CN119112817A

CN119112817A - A tadalafil tablet and preparation method thereof

Info

Publication number: CN119112817A
Application number: CN202411144907.5A
Authority: CN
Inventors: 符洁; 周凯; 刘诚; 汪洋; 黄恋清; 熊依铭; 瞿晓梅; 黄文莲; 王晓宇; 徐丹丹
Original assignee: Wuhan Jiulong Humanwell Pharmaceutical Co ltd
Current assignee: Wuhan Jiulong Humanwell Pharmaceutical Co ltd
Priority date: 2024-08-20
Filing date: 2024-08-20
Publication date: 2024-12-13

Abstract

The invention relates to a tadalafil tablet and a preparation method thereof. The tadalafil tablet comprises a tablet core and an outer coat wrapped outside the tablet core, wherein the tablet core comprises, by weight, 20 parts of tadalafil, 9-16 parts of a first disintegrating agent, 1.5-4 parts of a first adhesive, 3-8 parts of a second adhesive, 230-260 parts of a first diluent and 0.5-1.5 parts of a surfactant, the particle size distribution of the tadalafil is 20-70 mu m and 4-35 mu m, and the outer coat comprises, by weight, 40-70 parts of a second diluent, 7-14 parts of a second disintegrating agent and 1-3 parts of a lubricant. The invention avoids the crushing process of raw materials, reduces material loss, simplifies the production process, improves economic benefit, improves the in-vitro dissolution release rate of tadalafil by optimizing the production process, increases the in-vitro dissolution rate of tadalafil, and predicts better bioavailability.

Description

Tadalafil tablet and preparation method thereof

Technical Field

The invention relates to a tadalafil tablet and a preparation method thereof.

Background

Tadalafil is one of the first-line therapeutic drugs for male Erectile Dysfunction (ED), and not only has a fast onset of action and is unaffected by feeding, but also has a large market share. Tadalafil tablet stock research is US Gift, US Food and Drug Administration (FDA) approved for use in treating male sexual dysfunction in 2003. Tadalafil tablets were approved by the FDA in 2009 for the treatment of pulmonary hypertension. The prescription compositions of the tablet cores with four specifications (20 mg, 10mg, 5mg and 2.5 mg) of tadalafil tablet are the same, and according to the technical guidelines for researching human bioequivalence of chemical drugs imitated medicines by taking pharmacokinetic parameters as end point evaluation indexes issued by the national food and drug administration drug review Center (CDE), the 20mg specification can BE used as Bioequivalence (BE) specification, and other specifications BE can BE exempted according to the strategy of 'do big or small', the method is simple, and the cost is low.

Tadalafil is the only long-acting PDE-5 inhibitor approved by FDA and CFDA in the united states, and the active ingredient tadalafil has the chemical name 6- (1, 3-benzodioxol-5-yl) -2,3,6,7,12 a-hexahydro-2-methyl, (6 r,12 ar) -pyrazino [1',2':1,6] -pyrido [3,4-b ] indole-1, 4-dione, molecular formula C ₂₂H₁₉N₃O₄, is practically insoluble in water, soluble in dimethyl sulfoxide, slightly soluble in methylene chloride, very slightly soluble in ethanol, and slightly soluble in a buffer salt solution at ph=1.0-6.8. Tadalafil is rapidly absorbed after oral administration, and the median time after dosing reaches the mean maximum observed plasma concentration (C _max) for 2 hours. However, tadalafil itself has low solubility and poor bioavailability.

The US patent (patent number: US7182958B 1) discloses a method for preparing tadalafil tablets, which comprises the steps of mixing tadalafil, disintegrating agent, binder and diluent, using aqueous solution of binder and surfactant as binder, wet granulating, drying, adding disintegrating agent, diluent and lubricant, mixing, tabletting, and coating. The disintegrating agent and the internal and external additives are combined, the adhesive adopts an internal adding and pulping method, and the surfactant and other auxiliary materials are simultaneously used for internal adding, so that the solubility of the insoluble tadalafil is increased, and the bioavailability of the insoluble tadalafil is improved. However, the prescriptions of tablets with different specifications are inconsistent, and the strategy of avoiding multiple specifications cannot be realized in the original research patent. The patent mentions that the particle size D90 of tadalafil is 4 mu m, and for the tadalafil with coarse particle size, a jet milling process may be required, the preparation process is complex, and the operation is not suitable in the actual production process.

In the patent of Tadalafil coated tablet and its preparation method (application number: CN 202311735578) applied by Shandong Lukang Co., ltd., tadalafil, diluent, disintegrating agent and surfactant are mixed and then wet granulated, the wet granules are dried and mixed with lubricant and then tableted, and finally film coating is adopted. The tablet core prescription is an equal ratio prescription, the diluent, the disintegrating agent, the adhesive and the surfactant are all added internally, and the preparations (10 mg,5mg and 2.5 mg) with different specifications are prepared by controlling the tablet weight, so that the preparation process is simple. However, in vitro dissolution curves show that the dissolution platform is low, the dissolution rates of the first 15min are greatly different between different embodiments, the dissolution behavior is poor in similarity, and a certain clinical test risk exists. In stability studies, the trend of sample dissolution under long-term and accelerated conditions lacks powerful data support.

In the patent of "a preparation method of tadalafil tablet" (application number: CN 117503716A) filed by Tonghua Tongwantong pharmaceutical industry Co., ltd, tadalafil, a diluent and a binder. Mixing disintegrating agent, adding binder and surfactant, wet granulating, drying, adding disintegrating agent and lubricant, mixing, tabletting, and coating. On the basis of the original grinding patent, microcrystalline cellulose is fully added to participate in wet granulation, the material composition of the wet granulation is changed, the risk of unqualified dry mixing and mixing uniformity is reduced, but the RSD of the mixing uniformity after the premixing and total mixing and discharging is increased, and the risk of unqualified premixing and total mixing and mixing uniformity is increased. And the in-vitro dissolution rate of the product is low, the dissolution rate is about 85% in 15min, the dissolution platform is low, and a certain clinical test risk exists.

Disclosure of Invention

The invention provides a tadalafil tablet and a preparation method thereof, and aims to overcome the technical defects of low solubility, low bioavailability, complex preparation process and the like of the tadalafil tablet in the prior art. The tadalafil tablet disclosed by the invention has the advantages of higher solubility, good bioavailability, easiness in industrialization, stable product quality and the like.

In order to achieve the above purpose, the present invention adopts the following technical scheme:

in a first aspect, the present invention provides a tadalafil tablet comprising a tablet core and a garment wrapped around the tablet core;

The tablet core comprises, by weight, 20 parts of tadalafil, 9-16 parts of a first disintegrating agent, 1.5-4 parts of a first adhesive, 3-8 parts of a second adhesive, 230-260 parts of a first diluent and 0.5-1.5 parts of a surfactant, wherein the particle size distribution of the tadalafil satisfies that D90 is 20-70 mu m and D50 is 4-35 mu m;

The coat comprises, by weight, 40-70 parts of a second diluent, 7-14 parts of a second disintegrating agent and 1-3 parts of a lubricant.

In the present invention, the "parts" in the core and the garment represent the same unit of measure.

In the present invention, the tadalafil may not be crushed.

In the present invention, the tadalafil may be screened. The sieving treatment can be performed by using a 24-mesh sieve.

In the present invention, the first disintegrant is a conventional choice in the art, such as croscarmellose sodium and/or sodium carboxymethyl starch.

In the present invention, the first disintegrant may be 9.84 parts, 12.60 parts, or 15.75 parts by weight.

In the present invention, the first disintegrant may be subjected to a sieve treatment. The sieving treatment can be performed by using a 24-mesh sieve.

In the present invention, the first binder is selected conventionally in the art, and may be selected from one or more of hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, ethyl cellulose, and povidone.

In the present invention, the first adhesive may be subjected to a screen treatment. The sieving treatment can be performed by using a 24-mesh sieve.

In the present invention, the first adhesive may be 2.45 parts by weight.

In the present invention, the second binder is a conventional choice in the art and may be selected from one or more of hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, ethyl cellulose, and povidone.

In the present invention, the second adhesive may be subjected to a screen treatment. The sieving treatment can be performed by using a 24-mesh sieve.

In the present invention, the second adhesive may be 5.60 parts by weight.

Wherein the hydroxypropyl cellulose may be a first hydroxypropyl cellulose (EXF) and/or a second hydroxypropyl cellulose (EF) having different particle diameters from each other;

The particle size distribution of the first hydroxypropyl cellulose may be:

>150μm	≤20%
		>180μm	≤10%
>250μm	≤0.1%

the particle size distribution of the second hydroxypropyl cellulose may be:

>600μm	≤15%
		>850μm	≤1.0%

The mass ratio of the first hydroxypropyl cellulose to the second hydroxypropyl cellulose may be (3-8): (1.5-4), such as 8:3.5.

In the present invention, the first diluent is selected conventionally in the art, and may be selected from one or more of lactose, corn starch, mannitol and microcrystalline cellulose.

In the present invention, the first diluent may be subjected to a sieve treatment. The sieving treatment can be performed by using a 24-mesh sieve.

Wherein the lactose can be first lactose (200M) or second lactose (F100) with different particle sizes, and the particle size distribution of the first lactose can be:

<45μm	50~65%
		<100μm	≥90%
<150μm	≥96%
		<250μm	≥99%

The particle size distribution of the second lactose may be:

<32μm	≤10%
		<100μm	20~45%
<200μm	≥80%

The mass ratio of the first lactose to the second lactose may be (200-220): (30-40), preferably (5.5-6.5): 1, e.g. 5.82:1, 5.98:1 or 6.12:1.

In the present invention, the first diluent may be 235 to 250 parts by weight, for example 238.72 parts, 244.30 parts or 249.22 parts.

In the present invention, the surfactant is a conventional choice in the art and may be selected from one or more of sodium dodecyl sulfate, sodium cetyl sulfate, sodium stearyl sulfate and sulfated castor oil.

In the present invention, the surfactant may be 0.98 to 1.00 parts by weight.

In the present invention, the second diluent is selected conventionally in the art, and may be selected from one or more of lactose, corn starch, mannitol and microcrystalline cellulose.

In the present invention, the second diluent may be subjected to a sieve treatment. The sieving treatment is preferably performed using a 24 mesh sieve.

In the present invention, the second diluent may be 52.50 parts by weight.

In a specific embodiment of the present invention, the first diluent is a first lactose and the second diluent is microcrystalline cellulose, and the mass ratio of the first lactose, the second lactose and the microcrystalline cellulose is 203.72:35:52.5, 209.30:35:52.5 or 214.22:35:52.5.

In the present invention, the second disintegrant is a conventional choice in the art, such as croscarmellose sodium and/or sodium carboxymethyl starch.

In the present invention, the second disintegrant may be subjected to a sieve treatment. The sieving treatment is preferably performed using a 24 mesh sieve.

In the present invention, the second disintegrant may be 7.66 parts, 9.80 parts, or 12.25 parts by weight.

In the present invention, the sum of the parts by weight of the second disintegrant and the first disintegrant may be 20 to 30 parts.

In the present invention, the lubricant is a common choice in the art, such as magnesium stearate and/or calcium stearate.

In the present invention, the lubricant may be 1.75 to 1.80 parts by weight.

In the present invention, the tadalafil tablet may further comprise a coating layer coated outside the outer garment. The content of the coating layer is 2.0% -3.0%, and the percentage is the ratio of the mass of the coating layer to the weight of the tadalafil tablet without the coating layer. The ingredients of the coating layer may be film coating premixes conventional in the art.

In a second aspect, the present invention provides a method for preparing tadalafil tablets, comprising the steps of:

s1, granulating mixed slurry to obtain wet particles, wherein the mixed slurry comprises an adhesive solution and first mixed powder, the adhesive solution comprises 1.5-4 parts of a first adhesive, 0.5-1.5 parts of a surfactant and a solvent, the first mixed powder comprises 20 parts of tadalafil, 9-16 parts of a first disintegrating agent, 3-8 parts of a second adhesive and 230-260 parts of a first diluent, and the particle size distribution of the tadalafil is 20-70 mu m and 4-35 mu m;

S2, tabletting a mixture, wherein the mixture comprises a second mixed powder and the wet particles after drying, and the second mixed powder comprises 40-70 parts of a second diluent, 7-14 parts of a second disintegrating agent and 1-3 parts of a lubricant.

In the present invention, "parts" in step S1 and step S2 represent the same unit of measurement.

In the present invention, in step S1, the first adhesive may be mixed with a portion of the heated solvent. The temperature of the heating may be 60-80 ℃.

In the present invention, in step S1, the first adhesive may be as described above.

In the present invention, in step S1, the surfactant may be as described above.

In the present invention, in step S1, the solvent may be water.

In the present invention, in step S1, the tadalafil may be as described above.

In the present invention, in step S1, the first disintegrant may be as described above.

In the present invention, in step S1, the second adhesive may be as described above.

In the present invention, in step S1, the first diluent may be as described above.

In the present invention, in step S1, the mixed slurry may be added to a granulating apparatus before the granulating. The shear rate at which the mixed slurry is added may be 500 to 1500rpm, for example 800 to 1200rpm. The addition rate of the mixed slurry may be 31-93g/min, such as 31-62g/min.

In the present invention, in step S1, the stirring speed may be 150 to 250rpm, for example 180 to 220rpm, during the granulation.

In the present invention, in step S1, the shearing speed may be 1500-2000rpm, for example 1800-2000rpm, during the granulation.

In the present invention, in step S1, pressurized atomization may be used in the granulation. The pressure of the pressurized atomizing may be 0.01 to 0.05MPa, for example 0.02 to 0.04MPa.

In the present invention, in step S2, the inlet air temperature may be 50-70 ℃, for example 55-65 ℃.

In the present invention, in step S2, the air inlet amount during the drying may be 100-300m ³/h, for example 180-220m ³/h.

In the present invention, in step S2, the drying may be performed with a particle moisture of <2.0% as a drying end point.

In the present invention, in step S2, the equipment used in the drying is conventional equipment in the art, such as a fluidized bed.

In the present invention, in step S2, the drying may be followed by pelleting. The finishing can be carried out by adopting a 16-mesh screen.

In the present invention, in step S2, the wet granules after drying may be mixed with the second diluent and the second disintegrant before being mixed with the lubricant. The equipment used in the mixing is conventional in the art, such as a high-efficiency three-dimensional mixer. The mixing time may be 7-15min.

In the present invention, in step S2, the target tablet weight of the compressed tablet may be 350mg.

In the present invention, in step S2, the vickers hardness of the obtained tablet may be controlled to be in the range of 70 to 110N or 70 to 90N during the tabletting.

In the invention, when the tadalafil tablet further comprises a coating layer coated outside the coat, the preparation method of the tadalafil tablet further comprises the following step of coating the tablet obtained in the step S2 in a coating solution to obtain the coating layer.

Wherein the content of the coating layer can be 2.0% -3.0%, and the percentage is the ratio of the mass of the coating layer to the weight of the tadalafil tablet without the coating layer.

Wherein the coating solution comprises a coating precursor and a solvent. The coating precursor may be a film coating premix as is conventional in the art. The solvent may be water. The solids content of the coating solution may be 8% to 16%, for example 12%.

The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.

The reagents and materials used in the present invention are commercially available.

The invention has the positive progress effects that:

(1) In the tadalafil tablet, the tadalafil raw material medicine is not crushed, so that the mixing uniformity of the product is higher, the content of related substances of the product is ensured, the in-vitro dissolution and release rate of tadalafil is improved, the in-vitro dissolution rate of tadalafil is increased, and better bioavailability is indicated;

(2) In the preparation method of the tadalafil tablet, the tadalafil raw material medicine is subjected to sieving treatment, so that the caking of materials is effectively prevented, and the final quality of the product is ensured;

(3) In the preparation method of the tadalafil tablet, the surfactant is added in a slurry preparation manner, the disintegrating agent adopts an internal-external mode, and the adhesive is added in a slurry preparation manner, so that the solubility of the tadalafil tablet can be increased, and the bioavailability of the tadalafil tablet can be improved;

(4) In the preparation method of tadalafil tablets, the air flow crushing process is omitted, the energy consumption is low, the operation is conventional, industrialization is easier to realize, and better economic benefit is brought.

Drawings

FIG. 1 is a graph showing average blood concentration versus time for a test formulation and a reference formulation in effect example 4.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

In the following examples, comparative examples, the specific cases of the raw materials and formulations mentioned are as follows:

Tadalafil, zhejiang Huahai, has a particle size distribution D90 of 20-70 μm and D50 of 4-35 μm.

Lactose 200M, manufacturer DFE,200M is lactose specification model, its particle size distribution is as follows:

<45μm	50~65%
		<100μm	≥90%
<150μm	≥96%
		<250μm	≥99%

lactose F100, manufacturer Meggle, F100 is lactose specification model, its particle size distribution is as follows:

<32μm	≤10%
		<100μm	20~45%
<200μm	≥80%

microcrystalline cellulose, model SH102, manufacturer's Anhui mountain river.

Cross-linked sodium carboxymethylcellulose, manufacturer JRS, model VIVASOL, CAS:74811-65-7.

The particle size distribution of the hydroxypropyl cellulose EXF, ashland, model EXF of manufacturer is as follows:

>150μm	≤20%
		>180μm	≤10%
>250μm	≤0.1%

Hydroxypropyl cellulose EF, manufactured by Ashland, model EF, has the following particle size distribution:

>600μm	≤15%
		>850μm	≤1.0%

film coating, film coating premix, shanghai Kalekang, model number 32K620003-CN.

Hainan Zhuo Li Tadalafil tablets, lot number 20230301.

Example 1 preparation of Tadalafil tablet (wet granulation Process, tadalafil without jet milling)

Formulation recipe as in table 1-1:

TABLE 1-1

	Prescription dose/4500 granules
		Tadalafil	90g
Lactose 200M	941.94g
		Lactose F100	157.5g
Microcrystalline cellulose	236.25g
		Croscarmellose sodium (internal adding)	56.7g
Croscarmellose sodium (plus)	44.1g
		Hydroxypropyl cellulose EXF	25.2g
Hydroxypropyl cellulose EF	11.025g
		Sodium dodecyl sulfate	4.41g
Magnesium stearate	7.875g
		Totals to	1575g

The preparation process comprises the following steps:

a. slowly adding 16.54g of hydroxypropyl cellulose EF into 225g of purified water at 60-80 ℃, adding 171.9g of cold purified water, stirring for dissolution, adding 6.62g of sodium dodecyl sulfate, and adding a small amount of purified water to the total weight of 420g (prepared according to 1.5 times of the total weight) after dissolution to obtain a binder solution;

b. the croscarmellose sodium, tadalafil, hydroxypropyl cellulose EXF, lactose F100 and lactose 200M are respectively sieved by a 24-mesh sieve, and then added into a granulator according to the prescription amount (56.7 g of croscarmellose sodium, 90g of tadalafil, 25.2g of hydroxypropyl cellulose EXF, 100.5 g of lactose F and 200M 941.94g of lactose), and mixed for 10 minutes according to 120rpm, and then the next procedure is started;

c. The binder solution was slurried into a granulator using a peristaltic pump and granulated by pressurized atomizing, the parameters of the granulation process being as shown in tables 1-2:

TABLE 1-2

Parameters (parameters)	Range of
		Stirring speed/rpm	180-220
Shear speed/rpm during pulping	800-1200
		Shear speed/rpm during granulation	1800-2000
Peristaltic pump speed/rpm	10-20
		Peristaltic pump flow/g.min ^-1	31-62
Atomization pressure/MPa	0.02-0.04

D. The wet granules prepared by the granulator were added to a fluid bed for drying operation, and the parameters of the drying process were as shown in tables 1 to 3:

Tables 1 to 3

Parameters (parameters)	Control range
		Inlet air temperature/°c	55-65
Air intake/m ³·h^-1	180-220

When the moisture of the particles is less than 2.0%, the drying end point is reached, the dried particles are granulated by a 16-mesh screen, and then added into a high-efficiency three-dimensional mixer together with 236.25g of microcrystalline cellulose and 44.1g of crosslinked sodium carboxymethyl cellulose to be mixed for 15min, and then 7.875g of magnesium stearate is added to be mixed for 7min;

e. tabletting with 350mg tablet weight as target tablet weight, and controlling the Vickers hardness range to 70-110N.

F. film coating is carried out with the coating weight gain of 2.0% -3.0% as the target, and the percentage is the ratio of the increased mass of the coating to the weight of the tablet before coating.

Example 2 preparation of tadalafil tablets (wet granulation Process, tadalafil without jet milling, disintegrant 17.5 parts)

Formulation recipe as in table 2-1:

TABLE 2-1

The preparation process comprises the following steps:

b. Sieving croscarmellose sodium, tadalafil, hydroxypropyl cellulose EXF, lactose F100 and 200M with 24 mesh sieve respectively, adding into granulator according to prescription amount (croscarmellose sodium 44.28g, tadalafil 90g, hydroxypropyl cellulose EXF 25.2g, lactose F100.5 g, lactose 200M 963.99 g), mixing at 120rpm for 10min, and starting the next procedure;

c. the binder solution was slurried into a granulator using a peristaltic pump and granulated by pressurized atomizing, the parameters of the granulation process being as shown in tables 2-2:

TABLE 2-2

	Control range
		Stirring speed/rpm	180-220
Shear speed/rpm during pulping	800-1200
		Shear speed/rpm during granulation	1800-2000
Peristaltic pump speed/rpm	10-20
		Peristaltic pump flow/g.min ^-1	31-62
Atomization pressure/MPa	0.02-0.04

D. the wet granules prepared by the granulator were added to a fluid bed for drying operation, and the parameters of the drying process were as shown in tables 2 to 3:

Tables 2 to 3

When the moisture of the particles is less than 2.0%, the drying end point is reached, the dried particles are granulated by a 16-mesh screen, and then added into a high-efficiency three-dimensional mixer together with 236.25g of microcrystalline cellulose and 34.47g of crosslinked sodium carboxymethyl cellulose to be mixed for 15min, and then 7.875g of magnesium stearate is added to be mixed for 7min;

Example 3 preparation of tadalafil tablets (wet granulation Process, tadalafil without jet milling, disintegrant 28 parts)

Formulation recipe as in table 3-1:

TABLE 3-1

	Prescription dose/4500 granules
		Tadalafil	90g
Lactose 200M	916.74g
		Lactose F100	157.5g
Microcrystalline cellulose	236.25g
		Croscarmellose sodium (internal adding)	70.88g
Croscarmellose sodium (plus)	55.13g
		Hydroxypropyl cellulose EXF	25.2g
Hydroxypropyl cellulose EF	11.025g
		Sodium dodecyl sulfate	4.41g
Magnesium stearate	7.875g
		Totals to	1575g

The preparation process comprises the following steps:

b. sieving croscarmellose sodium, tadalafil, hydroxypropyl cellulose EXF, lactose F100 and 200M with 24 mesh sieve respectively, adding into granulator according to prescription amount (croscarmellose sodium 70.88g, tadalafil 90g, hydroxypropyl cellulose EXF 25.2g, lactose F100.5 g, lactose 200M 916.74 g), mixing at 120rpm for 10min, and starting the next procedure;

c. the binder solution was slurried into a granulator using a peristaltic pump and granulated by pressurized atomizing, the parameters of the granulation process being as shown in tables 3-2:

TABLE 3-2

D. The wet granules prepared by the granulator were added to a fluid bed for drying operation, and the parameters of the drying process were as shown in tables 3 to 3:

TABLE 3-3

When the moisture of the particles is less than 2.0%, the drying end point is reached, the dried particles are granulated by a 16-mesh screen, and then added into a high-efficiency three-dimensional mixer together with 236.25g of microcrystalline cellulose and 55.13g of croscarmellose sodium to be mixed for 15min, and then added with 7.875g of magnesium stearate to be mixed for 7min;

Example 4 preparation of Tadalafil tablet (wet granulation Process, tadalafil without jet milling, vickers hardness range controlled between 70-90N)

Formulation recipe as in table 4-1:

TABLE 4-1

The preparation process comprises the following steps:

b. The croscarmellose sodium, tadalafil, hydroxypropyl cellulose EXF, lactose F100 and 200M are respectively sieved by a 24-mesh sieve, and then added into a granulator according to the prescription amount (56.7 g of croscarmellose sodium, 90g of tadalafil, 25.2g of hydroxypropyl cellulose EXF, 100.5 g of lactose F and 200M 941.94g of lactose), and mixed for 10 minutes according to 120rpm, and then the next procedure is started;

c. The binder solution was slurried into a granulator using a peristaltic pump and granulated by pressurized atomizing, the parameters of the granulation process being as shown in tables 4-2:

TABLE 4-2

D. The wet granulation prepared by the granulator was fed to a fluid bed for drying, and the parameters of the drying process were as shown in tables 4-3:

TABLE 4-3

e. Tabletting with 350mg tablet weight as target tablet weight, and controlling the Vickers hardness range to 70-90N.

Example 5 preparation of Tadalafil tablet (wet granulation Process, tadalafil without jet milling, vickers hardness range controlled between 90 and 110N)

Formulation recipe as in table 5-1:

TABLE 5-1

The preparation process comprises the following steps:

c. The binder solution was slurried into a granulator using a peristaltic pump and granulated by pressurized atomizing, the parameters of the granulation process being as shown in tables 5-2:

TABLE 5-2

D. the wet granulation prepared by the granulator was fed to a fluid bed for drying operation, and the parameters of the drying process were as shown in tables 5-3:

TABLE 5-3

e. Tabletting with 350mg tablet weight as target tablet weight, and controlling the Vickers hardness range to 90-110N.

Comparative example 1 preparation of tadalafil tablets (direct compression Process, tadalafil jet milling)

Formulation recipe as in table 6-1:

TABLE 6-1

A. according to the mass ratio of the prescription of the preparation, tadalafil and sodium dodecyl sulfate are mixed and then subjected to jet milling to obtain co-milled materials, wherein the particle size distribution of the co-milled materials is D90 less than or equal to 10 mu m, and D50 less than or equal to 4 mu m;

b. Sieving the co-crushed materials, the hydroxypropyl cellulose, the croscarmellose sodium and the microcrystalline cellulose by a 40-mesh sieve respectively, and adding the co-crushed materials (100 g of the co-crushed materials, 26g of the hydroxypropyl cellulose, 96g of the croscarmellose sodium and 236g of the microcrystalline cellulose), 942g of lactose and 12g of silicon dioxide into a high-efficiency three-dimensional mixer together according to the prescription amount for mixing for 30min;

c. Adding 12g of magnesium stearate into the efficient three-dimensional mixer, and continuously mixing with the mixed material obtained in the step b for 7min;

d. tabletting with 356mg tablet weight as target tablet weight, and controlling Vickers hardness at 40-80N.

E. Film coating is carried out with the coating weight gain of 2.0% -3.0% as the target, and the percentage is the ratio of the increased mass of the coating to the weight of the tablet before coating.

Comparative example 2 preparation of tadalafil tablets (wet granulation process, tadalafil jet milled) formulation recipe, as shown in table 7-1:

TABLE 7-1

A. according to the mass ratio of the prescription of the preparation, tadalafil and lactose F100 are mixed and then subjected to air current crushing to obtain co-crushed materials, wherein the particle size distribution of the co-crushed materials is D90 less than or equal to 10 mu m, and D50 less than or equal to 4 mu m;

b. Slowly adding 16.54g of hydroxypropyl cellulose EF into 225g of purified water at 60-80 ℃, adding 171.9g of cold purified water, stirring for dissolution, adding 6.62g of sodium dodecyl sulfate, adding a small amount of purified water after dissolution until the total weight is 420g (prepared according to 1.5 times of the total weight), and obtaining a binder solution;

c. Sieving croscarmellose sodium, co-crushed material, hydroxypropyl cellulose EXF and lactose 200M with 24 mesh sieve respectively, adding into granulator according to prescription amount (croscarmellose sodium 56.7g, co-crushed material 247.5g, hydroxypropyl cellulose EXF 25.2g, lactose 200M 941.94 g), mixing at 120rpm for 10min, and starting the next procedure;

d. The binder solution was slurried into a granulator using a peristaltic pump and granulated by pressurized atomizing, the parameters of the granulation process being as shown in tables 7-2:

TABLE 7-2

	Control range
		Stirring speed/rpm	180-220
Shear speed/rpm during pulping	800-1200
		Shear speed/rpm during granulation	1800-2000
Peristaltic pump rate/rpm	10-20
		Peristaltic pump flow/g.min ^-1	31-62
Atomization pressure/MPa	0.02-0.04

E. the wet granulation prepared by the granulator was fed to a fluid bed for drying, and the parameters of the drying process were as shown in tables 7-3:

TABLE 7-3

f. Tabletting with 350mg tablet weight as target tablet weight, and controlling the Vickers hardness range to 70-110N.

G. Film coating is carried out with the coating weight gain of 2.0% -3.0% as the target, and the percentage is the ratio of the increased mass of the coating to the weight of the tablet before coating.

Effect example 1 detection of the content of the preparation

1. Test subjects 20mg tadalafil tablets of example 1, comparative examples 1-2 and Hainan Zhuo Li.

2. The test method is a content inspection method according to the rule of four parts of the edition 2020 of Chinese pharmacopoeia.

3. The content uniformity is shown in Table 8,

TABLE 8

Example 1	Example 2	Example 3	Example 4
				Average content of	101.26%	100.37%	99.77%	103.83%
Example 5	Comparative example 1	Comparative example 2	Hainan Zhuo Li
				Average content of	101.92%	99.67%	97.83%	98.69%

From the results in Table 8, it is clear that the formulation contents of 20mg tadalafil tablets of examples 1-5, comparative examples 1-2 and Hainan Zhuo Li all meet the specification of 95% -105% of the edition 2020 of Chinese pharmacopoeia.

It is further understood that the formulation contents of the formulation products prepared by wet process using the non-pulverized tadalafil of examples 1 to 5 are significantly better than those of the formulation products prepared by direct compression process after pulverizing tadalafil of comparative example 1 and wet granulation process after pulverizing tadalafil of comparative example 2, and 20mg tadalafil tablets of Hainan Zhuo Li.

In addition, in examples 1-5, the tadalafil crude drug was not pulverized, and the preparation process was simplified, and the material loss in the pulverization process was avoided. Also, the formulation process of examples 1-5 is superior to comparative examples 1-2 in achieving a blend uniformity of small gauge tadalafil flake products.

Effect example 2 preparation dissolution test

1. Test subjects 20mg tadalafil tablets of examples 1-5, comparative examples 1-2 and Hainan Zhuo Li.

2. The test method is a dissolution inspection method according to the rule of four parts of the edition 2020 of Chinese pharmacopoeia.

3. Test results as shown in table 9,

TABLE 9

Example 1	Example 2	Example 3	Example 4
				Dissolution (30 min)	94.1%	98.6%	99.0%	101.3%
Example 5	Comparative example 1	Comparative example 2	Hainan Zhuo Li
				Dissolution (30 min)	98.6%	89.5%	91.6%	93.5%

From the results of table 9, it is clear that the 30min dissolution rate of the formulation product prepared in comparative example 1 using the direct compression process after tadalafil pulverization and comparative example 2 using the wet granulation process after tadalafil pulverization is significantly lower. The 30min dissolution of the formulation products of examples 1-5 is significantly higher than comparative examples 1-2, comparable to 20mg tadalafil tablets of Hainan Zhuo Li, with higher dissolution, meaning good in vivo bioavailability.

In addition, the technological process of the embodiment 1-5 does not have the jet milling procedure, has low energy consumption and conventional operation, is easier to realize industrialization, and brings better economic benefit.

Effect example 3 detection of substances related to formulation

1. Test subjects 20mg tadalafil tablets of example 1, comparative example 1 and Hainan Zhuo Li.

2. The test method is a related substance inspection method according to the rule of four parts of Chinese pharmacopoeia 2020 edition.

3. Test results as shown in table 10,

Table 10

Related substances	Example 1	Comparative example 1	Hainan Zhuo Li
				Unknown list 1	0.008%	0.016%	0.028%
Unknown list of impurities 2	ND	ND	ND
				Total impurities	0.008%	0.016%	0.028%

From the results in table 10, the formulation of example 1 had lower levels of relevant substances, significantly lower than the 20mg tadalafil tablets sold by comparative example 1 and by hainan Zhuo Lishi.

Effect example 4 formulation bioequivalence results

1. Test subjects Tadalafil tablet of example 1 (20 mg) and commercially available Tadalafil tablet Xili (20 mg, lot number: D461242)

2. The testing method comprises the following steps:

(1) Experimental design Tadalafil tablet Hill (20 mg, lot number: D461242) as a reference formulation and Tadalafil tablet (20 mg) as a test formulation in example 1, bioequivalence study of fasting, single-center, random, open, two-cycle, double-crossover design was performed in 8 Chinese healthy male subjects, and 1 tablet at a time, 240mL water was taken orally.

(2) Blood sampling points were designed to sample blood 1h (0 h) before administration and 0.25h、0.50h、0.75h、1.00h、1.25h、1.50h、2.00h、2.50h、3.00h、4.00h、5.00h、6.00h、9.00h、12.00h、24.00h、48.00h、72.00h h and 96.00h (18 blood sampling points total) after administration, respectively, and to measure the concentration of tadalafil in blood plasma.

(3) The main evaluation index (effectiveness index) is C _max、AUC_0-t and AUC _0-∞.

3. The results of the experiment are shown in the following figure 1, and the results of the pharmacokinetic parameter estimation are shown in the following table 11 according to the blood concentration data:

TABLE 11

From the results in table 11, it can be seen that the 90% confidence intervals of the fasting single oral self-developing agents C _max、AUC_0-t and AUC _0-∞ fall within the range of 80% -125% compared to the reference formulation, i.e., the formulation of example 1 is bioequivalent to the reference formulation.

In summary, the tadalafil tablet and the preparation method thereof avoid the crushing procedure of raw materials in the production process, reduce material loss, simplify the production process and improve economic benefit, and improve the in-vitro dissolution release rate of tadalafil, increase the in-vitro dissolution rate of tadalafil, have good bioavailability and bioequivalence with a reference preparation by optimizing the production process.

Claims

1. A tadalafil tablet comprising a tablet core and a garment wrapped around the tablet core;

2. Tadalafil tablet according to claim 1, wherein the tadalafil is not broken;

and/or, the tadalafil is sieved, preferably by a 24-mesh sieve;

And/or, the first disintegrating agent is croscarmellose sodium and/or sodium carboxymethyl starch;

And/or 9.84 parts, 12.60 parts or 15.75 parts by weight of the first disintegrant;

and/or the first disintegrant is subjected to a sieving treatment, which is preferably carried out using a 24 mesh sieve;

and/or the second disintegrant is, for example, croscarmellose sodium and/or sodium carboxymethyl starch;

and/or the second disintegrant is 7.66 parts, 9.80 parts, or 12.25 parts by weight;

And/or the second disintegrant is subjected to a sieving treatment, which is preferably carried out using a 24 mesh sieve;

And/or, the sum of the parts by weight of the second disintegrating agent and the first disintegrating agent is 20-30 parts;

and/or the first binder is selected from one or more of hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, ethyl cellulose, and povidone;

and/or, the first adhesive is subjected to a sieving treatment, preferably with a 24 mesh sieve;

And/or, the first adhesive is 2.45 parts by weight;

and/or the second binder is selected from one or more of hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, ethyl cellulose, and povidone;

And/or the second binder is subjected to a sieving treatment, preferably using a 24 mesh sieve

And/or, the second adhesive is 5.60 parts by weight;

and/or the first diluent is selected from one or more of lactose, corn starch, mannitol and microcrystalline cellulose;

and/or, the first diluent is subjected to a sieving treatment, preferably a 24 mesh sieving treatment;

And/or the first diluent is 235-250 parts by weight, such as 238.72 parts, 244.30 parts, or 249.22 parts;

And/or the second diluent is selected from one or more of lactose, corn starch, mannitol and microcrystalline cellulose;

And/or, the second diluent is subjected to a sieving treatment, preferably with a 24 mesh sieve;

and/or, the second diluent is 52.50 parts by weight;

And/or the surfactant is selected from one or more of sodium dodecyl sulfate, sodium hexadecyl sulfate, sodium octadecyl sulfate and sulfated castor oil;

and/or, the weight part of the surfactant is 0.98-1.00 part;

and/or the lubricant is magnesium stearate and/or calcium stearate;

And/or, the weight part of the lubricant is 1.75-1.80 parts;

and/or the tadalafil tablet further comprises a coating layer coated outside the coat, wherein the content of the coating layer is preferably 2.0-3.0 percent, and the percentage is the ratio of the mass of the coating layer to the weight of the tadalafil tablet without the coating layer.

3. Tadalafil tablet according to claim 2, characterized in that the hydroxypropyl cellulose is a first and/or a second hydroxypropyl cellulose having particle sizes different from each other, the particle size distribution of the first hydroxypropyl cellulose being:

>150μm ≤20% >180μm ≤10% >250μm ≤0.1%

the particle size distribution of the second hydroxypropyl cellulose is as follows:

>600μm ≤15% >850μm ≤1.0%

Preferably, the mass ratio of the first hydroxypropyl cellulose to the second hydroxypropyl cellulose is (3-8): (1.5-4), e.g. 8:3.5.

4. Tadalafil tablet according to claim 2, wherein the lactose is a first lactose or a second lactose having different particle sizes from each other;

the particle size distribution of the first lactose is as follows:

<45μm 50~65% <100μm ≥90% <150μm ≥96% <250μm ≥99%

The particle size distribution of the second lactose is as follows:

<32μm ≤10% <100μm 20~45% <200μm ≥80%

Preferably, the mass ratio of the first lactose to the second lactose is (200-220): (30-40), more preferably 5.5-6.5:1, such as 5.82:1, 5.98:1 or 6.12:1.

5. Tadalafil tablet according to claim 4, wherein the first diluent is a first lactose and a second lactose, the second diluent is microcrystalline cellulose, and the mass ratio of the first lactose, the second lactose and the microcrystalline cellulose is 203.72:35:52.5, 209.30:35:52.5 or 214.22:35:52.5.

6. A method for preparing tadalafil tablets, which is characterized by comprising the following steps:

7. The process for the preparation of tadalafil tablets according to claim 6, characterized in that in step S1, the first binder is first mixed with a portion of heated solvent, preferably at a temperature of 60-80 ℃;

and/or, in step S1, the first adhesive is as defined in any one of claims 2 to 4;

and/or, in step S1, the surfactant is as defined in any one of claims 2 to 4;

and/or, in the step S1, the solvent is water;

And/or, in step S1, the tadalafil is as defined in any of claims 2-4;

and/or, in step S1, the first disintegrant is as defined in any of claims 2 to 4;

and/or, in step S1, the second binder is as defined in any one of claims 2 to 4;

and/or, in step S1, the first diluent is as defined in any one of claims 2 to 4;

and/or, in step S1, the mixed slurry is added to the granulating equipment before granulating, the shearing speed of the mixed slurry is preferably 500-1500rpm, such as 800-1200rpm, and the adding speed of the mixed slurry is preferably 31-93g/min, such as 31-62g/min;

and/or, in step S1, the stirring speed is preferably 150-250rpm, for example 180-220rpm, during said granulating;

And/or, in step S1, the shearing speed is preferably 1500-2000rpm, for example 1800-2000rpm, during said granulating;

And/or, in step S1, the granulation is preferably performed by pressurized atomization, and the pressure of the pressurized atomization is preferably 0.01-0.05MPa, for example 0.02-0.04MPa.

8. The process for the preparation of tadalafil tablets according to claim 6, characterized in that in step S2, the intake air temperature during the drying is 50-70 ℃, such as 55-65 ℃;

And/or, in step S2, the air inlet quantity is 100-300m ³/h, for example 180-220m ³/h;

And/or, in step S2, the drying is performed with a particle moisture <2.0% as a drying end point;

and/or, in step S2, the equipment used in the drying is a fluidized bed;

And/or, in step S2, after drying, finishing, wherein the finishing is preferably performed by adopting a 16-mesh screen;

And/or in step S2, the wet granules after drying are mixed with the second diluent and the second disintegrant and then mixed with the lubricant, wherein the equipment used in the mixing is preferably a high-efficiency three-dimensional mixer, and the mixing time is preferably 7-15min;

and/or, in step S2, the target tablet weight of the tabletting is 350mg;

and/or, in the step S2, controlling the Vickers hardness of the obtained tablet to be 70-110N or 70-90N during tabletting.

9. The method for preparing tadalafil tablets according to claim 6, wherein when the tadalafil tablets further comprise a coating layer coated outside the outer coat, the method for preparing tadalafil tablets further comprises the steps of coating the tablets obtained in step S2 in a coating solution to obtain a coating layer;

preferably, the content of the coating layer is 2.0% -3.0%, and the percentage is the ratio of the mass of the coating layer to the weight of the tadalafil tablet without the coating layer;

preferably, the coating solution comprises a coating precursor and a solvent, preferably water, and the coating solution preferably has a solids content of 8% to 16%, for example 12%.

10. A tadalafil tablet prepared by the process for preparing a tadalafil tablet as defined in any one of claims 6-9.