70% volatile solvent, and 5%-20% water; The peripheral vasodilator is selected from one or more of minoxidil, buprodil, cetiridil and their salts or derivatives, preferably minoxidil or its salts or derivatives; The 5α-reductase inhibitor is selected from finasteride, dutasteride, iridarone, or combinations thereof; preferably finasteride or dutasteride. The non-volatile solvent is selected from propylene glycol, ethylene glycol, polyethylene glycol, glycerin, or combinations thereof, preferably a combination of propylene glycol, propylene glycol, and glycerin; The volatile solvent is selected from ethanol, isopropanol, or a combination thereof, with ethanol being preferred.

2. The pharmaceutical composition according to claim 1, characterized in that, The peripheral vasodilator is preferably 2%-5% by weight; The 5α-reductase inhibitor is preferably 0.001%-0.5%, more preferably 0.005%-0.3%; The non-volatile solvent is preferably 20%-40%, more preferably 25%-35%; The volatile solvent is preferably 40%-60%, more preferably 45%-55%.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, It also includes 0-20% humectant, preferably 0-15% humectant, by weight percentage.

4. The pharmaceutical composition according to claim 3, characterized in that, The moisturizer is selected from urea, sorbitol, sodium hyaluronate, hydroxymethyl chitosan, or a combination thereof.

5. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The accelerator includes solutions, sprays, and liniments.

6. The use of the pharmaceutical composition according to any one of claims 1-5 in the treatment or prevention of hair loss.

7. The use of the pharmaceutical composition according to any one of claims 1-6 in the treatment of alopecia areata and androgenetic alopecia.

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