Dutasteride compound, preparation method thereof, dutasteride and tadalafil compound preparation, and preparation method and application of dutasteride and tadalafil compound preparation

Abstract

The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a dutasteride compound and a preparation method thereof, a dutasteride and tadalafil compound preparation and a preparation method and application thereof. According to the invention, dutasteride and lactose are crushed together, and are prepared into an oral solid preparation through wet granulation, so that the solubility of dutasteride is improved, and dutasteride can be dissolved out quickly. The dutasteride compound provided by the invention can be prepared into a compound preparation together with tadalafil, so that the dutasteride compound and the tadalafil are combined. According to the invention, the solubility of dutasteride is improved through wet granulation, so that the dutasteride is dosed in a solid form, a quick-dissolution preparation is obtained, the steps are simple, and the degree of controllability is high. The dutasteride and tadalafil compound preparation provided by the invention can be used for preparing medicines for treating benign prostatic hyperplasia with erectile dysfunction.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and in particular relates to a dutasteride complex and a preparation method thereof, a dutasteride and tadalafil compound preparation, and a preparation method and application thereof. Background Art

[0002] Benign prostatic hyperplasia (BPH) combined with erectile dysfunction (ED) is a common health problem in middle-aged and elderly men. Currently, common treatments include PDE5 inhibitors (such as tadalafil), 5α-reductase inhibitors, or dutasteride. Among them, the combined use of PDE5 inhibitors and 5α-reductase inhibitors has better therapeutic effects and fewer side effects than single-drug preparations. Related preparations are already on the market, such as Tadalafil Finasteride Capsules (trade name ).

[0003] Later, researchers discovered that dutasteride's inhibitory activity against type I 5α-reductase was 45 times higher than finasteride's, and its inhibitory activity against type II 5α-reductase was 2.5 times higher than finasteride's. Finasteride primarily inhibits type II 5α-reductase, while dutasteride can inhibit both type I and type II 5α-reductase (a dual inhibitor). Furthermore, finasteride can reduce serum DHT levels by 70%, and dutasteride can reduce serum DHT levels by 95%. Both can reduce DHT levels in the prostate by 85% to 90%. Therefore, a dutasteride-tadalafil combination preparation would be more effective than existing single- and combination preparations in treating BPH combined with ED.

[0004] However, due to the poor solubility of dutasteride, dutasteride is usually dissolved in an oil solution to prepare soft capsules to increase its solubility. Tadalafil is usually administered in an oral solid form, and the two cannot be prepared into a combined preparation. Summary of the Invention

[0005] The present invention aims to provide a dutasteride complex and a preparation method thereof, a dutasteride and tadalafil compound preparation and a preparation method and application thereof. The dutasteride complex provided by the present invention improves the solubility of dutasteride, and the dutasteride and tadalafil compound preparation realizes the combined use of the two.

[0006] In order to achieve the above object, the present invention provides the following technical solutions:

[0007] The present invention provides a dutasteride complex, comprising dutasteride, a first lactose interpenetrating and mixed with the dutasteride, and a second lactose coated on the surface of the dutasteride; the particle size D90 of the dutasteride is less than 10 μm.

[0008] Preferably, the ratio of the mass of the dutasteride to the total mass of the first lactose and the second lactose is 0.07-0.36:50-80.

[0009] Preferably, the particle size of the dutasteride complex is D90 not greater than 60 μm.

[0010] The present invention also provides a method for preparing the dutasteride complex described in the above scheme, comprising the following steps:

[0011] Dutasteride and lactose are crushed together to obtain the dutasteride complex.

[0012] Preferably, the crushing equipment is a universal crusher and a ziplock bag; the crushing parameters are: time is 30 to 120 seconds.

[0013] The present invention also provides a dutasteride and tadalafil compound preparation, comprising an inner core and a coating layer wrapped around the surface of the inner core; the inner core comprises, by weight, 50.07 to 80.36 parts of a dutasteride complex, 3.57 to 7.15 parts of tadalafil, and 0.5 to 2 parts of magnesium stearate; the dutasteride complex is the dutasteride complex described in the above scheme or the dutasteride complex obtained by the preparation method described in the above scheme.

[0014] Preferably, based on the mass fraction of the dutasteride complex, the coating layer comprises 10 to 30 parts of microcrystalline cellulose, 1 to 5 parts of hydroxypropyl cellulose and 2 to 6 parts of low-substituted hydroxypropyl cellulose.

[0015] The present invention also provides a method for preparing the dutasteride and tadalafil compound preparation of the above scheme, comprising the following steps:

[0016] granulating the dutasteride complex, tadalafil, and water to obtain wet granules;

[0017] The wet granules are sequentially subjected to wet granulation, drying and dry granulation to obtain dry granules;

[0018] The dry granules and magnesium stearate are mixed, and then tableting and coating are performed in sequence to obtain the dutasteride and tadalafil compound preparation.

[0019] Preferably, the drying temperature does not exceed 60° C. until the moisture content is ≤5.0%.

[0020] The present invention also provides the use of the dutasteride and tadalafil compound preparation described in the above scheme or the dutasteride and tadalafil compound preparation obtained by the preparation method described in the above scheme in preparing a drug for benign prostatic hyperplasia combined with erectile dysfunction.

[0021] The present invention provides a dutasteride complex. Dutasteride and lactose are co-pulverized and wet granulated to form an oral solid preparation, thereby increasing the solubility of dutasteride and enabling rapid dissolution of dutasteride. The specific mechanism is as follows:

[0022] (1) When lactose and dutasteride are crushed together, the particle size of both substances decreases as the degree of crushing increases. Lactose is a highly water-soluble substance that can wrap around dutasteride during the crushing process. At the microscopic level, lactose particles and dutasteride particles intersperse and mix with each other. This mixing causes the surface area of dutasteride to be "exposed" to a certain extent by lactose. When exposed to a solvent (such as water), the solvent molecules are more likely to contact the surface of dutasteride.

[0023] (2) Crushing increases the specific surface area of dutasteride. On the solid surface, molecules are in an unsaturated state and have a higher surface energy. This high surface energy makes dutasteride more easily wetted by solvent molecules in the solvent. The presence of lactose can further promote this wetting process. This is because lactose itself has a certain hydrophilicity and can attract water molecules. When it is crushed together with dutasteride, the hydrophilicity of lactose can drive the solvent molecules to better approach the dutasteride particles, thereby increasing the solubility of dutasteride.

[0024] (3) Lactose has good wettability. When lactose and dutasteride are crushed together, the lactose particles can be adsorbed on the surface of the dutasteride particles, forming a hydrophilic "shell". This "shell" can improve the wettability of dutasteride. In the solvent, this improved wettability allows the solvent molecules to be more evenly distributed around the dutasteride particles, thereby promoting the dissolution of dutasteride.

[0025] The present invention also provides a method for preparing the dutasteride complex described in the above scheme. The preparation method provided by the present invention has simple steps, convenient operation, and high feasibility.

[0026] The present invention also provides a compound preparation of dutasteride and tadalafil. The dutasteride complex provided by the present invention can be prepared into a compound preparation with tadalafil, thereby achieving combined use of the two.

[0027] The present invention also provides a method for preparing the dutasteride and tadalafil compound preparation described in the above scheme. The preparation method provided by the present invention improves the solubility of dutasteride through wet granulation, enabling dutasteride to be administered in solid form, resulting in a rapidly dissolving preparation, with simple steps and high controllability.

[0028] The present invention also provides the use of the dutasteride and tadalafil compound preparation described in the above scheme, or the dutasteride and tadalafil compound preparation obtained by the preparation method described in the above scheme, in preparing a drug for benign prostatic hyperplasia combined with erectile dysfunction. The dutasteride and tadalafil compound preparation provided by the present invention can be used to prepare a drug for benign prostatic hyperplasia combined with erectile dysfunction. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0030] Figure 1 This is a diagram showing the dissolution results of tadalafil in the dutasteride and tadalafil compound preparation of Example 1;

[0031] Figure 2 This is a diagram showing the dissolution results of dutasteride in the dutasteride and tadalafil compound preparation of Example 1;

[0032] Figure 3 This is a diagram showing the dissolution results of tadalafil in the dutasteride and tadalafil compound preparation of Comparative Example 1;

[0033] Figure 4 This is a diagram showing the dissolution results of dutasteride in the dutasteride and tadalafil compound preparation of Comparative Example 1;

[0034] Figure 5 This is a diagram showing the dissolution results of tadalafil in the dutasteride and tadalafil compound preparation of Comparative Example 2;

[0035] Figure 6 This is a diagram showing the dissolution results of dutasteride in the dutasteride and tadalafil compound preparation of Comparative Example 2;

[0036] Figure 7 This is a diagram showing the dissolution results of tadalafil in the dutasteride and tadalafil compound preparation of Comparative Example 3;

[0037] Figure 8 This is a diagram showing the dissolution results of dutasteride in the dutasteride and tadalafil compound preparation of Comparative Example 3;

[0038] Figure 9 This is a diagram showing the dissolution results of tadalafil in the dutasteride and tadalafil compound preparation of Comparative Example 4;

[0039] Figure 10 This is a diagram showing the dissolution results of dutasteride in the dutasteride and tadalafil compound preparation of Comparative Example 4;

[0040] Figure 11 This is a diagram showing the dissolution results of tadalafil in the dutasteride and tadalafil compound preparation of Comparative Example 5;

[0041] Figure 12 This is a diagram showing the dissolution results of dutasteride in the dutasteride and tadalafil compound preparation of Comparative Example 5;

[0042] Figure 13 This is a diagram showing the dissolution results of tadalafil in the dutasteride and tadalafil compound preparation of Comparative Example 6;

[0043] Figure 14 This is a diagram showing the dissolution results of dutasteride in the dutasteride and tadalafil compound preparation of Comparative Example 6;

[0044] Figure 15 This is a diagram showing the dissolution results of tadalafil in the dutasteride and tadalafil compound preparation of Comparative Example 7;

[0045] Figure 16 This is the dutasteride dissolution result diagram of the dutasteride and tadalafil compound preparation of Comparative Example 7. DETAILED DESCRIPTION

[0046] The present invention provides a dutasteride complex, comprising dutasteride, a first lactose interpenetrating and mixed with the dutasteride, and a second lactose coated on the surface of the dutasteride; the particle size D90 of the dutasteride is less than 10 μm.

[0047] In the present invention, the particle size of dutasteride may be D90 less than 8 μm, specifically 7 μm, 6 μm, 5 μm, 3 μm, 2 μm or 1 μm.

[0048] In the present invention, the particle size of the first lactose may be D90 not greater than 100 μm, specifically 80 μm, 70 μm, 60 μm, 50 μm or 40 μm, and the proportion of particles with a diameter less than 32 μm may be 45-75%, specifically 55%, 60% or 65%.

[0049] In the present invention, the particle size of the second lactose may be D90 not greater than 100 μm, specifically 80 μm, 70 μm, 60 μm, 50 μm or 40 μm, and the proportion of particles with a diameter less than 32 μm may be 45-75%, specifically 55%, 60% or 65%.

[0050] In the present invention, the ratio of the mass of dutasteride to the total mass of the first lactose and the second lactose can be 0.07-0.36:50-80, specifically 0.1:60, 0.1:70, 0.15:60, 0.15:70, 0.2:60, 0.2:70, 0.25:60, 0.25:70, 0.3:60, 0.3:70, 0.35:60 or 0.35:70.

[0051] In the present invention, the particle size of the dutasteride complex may be D90 not greater than 60 μm, specifically 55 μm, 50 μm, 45 μm, 40 μm, 35 μm, 30 μm, 25 μm or 20 μm.

[0052] The present invention also provides a method for preparing the dutasteride complex described in the above scheme, comprising the following steps:

[0053] Dutasteride and lactose are crushed together to obtain the dutasteride complex.

[0054] In the present invention, the crushing equipment can be a universal crusher and a ziplock bag; the crushing parameters can be: time is 30 to 120 seconds, specifically 60 seconds or 90 seconds.

[0055] The present invention also provides a dutasteride and tadalafil compound preparation, comprising an inner core and a coating layer wrapped around the surface of the inner core; the inner core comprises, by weight, 50.07 to 80.36 parts of a dutasteride complex, 3.57 to 7.15 parts of tadalafil, and 0.5 to 2 parts of magnesium stearate; the dutasteride complex is the dutasteride complex described in the above scheme or the dutasteride complex obtained by the preparation method described in the above scheme.

[0056] Calculated by weight, the dutasteride and tadalafil compound preparation provided by the present invention includes 50.07 to 80.36 parts of the dutasteride complex, specifically 55 parts, 60 parts, 65 parts, 70 parts or 75 parts.

[0057] Based on the mass fraction of the dutasteride complex, the dutasteride and tadalafil compound preparation provided by the present invention includes 3.57 to 7.15 parts of tadalafil, specifically 4 parts, 5 parts, 6 parts or 7 parts.

[0058] Based on the mass fraction of the dutasteride complex, the dutasteride and tadalafil compound preparation provided by the present invention includes 0.5 to 2 parts of magnesium stearate, specifically 1 part or 1.5 parts. Magnesium stearate is added as a lubricant in the present invention.

[0059] Based on the mass fraction of the dutasteride complex, the coating layer may include 10 to 30 parts of microcrystalline cellulose, 1 to 5 parts of hydroxypropyl cellulose and 2 to 6 parts of low-substituted hydroxypropyl cellulose.

[0060] Based on the mass fraction of the dutasteride complex, the dutasteride and tadalafil compound preparation provided by the present invention includes 10 to 30 parts of microcrystalline cellulose, specifically 15 parts, 20 parts or 25 parts.

[0061] Based on the mass fraction of the dutasteride complex, the dutasteride and tadalafil compound preparation provided by the present invention includes 1 to 5 parts of hydroxypropyl cellulose, specifically 2 parts, 3 parts or 4 parts.

[0062] Based on the mass fraction of the dutasteride complex, the dutasteride and tadalafil compound preparation provided by the present invention includes 2 to 6 parts of low-substituted hydroxypropyl cellulose, specifically 3 parts, 4 parts or 5 parts.

[0063] The present invention also provides a method for preparing the dutasteride and tadalafil compound preparation of the above scheme, comprising the following steps:

[0064] granulating the dutasteride complex, tadalafil, and water to obtain wet granules;

[0065] The wet granules are sequentially subjected to wet granulation, drying and dry granulation to obtain dry granules;

[0066] The dry granules and magnesium stearate are mixed, and then tableting and coating are performed in sequence to obtain the dutasteride and tadalafil compound preparation.

[0067] The present invention comprises mixing a dutasteride complex, tadalafil, and water (referred to as a first mixing step) and granulating the mixture to obtain wet granules. In the present invention, the mass ratio of the dutasteride and tadalafil complex to water can be 100:25 to 30, specifically 100:26, 100:27, 100:28, or 100:29.

[0068] In the present invention, the first mixing may be: premixing the dutasteride complex and tadalafil to obtain a premix, and then stirring the premix with water.

[0069] In the present invention, the premixing equipment may be a wet mixer; during the premixing, the stirring blade speed of the wet mixer may be 300 rpm, and the cutting blade speed may be 1000 rpm; and the premixing time may be 15 minutes.

[0070] In the present invention, the stirring and mixing device can be a wet mixer; during the stirring and mixing, the stirring paddle speed of the wet mixer can be 300 rpm, and the cutting blade speed can be 1000 rpm. In the present invention, the soft material is prepared by the first mixing, and the state of the soft material is observed to be a state in which it forms a clumping mass when held and falls apart when touched.

[0071] In the present invention, the granulation time may be 3 to 10 minutes, specifically 5 minutes or 7 minutes.

[0072] After obtaining the wet granules, the present invention sequentially performs wet granulation, drying, and dry granulation on the wet granules to obtain dry granules. In the present invention, the wet granulation may include placing the wet granules in a crushing and granulating machine and performing wet granulation using a screen; the aperture of the screen may be 8 mm×8 mm.

[0073] In the present invention, the drying equipment may be a fluidized bed; the drying temperature may not exceed 60° C., specifically 50° C. or 40° C., and the moisture content may be ≤5.0%. The present invention prepares dry particles through drying.

[0074] In the present invention, the dry granulation may include: placing the dry granules into a crushing and granulating machine, and installing a screen to perform dry granulation; the screen may be a round hole screen; and the diameter of the round hole screen may be 1.5 mm.

[0075] After obtaining the dry granules, the present invention mixes the dry granules with magnesium stearate and then compresses and coats the mixture to obtain the dutasteride and tadalafil compound preparation. In the present invention, the tableting die can be a circular hole screen; the diameter of the circular hole screen can be 7.5 mm.

[0076] In the present invention, the coating solution can be a suspension containing coating ingredients; the coating ingredients can include one or more of HPMC, HPC, titanium dioxide, polyethylene glycol and yellow iron oxide; the concentration of the coating solution can be 10wt%.

[0077] In the present invention, the preset weight gain of the coating may be 3-5 wt%, specifically 4 wt%.

[0078] The present invention also provides the use of the dutasteride and tadalafil compound preparation described in the above scheme or the dutasteride and tadalafil compound preparation obtained by the preparation method described in the above scheme in preparing a drug for benign prostatic hyperplasia combined with erectile dysfunction.

[0079] The dutasteride and tadalafil compound preparation provided by the present invention can be used to prepare a drug for benign prostatic hyperplasia combined with erectile dysfunction.

[0080] In order to further illustrate the present invention, the scheme of the present invention is described in detail below with reference to the accompanying drawings and embodiments, but they should not be understood as limiting the scope of protection of the present invention.

[0081] Example 1

[0082] The components and contents of the dutasteride and tadalafil compound preparation of this embodiment are shown in Table 1:

[0083] Table 1 Components and contents of the compound preparation of dutasteride and tadalafil in Example 1

[0084]

[0085] The specific steps of the preparation method of this embodiment are shown in Table 2:

[0086] Table 2 Preparation method of dutasteride and tadalafil compound preparation of Example 1

[0087]

[0088] The tadalafil dissolution ability of the dutasteride and tadalafil compound preparation prepared in this example was tested, and the results are shown in Table 3 and Figure 1 shown.

[0089] Table 3 Tadalafil dissolution results of Example 1

[0090]

[0091]

[0092] Note: The name of the tadalafil control preparation is tadalafil tablets, the trade name is Cialis, the batch number is D599244, and the holder is Eli Lilly's Dutch subsidiary (Eli Lilly Nederland B.V.).

[0093] According to Table 3 and Figure 1 It can be seen that the tadalafil dissolution effect of the dutasteride and tadalafil compound preparation of this example is better than that of the control preparation.

[0094] The dutasteride dissolution ability of the dutasteride and tadalafil compound preparation prepared in this example was tested, and the results are shown in Table 4 and Figure 2 shown.

[0095] Table 4 Example 1 Dutasteride dissolution results

[0096]

[0097] Note: The name of the dutasteride control preparation is dutasteride tablets, the batch number is 30061A, and the holder is Meiji Seika Pharmaceutical Co., Ltd.

[0098] According to Table 4 and Figure 2 It can be seen that the dutasteride dissolution effect of the dutasteride and tadalafil compound preparation of this embodiment is better than that of the control preparation. In summary, the dutasteride and tadalafil compound preparation of this embodiment achieves rapid dissolution of dutasteride and tadalafil.

[0099] Example 2

[0100] The preparation method of this embodiment is the same as that of Example 1, except that the D90 particle size of dutasteride in the dutasteride complex is 7.56 μm, the D90 particle size of lactose is 86 μm, and the particle size of lactose is less than 32 μm accounts for 57%. The components and contents of the dutasteride and tadalafil compound preparation are shown in Table 5:

[0101] Table 5 Components and contents of the compound preparation of dutasteride and tadalafil in Example 2

[0102]

[0103]

[0104] The tadalafil dissolution capacity and dutasteride dissolution capacity of the dutasteride and tadalafil compound preparation prepared in this example were tested, and the results are shown in Tables 6 and 7.

[0105] Table 6 Example 2 Tadalafil dissolution results

[0106]

[0107] Table 7 Example 2 Dutasteride dissolution results

[0108]

[0109] It can be seen from Tables 6 and 7 that the dutasteride and tadalafil compound preparation of this embodiment achieves rapid dissolution of dutasteride and tadalafil, especially in the 5-10 min period, the dissolution effect is more significantly improved.

[0110] Example 3

[0111] The preparation method of this embodiment is the same as that of Example 1, except that the D90 particle size of dutasteride in the dutasteride complex is 7.56 μm, the D90 particle size of lactose is 86 μm, and the particle size of lactose is less than 32 μm accounts for 57%. The components and contents of the dutasteride and tadalafil compound preparation are shown in Table 8:

[0112] Table 8 Components and contents of the compound preparation of dutasteride and tadalafil in Example 3

[0113]

[0114]

[0115] The tadalafil dissolution capacity and dutasteride dissolution capacity of the dutasteride and tadalafil compound preparation prepared in this example were tested, and the results are shown in Tables 9-10.

[0116] Table 9 Example 3 Tadalafil dissolution results

[0117]

[0118] Table 10 Example 3 Dutasteride dissolution results

[0119]

[0120] It can be seen from Tables 9 and 10 that the dutasteride and tadalafil compound preparation of this embodiment achieves rapid dissolution of dutasteride and tadalafil, especially in the 5-10 min period, the dissolution effect is more significantly improved.

[0121] Example 4

[0122] The preparation method of this embodiment is the same as that of Example 1, except that the D90 particle size of dutasteride in the dutasteride complex is 7.56 μm, the D90 particle size of lactose is 86 μm, and the particle size of lactose is less than 32 μm accounts for 57%. The components and contents of the dutasteride and tadalafil compound preparation are shown in Table 11:

[0123] Table 11 Components and contents of the compound preparation of dutasteride and tadalafil in Example 4

[0124]

[0125]

[0126] The tadalafil dissolution capacity and dutasteride dissolution capacity of the dutasteride and tadalafil compound preparation prepared in this example were tested, and the results are shown in Tables 12-13.

[0127] Table 12 Example 4 Tadalafil dissolution results

[0128]

[0129] Table 13 Example 4 Dutasteride dissolution results

[0130]

[0131] It can be seen from Table 12 and Table 13 that the dutasteride and tadalafil compound preparation of this embodiment achieves rapid dissolution of dutasteride and tadalafil, especially in the 5-10 min period, the dissolution effect is more significantly improved.

[0132] Example 5

[0133] The preparation method of this embodiment is the same as that of Example 1, except that the D90 particle size of dutasteride in the dutasteride complex is 7.56 μm, the D90 particle size of lactose is 86 μm, and the particle size of lactose is less than 32 μm accounts for 57%. The components and contents of the dutasteride and tadalafil compound preparation are shown in Table 14:

[0134] Table 14 Components and contents of the compound preparation of dutasteride and tadalafil in Example 5

[0135]

[0136]

[0137] The tadalafil dissolution capacity and dutasteride dissolution capacity of the dutasteride and tadalafil compound preparation prepared in this example were tested, and the results are shown in Tables 15-16.

[0138] Table 15 Example 5 Tadalafil dissolution results

[0139]

[0140] Table 16 Example 5 Dutasteride dissolution results

[0141]

[0142] It can be seen from Table 15 and Table 16 that the dutasteride and tadalafil compound preparation of this embodiment achieves rapid dissolution of dutasteride and tadalafil, especially in the 5-10 min period, the dissolution effect is more significantly improved.

[0143] Comparative Example 1: Reduce the amount of filler lactose

[0144] The preparation method of this comparative example is the same as that of Example 1, except that the components and contents of the compound preparation of dutasteride and tadalafil are as shown in Table 17:

[0145] Table 17 Components and contents of the compound preparation of dutasteride and tadalafil in Comparative Example 1

[0146]

[0147]

[0148] The tadalafil dissolution capacity and dutasteride dissolution capacity of the dutasteride and tadalafil compound preparation prepared in this comparative example were tested, and the results are shown in Tables 18 to 19 and Figures 3-4 shown.

[0149] Table 18 Comparative Example 1 Tadalafil dissolution results

[0150]

[0151] Table 19 Comparative Example 1 Dutasteride dissolution results

[0152]

[0153] According to Tables 18 and 19, it can be seen that as the amount of lactose decreases and the amount of microcrystalline cellulose increases, the overall dissolution of dutasteride and tadalafil slows down, and the dissolution end point cannot be completely dissolved. This is probably because the content of the insoluble excipient microcrystalline cellulose is too high, which hinders the dissolution of the active ingredient (API).

[0154] Comparative Example 2: Adjusting the amount of adhesive hydroxypropyl cellulose

[0155] The preparation method of this comparative example is the same as that of Example 1, except that the components and contents of the compound preparation of dutasteride and tadalafil are as shown in Table 20:

[0156] Table 20 Comparative Example 2 Components and contents of the compound preparation of dutasteride and tadalafil

[0157]

[0158]

[0159] The tadalafil dissolution capacity and dutasteride dissolution capacity of the dutasteride and tadalafil compound preparation prepared in this comparative example were tested, and the results are shown in Tables 21 to 22 and Figures 5-6 shown.

[0160] Table 21 Comparative Example 2 Tadalafil dissolution results

[0161]

[0162] Table 22 Comparative Example 2 Dutasteride dissolution results

[0163]

[0164] According to Tables 21-22 and Figures 5-6 It can be seen that the higher the amount of binder used, the more compact the particles, which results in the API being encapsulated in the particles after the tablet disintegrates, making it impossible to dissolve, and the overall dissolution rate is slow.

[0165] Comparative Example 3: Adjusting the amount of disintegrant low-substituted hydroxypropyl cellulose

[0166] The preparation method of this comparative example is the same as that of Example 1, except that the components and contents of the compound preparation of dutasteride and tadalafil are as shown in Table 23:

[0167] Table 23 Components and contents of the compound preparation of dutasteride and tadalafil in Comparative Example 3

[0168] Components Percentage content (%) Dutasteride 0.36 Tadalafil 3.57 Lactose monohydrate 68.11 microcrystalline cellulose 22.11 Hydroxypropylcellulose 2.89 Low-substituted hydroxypropyl cellulose 2 magnesium stearate 0.96

[0169] The tadalafil dissolution capacity and dutasteride dissolution capacity of the dutasteride and tadalafil compound preparation prepared in this comparative example were tested, and the results are shown in Tables 24 to 25 and Figures 7-8 shown.

[0170] Table 24 Comparative Example 3 Tadalafil dissolution results

[0171]

[0172] Table 25 Comparative Example 3 Dutasteride dissolution results

[0173]

[0174] According to Tables 24-25 and Figures 7-8 It can be seen that the lower the disintegrant content, the slower the disintegration rate of the preparation and the slower the overall dissolution rate.

[0175] Comparative Example 4: β-cyclodextrin inclusion method

[0176] The components and contents of the dutasteride and tadalafil compound preparation of this comparative example are shown in Table 26:

[0177] Table 26 Components and contents of the compound preparation of dutasteride and tadalafil in Comparative Example 4

[0178] Components Percentage content (%) Dutasteride 0.22 Beta-cyclodextrin 1.05 Poloxamer 188 0.10 Tadalafil 2.25 lactose 56.40 microcrystalline cellulose 21.19 Hydroxypropyl cellulose 1.80 Croscarmellose sodium 5.21 Sodium lauryl sulfate 0.90 Low-substituted hydroxypropyl cellulose (L-HPC) 9.50 magnesium stearate 1.38 purified water 20

[0179] The specific steps of the preparation method of this comparative example are shown in Table 27:

[0180] Table 27 Comparative Example 4 Preparation method of dutasteride and tadalafil compound preparation

[0181]

[0182] The tadalafil dissolution capacity and dutasteride dissolution capacity of the dutasteride and tadalafil compound preparation prepared in this comparative example were tested, and the results are shown in Tables 28 to 29 and Figures 9-10 shown.

[0183] Table 28 Comparative Example 4 Tadalafil dissolution results

[0184]

[0185] Table 29 Comparative Example 4 Dutasteride dissolution results

[0186]

[0187] According to Tables 28-29 and Figures 9-10 It can be seen that the dissolution of tadalafil in the preparation prepared by β-cyclodextrin inclusion is basically the same as that of the control preparation, but the dissolution of dutasteride is significantly lower than that of the control preparation.

[0188] Comparative Example 5: Preparation of Dutasteride Solid by Replacing the Carrier with Polyethylene Glycol 6000

[0189] The components and contents of the dutasteride and tadalafil compound preparation of this comparative example are shown in Table 30:

[0190] Table 30 Comparative Example 5 Components and contents of the compound preparation of dutasteride and tadalafil

[0191] Components Percentage content (%) Dutasteride 0.24 PEG6000 5.77 Poloxamer 188 0.58 Tadalafil 4.16 lactose 52.21 microcrystalline cellulose 10.82 Hydroxypropyl cellulose 1.66 Croscarmellose sodium 4.83 Sodium lauryl sulfate 0.83 Low-substituted hydroxypropyl cellulose (L-HPC) 17.64 magnesium stearate 1.27 purified water 20

[0192] The specific steps of the preparation method of this comparative example are shown in Table 31:

[0193] Table 31 Comparative Example 5 Preparation Method of Dutasteride and Tadalafil Compound Preparation

[0194]

[0195]

[0196] The tadalafil dissolution capacity and dutasteride dissolution capacity of the dutasteride and tadalafil compound preparation prepared in this comparative example were tested, and the results are shown in Tables 32 to 33 and Figures 11-12 shown.

[0197] Table 32 Comparative Example 5 Tadalafil dissolution results

[0198]

[0199] Table 33 Comparative Example 5 Dutasteride dissolution results

[0200]

[0201] According to Tables 32-33 and Figures 11-12 It can be seen that the dissolution behavior of tadalafil in the solid dispersion prepared using PEG is basically the same as that of the control preparation, but the dissolution of dutasteride is significantly slower than that of the control preparation.

[0202] Comparative Example 6: Preparation of Dutasteride Solid by Replacing the Carrier with Copovidone

[0203] The components and contents of the dutasteride and tadalafil compound preparation of this comparative example are shown in Table 34:

[0204] Table 34 Components and contents of the compound preparation of dutasteride and tadalafil in Comparative Example 6

[0205]

[0206]

[0207] The specific steps of the preparation method of this comparative example are shown in Table 35:

[0208] Table 35 Comparative Example 6 Preparation method of dutasteride and tadalafil compound preparation

[0209]

[0210] The tadalafil dissolution capacity and dutasteride dissolution capacity of the dutasteride and tadalafil compound preparation prepared in this comparative example were tested, and the results are shown in Tables 36 to 37 and Figures 13-14 shown.

[0211] Table 36 Comparative Example 6 Tadalafil dissolution results

[0212]

[0213] Table 37 Comparative Example 5 Dutasteride dissolution results

[0214]

[0215]

[0216] According to Tables 36-37 and Figures 13-14 It can be seen that the dissolution of tadalafil in the solid dispersion prepared using copovidone is basically the same as that of the control preparation, but the dissolution of dutasteride is significantly lower than that of the control preparation.

[0217] Comparative Example 7: Preparation of Dutasteride Solid by Replacing the Carrier with Hydroxypropyl Methylcellulose

[0218] The components and contents of the dutasteride and tadalafil compound preparation of this comparative example are shown in Table 38:

[0219] Table 38 Components and contents of the compound preparation of dutasteride and tadalafil in Comparative Example 7

[0220] Components Percentage content (%) Dutasteride 0.22 HPMC 1.05 Poloxamer 188 0.10 Tadalafil 2.25 lactose 56.40 microcrystalline cellulose 21.19 Hydroxypropyl cellulose 1.80 Croscarmellose sodium 5.21 SDS 0.90 L-HPC 9.50 magnesium stearate 1.38 purified water 20

[0221] The specific steps of the preparation method of this comparative example are shown in Table 39:

[0222] Table 39 Comparative Example 7 Preparation Method of Dutasteride and Tadalafil Compound Preparation

[0223]

[0224]

[0225] The tadalafil dissolution capacity and dutasteride dissolution capacity of the dutasteride and tadalafil compound preparation prepared in this comparative example were tested, and the results are shown in Tables 40 to 41 and Figures 15-16 shown.

[0226] Table 40 Comparative Example 7 Tadalafil dissolution results

[0227]

[0228] Table 41 Comparative Example 7 Dutasteride dissolution results

[0229]

[0230] According to Tables 40-41 and Figures 15-16 It can be seen that the dissolution behavior of dutasteride solid dispersion prepared with HPMC as the matrix is significantly slower than that of the control preparation.

[0231] It can be seen from the above examples that the dutasteride complex provided by the present invention improves the solubility of dutasteride, and the compound preparation of dutasteride and tadalafil achieves the combined use of the two.

[0232] Although the above embodiment provides a detailed description of the present invention, it is only a part of the embodiments of the present invention, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the scope of protection of the present invention.

Claims

1. A dutasteride complex, characterized in that The invention comprises dutasteride, a first lactose interpenetrating and mixed with the dutasteride, and a second lactose coated on the surface of the dutasteride; The particle size of the dutasteride is D90 less than 10 μm.

2. The dutasteride complex according to claim 1, characterized in that The ratio of the mass of the dutasteride to the total mass of the first lactose and the second lactose is 0.07-0.36:50-80.

3. The dutasteride complex according to claim 1 or 2, characterized in that The particle size D90 of the dutasteride complex is no greater than 60 μm.

4. The method for preparing the dutasteride complex according to any one of claims 1 to 3, characterized in that: The following steps are involved: Dutasteride and lactose are crushed together to obtain the dutasteride complex.

5. The preparation method according to claim 4, characterized in that The crushing equipment is a universal crusher and a ziplock bag; the crushing parameters are: the time is 30 to 120 seconds.

6. A compound preparation of dutasteride and tadalafil, characterized in that: It comprises a core and a coating layer wrapped on the surface of the core; Calculated by weight, the inner core comprises 50.07 to 80.36 parts of a dutasteride complex, 3.57 to 7.15 parts of tadalafil, and 0.5 to 2 parts of magnesium stearate; the dutasteride complex is the dutasteride complex according to any one of claims 1 to 3 or the dutasteride complex obtained by the preparation method according to any one of claims 4 to 5.

7. The dutasteride and tadalafil compound preparation according to claim 6, characterized in that: The coating layer comprises 10 to 30 parts of microcrystalline cellulose, 1 to 5 parts of hydroxypropyl cellulose and 2 to 6 parts of low-substituted hydroxypropyl cellulose.

8. The method for preparing the dutasteride and tadalafil compound preparation according to any one of claims 6 to 7, characterized in that: The following steps are involved: granulating the dutasteride complex, tadalafil, and water to obtain wet granules; The wet granules are sequentially subjected to wet granulation, drying and dry granulation to obtain dry granules; The dry granules and magnesium stearate are mixed, and then tableting and coating are performed in sequence to obtain the dutasteride and tadalafil compound preparation.

9. The preparation method according to claim 8, characterized in that The drying temperature does not exceed 60° C. until the moisture content is ≤5.0%.

10. Use of the dutasteride and tadalafil compound preparation according to any one of claims 6 to 7 or the dutasteride and tadalafil compound preparation obtained by the preparation method according to any one of claims 8 to 9 in the preparation of a drug for benign prostatic hyperplasia combined with erectile dysfunction.

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