Sustained-release capsule containing minoxidil and dutasteride and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations. The invention provides a sustained-release capsule containing minoxidil and dutasteride and a preparation method of the sustained-release capsule, the sustained-release capsule is composed of a capsule shell and content, and the content comprises minoxidil, dutasteride, spirolactone, isovitamin A, a traditional Chinese medicine composition, a sustained-release material, a filling material, an adhesive, a lubricant, a traditional Chinese medicine solubilizing dispersant and a stabilizer. According to the sustained-release capsule, through the synergistic effect of chemical components and traditional Chinese medicine components, the medicine components are better and more stable, the duration time of the medicine effect is prolonged, and the side effects of hirsutism, edema and the like caused by minoxidil and the side effects of transaminase abnormality and the like caused by dutasteride are reduced; meanwhile, by means of the liver protecting and blood nourishing effects of the traditional Chinese medicine components, the liver metabolism pressure is better reduced, and the long-term medication safety is improved; the hair regeneration capability is enhanced, and a better alopecia prevention and treatment effect is achieved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical preparations, in particular to a sustained-release capsule containing minoxidil and dutasteride and a preparation method thereof. BACKGROUND

[0002] In recent years, due to the increase of social pressure, environmental pollution, unhealthy diet, heavy life pressure, wrong scalp care, sex hormone disorder, vitamin and mineral deficiency, etc., the hair loss phenomenon is becoming more and more serious. Hair loss not only affects appearance, but also easily causes anxiety, inferiority and other psychological problems, reduces the quality of life of patients.

[0003] In the international, the clinically commonly used hair loss treatment drugs mainly include finasteride, dutasteride and minoxidil. Finasteride, also a 5a-reductase inhibitor, only has inhibitory effect on type II 5a-reductase, while dutasteride has inhibitory effect on type I and type II 5a-reductase. Compared with finasteride, dutasteride has better efficacy and is more favored by patients. As a type I and type II 5a-reductase inhibitor, dutasteride can efficiently reduce the content of dihydrotestosterone to provide a suitable environment for hair recovery and growth for the scalp, but long-term use is easy to accumulate in the liver and easily cause abnormal liver function and elevated transaminase.

[0004] Minoxidil, as a peripheral vasodilator, can stimulate hair follicle activity and promote hair growth from the resting phase to the growth phase when used topically or orally, thereby achieving hair regeneration. However, there are obvious defects in actual application, including: high drug frequency and poor compliance; minoxidil dosage is usually high, drug concentration fluctuates greatly and effect is unstable, which may cause dizziness, heart rate disorder, hypotension, edema, local skin irritation (when used topically) and other adverse reactions. Based on the above, it is necessary to develop a product that can ensure anti-hair loss effect, prolong effective time, reduce drug frequency and reduce drug side effects while improving the stability of the preparation, which is a technical problem to be solved in the current hair loss treatment field. SUMMARY

[0005] The purpose of the present application is to provide a sustained-release capsule containing minoxidil and dutasteride, which can further enhance hair regeneration ability, reduce liver metabolism pressure, improve long-term drug safety and prolong drug efficacy duration through the synergistic effect of chemical components and traditional Chinese medicine components while reducing drug use frequency.

[0006] In order to achieve the above-mentioned purpose of the application, the present application provides the following technical solutions: The application provides a sustained-release capsule containing minoxidil and dutasteride, which is composed of a capsule shell and a content, and the content contains the following components in percentage by weight: minoxidil 1-2.5%, dutasteride 0.1-0.5%, spironolactone 10-13%, isotretinoin 5-8%, a traditional Chinese medicine combination 10-20%, a sustained-release material 10-20%, a filling material 30-55%, a binder 2-5%, a lubricant 0.5-2%, a traditional Chinese medicine solubilizing dispersant 0.5-1% and a stabilizer 0.5-1%.

[0007] Preferably, the traditional Chinese medicine combination is composed of the following raw material components in percentage by weight: radix polygoni multiflori 15-25 parts, biota orientalis 8-15 parts, lonicera japonica 6-12 parts, dried ginger 5-10 parts, safflower 5-8 parts and radix rehmanniae preparata 3-8 parts.

[0008] Preferably, the sustained-release material is any one or several of ethyl cellulose, hydroxypropyl methyl cellulose or acrylic resin.

[0009] Preferably, the filling material is any one or several of microcrystalline cellulose, lactose, mannitol or sorbitol.

[0010] Preferably, the binder is any one or several of povidone K30, polyvinylpyrrolidone or hydroxypropyl methyl cellulose.

[0011] Preferably, the traditional Chinese medicine solubilizing dispersant is β-cyclodextrin.

[0012] Preferably, the lubricant is magnesium stearate.

[0013] Preferably, the stabilizer is vitamin E and / or sodium carboxymethyl cellulose.

[0014] The application further provides a preparation method of the sustained-release capsule, which comprises the following steps: (1) mixing minoxidil, dutasteride, spironolactone, isotretinoin and a stabilizer to obtain a mixture A; (2) mixing the traditional Chinese medicine combination and a traditional Chinese medicine solubilizing dispersant, and then mixing the mixture A, a filling material and a sustained-release material to obtain a mixture B; (3) mixing the mixture B and a binder to obtain a soft material; (4) granulating and drying the soft material, and then adding a lubricant and mixing to obtain a mixed granule; (5) filling the mixed granule into a capsule shell.

[0015] Preferably, the step (1) further comprises a sieving treatment before the mixing, and the mesh number of the sieve is 70-100.

[0016] Preferably, the preparation process of the traditional Chinese medicine combination agent in step (2) is as follows: the Radix Polygoni Multiflori, Platycladi Cacumen, Ligustri Lucidi Fructus, Flos Lonicerae, Zingiberis Rhizoma Recens and Radix Rehmanniae Praeparatae are mixed, then water is added for decoction, and then concentration, spray drying are performed to obtain the traditional Chinese medicine combination agent.

[0017] Preferably, the total mass of the Radix Polygoni Multiflori, Platycladi Cacumen, Ligustri Lucidi Fructus, Flos Lonicerae, Zingiberis Rhizoma Recens and Radix Rehmanniae Praeparatae is 4-8 times the mass of water; the decoction time is 30-40 min / time, and the decoction times is 2-3 times.

[0018] Preferably, the drying temperature in step (4) is 40-50 DEG C, and the water content of the granules is 2-4% after drying.

[0019] By adopting the technical scheme, the present application has the following beneficial effects: 1. In the technical scheme of the present application, minoxidil and dutasteride synergistically act, dutasteride inhibits the generation of dihydrotestosterone to protect hair follicles, and minoxidil stimulates hair follicle regeneration, so that the combination of the two has a better effect from the two dimensions of “prevention” and “promotion”, and the hair regeneration ability and the effect of preventing and treating hair loss are better.

[0020] 2. The present application further enhances the hair regeneration ability and achieves a better effect of preventing and treating hair loss by the synergistic action of the chemical components and the traditional Chinese medicine components while reducing the frequency of drug use. Meanwhile, the increase in the sustained-release effect further reduces the side effects, and the liver protection and blood nourishing effects of the traditional Chinese medicine components further reduce the liver metabolic pressure and improve the long-term drug safety.

[0021] 3. The technical scheme of the present application controls the drug release rate by using a sustained-release material, so that the effective action time of the drug in the body is prolonged, and the frequency of drug use is reduced. DETAILED DESCRIPTION

[0022] The present application provides a sustained-release capsule containing minoxidil and dutasteride, which is composed of a capsule shell and contents, wherein the contents include minoxidil, dutasteride, spironolactone, isotretinoin, a traditional Chinese medicine combination agent, a sustained-release material, a filling material, a binder, a lubricant, a traditional Chinese medicine solubilizing dispersant and a stabilizer. The capsule shell of the present application is preferably a medical-grade capsule shell commonly used in the art.

[0023] In the present application, the minoxidil can stimulate hair follicle regeneration, and dutasteride can inhibit dihydrotestosterone production to protect hair follicles, both of which work from the "prevention" and "promotion" dimensions to enhance hair regeneration while preventing and treating hair loss. The spironolactone is beneficial to promote water metabolism in the body, and can also accelerate androgen consumption, thereby inhibiting the effect of androgens, reducing the damage of androgens to hair follicles, thereby delaying hair follicle atrophy and promoting new hair growth. The isotretinoin has an anti-inflammatory effect, can regulate epidermal cell differentiation and proliferation, thereby reducing sebaceous gland secretion, improving abnormal keratinization of hair follicle orifices, and creating a healthier microenvironment for hair growth. Therefore, the addition of spironolactone and isotretinoin in the present application can further enhance the effect of preventing and treating hair loss and promote hair growth, and the presence of spironolactone can also reduce the side effect of edema to some extent.

[0024] In the present application, the content preferably includes the following components by weight percentage: minoxidil 1-2.5%, dutasteride 0.1-0.5%, spironolactone 10-13%, isotretinoin 5-8%, traditional Chinese medicine combination 10-20%, sustained-release material 10-20%, filling material 35-55%, adhesive 2-5%, lubricant 0.5-2%, traditional Chinese medicine solubilizing dispersant 0.5-1%, and stabilizer 0.5-1%; further preferably including minoxidil 1.5-2.2%, dutasteride 0.2-0.4%, spironolactone 10.5-12.5%, isotretinoin 5.5-7.5%, traditional Chinese medicine combination 12-18%, sustained-release material 13-18%, filling material 35-50%, adhesive 2.5-4.8%, lubricant 0.8-1.6%, traditional Chinese medicine solubilizing dispersant 0.6-0.9%, and stabilizer 0.6-0.8%; and more preferably including minoxidil 2%, dutasteride 0.35%, spironolactone 12%, isotretinoin 6.65%, traditional Chinese medicine combination 15.7%, sustained-release material 15%, filling material 42%, adhesive 3.5%, lubricant 1.3%, traditional Chinese medicine solubilizing dispersant 0.8%, and stabilizer 0.7%.

[0025] In the present application, the traditional Chinese medicine combination is composed of the following raw material components: Radix Polygoni Multiflori, Cacumen Platycladi, Fructus Ligustri Lucidi, Flos Lonicerae, Rhizoma Zingiberis Recens, Flos Carthami, and Radix Rehmanniae Praeparata.

[0026] In the present application, the components in the traditional Chinese medicine combination can improve scalp blood circulation, activate hair follicle tissue, promote hair metabolism; nourish liver and kidney; improve hair follicle nutrition, promote hair growth; at the same time, honeysuckle and safflower can also relieve inflammation of hair follicles and improve the health environment of hair follicles. Through the synergistic effect of the traditional Chinese medicine components and the chemical components, the frequency of drug use is reduced, the hair regeneration ability is further enhanced, and better hair loss prevention and treatment effect is achieved. At the same time, the increase of the sustained-release effect will further reduce the side effects, and combined with the liver protection and blood nourishing effect of the traditional Chinese medicine components, the liver metabolic pressure is better reduced, and the long-term drug safety is improved.

[0027] In the present application, the weight fraction of the prepared Radix Polygoni Multiflori is preferably 15-25 parts, further preferably 18-22 parts, and more preferably 20 parts; the weight fraction of the Cacumen Platycladi is preferably 10-18 parts, further preferably 12-16 parts, and more preferably 15 parts; the weight fraction of the Ligustrum Lucidum is preferably 8-15 parts, further preferably 10-13 parts, and more preferably 12 parts; the weight fraction of the Lonicera Japonica is preferably 6-12 parts, further preferably 7-10 parts, and more preferably 9 parts; the weight fraction of the Drynaria fortunei is preferably 5-10 parts, further preferably 6-9 parts, and more preferably 8 parts; the weight fraction of the Safflower is preferably 5-8 parts, further preferably 5.5-7.5 parts, and more preferably 6 parts; and the weight fraction of the Radix Rehmanniae Preparata is preferably 3-8 parts, further preferably 4-6 parts, and more preferably 4.5 parts.

[0028] In the present application, the sustained-release material is preferably any one or several of ethyl cellulose, hydroxypropyl methyl cellulose or acrylic resin, and further preferably hydroxypropyl methyl cellulose and acrylic resin. The mass ratio of the hydroxypropyl methyl cellulose and the acrylic resin in the present application is preferably (2-6):1, further preferably (3-5):1, and more preferably 4:1. The acrylic resin in the present application is preferably acrylic resin No. IV.

[0029] In the present application, the filling material is preferably any one or several of microcrystalline cellulose, lactose, mannitol or sorbitol, and further preferably microcrystalline cellulose or lactose.

[0030] In the present application, the binder is preferably any one or several of povidone K30, polyvinylpyrrolidone or hydroxypropyl methyl cellulose, and further preferably povidone K30.

[0031] In the present application, the traditional Chinese medicine solubilizing dispersant is β-cyclodextrin.

[0032] In the present application, the lubricant is magnesium stearate.

[0033] In the present application, the stabilizer is preferably vitamin E and / or sodium carboxymethyl cellulose, further preferably vitamin E and sodium carboxymethyl cellulose. The mass ratio of vitamin E and sodium carboxymethyl cellulose in the present application is preferably 1: (2-4), further preferably 1: (2.5-3.5), and more further preferably 1:3.

[0034] The present application also provides a preparation method of the sustained-release capsule, comprising the following steps: (1) mixing minoxidil, dutasteride, spironolactone, isotretinoin and a stabilizer to obtain a mixture A; (2) mixing the traditional Chinese medicine combination agent and a traditional Chinese medicine solubilizing dispersant, and then mixing the mixture A, a filling material and a sustained-release material to obtain a mixture B; (3) mixing the mixture B and a binder to obtain a soft material; (4) granulating and drying the soft material, and then adding a lubricant and mixing to obtain a mixed granule; (5) filling the mixed granule into a capsule shell to obtain the sustained-release capsule.

[0035] In the present application, the minoxidil, dutasteride, spironolactone, isotretinoin and stabilizer are preferably sieved before mixing, and the undersize is collected for use. The mesh number of the sieve in the present application is preferably 70-100 mesh, further preferably 80-95 mesh, and more further preferably 90 mesh.

[0036] In the present application, the preparation process of the traditional Chinese medicine combination agent is as follows: mixing prepared radix polygoni multifidi, leaf of biota orientalis, ligustrum lucidum ait, honeysuckle, dried ginger and radix rehmanniae preparata, and then decocting with water, and then concentrating, spray drying to obtain the traditional Chinese medicine combination agent.

[0037] In the present application, the total mass of the prepared radix polygoni multifidi, leaf of biota orientalis, ligustrum lucidum ait, honeysuckle, dried ginger and radix rehmanniae preparata is preferably 4-8 times, further preferably 5-7 times, and more further preferably 6 times the mass of water. The decocting time in the present application is preferably 30-40 min / time, further preferably 32-38 min / time, and more further preferably 35 min / time. The decocting times are preferably 2-3 times, and further preferably 2 times. In the present application, the concentration is preferably to a relative density of 1.10-1.15. The inlet air temperature of the spray drying in the present application is preferably 160-190℃, further preferably 170-185℃, and more further preferably 180℃. The outlet air temperature of the spray drying is preferably 70-90℃, further preferably 75-85℃, and more further preferably 80℃.

[0038] In the present application, the traditional Chinese medicine combined agent is mixed with the traditional Chinese medicine solubilizing dispersant, and preferably subjected to grinding treatment, the grinding time is preferably 10-20 min, further preferably 12-18 min, and more preferably 15 min. In the present application, the grinding is preferably followed by sieving treatment, and the undersize is collected for use, the mesh number of the sieve is preferably 80-120 mesh, further preferably 90-110 mesh, and more preferably 100 mesh.

[0039] In the present application, the binder is dissolved in an ethanol solution to prepare a binder solution. Then the binder solution is mixed with the mixture B to obtain a soft material.

[0040] In the present application, the soft material is granulated and dried, the drying temperature is preferably 40-50℃, further preferably 42-48℃, and more preferably 45℃; the drying is preferably performed until the moisture content of the granules is 2-4%, further preferably 2.5-3.5%, and more preferably 3%.

[0041] In the present application, the granules are preferably subjected to sizing treatment before the lubricant is added, the sizing treatment is: the dried granules are sized through a 20-mesh sieve to remove oversized or undersized granules, and the particle size of the granules is controlled within the range of 20-80 mesh.

[0042] The technical solutions provided by the present application are described in detail below in conjunction with the examples, but they should not be understood as limiting the scope of protection of the present application.

[0043] The capsule shell used in the present application is a medical-grade capsule shell commonly used in the art.

[0044] The content dose of the sustained-release capsule is 200 mg per capsule.

[0045] Example 1

[0046] A sustained-release capsule containing minoxidil and dutasteride, which is composed of a capsule shell and a content, the content is in terms of weight percentage: minoxidil 2%, dutasteride 0.35%, spironolactone 12%, isotretinoin 6.65%, traditional Chinese medicine combined agent 15.7%, sustained-release material 15%, microcrystalline cellulose 42%, povidone K30 3.5%, magnesium stearate 1.3%, β-cyclodextrin 0.8%, and stabilizer 0.7%; The traditional Chinese medicine combined agent is: 20 parts of Radix Polygoni Multiflori, 15 parts of Biota orientalis, 12 parts of Ligustri Lucidi Fructus, 9 parts of Honeysuckle, 8 parts of dried ginger, 6 parts of safflower, and 4.5 parts of Radix Rehmanniae Praeparata are crushed and mixed, 6 times the weight of the raw materials of water is added, and 2 times of 35 min / each of decoction is performed; then the obtained traditional Chinese medicine extract is concentrated to a relative density of 1.12, and spray dried at an inlet temperature of 180℃ and an outlet temperature of 80℃, to obtain the traditional Chinese medicine combined agent; The sustained-release material is hydroxypropyl methyl cellulose and acrylic resin with a mass ratio of 4:1; the stabilizer is vitamin E and sodium carboxymethyl cellulose with a mass ratio of 1:3.

[0047] Example 2

[0048] A sustained-release capsule containing minoxidil and dutasteride, which is composed of a capsule shell and contents, the contents being in percentage by weight: minoxidil 2.5%, dutasteride 0.4%, spironolactone 10%, isotretinoin 5%, traditional Chinese medicine combined agent 12%, hydroxypropyl methyl cellulose 17%, lactose 47%, povidone K30 4%, magnesium stearate 1.1%, β-cyclodextrin 0.5%, and sodium carboxymethyl cellulose 0.5%; The traditional Chinese medicine combined agent is: after crushing and mixing radix polygoni multiflori praeparata 15 parts, biota orientalis 18 parts, lonicera japonica 6 parts, dried ginger 10 parts, safflower 5 parts, and prepared rehmannia 3 parts, 8 times the weight of the raw materials of water is added, and decocted twice at 30 min / time; then the traditional Chinese medicine extract liquid obtained is concentrated to a relative density of 1.10, and spray dried at an inlet temperature of 180℃ and an outlet temperature of 80℃, to obtain the traditional Chinese medicine combined agent.

[0049] Example 3

[0050] A sustained-release capsule containing minoxidil and dutasteride, which is composed of a capsule shell and contents, the contents being in percentage by weight: minoxidil 1.5%, dutasteride 0.2%, spironolactone 13%, isotretinoin 7.5%, traditional Chinese medicine combined agent 17%, acrylic resin 13.5%, microcrystalline cellulose 42%, polyvinylpyrrolidone 3%, magnesium stearate 0.8%, β-cyclodextrin 0.7%, and sodium carboxymethyl cellulose 0.8%; The traditional Chinese medicine combined agent is: after crushing and mixing radix polygoni multiflori praeparata 25 parts, biota orientalis 10 parts, lonicera japonica 12 parts, dried ginger 5 parts, safflower 8 parts, and prepared rehmannia 8 parts, 5 times the weight of the raw materials of water is added, and decocted twice at 40 min / time; then the traditional Chinese medicine extract liquid obtained is concentrated to a relative density of 1.10, and spray dried at an inlet temperature of 180℃ and an outlet temperature of 80℃, to obtain the traditional Chinese medicine combined agent.

[0051] Example 4

[0052] Based on the preparation method of the sustained-release capsule containing minoxidil and dutasteride in Example 1, the steps are as follows: (1) Minoxidil, dutasteride, spironolactone, isotretinoin, and the stabilizer are respectively passed through a 90-mesh sieve, and the undersize is collected, and then mixed to obtain a mixture A; (2) The traditional Chinese medicine combined agent and the traditional Chinese medicine solubilizing and dispersing agent are mixed and ground for 15 min, and then mixed with the mixture A, the filling material, and the sustained-release material to obtain a mixture B; (3) dissolving the binder in ethanol solution to prepare a binder solution, and then mixing the mixture B with the binder solution to obtain a soft material; (4) drying the soft material at 45°C until the water content of the granules is 3%, and then sieving the dried granules through a 20-mesh screen to remove oversized or undersized granules, and then adding a lubricant and mixing to obtain mixed granules; (5) filling the mixed granules into a capsule shell to obtain the product.

[0053] Example 5

[0054] Based on the preparation method of the sustained-release capsule containing minoxidil and dutasteride described in Example 1, the steps are as follows: (1) sieving minoxidil, dutasteride, spironolactone, isotretinoin, and stabilizers through a 70-mesh screen, collecting the undersize, and then mixing to obtain a mixture A; (2) mixing the traditional Chinese medicine combination agent with the traditional Chinese medicine solubilizing and dispersing agent, grinding for 10 min, and then mixing with the mixture A, the filling material, and the sustained-release material to obtain a mixture B; (3) dissolving the binder in ethanol solution to prepare a binder solution, and then mixing the mixture B with the binder solution to obtain a soft material; (4) drying the soft material at 40°C until the water content of the granules is 4%, and then sieving the dried granules through a 20-mesh screen to remove oversized or undersized granules, and then adding a lubricant and mixing to obtain mixed granules; (5) filling the mixed granules into a capsule shell to obtain the product.

[0055] Example 6

[0056] Based on the preparation method of the sustained-release capsule containing minoxidil and dutasteride described in Example 2, the steps are as follows: (1) sieving minoxidil, dutasteride, spironolactone, isotretinoin, and stabilizers through a 90-mesh screen, collecting the undersize, and then mixing to obtain a mixture A; (2) mixing the traditional Chinese medicine combination agent with the traditional Chinese medicine solubilizing and dispersing agent, grinding for 15 min, and then mixing with the mixture A, the filling material, and the sustained-release material to obtain a mixture B; (3) dissolving the binder in ethanol solution to prepare a binder solution, and then mixing the mixture B with the binder solution to obtain a soft material; (4) drying the soft material at 45°C until the water content of the granules is 3%, and then sieving the dried granules through a 20-mesh screen to remove oversized or undersized granules, and then adding a lubricant and mixing to obtain mixed granules; (5) filling the mixed granules into a capsule shell to obtain the product.

[0057] Example 7

[0058] Based on the preparation method of the sustained-release capsule containing minoxidil and dutasteride described in Example 3, the steps are as follows: (1) Collect the undersize after passing 90-mesh screen of minoxidil, dutasteride, spironolactone, isotretinoin, and stabilizer, and then mix to obtain mixture A; (2) Mix the traditional Chinese medicine combination agent and the traditional Chinese medicine solubilizing and dispersing agent, grind for 15 min, and then mix with mixture A, the filling material, and the sustained-release material to obtain mixture B; (3) Dissolve the binder in an ethanol solution to prepare a binder solution, and then mix mixture B with the binder solution to obtain a soft material; (4) Granulate the soft material, dry at 45°C until the moisture content of the granules is 3%, pass the dried granules through a 20-mesh screen to size the granules, remove oversized or undersized granules, add a lubricant, and mix to obtain mixed granules; (5) Fill the mixed granules into a capsule shell to obtain the sustained-release capsule containing minoxidil and dutasteride.

[0059] Comparative Example 1

[0060] The same as Example 4, only replace “minoxidil 2%, dutasteride 0.35%, spironolactone 12%, isotretinoin 6.65%, traditional Chinese medicine combination agent 15.7%, sustained-release material 15%, microcrystalline cellulose 42%, povidone K30 3.5%, magnesium stearate 1.3%, β-cyclodextrin 0.8%, and stabilizer 0.7%” with “minoxidil 2%, dutasteride 0.35%, spironolactone 12%, isotretinoin 6.65%, traditional Chinese medicine combination agent 2.8%, sustained-release material 15.7%, microcrystalline cellulose 55%, povidone K30 3.5%, magnesium stearate 1.3%, and stabilizer 0.7%”.

[0061] Comparative Example 2

[0062] The same as Example 4, only replace “minoxidil 2%, dutasteride 0.35%, spironolactone 12%, isotretinoin 6.65%, traditional Chinese medicine combination agent 15.7%, sustained-release material 15%, microcrystalline cellulose 42%, povidone K30 3.5%, magnesium stearate 1.3%, β-cyclodextrin 0.8%, and stabilizer 0.7%” with “minoxidil 2%, dutasteride 0.35%, spironolactone 12%, traditional Chinese medicine combination agent 15.7%, sustained-release material 15%, microcrystalline cellulose 47.65%, povidone K30 4.5%, magnesium stearate 1.3%, β-cyclodextrin 0.8%, and stabilizer 0.7%”, and replace “prepared rehmannia 20 parts, Chinese arborvitae leaf 15 parts, privet fruit 12 parts, honeysuckle flower 9 parts, dried ginger 8 parts, safflower 6 parts, and prepared rehmannia 4.5 parts” with “prepared rehmannia 20 parts, Chinese arborvitae leaf 15 parts, privet fruit 12 parts, dried ginger 8 parts, and prepared rehmannia 4.5 parts”.

[0063] Comparative Example 3

[0064] As in Example 4, only "minoxidil 2%, dutasteride 0.35%, spironolactone 12%, isotretinoin 6.65%, Chinese medicine combination 15.7%, sustained-release material 15%, microcrystalline cellulose 42%, povidone K30 3.5%, magnesium stearate 1.3%, β-cyclodextrin 0.8%, and stabilizer 0.7%" is replaced with "minoxidil 2%, dutasteride 0.35%, isotretinoin 6.65%, Chinese medicine combination 15.7%, sustained-release material 11%, microcrystalline cellulose 46.35%, povidone K30 3.5%, magnesium stearate 1.3%, β-cyclodextrin 0.8%, and stabilizer 0.7%".

[0065] Comparative Example 4

[0066] As in Example 4, only "minoxidil 2%, dutasteride 0.35%, spironolactone 12%, isotretinoin 6.65%, Chinese medicine combination 15.7%, sustained-release material 15%, microcrystalline cellulose 42%, povidone K30 3.5%, magnesium stearate 1.3%, β-cyclodextrin 0.8%, and stabilizer 0.7%" is replaced with "minoxidil 2%, dutasteride 0.35%, isotretinoin 6.65%, Chinese medicine combination 15.7%, sustained-release material 19%, microcrystalline cellulose 50%, povidone K30 3.5%, magnesium stearate 1.3%, β-cyclodextrin 0.8%, and stabilizer 0.7%".

[0067] Comparative Example 5

[0068] As in Example 4, only "minoxidil 2%, dutasteride 0.35%, spironolactone 12%, isotretinoin 6.65%, Chinese medicine combination 15.7%, sustained-release material 15%, microcrystalline cellulose 42%, povidone K30 3.5%, magnesium stearate 1.3%, β-cyclodextrin 0.8%, and stabilizer 0.7%" is replaced with "minoxidil 2%, dutasteride 0.35%, spironolactone 12%, isotretinoin 6.65%, Chinese medicine combination 15.7%, microcrystalline cellulose 55%, povidone K30 4.3%, magnesium stearate 2%, β-cyclodextrin 1%, and stabilizer 1%".

[0069] Test Example 1

[0070] (I) In vitro sustained-release test

[0071] The sustained-release capsules prepared based on Examples 4-7 and Comparative Examples 1-5 were subjected to in vitro release test.

[0072] The release test was carried out at 37±0.5℃ and 80r / min by placing the sustained-release capsules prepared in Examples 4-7 and Comparative Examples 1-5 in a phosphate buffer solution with pH 6.8 as the release medium. The samples were taken at 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h, respectively, and filtered through a 0.45μm microporous filter. The content of minoxidil (%) was determined.

[0073] The results showed that the content of minoxidil in the sustained-release capsules prepared in Examples and Comparative Examples was about 7.0-9.0% at 0.5h, about 14.5-16.0% at 1h, about 27.5-29.0% at 2h, about 43.0-45.0% at 4h, about 57.0-60.0% at 6h, about 74.0-76.0% at 8h, about 89-91.5% at 12h and about 95.0-97.0% at 24h, except for the sustained-release capsules prepared in Comparative Example 5, which had a content of minoxidil of about 24.5-26.0% at 0.5h, about 63.5-65.0% at 1h and about 95.0-97.5% at 2h.

[0074] (II) Toxicity test

[0075] Fifty male C57BL / 6 mice with a body weight of 22-28g were randomly selected and divided into 5 groups after being adapted to the environment for 1 week: a control group, Example 4 group, Example 5 group, Example 6 group and Example 7 group, with 10 mice in each group. The contents of the sustained-release capsules prepared in Examples were dissolved in distilled water and administered by gavage, with the control group being given distilled water. The dosage for mice was calculated according to the clinical dosage for humans (0.04 / kg). The toxicity and death of the mice were observed immediately after administration, and the body weight and food intake were recorded daily for 14 days. Blood biochemistry and organ morphology were also detected.

[0076] The results showed that there was no death in the mice in each group, and the mice were generally normal. Compared with the control group, there was no significant difference in body weight, food intake, blood biochemistry and organ coefficient.

[0077] Test Example 2

[0078] One hundred and ten male C57BL / 6 mice with a body weight of 22-28g were randomly selected and divided into 11 groups after being adapted to the environment for 1 week: a blank group, a model group, Example 4 group, Example 5 group, Example 6 group, Example 7 group, Comparative Example 1 group, Comparative Example 2 group, Comparative Example 3 group, Comparative Example 4 group and Comparative Example 5 group, with 10 mice in each group.

[0079] The central area of the back of all mice was shaved with a skinning knife one day before modeling, and the skinning area of each mouse was about 2 cm x 3 cm. After 24 h of thorough depilation, the mice in each group were subcutaneously injected with testosterone propionate solution at a dose of 5 mg / (kg·d) except for the blank group, and the injection was performed once a day. After 4 weeks of continuous injection, 2 mice were randomly selected from each group for evaluation of whether the model was successful. The results showed that the mouse back hair was sparse, the hair color was dull, and the skin on the back was visible seborrhea; the number of hair follicles was reduced, the hair shaft pigment was lighter, the diameter was smaller, and the hair follicle was miniaturized. That is, the modeling was successful.

[0080] After the modeling was successful, the central area of the back of the mice was again thoroughly depilated, and the mice in each group were subcutaneously injected with testosterone propionate at a dose of 5 mg / (kg·d) to maintain the model state except for the blank group; at the same time, the mice were orally administered with the corresponding drugs every day. The blank group and the model group were orally administered with an equal amount of normal saline, respectively; the contents of the prepared sustained-release capsules in the other groups were dissolved in distilled water and administered orally. The drug dosage for mice was calculated according to the clinical drug dosage for humans (70 kg) (0.035 / kg), and the drug was administered once a day for 13 consecutive weeks. On the 30th day, the 60th day, and the 90th day, 5 newly born hairs in the depilated area of the mice were randomly pulled out, and the length of the hairs was measured under a magnifying glass using a vernier caliper. The results are shown in Table 1.

[0081] Table 1 Length of newly born hair of mice in different treatment groups

[0082] It can be seen that, compared with the comparative example groups, the product prepared by the embodiment of the present application can significantly promote the hair growth of mice and is better than the comparative examples. Among the comparative examples 1-5, only comparative example 5 has no sustained-release process, and its effect is the weakest.

[0083] (II) Skin histological examination

[0084] On the 90th day of administration, the mice in each group were sacrificed by cervical dislocation, the newly grown hairs in the depilated area were cut, and 1 cm x 1 cm of skin was cut parallel to the spine. After slicing and staining, the differences in the number and morphology of hair follicles in each treatment group were observed under an optical microscope.

[0085] The results showed that, compared with the comparative example groups and the model group, the number of hair follicles in the mice of each embodiment group was relatively more, the hair follicles were long and large, the dermis layer was relatively thicker, and the hair loss area was significantly reduced, and a large number of newly born hairs were visible.

[0086] Test Example 3

[0087] Social collection of 210 male androgenetic alopecia volunteers as the research object, the inclusion criteria: (1) 18-35 years old male patients; (2) know about the related situation of this study, and has signed the informed consent form; (3) Hamilton-Norwood alopecia classification Ⅱ, Ⅲ, Ⅳ grade; (4) meet the AGA spleen deficiency and wet accumulation syndrome of Chinese and Western medicine diagnostic criteria. Exclusion criteria: (1) within 6 months due to alopecia received oral or external drug treatment; (2) patients with systemic diseases; (3) patients with poor compliance; (4) patients with other scalp skin diseases such as tinea capitis, psoriasis, seborrheic dermatitis, alopecia areata, etc.; (5) known minoxidil solution allergy; (6) has done hair transplantation surgery.

[0088] The 210 volunteers were randomly divided into 11 groups, 20 in each group, namely the blank group, the positive control group, the example 4 group, the example 5 group, the example 6 group, the example 7 group, the comparative example 1 group, the comparative example 2 group, the comparative example 3 group, the comparative example 4 group and the comparative example 5 group. The blank group was not treated; the positive control group was given oral corresponding dose of commercially available dutasteride and minoxidil; the rest of the groups respectively took the corresponding prepared sustained-release capsules, 1 grain / time, once a day. The treatment course was 24 weeks. (I)

[0090] Before treatment and after treatment for 6 weeks, 12 weeks, 18 weeks and 24 weeks, the hair density (root / cm 2 ) and hair diameter (mm) of the patients were measured at the same test site by using the hair mirror image analysis system, 5 times respectively, and the average value was taken.

[0091] Table 2 Hair density and hair diameter of patients in different treatment groups before and after treatment

[0092] According to table 2, it can be seen that the hair density and hair diameter of the patients in the example groups of the application are significantly different from those in the positive control group and the comparative example group, and are obviously increased compared with the blank group, among which the comparative example 5 has no sustained-release process, and its effect is weaker than that of other examples and comparative examples, but its effect is still better than that of the commercially available drug positive control group. Compared with the positive control group, the comparative example 5 adds Chinese medicine which has the effects of promoting hair growth and reducing side effects of western medicine, which further verifies the applicability of Chinese medicine in the field of hair. (II)

[0094] Before treatment and 24 weeks after treatment, the side effects of the patients in each treatment group were analyzed, including edema, hair hyperplasia (face, back and arm), decreased libido, whether the transaminase of liver function is abnormally increased, etc.

[0095] Table 3 Side effects of patients in different treatment groups after 24 weeks of treatment

[0096] The results show that the blank group has no edema, no hypertrichosis, no abnormal elevation of liver function transaminase, and part of the sexual desire is reduced, and there is a placebo effect; each example group does not appear edema, hypertrichosis, abnormal elevation of liver function transaminase and sexual desire reduction; Comparative Examples 1-4 do not appear hypertrichosis, abnormal elevation of liver function transaminase and sexual desire reduction, wherein Comparative Examples 1-3 do not appear edema, and Comparative Example 4 only appears 1 case of edema; Comparative Example 5 appears 4 cases of edema, 1 person appears facial, back or arm hypertrichosis, 3 people appear sexual desire reduction, and 1 person appears abnormal elevation of liver function transaminase, but compared with the positive control group, the side effect occurrence is obviously improved. It can be seen that the sustained-release capsule of the application can promote the drug to play a role and reduce the occurrence of side effects, and the internally added Chinese medicine also has good effect of reducing side effects.

[0097] In summary, the application is based on the sustained-release process, and through the synergistic effect of chemical components and traditional Chinese medicine components, the hair regeneration ability is further enhanced, the liver metabolic pressure is reduced, the probability of edema and hirsutism is reduced, the long-term drug safety is improved, and the drug efficacy duration is prolonged.

[0098] The above only describes the preferred embodiments of the application, and it should be pointed out that for ordinary skilled persons in the art, without departing from the principles of the application, a number of improvements and refinements can be made, and these improvements and refinements should also be considered as the protection scope of the application.

Claims

1. A sustained release capsule comprising minoxidil and dutasteride, characterized in that, The capsule shell and the content, the content includes the following components by weight percentage: minoxidil 1-2.5%, dutasteride 0.1-0.5%, spironolactone 10-13%, isotretinoin 5-8%, traditional Chinese medicine combination 10-20%, sustained-release material 10-20%, filling material 30-55%, adhesive 2-5%, lubricant 0.5-2%, traditional Chinese medicine solubilizing dispersant 0.5-1% and stabilizer 0.5-1%.

2. The sustained release capsule of claim 1, wherein, The traditional Chinese medicine combination is composed of the following raw material components by weight percentage: Radix Polygoni Multiflori 15-25 parts, Platycladi Cacumen 10-18 parts, Ligustri Lucidi Fructus 8-15 parts, Lonicerae Japonicae Flos 6-12 parts, Zingiberis Rhizoma 5-10 parts, Carthami Flos 5-8 parts and Radix Rehmanniae Preparata 3-8 parts.

3. The sustained release capsule of claim 1, wherein, The sustained-release material is any one or several of ethyl cellulose, hydroxypropyl methyl cellulose or acrylic acid resin; The filling material is any one or several of microcrystalline cellulose, lactose, mannitol or sorbitol.

4. The sustained release capsule of claim 1, wherein, The adhesive is any one or several of polyvinylpyrrolidone K30, polyvinylpyrrolidone or hydroxypropyl methyl cellulose; The traditional Chinese medicine solubilizing dispersant is β-cyclodextrin; The lubricant is magnesium stearate; The stabilizer is vitamin E and / or sodium carboxymethyl cellulose.

5. Process for the preparation of sustained release capsules according to any one of claims 1 to 4, characterized in that, The method comprises the following steps: (1) mixing minoxidil, dutasteride, spironolactone, isotretinoin and stabilizer to obtain mixture A; (2) mixing traditional Chinese medicine combination and traditional Chinese medicine solubilizing dispersant, and then mixing with mixture A, filling material and sustained-release material to obtain mixture B; (3) mixing mixture B with adhesive to obtain soft material; (4) granulating and drying the soft material, then adding lubricant and mixing to obtain mixed granules; (5) filling the mixed granules into the capsule shell.

6. The production method according to claim 5, wherein The step (1) further comprises sieving treatment before mixing, and the mesh size of the sieve is 70-100 mesh.

7. The preparation method according to claim 5, characterized in that, The preparation process of the traditional Chinese medicine combination in step (2) is as follows: mixing Radix Polygoni Multiflori, Platycladi Cacumen, Ligustri Lucidi Fructus, Lonicerae Japonicae Flos, Zingiberis Rhizoma and Radix Rehmanniae Preparata, then decocting with water, and then concentrating, spray drying to obtain the traditional Chinese medicine combination.

8. The preparation method according to claim 7, characterized in that, The total mass of Radix Polygoni Multiflori, Platycladi Cacumen, Ligustri Lucidi Fructus, Lonicerae Japonicae Flos, Zingiberis Rhizoma and Radix Rehmanniae Preparata is 4-8 times the mass of water; The decocting time is 30-40 min / time, and the decocting times is 2-3 times.

9. The preparation method according to claim 5, characterized in that, The drying temperature in step (4) is 40-50℃, and the drying is performed until the water content of the granules is 2-4%.

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