Minoxidil and finasteride compound preparation and application thereof

Abstract

The invention belongs to the technical field of medicines, and provides a minoxidil and finasteride compound preparation and application thereof. The compound preparation comprises the following components: minoxidil, finasteride, a filler, an adhesive, a disintegrating agent, a lubricant and a surfactant, the minoxidil accounts for 1 to 4 weight percent of the compound preparation; the finasteride accounts for 0.3 to 1 weight percent of the compound preparation. The compound preparation is simple in preparation process, efficient, low in cost, small in active ingredient dissolution behavior difference and good in stability; and a patient can use and carry the device conveniently, and the compliance is higher. The comprehensive performance is excellent, and the application prospect is very good.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology and relates to a minoxidil and finasteride compound preparation and its application. Background Art

[0002] Hair loss can be divided into cicatricial alopecia and non-cicatricial alopecia. Cicatricial alopecia is characterized by scars on the affected skin and damaged hair follicles, resulting in permanent hair loss. Non-cicatricial alopecia is characterized by intact hair follicles and is caused by abnormal hair growth cycles, changes in hair follicle size, etc. Types include telogen effluvium, alopecia areata, androgenetic alopecia, etc. Among all types of hair loss, androgenetic alopecia is the most common form. Androgenetic alopecia is characterized by a shortened hair growth cycle and miniaturization of hair follicles, where the hair does not grow fully and becomes thin and soft, and sometimes cannot even penetrate the scalp.

[0003] Currently, the only drugs officially approved by the US FDA for the clinical treatment of androgenetic alopecia are minoxidil and finasteride. Minoxidil is a potassium ion channel agonist that can increase the mitosis of keratinocytes in the hair matrix, promote hair growth and increase hair diameter; it can also prolong the growth phase of hair follicles and stimulate the hair follicles to initiate a new growth cycle. However, all the currently approved dosage forms in China are topical, and there is no oral dosage form on the market. Finasteride is a type II 5α-reductase inhibitor that can inhibit 5α-reductase, thereby reducing the levels of dihydrotestosterone in the serum and scalp, preventing hair loss, and significantly increasing the total number of hairs. Currently, all the approved products in China are oral preparations with a specification of 1 mg. From the mechanisms of action of minoxidil and finasteride, it can be seen that minoxidil is used for "hair growth" and finasteride is used for "anti-hair loss", and there is a potential synergistic effect between the two. However, there is no compound preparation of the two on the market in China.

[0004] Chinese invention patent CN104755075B discloses a finasteride and minoxidil polymer nanoparticle, its preparation method, pharmaceutical composition and its use. The main active ingredients are finasteride, minoxidil, and pharmaceutically acceptable additives and carriers, which are used to prepare a pharmaceutical composition for local treatment of hair loss in the form of a solution, gel or lotion. Its usage method is topical, the preparation process is relatively complex, and organic solvents such as acetone are used in the formulation, which is highly irritating to the skin.

[0005] Chinese Patent Application CN113712968A discloses the use of a pharmaceutical composition containing minoxidil in preventing hair loss. The pharmaceutical composition contains minoxidil or its pharmaceutically acceptable non-covalent derivative and active ingredients of traditional Chinese medicine, and further includes one or more hair growth-promoting substances, and the hair growth-promoting substances are 5α-reductase inhibitors, specifically including that the 5α-reductase inhibitor is finasteride, dutasteride, epristeride, azelaic acid, β-sitosterol, zinc and / or vitamin B6. The pharmaceutical composition quantitatively combines and uses active ingredients of traditional Chinese medicine with different action mechanisms and minoxidil, which can synergistically enhance the ability to promote hair regeneration, achieve better hair loss prevention and treatment effects, and at the same time reduce the dosage of minoxidil, thereby avoiding the adverse reactions associated with high-dose minoxidil and improving the curative effect and medication safety. When the active ingredient finasteride and minoxidil are used in combination, there will be problems such as decreased stability and differences in dissolution, which will lead to a significant reduction in the bioavailability of the drug. And dissolution is one of the necessary inspection items for drug quality control. Therefore, the crystal form and particle size of the main drug, or the prescription composition, type of excipients, dosage of raw and auxiliary materials, preparation process, etc. can be improved to reduce the dissolution difference, thereby improving the bioavailability of the preparation. Summary of the Invention

[0006] In view of the problems of poor preparation stability and differences in dissolution in the prior art, the present invention provides a minoxidil finasteride compound preparation and its application. The preparation has good stability and small dissolution difference, thereby improving the bioavailability of the preparation.

[0007] One of the technical solutions of the present invention is:

[0008] Provide a minoxidil finasteride compound preparation, the compound preparation includes the following components: minoxidil or its pharmaceutically acceptable salt, finasteride or its pharmaceutically acceptable salt, filler, binder, disintegrant, lubricant and surfactant; the proportion of minoxidil or its pharmaceutically acceptable salt in the compound preparation is 1-4wt%; the proportion of finasteride or its pharmaceutically acceptable salt in the compound preparation is 0.3-1wt%.

[0009] Furthermore, the filler is at least one of lactose, microcrystalline cellulose, sucrose and corn starch.

[0010] Preferably, the filler is lactose and microcrystalline cellulose.

[0011] Furthermore, the binder is at least one of polyvinylpyrrolidone K30, pregelatinized starch, hydroxypropyl cellulose, methyl cellulose and ethyl cellulose.

[0012] Preferably, the binder is pregelatinized starch.

[0013] More preferably, the mass ratio of the lactose, microcrystalline cellulose and pregelatinized starch is 20 - 120:10 - 100:5 - 20.

[0014] Further preferably, the compound preparation comprises the following components in parts by weight:

[0015]

[0016]

[0017] Even further preferably, the compound preparation comprises the following components in parts by weight:

[0018]

[0019] Further, the disintegrant is at least one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium and cross-linked polyvinylpyrrolidone.

[0020] Preferably, the disintegrant is sodium carboxymethyl starch.

[0021] Further, the lubricant is at least one of magnesium stearate, sodium stearyl fumarate, polyethylene glycol and talc powder.

[0022] Preferably, the lubricant is magnesium stearate.

[0023] Further, the surfactant is at least one of sodium dodecyl sulfate, sodium dioctyl sulfosuccinate, Tween 60 and Tween 80.

[0024] Preferably, the surfactant is sodium dioctyl sulfosuccinate.

[0025] The second technical solution of the present invention is:

[0026] To provide the use of any of the above compound preparations in the preparation of a drug for preventing and / or treating androgenetic alopecia.

[0027] The third technical solution of the present invention is:

[0028] To provide a minoxidil finasteride tablet, which is prepared by granulating, tabletting and coating a minoxidil finasteride preparation.

[0029] Further, the coating material is selected from any one of polyvinyl alcohol, hydroxypropyl methylcellulose and Opadry.

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] (1) The minoxidil and finasteride compound preparation has a synergistic effect under the specific ratio of the active ingredients minoxidil and finasteride, enhancing the ability to promote hair growth and achieving a better effect in preventing and treating hair loss;

[0032] (2) Under the specific combination of excipients, especially the combination of the specific fillers lactose and microcrystalline cellulose and the specific binder pregelatinized starch, the intermediate granules prepared within a reasonable ratio range have good fluidity, and the physical properties such as tablet hardness and friability are significantly improved; at the same time, the dissolution curves of the two active ingredients are basically the same, the dissolution behavior differences are small, and the comprehensive performance is excellent;

[0033] (3) The preparation process of the minoxidil and finasteride compound preparation is simple, efficient, and low-cost, and the drug quality of different batches is comparable, and the process is more mature and stable;

[0034] (4) The minoxidil and finasteride tablets prepared by the present invention using the film coating technology have better stability; and are convenient for patients to use, carry, and have higher compliance. Detailed implementation mode

[0035] The following non-limiting examples can enable those of ordinary skill in the art to more comprehensively understand the present invention, but do not limit the present invention in any way. The following content is only an exemplary illustration of the scope claimed by the present invention. Those skilled in the art can make various changes and modifications to the invention according to the disclosed content, and it should also fall within the scope claimed by the present invention.

[0036] Examples 1-6

[0037] The prescription composition of the minoxidil and finasteride tablets is shown in Table 1: Prescription amount (1000 tablets, unit: g).

[0038] Table 1 Prescription composition of minoxidil and finasteride tablets

[0039]

[0040]

[0041] Note: "*" is the solvent used and finally removed in the process; "N / A" represents that the excipient is not used in the prescription.

[0042] The preparation method of the minoxidil and finasteride tablets includes the following steps:

[0043] (1) Preparation of wetting agent: Weigh purified water, add the prescription amount of sodium docusate, and stir to dissolve;

[0044] (2) Pass lactose and sodium carboxymethyl starch through a 60-mesh sieve and set aside;

[0045] (3) Weigh the prescribed amounts of minoxidil, finasteride, fillers (lactose and / or microcrystalline cellulose), binder (pre-gelatinized starch), and 1 / 2 of the disintegrant (sodium carboxymethyl starch). Add them to a wet granulator and mix at a stirring speed of 150 ± 10 rpm and a shear speed of 1500 ± 100 rpm for 5 minutes to obtain mixture 1.

[0046] (4) Under the conditions of a stirring speed of 150 ± 10 rpm, a shear speed of 1500 ± 100 rpm, and an atomization pressure of 0.2 MPa, add the wetting agent prepared in step (1) to mixture 1 within 40 seconds, and then continue to run for 2 minutes to obtain mixture 2. Use a granulating machine to granulate mixture 2 at a speed of 600 ± 10 rpm to obtain wet granules.

[0047] (5) Transfer the wet granules to a fluidized bed and operate at an inlet air temperature of 50 - 60 °C, a fan frequency of 20 - 30 Hz, and a damper opening of 100% until the moisture content of the granules ≤ 2.0%.

[0048] (6) Use a lifting granulating machine to granulate the dried granules at a rotational speed of 600 ± 10 rpm through a sieve.

[0049] (7) Add the lubricant (magnesium stearate) and the remaining disintegrant (sodium carboxymethyl starch) to the granules after granulation, and mix in a total mixer at a speed of 8 ± 1 rpm for 5 minutes to obtain intermediate granules.

[0050] (8) Use a regular octagon punch die for tableting to obtain tablet cores. Use Opadry film coating agent for coating to obtain coated tablets.

[0051] Test Examples 1 - 6

[0052] I. Test the physical property parameters of the intermediate granules, tablet cores, and coated tablets during the preparation process of Examples 1 - 6. The results are shown in Tables 2 and 3:

[0053] Table 2 Physical Property Test Results of Intermediate Granules

[0054]

[0055] It can be seen from the above table that: The fluidity of the intermediate granules in Example 3 is poor. In Example 6, due to inappropriate dosages of lactose, microcrystalline cellulose, and pre-gelatinized starch, the samples could not be prepared smoothly and did not meet the requirements. Therefore, the above two batches of samples were not tableted and coated.

[0056] The cores of the remaining examples were tested for hardness and friability, and the test results are shown in Table 3. Among them, in Example 1, the core had a low hardness and the friability did not meet the requirements, so no coating treatment was carried out; the cores of Examples 2, 4, and 5 were coated to obtain coated tablets, and the hardness and friability of the coated tablets of Examples 2, 4, and 5 all met the requirements.

[0057] Table 3 Test Results of Hardness and Friability of Cores and Coated Tablets

[0058]

[0059]

[0060] Note: "N / A" represents uncoated.

[0061] Second, according to the results of the saturated solubility of the active pharmaceutical ingredient, an aqueous solution was used as the discrimination medium for finasteride, and a pH 7.2 phosphate solution was used as the discrimination medium for minoxidil. The specific dissolution curve method is shown in Table 4:

[0062] Table 4 Dissolution Curve Method

[0063]

[0064] The dissolution curves of the coated tablets prepared in Examples 2, 4, and 5 were tested, and the results are shown in Table 5.

[0065] Table 5 Dissolution Curve Results

[0066]

[0067] It can be seen from the above table that the cumulative dissolution of the coated tablets in Example 2 did not reach 85% within 15 minutes, which did not meet the internal control standard.

[0068] It can be seen from the above screening process that: ① During the sample preparation process, pregelatinized starch, etc. must be used as a binder in the formulation, otherwise granulation cannot be carried out; ② If microcrystalline cellulose is not included in the formulation, the core has a low hardness and is not suitable for coating. On the contrary, if the content of microcrystalline cellulose is high, the hardness is high and the dissolution of the sample is slow; ③ If lactose is not included in the formulation, the dissolution of finasteride and minoxidil in the coated tablets will decrease; ④ When lactose, microcrystalline cellulose, and pregelatinized starch are within a specific dosage range, the relevant physical properties of the core and the coated tablets can meet the requirements.

[0069] Examples 7 - 10: Investigation of the preparation of samples with different specifications

[0070] The prescription composition of minoxidil finasteride tablets is shown in Table 6: Prescription amount (1000 tablets, unit: g).

[0071] Table 6 Prescription Composition of Minoxidil Finasteride Tablets

[0072]

[0073] Note: "*" is the solvent used and finally removed in the process.

[0074] The preparation method is the same as that of Examples 1-6.

[0075] Test Examples 7-10:

[0076] I. Physical property tests of the intermediate particles, tablet cores and coated tablets of Examples 4, 7-10 of the present invention. Take the intermediate particles, tablet cores and coated tablets of Examples 4, 7-10, test the fluidity of the intermediate particles, and the results are shown in Table 7; test the hardness and friability of the tablet cores and coated tablets, and the results are shown in Table 8.

[0077] Table 7 Physical property test results of intermediate particles

[0078]

[0079] Table 8 Hardness and friability test results of tablet cores and coated tablets

[0080]

[0081]

[0082] It can be seen from the above table that the relevant physical property parameters of the intermediate particles, tablet cores and coated tablets prepared in Examples 4, 7-10 of the present invention all meet the requirements.

[0083] II. Test the dissolution curves of the coated tablets of Examples 4, 7-10, and the results are shown in Table 9 (the test method is the same as that in Table 4).

[0084] Table 9 Dissolution curve test results

[0085]

[0086] The cumulative dissolution degrees of finasteride and minoxidil in the coated tablets prepared in Examples 4, 7-10 of the present invention within 15 minutes are all above 85%, meeting the requirements.

[0087] III. Stability study of Examples 4, 7-10

[0088] The stability results of the coated tablets of Examples 4, 7-10 placed under accelerated conditions (40 °C / 75% RH) for 6 months are shown in Table 10.

[0089] Table 10 Stability results of coated tablets

[0090]

[0091]

[0092] Note: Related substances are total impurities.

[0093] It can be seen from the above table that: The coated tablets prepared in Examples 4 and 7-10 of the present invention have high stability. Compared with day 0, after 6 months of accelerated test, there are no significant changes in the content of active ingredient, dissolution and related substances.

[0094] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the protection scope of the present invention. Any simple modification or equivalent replacement of the technical solution of the present invention by those of ordinary skill in the art shall not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A minoxidil and finasteride compound preparation, characterized in that, The compound preparation comprises the following components: minoxidil or a pharmaceutically acceptable salt thereof, finasteride or a pharmaceutically acceptable salt thereof, a filler, a binder, a disintegrant, a lubricant and a surfactant; the proportion of minoxidil or a pharmaceutically acceptable salt thereof in the compound preparation is 1-4 wt%; the proportion of finasteride or a pharmaceutically acceptable salt thereof in the compound preparation is 0.3-1 wt%.

2. The minoxidil and finasteride compound preparation according to claim 1, characterized in that, The filler is at least one of lactose, microcrystalline cellulose, sucrose and corn starch; the binder is at least one of polyvinylpyrrolidone K30, pregelatinized starch, hydroxypropyl cellulose, methyl cellulose and ethyl cellulose.

3. The minoxidil and finasteride compound preparation according to claim 1, characterized in that, The filler is lactose and microcrystalline cellulose; the binder is pregelatinized starch.

4. The minoxidil and finasteride compound preparation according to claim 3, characterized in that, The mass ratio of lactose, microcrystalline cellulose and pregelatinized starch is 20-120:10-100:5-20.

5. The minoxidil and finasteride compound preparation according to claim 4, characterized in that, By weight, it comprises the following components:

6. The minoxidil and finasteride compound preparation according to claim 5, characterized in that, By weight, it comprises the following components:

7. The minoxidil and finasteride compound preparation according to claim 1, characterized in that, The disintegrant is at least one of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium and cross-linked polyvinylpyrrolidone; the lubricant is at least one of magnesium stearate, sodium stearyl fumarate, polyethylene glycol and talc powder; the surfactant is at least one of sodium dodecyl sulfate, sodium docusate, Tween 60 and Tween 80.

8. The minoxidil and finasteride compound preparation according to claim 7, characterized in that, The disintegrant is sodium carboxymethyl starch; the lubricant is magnesium stearate; the surfactant is sodium docusate.

9. Use of the minoxidil and finasteride compound preparation according to any one of claims 1-8 in the preparation of a drug for preventing and / or treating androgenetic alopecia.

10. A minoxidil and finasteride tablet, characterized in that, It is prepared by granulating, tabletting and coating the minoxidil and finasteride compound preparation according to any one of claims 1-8; the coating material is selected from any one of polyvinyl alcohol, hydroxypropyl methyl cellulose and Opadry.

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