Orally disintegrating tablet containing finasteride and tadalafil and preparation method thereof

Abstract

The invention provides an orally disintegrating tablet containing finasteride and tadalafil and a preparation method thereof. The orally disintegrating tablet comprises the following raw materials in percentage by weight: 3%-5% of finasteride, 3%-5% of tadalafil, 78%-85% of mannitol, 2%-5% of croscarmellose sodium, 3%-5% of povidone, 1%-5% of sucralose, 1%-3% of aspartame, 1%-2% of apple powder essence and 1%-3% of colloidal silicon dioxide. 1%-3% of magnesium stearate; according to the orally disintegrating tablet, the defects of capsule preparations in the prior art are overcome, the medication compliance of old men and patients with swallowing difficulty is greatly improved by taking the orally disintegrating tablet, and the orally disintegrating tablet provided by the invention is good in dissolution behavior, quick to disintegrate in the oral cavity, good in taste, obvious in taste modifying effect and free of gravel taste.

Description

Technical Field

[0001] The present application relates to the technical field of pharmaceutical preparations, and more specifically, to an orally disintegrating tablet containing finasteride and tadalafil and a preparation method thereof. Background Art

[0002] Prostatic hyperplasia, also known as benign prostatic hyperplasia (BPH), is related to age. It is a common disease and a frequently-occurring disease in elderly men, and the incidence rate increases with age. From a histological perspective, BPH in men worldwide generally occurs after the age of 40, and the incidence rate increases year by year with age. It is about 10% in men aged 31 to 40, about 20% in men aged 41 to 50, 50% to 60% in men aged 61 to 70, about 80% in men aged 71 to 80, and as high as 90% in men aged 81 to 90. Epidemiological studies have shown that the incidence rate of prostatic hyperplasia is low in men before the age of 40, reaching 40% after the age of 50, and approaching 90% after the age of 80. At the age of 90, if a prostate histological examination is performed, almost 100% of men will be found to have prostatic hyperplasia. The main causes of prostatic hyperplasia are divided into dynamic factors and static factors. The dynamic factors are mainly caused by the increase in the tension of the prostate capsule and smooth muscles rich in α-receptors, which causes bladder irritation, manifested as frequent urination and urgency. In severe cases, urgency urinary incontinence may occur. The static factors are mainly the enlarged gland protruding to the sides and into the bladder, compressing the urethra and causing bladder outlet obstruction, causing urination hesitation, weak urine flow and other symptoms. The initial clinical manifestations of prostatic hyperplasia are lower urinary tract symptoms (LUTS), which are an independent factor in the occurrence of erectile dysfunction (ED). The ED complication rate of moderate LUTS patients is 36%, and the ED complication rate of severe LUTS patients can reach 94%.

[0003] At present, the single-ingredient preparations on the market for the treatment of benign prostatic hyperplasia and erectile dysfunction are mainly PDE5 (5-phosphodiesterase) inhibitors and 5α-reductase inhibitors, but the single-ingredient preparations have the defects of poor administration effect, increased cost for patients to take multiple drugs at the same time, and poor medication compliance; On December 13, 2021, Veru announced that the U.S. Food and Drug Administration (FDA) has approved Entadfi (finasteride and tadalafil) capsules for the treatment of urinary tract symptoms caused by benign prostatic hyperplasia (BPH). Entadfi is a combination of the 5a-reductase inhibitor finasteride and the 5-phosphodiesterase (PDE5) inhibitor tadalafil. It is suitable for the initial treatment of signs and symptoms of benign prostatic hyperplasia (BPH) in male patients with enlarged prostate for up to 26 weeks.

[0004] However, capsule preparations have the defect of being inconvenient to swallow, and hot water delivery will cause the capsule to dissolve quickly, and the capsule skin is very easy to stick to the throat or esophagus, weakening or losing the effect that the capsule should have. In addition, some patients will swallow the capsule dry because there is no water around them, which will also increase the risk of the capsule sticking in the esophagus, or release the drug in advance, damaging the esophagus or stomach. In order to solve the above technical problems, the present invention provides an orodisintegrating tablet containing finasteride and tadalafil, which is easy to take, has extremely high compliance, can disintegrate quickly in the oral cavity, does not need to be taken with water, can be quickly dissolved or disintegrated in saliva, and can take effect quickly in the stomach after swallowing, especially for elderly men, patients with dysphagia, taking orodisintegrating tablets can greatly improve medication compliance. In addition, the orodisintegrating tablet containing finasteride and tadalafil provided by the present invention has a good taste, obvious taste correction effect, and no gritty taste. Summary of the invention

[0005] In view of the technical problems existing in the prior art, the purpose of the present invention is to provide an orodisintegrating tablet containing finasteride and tadalafil and a preparation method thereof, which solves the defects of the capsule preparations used in the prior art. For elderly men and patients with dysphagia, taking orodisintegrating tablets can greatly improve medication compliance. The orodisintegrating tablets containing finasteride and tadalafil provided by the present invention have good dissolution behavior, can be quickly disintegrated in the oral cavity, and have a quick onset of effect. After disintegration in the oral cavity, the orodisintegrating tablets have a good taste, an obvious taste correction effect, and no gritty taste.

[0006] The purpose of the present invention is achieved through the following technical solutions:

[0007] The invention provides an orally disintegrating tablet containing finasteride and tadalafil. The orally disintegrating tablet comprises the following raw materials in percentage by weight: 3% to 5% of finasteride, 3% to 5% of tadalafil, 78% to 85% of mannitol, 2% to 5% of cross-linked carboxymethyl cellulose sodium, 3% to 5% of povidone, 1% to 5% of sucralose, 1% to 3% of aspartame, 1% to 2% of apple powder flavor, 1% to 3% of colloidal silicon dioxide, and 1% to 3% of magnesium stearate.

[0008] Further, the raw materials are included in the following weight percentages: 3.33% finasteride, 3.33% tadalafil, 78.83% mannitol, 5% croscarmellose sodium, 3% povidone, 1.5% sucralose, 1% aspartame, 2% apple powder flavor, 1% colloidal silicon dioxide, and 1% magnesium stearate. Preferably, 1.5% sucralose is used.

[0009] Preferably, the particle size distribution of finasteride and tadalafil in the range of 20 mesh to 45 mesh is controlled to be above 15%.

[0010] The present invention also provides a method for preparing an orally disintegrating tablet containing finasteride and tadalafil, comprising the following steps:

[0011] 1) Premix finasteride and tadalafil with about 1 / 2 of the filler mannitol, then add the premixed materials and cross-linked sodium carboxymethyl cellulose, sucralose, aspartame, apple powder flavor, and the remaining about 1 / 2 of the mannitol into a granulator in sequence and mix; after the parameters are stabilized, add the povidone solution to prepare a soft material discharge;

[0012] 2) Wet granulation: The prepared soft material is wet granulated using a square hole screen, and the granulator speed is set to 300 rpm. After the parameters are stable, the soft material is added to the crushing and granulating machine for wet granulation;

[0013] 3) adding the wet granules to a fluidized bed for drying;

[0014] 4) adding the granules dried in step 3) into a pulverizing and granulating machine for granulation to obtain dry granules;

[0015] 5) adding the dry granules obtained in step 4), colloidal silicon dioxide and magnesium stearate into a mixer for total mixing;

[0016] 6) Tableting to obtain orally disintegrating tablets of finasteride and tadalafil.

[0017] Furthermore, in the step 1), the granulator is set to have a stirring blade speed of 300 rpm and a cutting blade speed of 1000 rpm, and the mixture is mixed for 5 minutes. In the step 1), the addition time of the povidone solution is controlled within 1 minute, the granulation is performed for 1 minute, the material state is observed, and the granulation is performed for a total of 5 minutes to prepare the soft material.

[0018] Preferably, in step 3), the temperature of the fluidized bed heater is 60° C., the fan frequency is 1000-2000 rpm, and the moisture content of the particles is controlled to be 1%-3%.

[0019] In step 4), the pulverizer and granulator are 0.9 mm, the circular aperture screen is set at a speed of 500 rpm;

[0020] In the step 5), the main shaft speed of the mixer is set to 15 rpm, the secondary shaft speed is set to 15 rpm, and the mixing is performed for 10 minutes.

[0021] Preferably, the tableting hardness in step 6) is 30-50N.

[0022] Beneficial effects achieved by the present invention:

[0023] 1. The orodisintegrating tablet containing finasteride and tadalafil and the preparation method thereof provided by the present invention solve the defect that the capsule preparation used in the prior art is inconvenient for elderly male patients with dysphagia. By taking the orodisintegrating tablet developed by the present invention, the compliance of medication can be greatly improved.

[0024] 2. The orally disintegrating tablets containing finasteride and tadalafil provided by the present invention have good dissolution behavior, can disintegrate quickly in the oral cavity, and have a quick onset of effect. They can disintegrate completely within 32 seconds without the need for additional cosolvents, such as surfactants.

[0025] 3. The orodisintegrating tablets containing finasteride and tadalafil provided by the present invention have a good taste after oral disintegration, a significant taste correction effect, and no gritty taste. In particular, when mannitol is used as a filler and sucralose, aspartame and apple essence are mixed as a flavoring agent, the taste is the best, and the taste score can reach 9.6.

[0026] Instruction Manual

[0027] Attached Figure 1 -In vitro dissolution curves of the control preparation of finasteride tablets (batch number: W035225) in different media including water, pH 1.2 and pH 4.5;

[0028] Attached Figure 2 - The in vitro dissolution curve of the control preparation of tadalafil tablets (batch number: D509108) in different media including water, pH 1.2 and pH 4.5;

[0029] Attached Figure 3 - is the in vitro dissolution curve of the self-prepared finasteride tadalafil orodisintegrating tablets (batch number: 24061801) in Example 1 of the present invention in different media of water, pH 1.2 and pH 4.5; DETAILED DESCRIPTION

[0030] The technical solution of the present invention is clearly and completely described below through embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments, and are not intended to limit the protection scope of the present invention.

[0031] Example 1

[0032] The raw material prescription of this embodiment is shown in Table 1:

[0033] Table 1 Prescription and ratio of Example 1

[0034] Prescription ingredients Proportion(%) Finasteride 3.33 Tadalafil 3.33 Mannitol 78.83 Croscarmellose Sodium 5.00 Povidone 3.00 Sucralose 1.50 Aspartame 1.00 Apple powder flavor 2.00 Colloidal Silica 1.00 Magnesium Stearate 1.00

[0035] The preparation method of the orally disintegrating tablet containing finasteride and tadalafil in this embodiment:

[0036] 1) Weigh the amount of each raw material and auxiliary material used in the prescription, label them separately and keep them ready for use;

[0037] 2) Premix finasteride and tadalafil with about 1 / 2 of the filler mannitol, then add the premixed materials and cross-linked sodium carboxymethyl cellulose, sucralose, aspartame, apple powder flavor, and the remaining about 1 / 2 of mannitol into the granulator in sequence, set the stirring blade speed to 300 rpm, the cutting blade speed to 1000 rpm, and mix for 5 minutes; after the parameters are stable, add the povidone solution (the addition time is controlled within 1 minute), granulate for 1 minute, observe the material state, granulate for a total of 5 minutes, and prepare the soft material for discharge.

[0038] 3) Wet granulation: The prepared soft material is wet granulated using a 4×4 square hole screen, and the granulator speed is set to 300 rpm. After the parameters are stable, the soft material is added to the crushing and granulating machine for wet granulation.

[0039] 4) Add the wet granules into a fluidized bed for drying. The temperature of the fluidized bed heater is 60° C., the fan frequency is 1000-2000 rpm, and the moisture content of the granules is controlled to be 1%-3%.

[0040] 5) Add the dried granules from step 4) into a pulverizer for granulation to obtain dry granules; wherein the pulverizer has a 0.9 mm circular aperture screen and a rotation speed of 500 rpm.

[0041] 6) Add the dry granules obtained in step 5) into a mixer, colloidal silicon dioxide and magnesium stearate for total mixing, set the main shaft speed of the mixer to 15 rpm, the secondary shaft speed to 15 rpm, and mix for 10 minutes.

[0042] 7) Orally disintegrating tablets of finasteride and tadalafil are obtained by tableting.

[0043] Example 2

[0044] The raw material prescription of this embodiment is shown in Table 2:

[0045] Table 2 Example 2 Prescription and ratio

[0046] Prescription ingredients Proportion(%) Finasteride 3.33 Tadalafil 3.33 starch 68.83 Croscarmellose Sodium 5.00 Microcrystalline Cellulose 10.00 Hydroxypropylcellulose 3.00 Sucralose 1.50 Aspartame 1.00 Apple powder flavor 2.00 Colloidal Silica 1.00 Magnesium Stearate 1.00

[0047] The preparation method of the orally disintegrating tablet containing finasteride and tadalafil in this example is the same as that in Example 1.

[0048] Example 3

[0049] The raw material prescription of this embodiment is shown in Table 3:

[0050] Table 3 Prescription and ratio of Example 3

[0051]

[0052]

[0053] The preparation method of the orally disintegrating tablet containing finasteride and tadalafil in this example is the same as that in Example 1.

[0054] Comparative Example 1

[0055] The raw material prescription of this comparative example is shown in Table 4:

[0056] Table 4 Comparative Example 1 Prescription and Ratio

[0057] Composition of penalties Proportion(%) Finasteride 3.33 Tadalafil 3.33 Mannitol 68.83 Croscarmellose Sodium 5.00 Microcrystalline Cellulose 10.00 Povidone 3.00 Sucralose 1.50 Stevioside 1.00 Apple powder flavor 2.00 Colloidal Silica 1.00 Magnesium Stearate 1.00

[0058] The preparation method of the orally disintegrating tablet containing finasteride and tadalafil in this comparative example is the same as that in Example 1.

[0059] Comparative Example 2

[0060] The raw material prescription of this comparative example is shown in Table 5

[0061] Table 5 Comparative Example 2 Prescription and Ratio

[0062] Composition of penalties Proportion(%) Finasteride 3.33 Tadalafil 3.33 Mannitol 68.83 Croscarmellose Sodium 5.00 Microcrystalline Cellulose 12.50 Povidone 3.00 Apple powder flavor 2.00 Colloidal Silica 1.00 Magnesium Stearate 1.00

[0063] The preparation method of the orally disintegrating tablet containing finasteride and tadalafil in this comparative example is the same as that in Example 1.

[0064] Comparative Example 3

[0065] The raw material prescription of this comparative example is shown in Table 6

[0066] Table 6 Prescription and ratio of comparative example 3

[0067] Composition of penalties Proportion(%) Finasteride 3.33 Tadalafil 3.33 Mannitol 68.83 Croscarmellose Sodium 5.00 Microcrystalline Cellulose 13.50 Povidone 3.00 Aspartame 1.00 Colloidal Silica 1.00 Magnesium Stearate 1.00

[0068] The preparation method of the orally disintegrating tablet containing finasteride and tadalafil in this comparative example is the same as that in Example 1.

[0069] Comparative Example 4

[0070] The raw material prescription of this comparative example is shown in Table 7

[0071] Table 7 Comparative Example 4 Prescription and Ratio

[0072] Composition of penalties Proportion(%) Finasteride 3.33 Tadalafil 3.33 Mannitol 81.83 Croscarmellose Sodium 5.00 Povidone 3.00 Sucralose 1.50 Colloidal Silica 1.00 Magnesium Stearate 1.00

[0073] The preparation method of the orally disintegrating tablet containing finasteride and tadalafil in this comparative example is the same as that in Example 1.

[0074] Comparative Example 5

[0075] The raw material prescription of this comparative example is shown in Table 8

[0076] Table 8 Prescription and ratio of comparative example 5

[0077]

[0078]

[0079] The preparation method of the orally disintegrating tablet containing finasteride and tadalafil in this comparative example is the same as that in Example 1.

[0080] Comparative Example 6

[0081] The raw material prescription of this comparative example is shown in Table 9

[0082] Table 9 Prescription and ratio of comparative example 6

[0083] Prescription ingredients Proportion (%) Finasteride 3.33 Tadalafil 3.33 Mannitol 78.83 Croscarmellose Sodium 5.00 Hydroxypropyl methylcellulose 3.00 Sucralose 1.50 Aspartame 1.00 Apple powder flavor 2.00 Colloidal Silica 1.00 Magnesium Stearate 1.00

[0084] The preparation method of the orally disintegrating tablet containing finasteride and tadalafil in this comparative example is the same as that in Example 1.

[0085] Comparative Example 7

[0086] The raw material prescription of this comparative example is shown in Table 10

[0087] Table 10 Prescription and ratio of Comparative Example 7-1 and Comparative Example 7-2

[0088]

[0089]

[0090] The preparation method of the orally disintegrating tablet containing finasteride and tadalafil in this comparative example is the same as that in Example 1.

[0091] Comparative Example 8

[0092] The raw material prescription of this comparative example is shown in Table 11

[0093] Table 11 Prescription and ratio of Comparative Example 8-1 and Comparative Example 8-2

[0094]

[0095] The preparation method of the orally disintegrating tablet containing finasteride and tadalafil in this comparative example is the same as that in Example 1.

[0096] Comparative Example 9

[0097] The raw material prescription of this comparative example is shown in Table 12

[0098] Table 12 Prescription and ratio of Comparative Example 9-1 and Comparative Example 9-2

[0099]

[0100]

[0101] The preparation method of the orally disintegrating tablet containing finasteride and tadalafil in this comparative example is the same as that in Example 1.

[0102] Comparative Example 10

[0103] The raw material prescription of this comparative example is shown in Table 13

[0104] Table 13 Prescription and ratio of Comparative Example 10-1 and Comparative Example 10-2

[0105]

[0106] The preparation method of the orally disintegrating tablet containing finasteride and tadalafil in this comparative example is the same as that in Example 1.

[0107] Performance testing methods

[0108] The particle size distribution of each embodiment is shown in Table 14:

[0109] Table 14

[0110]

[0111]

[0112] Conclusion: As can be seen from Table 14, most of the particle size distribution of Example 2 is concentrated in 60-100 mesh, accounting for 71.57%, while 20-45 mesh accounts for only 8.51%, resulting in poor material filling fluidity during tableting and large differences in tablet weight, which is not conducive to tableting. In Example 1, the particle size distribution of 20 mesh to 45 mesh is controlled at 19.3%, the material filling fluidity is good, and the tablet weight uniformity is good.

[0113] Disintegration time test:

[0114] The disintegration time of the tadalafil dapoxetine orodisintegrating tablets in the examples and comparative examples was measured using the relevant methods in the 2020 edition of the Chinese Pharmacopoeia, Part IV, General Rules 0921 Disintegration Time Limit Test Method. The measurement results are shown in Table 15 below:

[0115] Table 15

[0116] Example Disintegration time Example 1 32s Example 2 58S Example 3 65S Comparative Example 1 45S Comparative Example 2 52s Comparative Example 3 53S Comparative Example 4 49s Comparative Example 5 77S Comparative Example 6 83s Comparative Example 7-1 / Comparative Example 7-2 43S / 22S Comparative Example 8-1 / Comparative Example 8-2 33S / 56s Comparative Example 9-1 / Comparative Example 9-2 42S / 38S Comparative Example 10-1 / Comparative Example 10-2 45S / 42S

[0117] Conclusion: As can be seen from Table 15, Example 1 can be completely disintegrated within 32 seconds, while Example 3, as well as Comparative Examples 5 and 6 have a disintegration time limit of more than 1 minute, which does not meet the requirements for orally disintegrating tablets. The disintegration time limit exceeds the standard and does not meet the requirements.

[0118] Dissolution test:

[0119] The dissolution comparison test was conducted on the samples of the embodiment and the control preparations of finasteride tablets and tadalafil tablets, respectively. The dissolution of the finasteride tadalafil orally disintegrating tablets obtained in the embodiment and the control preparations in different media of water, pH 1.2 and pH 4.5 was determined by HPLC method. The test data are shown in Table 16 and Table 17:

[0120] Table 16 Dissolution behavior of control preparations in different media

[0121]

[0122] Table 17 Dissolution behavior of self-prepared finasteride tadalafil orally disintegrating tablets in different media

[0123]

[0124] Experimental conclusion: From Table 17, it can be seen that the self-prepared preparation containing finasteride and tadalafil orally disintegrating tablets has good dissolution behavior in the media pH 4.5 acetate buffer, pH 1.2 hydrochloric acid solution and water.

[0125] Friability test:

[0126] The friability of the orally disintegrating tablets of finasteride and tadalafil in the examples and comparative examples was measured using a CJY300D tablet friability tester. The test results are shown in Table 18 below:

[0127] Table 18

[0128] Example Friability (%) Example 1 0.2 Example 2 0.9 Example 3 0.7 Comparative Example 1 0.6 Comparative Example 2 0.5 Comparative Example 3 0.6 Comparative Example 4 0.5 Comparative Example 5 1.0 Comparative Example 6 1.1 Comparative Example 7-1 / Comparative Example 7-2 0.8 / 0.7 Comparative Example 8-1 / Comparative Example 8-2 0.8 / 0.3 Comparative Example 9-1 / Comparative Example 9-2 0.5 / 0.5 Comparative Example 10-1 / Comparative Example 10-2 0.6 / 0.5

[0129] Conclusion: From Table 18, it can be seen that the reduction in the amount of Example 1 before and after the test is the smallest compared with other batches of samples, proving that the product is least worn when damaged by external force. Among them, the brittleness of Comparative Example 6 is greater than 1%, which does not meet the product requirements.

[0130] Hardness test:

[0131] The hardness of the orally disintegrating tablets of finasteride and tadalafil in the examples and comparative examples was measured using a YD3 tablet hardness tester. The results are shown in Table 19 below:

[0132] Table 19

[0133] Example Hardness(N) Example 1 48.3 Example 2 35.4 Example 3 44.5 Comparative Example 1 42.0 Comparative Example 2 32.5 Comparative Example 3 31.5 Comparative Example 4 33.6 Comparative Example 5 28.6 Comparative Example 6 25.7 Comparative Example 7-1 / Comparative Example 7-2 33.4 / 35.8 Comparative Example 8-1 / Comparative Example 8-2 35.8 / 50.2 Comparative Example 9-1 / Comparative Example 9-2 35.8 / 35.9 Comparative Example 10-1 / Comparative Example 10-2 34.7 / 38.2

[0134] Taste test:

[0135] Twenty volunteers with normal sense organs and no physical diseases were selected to conduct a taste test on the orodisintegrating tablets of finasteride and tadalafil in the examples and comparative examples. Specifically, one tablet of the sample was placed in the oral cavity, and after it was completely disintegrated in the oral cavity, it was spit out, and the mouth was rinsed with 0.9% sodium chloride solution for at least 5 times until there was no obvious bitterness in the oral cavity, and the volunteers' evaluations on sweetness and grittiness were recorded.

[0136] Taste scoring criteria: sweet taste without gritty feeling: 8-10 points; sweet taste with gritty feeling: 6-7 points; bitter taste without gritty feeling: 3-5 points; bitter taste with gritty feeling: 0-3 points; the average calculation results of the measurement are as follows in Table 20:

[0137] Table 20

[0138] Example Is there a sense of grit? Sweet / Bitter Taste score Example 1 none Sweetness 9.6 Example 2 have Sweetness 7.0 Example 3 have Sweetness 6.8 Comparative Example 1 none There is bitterness 5.3 Comparative Example 2 none Bitter 4.7 Comparative Example 3 none Bitter 4.8 Comparative Example 4 none Bitter 4.9 Comparative Example 5 have Sweetness 6.5 Comparative Example 6 have Sweetness 6.4 Comparative Example 7-1 / Comparative Example 7-2 No / Yes Sweetness / Sweetness 8.5 / 6.9 Comparative Example 8-1 / Comparative Example 8-2 None / None Sweetness / Sweetness 9.0 / 9.5 Comparative Example 9-1 / Comparative Example 9-2 None / None Sweetness / Sweetness 8.8 / 9.3 Comparative Example 10-1 / Comparative Example 10-2 None / None Sweetness / Sweetness 8.5 / 9.4

[0139] Conclusion: As can be seen from Table 20, Example 1 uses mannitol as a filler. Compared with other fillers starch and lactose used in Examples 2 and 3, mannitol has the weakest gritty feeling. At the same time, when the amount of mannitol is reduced, the gritty feeling becomes worse, such as Comparative Example 7-2. In addition, the inventor unexpectedly found that when the binder povidone in Example 1 is replaced with hydroxypropyl cellulose or hydroxypropyl methylcellulose, such as Comparative Examples 5 and 6, even if mannitol is used as a filler, it still has a gritty feeling.

[0140] When one or two of apple powder flavor, aspartame, and sucralose are used as flavoring agents, such as in Comparative Examples 2, 3, and 4, the prescription tastes bitter; when aspartame in Example 1 is replaced with stevioside, such as in Comparative Example 1, when sucralose, stevioside, and apple powder flavor are mixed as flavoring agents, there is a bitter aftertaste; it can be seen that the sweetness of the prescription using three mixed flavoring agents is better than that of a single or two mixed flavoring agents, especially, when mannitol is used as a filler at the same time, sucralose, aspartame, and apple flavor are mixed as flavoring agents, and the taste is the best.

[0141] Related substances testing:

[0142] The standards in the 2020 edition of the Chinese Pharmacopoeia were used to test the related substances of finasteride and tadalafil in Examples 1 to 3 and Ratios 1 to 10-1. The test results are shown in Table 21 below:

[0143] Finasteride related substances detection method:

[0144] Detection method: HPLC

[0145] Mobile phase: acetonitrile-tetrahydrofuran-purified water (10:10:80)

[0146] Diluent: water-acetonitrile (50:50)

[0147] Chromatographic column: Thermo scientific BDS Hypersil TM C18, 4×250 mm, 5 μ m

[0148] Flow rate: 1.5ml / min

[0149] Detection wavelength: 210nm, 190nm-400nm

[0150] Column temperature: 60°C

[0151] Injection volume: 50μ L

[0152] Blank solution: water-acetonitrile (50:50)

[0153] System suitability solution: Dissolve the reference substance in diluent to a concentration of 0.2%.

[0154] Test solution

[0155] (1) Weigh a tablet powder containing 100 mg of finasteride into a 50 ml volumetric flask, dissolve it in 30 ml of diluent, then make up the volume with the diluent, and centrifuge to obtain the supernatant.

[0156] (2) Take 2 ml of the supernatant in (1) and transfer it to a 100 ml volumetric flask, dilute it to volume with a diluent, and then take 1 ml of the above solution and transfer it to a 10 ml volumetric flask, dilute it to volume with a diluent.

[0157] Reference solution: Take 25 ml of solution (2) and make up to 100 ml with diluent.

[0158] Detection method of tadalafil related substances:

[0159] Detection method: HPLC

[0160] Mobile phase: Mobile phase A: 0.1% trifluoroacetic acid; Mobile phase B: acetonitrile

[0161] Chromatographic column: Zorbax SB-C8 column, 5μm, 250mm×4.6mm

[0162] Column temperature: 40°C

[0163] Injection volume: 50 μl

[0164] Flow rate: 1.0ml / min

[0165] Detection wavelength: 285nm

[0166] Elution gradient:

[0167]

[0168]

[0169] Diluent: acetonitrile, 0.1 trifluoroacetic acid

[0170] Test solution: Weigh an appropriate amount of homemade preparation (equivalent to 10 mg of tadalafil) and place it in a 25 ml volumetric flask, add about 10 ml of diluent and sonicate for 30 min, shake for 30 seconds every 5 min, let it stand at room temperature, dilute to the scale with diluent, centrifuge (10000 rpm, 5 min), filter, and take the filtrate for sampling.

[0171] Table 21

[0172]

[0173]

[0174] Conclusion: As can be seen from Table 21, the finasteride and tadalafil orally disintegrating tablets prepared by the prescription of Example 1 have the lowest comprehensive impurity level and the best control of related substance limits.

Claims

1. An orally disintegrating tablet containing finasteride and tadalafil, characterized in that: The invention comprises the following raw materials in percentage by weight: 3% to 5% of finasteride, 3% to 5% of tadalafil, 78% to 85% of mannitol, 2% to 5% of cross-linked carboxymethyl cellulose sodium, 3% to 5% of povidone, 1% to 5% of sucralose, 1% to 3% of aspartame, 1% to 2% of apple powder flavor, 1% to 3% of colloidal silicon dioxide and 1% to 3% of magnesium stearate.

2. An orally disintegrating tablet containing finasteride and tadalafil according to claim 1, characterized in that: The invention comprises the following raw materials in percentage by weight: 3.33% of finasteride, 3.33% of tadalafil, 78.83% of mannitol, 5% of cross-linked carboxymethyl cellulose sodium, 3% of povidone, 1.5% of sucralose, 1% of aspartame, 2% of apple powder flavor, 1% of colloidal silicon dioxide and 1% of magnesium stearate.

3. An orally disintegrating tablet containing finasteride and tadalafil according to claim 2, characterized in that: The particle size distribution of finasteride and tadalafil in the range of 20 mesh to 45 mesh is controlled to be above 15%.

4. The method for preparing an orally disintegrating tablet containing finasteride and tadalafil according to any one of claims 1 to 3, characterized in that: The following steps are involved: 1) Premix finasteride and tadalafil with about 1 / 2 of the filler mannitol, then add the premixed materials and cross-linked sodium carboxymethyl cellulose, sucralose, aspartame, apple powder flavor, and the remaining about 1 / 2 of the mannitol into a granulator in sequence and mix; after the parameters are stabilized, add the povidone solution to prepare a soft material discharge; 2) Wet granulation: The prepared soft material is wet granulated using a square hole screen, and the granulator speed is set to 300 rpm. After the parameters are stable, the soft material is added to the crushing and granulating machine for wet granulation; 3) adding the wet granules to a fluidized bed for drying; 4) adding the granules dried in step 3) into a pulverizing and granulating machine for granulation to obtain dry granules; 5) adding the dry granules obtained in step 4), colloidal silicon dioxide and magnesium stearate into a mixer for total mixing; 6) Orally disintegrating tablets of finasteride and tadalafil are obtained by tableting.

5. The method for preparing an orally disintegrating tablet containing finasteride and tadalafil according to claim 4, characterized in that: In the step 1), the granulator is set to have a stirring blade speed of 300 rpm and a cutting blade speed of 1000 rpm, and the mixing is performed for 5 minutes.

6. The method for preparing an orally disintegrating tablet containing finasteride and tadalafil according to claim 4, characterized in that: In the step 1), the time of adding the povidone solution is controlled within 1 minute, granulation is performed for 1 minute, the state of the material is observed, and the total granulation time is 5 minutes to prepare the soft material.

7. The method for preparing an orally disintegrating tablet containing finasteride and tadalafil according to claim 4, characterized in that: In the step 3), the temperature of the fluidized bed heater is 60° C., the fan frequency is 1000-2000 rpm, and the moisture content of the particles is controlled to be 1%-3%.

8. The method for preparing an orally disintegrating tablet containing finasteride and tadalafil according to claim 4, characterized in that: In the step 4), the pulverizer and granulator are 0.9 mm in diameter, with a circular aperture screen and a rotation speed of 500 rpm.

9. The method for preparing an orally disintegrating tablet containing finasteride and tadalafil according to claim 4, characterized in that: In the step 5), the main shaft speed of the mixer is set to 15 rpm, the secondary shaft speed is set to 15 rpm, and the mixing is performed for 10 minutes.

10. The method for preparing an orally disintegrating tablet containing finasteride and tadalafil according to any one of claims 4 to 9, wherein the tableting hardness in step 6) is 30-50N.

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