WO2017041679A1 - Solid dispersion of tadalafil and pharmaceutical excipients, and preparation method for solid dispersion - Google Patents

Abstract

Provided are a solid dispersion of tadalafil and pharmaceutical excipients, and a preparation method for the solid dispersion. The tadalafil is in an amorphous state. Also provided are a pharmaceutical composition containing the solid dispersion, and a preparation method for the pharmaceutical composition. Also provided is a use of the solid dispersion in the preparation of a drug treating male erectile dysfunction.

Description

Solid dispersion of tadalafil and medicinal adjuvant and preparation method thereof Technical field

The invention belongs to the field of pharmaceutical preparations, in particular to a solid dispersion of tadalafil and a medicinal adjuvant and a preparation method thereof, and to a pharmaceutical composition containing an amorphous tadalafil solid dispersion and preparation thereof A method, and the use of the composition for the manufacture of a medicament for treating male erectile dysfunction.

Background technique

Tadalafil, chemical name (6R, 12aR)-6-(1,3-benzodioxan-5-yl)-2-methyl-2,3,6,7,12, 12a-hexahydropyrazino[1',2'-1,6]-pyrido[3,4-b]indole-1,4-dione, sold under the trade name Calais, by American It was developed by the company and was launched in the United States in January 2008 for the treatment of male erectile dysfunction.

There is a polymorphic phenomenon in tadalafil. Patent CN1045777 discloses a white needle crystal of tadalafil, Form I. Patent WO2006/049986 discloses crystalline form Form A, Form B and amorphous of tadalafil. Patents WO2006/050458 disclose Forms II, III, IV, VI, VII and VIII of tadalafil. Although a variety of solid forms of tadalafil have been disclosed, patent WO2001/008688 states that he is a poorly soluble drug and that the resulting Form I must be further comminuted to increase the feedstock. The dissolution rate of the drug, the dissolution of the formulation, and the bioavailability. The patent states that it is necessary to prepare a crystalline drug powder or an amorphous drug powder into particles having a particle size distribution d90 equal to 40 micrometers, that is, more than 90% of the particles are less than 40 micrometers, in order to have a better therapeutic effect.

The solid form of the drug directly affects the dissolution rate of the drug substance, the dissolution rate of the drug, and the bioavailability. In order to improve the bioavailability of the drug, reduce the dosage, and reduce the side effects, a new solid form of the drug is usually developed. Solid forms with better drug solubility and higher bioavailability are necessary.

In addition to the crystalline state, the solid form of the drug has an amorphous state. The amorphous state of the drug, as a special form of solid matter, has an important use in drug preparation. Amorphous drugs can be widely used not only in pharmaceutical preparations, but also in a variety of technical means and methods to improve the stability of amorphous drugs, making them a good quality drug.

Due to the lack of bioavailability of tadalafil and the good application prospects of the active ingredients of amorphous drugs in pharmaceutical preparations, it is necessary to find a new amorphous form of tadalafil and its preparation method.

Summary of the invention

The object of the present invention is to provide a solid dispersion of tadalafil and a medicinal adjuvant, and a preparation method thereof, which can obtain a solid dispersion of an amorphous form of tadalafil and a pharmaceutically acceptable excipient with good stability and dispersibility. , added Tada The dissolution rate is not limited by the drying process, nor is it limited by the type of solvent and the amount of solvent, and the operation is simple, the cost is low, the implementation is easy, and industrial production can be realized.

In order to achieve the above object, the technical solution of the present invention is as follows:

A solid dispersion of tadalafil and a pharmaceutical excipient comprising tadalafil and a pharmaceutically acceptable excipient in a weight ratio of 1:0.1 to 100, wherein the tadalafil In the amorphous state, the X-ray powder diffraction spectrum of the solid dispersion deducts the characteristic peak of the crystal of tadalafil after subtracting the background peak of the pharmaceutical excipient.

Further, the medicinal adjuvant is selected from the group consisting of an excipient, a propellant, a solubilizer, a cosolvent, an emulsifier, a colorant, a binder, a disintegrant, a filler, a lubricant, a wetting agent, an osmotic pressure regulator, Stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surface active agents Agent, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, antioxidant, adsorbent, filter aid, release retardant At least one.

Preferably, the medicinal adjuvant is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymer, polyacetic acid Ethylene, carboxymethylethylcellulose, carboxymethylcellulose phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin , carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan At least one of chitosan, ion exchange resin and collagen.

Further, the present invention provides a pharmaceutical composition comprising a solid dispersion of tadalafil, which forms a solid dispersion with an organic vehicle, the solid dispersion forming a composition with a pharmaceutical formulation adjuvant, The weight of tadalafil is 20-80% of the total weight of the solid dispersion, and the weight of the auxiliary material is 0.1-80% by weight of the solid dispersion, wherein the tadalafil is an amorphous state. In the X-ray powder diffraction spectrum of the composition, the characteristic peak of the tadalafil crystal is absent after subtracting the background peak of the carrier and the pharmaceutically acceptable excipient.

Further, the organic vehicle is selected from a pharmaceutically acceptable polymer or copolymer.

Preferably, the organic vehicle is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymer, polyvinyl acetate. , carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, polyacrylic resin, Carbopol, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, At least one of chitosan, ion exchange resin, and collagen.

Further, the pharmaceutical preparation auxiliary is selected from the group consisting of an excipient, a propellant, a solubilizer, a solubilizer, an emulsifier, a colorant, a binder, a disintegrator, a filler, a lubricant, a wetting agent, and an osmotic pressure adjustment. Agents, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, Surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, antioxidant, adsorbent, filter aid, release retarder Medium At least one of them.

The preparation method of the solid dispersion of tadalafil and the medicinal adjuvant of the invention comprises the following steps:

1) mixing tadalafil with a medicinal adjuvant, heating until the medicinal adjuvant melts; wherein the weight ratio of tadalafil to the medicinal adjuvant is 1:0.1-100;

2) After mixing and cooling, the mixture was pulverized to obtain a solid dispersion of an amorphous form of tadalafil and a pharmaceutically acceptable adjuvant.

The invention provides a preparation method of another solid dispersion of tadalafil and a medicinal adjuvant, comprising the following steps:

1) mixing tadalafil with a medicinal adjuvant in a solvent at a mixing temperature of -50 to 150 ° C to form a solution or suspension containing tadalafil and a pharmaceutical excipient, wherein tadalafil and a solvent are used. The weight ratio is 0.001 to 100:1, and the weight ratio of tadalafil to the medicinal excipient is 1:0.1 to 100;

2) The solvent in the solution or suspension obtained in the step 1) is removed to obtain a solid dispersion of the amorphous form of tadalafil and a pharmaceutically acceptable adjuvant.

Further, in the above two preparation methods, the pharmaceutical auxiliary is selected from the group consisting of an excipient, a propellant, a solubilizer, a co-solvent, an emulsifier, a colorant, a binder, a disintegrant, a filler, a lubricant, and a wetting agent. Agent, osmotic pressure regulator, stabilizer, glidant, flavoring agent, preservative, suspending agent, coating material, fragrance, anti-adhesive agent, integrator, penetration enhancer, pH adjuster, buffer , plasticizer, surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and deflocculant, antioxidant, adsorbent, filter aid And releasing at least one of the retarders.

Preferably, the pharmaceutical excipient described in step 1) is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymerization. , polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate , polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide At least one of chitosan, chitosan, ion exchange resin, and collagen.

Further, in the second method, the solvent in the step 1) is selected from the group consisting of alcohols having 12 or less carbon atoms, phenols, ethers, halogenated hydrocarbons, ketones, aldehydes, nitriles, amides, sulfones, The at least one of the sulfoxide, the carboxylic acid and the water, the step 2) the method of removing the solvent comprises: evaporation, vacuum evaporation, spray drying, freeze drying, hot melt extrusion, filtration, centrifugation or stirring film drying.

The preparation method of the pharmaceutical composition containing the tadalafil solid dispersion of the present invention comprises the following steps:

1) mixing tadalafil, at least one organic vehicle and at least one pharmaceutical preparation auxiliary, and heating to melt, wherein the weight of tadalafil is 20 to 80% of the total weight of the solid dispersion, the auxiliary material The weight is 0.1 to 80% by weight of the solid dispersion;

2) The mixture was uniformly cooled, and the resulting mixture was pulverized to obtain a pharmaceutical composition containing an amorphous form of the tadalafil solid dispersion.

The present invention provides a process for the preparation of a pharmaceutical composition comprising a solid dispersion of tadalafil comprising the steps of:

1) mixing tadalafil, at least one organic vehicle and at least one pharmaceutical preparation auxiliary in a solvent at a mixing temperature of -50 to 150 ° C to form an intermediate containing tadalafil, an organic vehicle and a pharmaceutical preparation. a solution or suspension wherein the weight ratio of tadalafil to the solvent is from 0.001 to 100:1, the weight of tadalafil is from 20 to 80% by weight based on the total weight of the solid dispersion, and the weight of the auxiliary material is a solid dispersion. 0.1 to 80% by weight;

2) The solvent in the solution or suspension obtained in the step 1) is removed to obtain a pharmaceutical composition containing the amorphous form of the tadalafil solid dispersion.

Further, in the above two preparation methods, the organic vehicle described in the step 1) is selected from a pharmaceutically acceptable polymer or copolymer.

Preferably, the organic vehicle described in the step 1) is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, polyethylene glycol, ethylcellulose, liposome, methacrylic acid copolymer , polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, Polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, At least one of chitosan, chitosan, and collagen.

Further, the pharmaceutical preparation auxiliary agent described in the step 1) is selected from the group consisting of an excipient, a propellant, a solubilizer, a solubilizer, an emulsifier, a colorant, a binder, a disintegrant, a filler, a lubricant, and a wetting agent. , osmotic pressure regulator, stabilizer, glidant, flavoring agent, preservative, suspending agent, coating material, fragrance, anti-adhesive agent, integrator, penetration enhancer, pH adjuster, buffer, Plasticizers, surfactants, foaming agents, defoamers, thickeners, inclusion agents, humectants, absorbents, diluents, flocculants and deflocculants, antioxidants, adsorbents, filter aids, At least one of releasing a retarder.

Preferably, if there is a solvent in the step 1), the solvent is selected from the group consisting of alcohols having 12 or less carbon atoms, phenols, ethers, halogenated hydrocarbons, ketones, aldehydes, nitriles, amides, sulfones. And at least one of sulfoxide, carboxylic acid and water, and step 2) removing the solvent comprises: evaporation, vacuum evaporation, spray drying, freeze drying, hot melt extrusion, filtration, centrifugation or stirring film drying.

The solid dispersion pharmaceutical composition of the present invention containing amorphous tadalafil can be used to treat male erectile dysfunction.

The composition in the present invention means a mixture, a composite, a copolymer, a coprecipitate, a eutectic, a solid dispersion, a solvate, and a hydrate.

The pharmaceutically acceptable excipients and pharmaceutically acceptable excipients in the present invention refer to excipients and additives used in the production of pharmaceuticals and formulation, including excipients, propellants, solubilizers, solubilizers, emulsifiers, colorants, Adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives , integrator, penetration enhancer, pH adjuster, buffer, plasticizer, surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, Thinner, flocculant and deflocculant, antioxidant, adsorbent, filter aid, release retarder, etc.

The solid dispersion of tadalafil and the medicinal excipient of the present invention, using Cu-Kα radiation, deducting the background peak of the medicinal excipient from the X-ray powder diffraction spectrum expressed by degree 2θ The peak indicates that he is not amorphous. The crystalline state of tadalafil is generally used in the prior art, and no report of its amorphous state has been reported. Generally, due to the ordered and periodic arrangement of crystalline material molecules, the energy of the interaction between molecules is reduced, and the energy is low. However, the tadalafil of the present invention is an amorphous state, and the molecules are in a highly disordered state. The surface free energy is larger, the molecules in the solid matter have higher energy than the molecules in the crystalline solid matter, are more easily dispersed, increase the dissolution rate, and improve the bioavailability of tadalafil.

The invention combines tadalafil and medicinal auxiliary materials uniformly, and uses the "solid dispersing agent" method to block the drug molecules through the polymer network structure of the medicinal auxiliary materials, thereby not only inhibiting the occurrence of crystallization, but also preventing the drug molecules from being preserved. The stereotyped state; at the same time, the drug molecules are highly dispersed, and the drug molecules can be formed into particles having extremely small particle size without further pulverization. The invention adopts the medicinal excipients which are widely used, low in price and good in solubility, and the medicinal excipients are mixed with tadalafil, and can be obtained by the techniques of evaporation, spray drying, freeze drying and hot melt extrusion to obtain tadalafil. The amorphous form increases the stability of the amorphous form of tadalafil in the solid dispersion of the tadalafil of the present invention.

The invention selects a pharmaceutically acceptable and inexpensive auxiliary material, obtains a solid dispersion of tadalafil and a medicinal adjuvant, and is easy to develop a formulation, and the preparation method of the invention is not limited by the drying process and is not affected by the solvent. The type and amount of solvent are limited, easy to operate, low in cost, easy to implement, and industrially achievable.

The object of the present invention is to provide a pharmaceutical composition containing an amorphous form of tadalafil solid dispersion and a preparation method thereof, and to obtain a pharmaceutical form of an amorphous form of tadalafil having good stability and dispersibility. The composition increases the dissolution rate of tadalafil. The preparation method is not limited by the drying process, and is not limited by the type of solvent and the amount of solvent. The operation is simple, the cost is low, the implementation is easy, and industrial production can be realized.

Compared with the prior art, the beneficial effects of the present invention are:

1) The solid dispersion of the amorphous tadalafil prepared by the present invention and the medicinal adjuvant has high dispersibility and stability, and the drug molecule forms fine particles having a very small particle size in the solid dispersion, after being prepared into a solid preparation, After disintegration, the dispersion of the drug particles is better, the dispersion and dissolution rate are faster, and the absorption of the drug is facilitated. Therefore, the dissolution rate of the drug in the amorphous state is significantly increased, which is more conducive to the absorption of the drug by the body, and the bioavailability of the drug is improved, so that the drug can better exert the therapeutic effect of the clinical disease.

2) The preparation method of the solid dispersion of tadalafil and the medicinal auxiliary material in the amorphous state of the invention is not limited by the drying process, and is not limited by the kind of the solvent and the amount of the solvent, and is easy to operate, low in cost, and easy to realize. Industrial production can be achieved.

3) The solid dispersion of tadalafil and the medicinal excipient in the amorphous state prepared by the present invention can maintain good physical stability and chemistry under accelerated test conditions (40±2° C., humidity 75%±5%). stability. Therefore, the present invention will have broad application prospects.

DRAWINGS

1 is an X-ray powder diffraction pattern of a solid dispersion of amorphous tadalafil and povidone K30 of Example 1 of the present invention.

2 is an X-ray powder diffraction pattern of a solid dispersion of amorphous tadalafil and polyacrylic resin L100 of Example 12 of the present invention.

Figure 3 is an X-ray powder diffraction pattern of a composition of an amorphous tadalafil solid dispersion and microcrystalline cellulose of Example 53 of the present invention.

4 is an X-ray powder diffraction pattern of microcrystalline cellulose used in an embodiment of the present invention.

Figure 5 is an X-ray powder diffraction pattern of a composition of an amorphous tadalafil solid dispersion and colloidal silica Aerosil 200 of Example 73 of the present invention.

detailed description

The invention is further illustrated by the following specific examples, but the scope of the invention is not limited by the following examples.

The X-ray powder diffraction pattern of the present invention was collected on a Ultima IV X-ray diffractometer. The method parameters of the X-ray powder diffraction according to the present invention are as follows:

X-ray powder parameters: Cu-Kα;

：1.5418；Kα

:1.5418;

Voltage: 40 kV;

Current: 40 mA;

Divergence slit: automatic;

Scan mode: continuous;

Scanning range: from 2.0 to 60.0 degrees;

Sampling step size: 0.0200 degrees;

Scan rate: 60 degrees / minute.

Any physical form of tadalafil can be used to prepare the amorphous tadalafil solid dispersion of the present invention.

Example 1

Tadanafil (50 mg) and povidone K30 (100 mg) were dissolved in methanol (600 μl) and heated to 60 ° C to dissolve. The above solution was rapidly cooled to -10 ° C, a white solid was precipitated, filtered, and dried to obtain a solid dispersion of amorphous tadalafil and povidone K30. The X-ray powder diffraction pattern of the solid dispersion is shown in FIG. It can be seen from Fig. 1 that the X-ray powder diffraction pattern deducts the characteristic peak of the amorphous form after subtracting the background peak of the medicinal adjuvant.

Example 2

Tatanafil (50 mg) and polyethylene glycol 4000 (200 mg) were dissolved in ethanol (600 μl) and water (600 μl), and mixed at -40 ° C with stirring. The above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid to give a solid dispersion of amorphous tadanafil and polyethylene glycol 4000. The X-ray powder diffraction pattern of the solid dispersion was deducted. After the background peak of the excipient, there is no characteristic peak of the amorphous state of Tada.

Example 3

Tadanafil (5 g) and polyethylene glycol 8000 (10 g) were added to methanol (300 ml) and water (300 ml), and the mixture was heated to 60 ° C and stirred to dissolve. The above solution was dried with JISL micro spray dryer LSD-48, the inlet temperature was maintained at 60 ° C, the outlet temperature was 50 ° C, and the outlet material was collected to obtain a white solid, which was further dried under vacuum to obtain an amorphous form of tadalafil and polyethylene glycol 8000. In the X-ray powder diffraction pattern of the solid dispersion, the solid dispersion has no characteristic peak of the amorphous form after deducting the background peak of the pharmaceutically acceptable adjuvant.

Example 4

Tadalafil (1 g) and hydroxypropylmethylcellulose E50 (0.2 g) were added to water (10 ml) and heated to 40 ° C to stir and dissolve. The above solution was freeze-dried to obtain a white solid, a solid dispersion of amorphous tadalafil and hydroxypropylmethylcellulose E50, in which the background peak of the pharmaceutically acceptable excipient was subtracted from the X-ray powder diffraction pattern of the solid dispersion. After the absence of the amorphous peak of Tata.

Example 5

Tadanafil (1 g) and polyethylene glycol 8000 (10 g) were heated to melt, and rapidly cooled to room temperature with stirring to give a white solid. The solid is pulverized to obtain a white powdery solid, that is, a solid dispersion of amorphous tadalafil and polyethylene glycol 8000. The X-ray powder diffraction pattern of the solid dispersion is deducted from the background peak of the medicinal adjuvant. There is no amorphous characteristic peak of Tata.

Example 6

The tadalafil (1 g), tetrahydrofuran (0.1 g) and polyethylene glycol 10000 (100 g) were heated to 240 ° C, mixed well and rapidly cooled to room temperature to give a white solid. The solid is pulverized to obtain a white powdery solid, that is, a solid dispersion of amorphous tadalafil and polyethylene glycol 10000. The X-ray powder diffraction pattern of the solid dispersion is deducted from the background peak of the medicinal adjuvant. There is no amorphous characteristic peak of Tata.

Example 7

A mixture of tadalafil (1 g), tetrahydrofuran (10 g), ethanol (20 g) and liposomes (4 g) was heated to 90 ° C and mixed well with stirring. The above solution was slowly concentrated to dryness in a rotary evaporator, and cooled to room temperature to give a white solid, a solid dispersion of amorphous tadalafil and liposome, which was deducted from the X-ray powder diffraction pattern of the solid dispersion. There is no characteristic peak of the amorphous form of the medicinal excipient after the background peak.

Example 8

A mixture of tadalafil (1 g), methanol (20 g) and methacrylic acid copolymer type A (4 g) was heated to 50 ° C and dissolved under stirring. The solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, that is, a solid dispersion of an amorphous form of tadalafil and a methacrylic acid copolymer, in an X-ray powder diffraction pattern of the solid dispersion. After subtracting the background peak of the medicinal excipients, there is no characteristic peak of the amorphous state of Tada.

Example 9

A mixture of tadalafil (1 g), ethanol (20 g), tetrahydrofuran (10 g) and ethyl cellulose (2 g) was heated to 30 ° C and mixed well with stirring. The solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, a solid dispersion of amorphous tadalafil and ethylcellulose, which was deducted from the X-ray powder diffraction pattern of the solid dispersion. After the background peak of the excipient, there is no amorphous characteristic peak of Tada.

Example 10

A mixture of tadalafil (1 g), methanol (20 g) and hydroxypropylcellulose SSL (4 g) was heated to 30 ° C and stirred to dissolve. The solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, a solid dispersion of amorphous tadalafil with hydroxypropylcellulose SSL, deducted from the X-ray powder diffraction pattern of the solid dispersion. There is no characteristic peak of the amorphous form of the medicinal excipient after the background peak.

Example 11

A mixture of tadalafil (1 g), methanol (20 g), water (10 g) and polyvinyl acetate (4 g) was heated to 30 ° C and dissolved under stirring. The solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, a solid dispersion of amorphous tadalafil and polyvinyl acetate. The X-ray powder diffraction pattern of the solid dispersion was deducted from the excipients. After the background peak, there is no amorphous characteristic peak of Tata.

Example 12

Tadanafil (50 mg) and polyacrylic resin Eudragit L100 (100 mg) were added to methanol (750 μl), and the solution was dissolved by stirring at room temperature. The solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, that is, a solid dispersion of amorphous tadalafil and polyacrylic resin Eudragit L100. The X-ray powder diffraction pattern of the solid dispersion is shown in Fig. 2. It can be seen from Fig. 2 that the X-ray powder diffraction pattern deducts the characteristic peak of the amorphous form after subtracting the background peak of the medicinal adjuvant.

Example 13

Tadanafil (50 mg) and polyacrylic resin Eudragit S100 (5 mg) were added to methanol (4 ml) and ethyl acetate (1 ml), and the mixture was stirred at -30 °C. Slowly thicken the above solution in a rotary evaporator Reducing to dryness, a white solid is obtained, and a white solid is precipitated under stirring, that is, a solid dispersion of amorphous tadalafil and polyacrylic resin Eudragit S100. The X-ray powder diffraction pattern of the solid dispersion is deducted from the excipients of the pharmaceutical preparation. There is no amorphous characteristic peak of the Tatana after the background peak.

Example 14

Tadanafil (50 mg) and Carbopol Carbomer 940 (50 mg) were added to methanol (4 ml) and tetrahydrofuran (1 ml), and the mixture was stirred and mixed at -30 °C. The solution was slowly concentrated to dryness in a rotary evaporator to give a white solid which crystallised as a white solid, a solid dispersion of the amorphous tadalafil and carbomer carbomer 940, X-ray powder of the solid dispersion. In the diffraction pattern, after subtracting the background peak of the medicinal excipient, there is no characteristic peak of the amorphous form of Tada.

Example 15

Tadanafil (50 mg) and pregelatinized starch Pharma-Gel (100 mg) were added to methanol (4 ml) and water (1 ml) and mixed well at room temperature. The solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, which crystallised as a white solid, a solid dispersion of amorphous tadanafil and Pharma-Gel pregelatinized starch, X- of the solid dispersion In the ray powder diffraction pattern, after deducting the background peak of the medicinal excipient, there is no characteristic peak of the amorphous form.

Example 16

Add tadalafil (50 mg) and high-branched cross-linked starch (50 mg) to methanol (4 ml) and water (1 ml), stir to dissolve at room temperature, and slowly concentrate the solution to dryness on a rotary evaporator. , a white solid is obtained, and a white solid is precipitated under stirring, that is, a solid dispersion of amorphous tadalafil and a high-branched crosslinked starch. The X-ray powder diffraction pattern of the solid dispersion is deducted from the background peak of the medicinal excipient. He is the amorphous peak of the amorphous type.

Example 17

Tadanafil (50 mg) and sodium carboxymethylcellulose SCMC (500 mg) were added to water (5 ml) and dimethyl sulfoxide (5 ml), and the mixture was stirred at room temperature. The solution was rapidly cooled to -20 ° C, a white solid precipitated, filtered, and dried to give a white solid, a solid dispersion of amorphous tadalafil with sodium carboxymethylcellulose SCMC, X-ray of the solid dispersion In the powder diffraction pattern, after subtracting the background peak of the medicinal excipient, there is no characteristic peak of the amorphous form.

Example 18

Add tadalafil (50 mg) and chitosan (500 mg) to ethanol (5 ml), stir to dissolve at room temperature, and slowly concentrate the solution to dryness on a rotary evaporator to give a white solid. Amorphous Tada That is not a solid dispersion with chitosan, the X-ray powder diffraction pattern of the solid dispersion, after deducting the background peak of the pharmaceutical excipient, there is no characteristic peak of the amorphous form of Tedana.

Example 19

Add tadalafil (50 mg) and sodium carboxymethyl starch Explotab (500 mg) to ethanol (5 ml), mix well at room temperature, and slowly concentrate the solution to dryness on a rotary evaporator to give a white solid. , a solid dispersion of an amorphous form of tadalafil with sodium carboxymethyl starch, Explotab, the X-ray powder diffraction pattern of the solid dispersion, after deducting the background peak of the medicinal excipient peak.

Example 20

Add tadalafil (50 mg) and alginate E401 (500 mg) to ethanol (5 ml) and mix well at room temperature. The above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, a solid dispersion of amorphous tadalafil with alginate E401, which was deducted from the X-ray powder diffraction pattern of the solid dispersion. After the background peak of the excipient, there is no amorphous characteristic peak of Tada.

Example 21

Tadalafil (50 mg) and carboxymethylcellulose phthalate Agucoat CPD (5 g) were suspended in methanol (30 ml), heated to 50 ° C and stirred to mix well. The above solution was slowly concentrated in a rotary evaporator to remove most of the solvent, filtered and dried to give a white solid, a solid dispersion of amorphous tadalafil and carboxymethylcellulose phthalate Agucoat CPD. In the X-ray powder diffraction pattern of the solid dispersion, there is no characteristic peak of the amorphous form after deducting the background peak of the pharmaceutical excipient.

Example 22

Add tadalafil (50 mg) and carrageenan E407 (500 mg) to methanol (30 ml), heat to 50 ° C and mix well. Slowly concentrate the above solution in a rotary evaporator to remove most of the solvent and filter. Drying to give a white solid, a solid dispersion of amorphous tadalafil and carrageenan E407, the X-ray powder diffraction pattern of the solid dispersion, after subtracting the background peak of the pharmaceutical excipient Characteristic peak.

Example 23

Add tadalafil (50 mg) and chitosan (5 g) to methanol (50 ml), heat to 50 ° C and mix well. The above solution was slowly concentrated in a rotary evaporator to remove most of the solvent, filtered and dried to give a white solid, a solid dispersion of amorphous tadalafil and chitosan, X-ray powder diffraction pattern of the solid dispersion. In the middle, after deducting the background peak of the medicinal excipients, there is no characteristic peak of the amorphous form of Tada.

Example 24

Tadanafil (30 mg) and polyacrylic resin Eudragit E100 (30 mg) were dissolved in ethanol (600 μL), tetrahydrofuran (900 μL) and N,N-dimethylformamide (600 μL) The mixture was heated to 50 ° C to dissolve the solution, and the solution was cooled to -10 ° C to precipitate a white solid, which was filtered and dried to obtain a solid dispersion of amorphous tadalafil and polyacrylic resin Eudragit E100, X of the solid dispersion. In the ray powder diffraction pattern, after deducting the background peak of the medicinal excipient, there is no characteristic peak of the amorphous form.

Example 25

Tadalafil (30 mg) and collagen Peptan (300 mg) were dissolved in ethanol (600 μl), tetrahydrofuran (900 μl) and acetonitrile (600 μl), and heated to 50 ° C to dissolve. The solution was cooled to 10 ° C, a white solid was precipitated, filtered, and dried to obtain a solid dispersion of amorphous tadalafil and collagen Peptan. The X-ray powder diffraction pattern of the solid dispersion was deducted from the excipient of the pharmaceutical excipient. There is no amorphous characteristic peak of the Tatana after the background peak.

Example 26

Tadalafil (30 mg) and gum Galactosol (300 mg) were dissolved in ethanol (600 μL) and tetrahydrofuran (900 μL), and heated to 50 ° C to stir and dissolve. The solution was cooled to -10 ° C, a white solid was precipitated, filtered and dried to obtain a solid dispersion of amorphous tadalafil and gum Galactosol. The X-ray powder diffraction pattern of the solid dispersion was deducted from the excipients of the pharmaceutical excipients. There is no amorphous characteristic peak of the Tatana after the background peak.

Example 27

Add tadalafil (30 mg) and hydroxypropylmethylcellulose phthalate HPMCP (30 mg) to ethanol (750 μl) and water (750 μl), heat to 80 ° C and mix well. . The above solution was slowly concentrated in a rotary evaporator to remove the solvent to give a white solid, a solid dispersion of amorphous tadalafil with hydroxypropylmethylcellulose phthalate HPMCP, X- of the solid dispersion In the ray powder diffraction pattern, after deducting the background peak of the medicinal excipient, there is no characteristic peak of the amorphous form.

Example 28

Tadanafil (30 mg) and carboxyacetic acid lactone (300 mg) were added to ethanol (750 μl) and water (750 μl), heated to 80 ° C and stirred to mix well. The solution was slowly concentrated in a rotary evaporator to remove the solvent to obtain a brown solid, a solid dispersion of amorphous tadalafil and carboxyacetolactone. The solid dispersion was deducted from the X-ray powder diffraction pattern. After the background peak of the excipient, there is no amorphous characteristic peak of Tada.

Example 29

Add tadalafil (30 mg) and dextrin Maltrin M100 (300 mg) to ethanol (750 μl) and water (750 μl), heat to 80 ° C and mix well. Slowly concentrate the above solution in a rotary evaporator The solvent was removed to give a white solid, a solid dispersion of amorphous tadalafil with dextrin Maltrin M100. In the X-ray powder diffraction pattern of the solid dispersion, there was no tadalafil after subtracting the background peak of the pharmaceutical excipient. Characteristic peak of the crystal form.

Example 30

Add tadalafil (30 mg) and sodium carboxymethylcellulose SCMS (3 mg) to water (30 ml), heat to 100 ° C and mix well. The solution was slowly concentrated in a rotary evaporator to remove the solvent to give a white solid, a solid dispersion of amorphous tadalafil and sodium carboxymethylcellulose SCMC, in an X-ray powder diffraction pattern of the solid dispersion. After subtracting the background peak of the medicinal excipients, there is no characteristic peak of the amorphous state of Tada.

Example 31

Tadanafil (30 mg) and β-cyclodextrin (30 mg) were added to methanol (300 μl) and water (300 μl), and the mixture was stirred at room temperature. The above solution was slowly concentrated in a rotary evaporator to remove the solvent to obtain a white solid, a solid dispersion of amorphous tadalafil and β-cyclodextrin, which was deducted from the X-ray powder diffraction pattern of the solid dispersion. There is no characteristic peak of the amorphous form of the medicinal excipient after the background peak.

Example 32

Tadanafil (30 mg) and sodium carboxymethylcellulose SCMC (30 mg) were added to methanol (300 μl) and water (60 μL), and the mixture was stirred and mixed at 60 ° C. The solution was slowly concentrated in a rotary evaporator to remove the solvent to give a white solid, a solid dispersion of amorphous tadalafil and sodium carboxymethylcellulose SCMC, in an X-ray powder diffraction pattern of the solid dispersion. After subtracting the background peak of the medicinal excipients, there is no characteristic peak of the amorphous state of Tada.

Example 33

Tadanafil (5 mg) and polyethylene oxide Polyox WSR301 (60 mg) were added to methanol (300 μl) and water (60 μL), and the mixture was stirred and homogenized at 60 °C. The solution was slowly concentrated in a rotary evaporator to remove the solvent to give a white solid, that is, a solid dispersion of amorphous tadalafil and polyethylene oxide Polyox WSR301, in an X-ray powder diffraction pattern of the solid dispersion, After subtracting the background peak of the medicinal excipients, there is no characteristic peak of the amorphous state of Tada.

Example 34

Add tadalafil (30 mg) and polyvinyl alcohol EG-40 (60 mg) to methanol (300 μl) and water (60 μl), stir at 60 ° C, and dissolve the above solution on a rotary evaporator. The solvent is slowly concentrated to remove a white solid, that is, a solid dispersion of amorphous tadalafil and polyvinyl alcohol EG-40. The X-ray powder diffraction pattern of the solid dispersion is deducted from the background peak of the pharmaceutical excipient. There is no amorphous characteristic peak of Tata.

Example 35

Add tadalafil (50 mg) and hydroxypropylmethylcellulose acetate succinate Agoat MG (2 g) to ethanol (10 ml) and water (2 ml), and mix well at 80 ° C. The solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, a solid dispersion of amorphous tadalafil with hydroxypropylmethylcellulose acetate succinate Agoat MG, X-ray powder of the solid dispersion In the diffraction pattern, after subtracting the background peak of the medicinal excipient, there is no characteristic peak of the amorphous form of Tada.

Example 36

Add tadalafil (50 mg) and carboxymethylethylcellulose (2 g) to ethanol (10 ml) and water (1 ml), mix well at 80 ° C, and dissolve the above solution in a rotary evaporator. Slowly concentrated to dryness to give a white solid, a solid dispersion of amorphous tadalafil and carboxymethylethylcellulose, in the X-ray powder diffraction pattern of the solid dispersion, after subtracting the background peak of the pharmaceutical excipient There is no amorphous characteristic peak of Tata.

Example 37

Add tadalafil (50 mg) and povidone K30 (2 g) to ethanol (1.5 ml) and acetone (1.5 ml), mix well at 80 ° C, and slowly concentrate the above solution in a rotary evaporator. To dryness, a white solid, a solid dispersion of amorphous tadalafil and povidone K30, obtained in an X-ray powder diffraction pattern of the solid dispersion, after deducting the background peak of the pharmaceutical excipient, is free of tadalafil. Characteristic peak of the crystal form.

Example 38

Add tadalafil (50 mg) and hydroxypropylcellulose HPC SSL (2 g) to ethanol (1.5 ml) and acetone (1.5 ml), mix well at 80 ° C, and dissolve the above solution on a rotary evaporator. Slowly concentrated to dryness to give a white solid, a solid dispersion of amorphous tadalafil with hydroxypropylcellulose HPC SSL. The X-ray powder diffraction pattern of the solid dispersion is subtracted from the background peak of the pharmaceutical excipient. After the absence of the amorphous peak of Tata.

Example 39: Influencing Factors of Amorphous Tadalafil and Povidone K30 Solid Dispersion

MATERIALS: Solid dispersion of amorphous tadalafil and povidone K30 obtained in Example 1.

Table 1:

Table 1 shows that the amorphous dispersion of the amorphous tadalafil and povidone K30 of the present invention was allowed to stand under high temperature and high humidity conditions for 10 days, and there was no significant change in the related substances, and no statin was precipitated.

Example 40: Accelerated test of amorphous tadalafil and povidone K30 solid dispersion

MATERIALS: Solid dispersion of amorphous tadalafil and povidone K30 obtained in Example 1.

Experimental conditions: temperature 40 ° C ± 2 ° C, humidity 75% ± 5%, the results see Table 2.

Table 2:

Table 2 illustrates that the amorphous dispersion of the amorphous tadalafil and povidone K30 of the present invention was allowed to stand for 6 months under accelerated test conditions, and there was no significant change in the related substance, and no statin was precipitated.

Example 41: Determination of apparent solubility

The apparent solubility of a mixture of the tadalafil-free solid dispersion of the present invention and the Tatatan amorphous form was compared.

The objects to be measured were respectively: the composition obtained in Example 1 of the present invention; the mixture of the Tardana amorphous form (Form I) and the povidone K30 were physically mixed at a weight ratio of 1: 2. The Tana amorphous form (Form I) was prepared according to the method of Example 95 of the patent CN 1045777 and micronized to D90 = 8.4 μm.

Determination of Apparent Solubility: Sufficiently weighed a sufficient amount of the solid dispersion obtained in Example 1 of the present invention and the above-mentioned Tata The mixture of amorphous materials was placed in two stoppered Erlenmeyer flasks, and a dilution of the specified pH was added to prepare a supersaturated solution, which was tightly sealed. Three samples were prepared in parallel for each pH dilution. It was shaken in a constant temperature water bath shaker at 37 ° C ± 0.5 ° C for 12 h to fully dissolve to achieve saturation. The supernatant was filtered with a 0.45 μm microporous membrane, diluted appropriately, shaken, and injected into the liquid chromatograph. The apparent solubility of the three parallel samples in this pH buffer was calculated by external standard method and averaged.

Preparation of various pH dilutions:

(1) Diluent of pH = 1.0: 9 ml of concentrated hydrochloric acid was diluted with water to 1000 ml.

(2) Diluent of pH=2.0: Liquid A: Take 16.6 ml of phosphoric acid, and add water to 100 ml to shake. Solution B: Take 71.63 g of disodium hydrogen phosphate and dissolve it into 1000 ml with water. Take 72.5 ml of the above liquid A and 27.5 ml of the liquid B, and shake well to obtain.

(3) Diluent of pH=3.0: 50 ml of glacial acetic acid, 800 ml of water was added, and the p H value was adjusted to 3.0 with lithium hydroxide, and then diluted with water to 1000 ml.

(4) Diluent of pH=4.5: Take 7.7 g of ammonium acetate, add 50 ml of water to dissolve, add 6 ml of glacial acetic acid and make an appropriate amount of water to make 100 ml.

(5) Dilution solution with pH=5.6: Take 10 g of potassium hydrogen phthalate, add 900 ml of water, stir to dissolve, adjust the pH to 5.6 with sodium hydroxide test solution (diluted hydrochloric acid if necessary), dilute with water until 1000 ml, mix well, that is.

(6) Dilution solution of pH=6.8: Take 250 ml of a 0.2 mol/L potassium dihydrogen phosphate solution, add 118 ml of a 0.2 mol/L sodium hydroxide solution, dilute to 1000 ml with water, and shake well.

(7) Diluent of pH=7.4: Take 1.36 g of potassium dihydrogen phosphate, add 79 ml of 0.1 mol/L sodium hydroxide solution, and dilute to 200 ml with water to obtain.

The experimental results are shown in Table 3:

table 3:

Table 3 shows that at each pH value, the apparent solubility of amorphous solids of the amorphous and non-retinophene K30 solid dispersion is significantly higher than that of the crystalline form (Form I) and povidone K30. Apparent solubility.

Example 42

Add tadalafil (50 mg) and povidone K30 (100 mg) in tetrahydrofuran (900 μl) and methanol (600 μl), heat to 60 ° C, stir to dissolve, and then add microcrystalline cellulose ( 50 mg). The solution was rapidly cooled to -10 ° C, a white solid was precipitated, filtered, and dried in vacuo to give a composition of an amorphous tadanafil solid dispersion and microcrystalline cellulose, which was deducted from the X-ray powder diffraction pattern. There is no characteristic peak of the amorphous form of the carrier after the background peak of the carrier and the medicinal adjuvant.

Example 43

Dissolve tadalafil (50 mg) and polyethylene glycol 4000 (200 mg) in acetic acid (800 μl) and ethanol (600 μl), mix well at 60 ° C, and add microcrystalline cellulose. (50 mg). The solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, that is, a combination of amorphous tadalafil and microcrystalline cellulose. The X-ray powder diffraction pattern of the composition was deducted from the carrier and medicinal. After the background peak of the excipient, there is no amorphous characteristic peak of Tada.

Example 44

Tadanafil (5 g) and polyethylene glycol 8000 (10 g) were added to methanol (600 ml), heated to 60 ° C to stir and dissolve, and then croscarmellose sodium (0.1 g) was added. The above solution was dried with JISL micro spray dryer LSD-48, the inlet temperature was maintained at 60 ° C, the outlet temperature was 50 ° C, and the outlet material was collected to obtain a white solid, which was further dried under vacuum to obtain an amorphous tadalafil solid dispersion and a crosslinked carboxylic acid. A composition of sodium methylcellulose in which the background peak of the carrier and the pharmaceutically acceptable excipient is free of characteristic peaks of the amorphous form in the X-ray powder diffraction pattern of the composition.

Example 45

Tadalafil (1 g) and hydroxypropylmethylcellulose E50 (0.2 g) were added to methanol (200 ml), heated to 40 ° C, stirred and mixed, and crospovidone (0.2 g) was added. The above solution is freeze-dried to obtain a white solid, that is, a composition of an amorphous tadalafil solid dispersion and crospovidone, in which the background of the carrier and the pharmaceutically acceptable excipient are subtracted in the X-ray powder diffraction pattern of the composition. There is no amorphous peak of the Tatana after the peak.

Example 46

Tadalafil (1 g), mannitol (5 g) and polyethylene glycol 8000 (5 g) were heated to melt, and rapidly cooled to room temperature with stirring to give a white solid. The solid is pulverized to obtain a white powdery solid, that is, a composition of an amorphous tadalafil solid dispersion and mannitol, which is deducted from the X-ray powder diffraction pattern of the composition. There is no characteristic peak of the amorphous form of the carrier after the background peak of the carrier and the medicinal adjuvant.

Example 47

Tadalafil (1 g), mannitol (0.1 g) and polyethylene glycol 10000 (10 g) were heated to 240 ° C, mixed well and rapidly cooled to room temperature to give a white solid. The solid is pulverized to obtain a white powdery solid, that is, a composition of an amorphous tadalafil solid dispersion and mannitol. The X-ray powder diffraction pattern of the composition is deducted from the background peak of the carrier and the pharmaceutically acceptable excipient. There is no amorphous characteristic peak of Tata.

Example 48

A mixture of tadalafil (1 g), acetic acid (20 g) and liposomes (4 g) was heated to 90 ° C and mixed well with stirring. Further adding microcrystalline cellulose (2 g), stirring uniformly, and evaporating the solvent in vacuo to obtain a white solid, that is, a composition of an amorphous tadalafil solid dispersion and microcrystalline cellulose, the X-ray powder of the composition In the diffraction pattern, after subtracting the background peak of the carrier and the medicinal excipient, there is no characteristic peak of the amorphous state of Tada.

Example 49

A mixture of tadalafil (1 g), tetrahydrofuran (60 g) and methacrylic acid copolymer type A (4 g) was heated to 50 ° C, dissolved under stirring, and then crospovidone (1 g) was added. The solvent is removed by evaporation in vacuo, and cooled to room temperature to give a white solid, that is, a composition of the amorphous tadanafil solid dispersion and crospovidone. The X-ray powder diffraction pattern of the composition is deducted from the carrier and medicinal. There is no characteristic peak of the non-hydrobromide crystal form after the background peak of the excipient.

Example 50

A mixture of tadalafil (1 g), ethanol (300 g) and ethyl cellulose (2 g) was heated to 70 ° C, stirred, mixed well, then magnesium stearate (0.1 g) was added and evaporated in vacuo. The solvent is cooled to room temperature to give a white solid, that is, a combination of an amorphous tadalafil solid dispersion and magnesium stearate. The X-ray powder diffraction pattern of the composition is deducted from the background peak of the carrier and the pharmaceutically acceptable excipient. There is no amorphous characteristic peak of Tata.

Example 51

Heat a mixture of tadalafil (1 g), methanol (100 g), dichloromethane (30 g) and hydroxypropyl cellulose SSL (4 g) to 30 ° C, stir to dissolve, and then add microcrystalline fiber (0.5 g), the solvent was evaporated in vacuo, and cooled to room temperature to give a white solid, that is, a combination of amorphous tadanafil solid dispersion and microcrystalline cellulose, which was deducted from the X-ray powder diffraction pattern of the composition. The background peaks of the carrier and the pharmaceutically acceptable adjuvant have no characteristic peaks of the crystalline form of the tadalafil hydrochloride.

Example 52

A mixture of tadalafil (1 g), tetrahydrofuran (50 g), dichloromethane (10 g) and polyvinyl acetate (4 g) was heated to 30 ° C, stirred and dissolved, and then microcrystalline cellulose was added (0.5克) The solvent is removed by evaporation in vacuo and cooled to room temperature to give a white solid, that is, a combination of an amorphous solid and saponin and microcrystalline cellulose. The X-ray powder diffraction pattern of the composition is deducted from the carrier and medicinal. After the background peak of the excipient, there is no characteristic peak of the crystalline form of statin.

Example 53

Tadalafil (50 mg) and polyacrylic resin Eudragit L100 (100 mg) were added to acetic acid (750 μl), stirred at 90 ° C, and microcrystalline cellulose (100 mg) was added. The suspension was rapidly cooled to 20 ° C to precipitate a white solid. Filtration, vacuum drying, to obtain a white solid, that is, a combination of amorphous tadalafil solid dispersion and microcrystalline cellulose, the X-ray powder diffraction pattern of the composition is shown in Figure 3, X-ray powder diffraction pattern After subtracting the background peak of the carrier and the medicinal excipient, there is no characteristic peak of the amorphous form of Tada. The X-ray powder diffraction pattern of microcrystalline cellulose is shown in Fig. 4.

Example 54

Tadanafil (50 mg) and polyacrylic resin Eudragit S100 (5 mg) were added to acetic acid (4 ml) and ethyl acetate (1 ml), and the mixture was stirred at -30 °C. Add sodium carboxymethyl starch (100 mg). The above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, that is, a combination of an amorphous tadanafil solid dispersion and sodium carboxymethyl starch, which was deducted from the X-ray powder diffraction pattern of the composition. There is no characteristic peak of the amorphous form of the carrier after the background peak of the carrier and the medicinal adjuvant.

Example 55

Add tadalafil (50 mg) and Carbopol 940 (50 mg) to methanol (4 ml) and tetrahydrofuran (1 ml), mix well at 30 ° C, then add microcrystalline cellulose (50 mg) ). The above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, that is, a combination of an amorphous tadalafil solid dispersion and microcrystalline cellulose. The X-ray powder diffraction pattern of the composition was subtracted from the carrier. And the background peak of the medicinal excipients has no characteristic peak of the amorphous state of Tada.

Example 56

Add tadalafil (50 mg) and pregelatinized starch Pharma-Gel (100 mg) to methanol (4 ml) and ethyl acetate (1 ml), mix well at room temperature, then add cross-linked carboxymethyl Cellulose sodium (100 mg). The above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, i.e., a combination of an amorphous tadanafil solid dispersion and croscarmellose sodium, the X-ray powder diffraction pattern of the composition. In the absence of the background peak of the carrier and the medicinal excipient, there is no characteristic peak of the amorphous form.

Example 57

Add tadalafil (50 mg) and high-branched cross-linked starch (50 mg) to n-butanol (4 ml) and acetone (1 ml), stir at room temperature, and add croscarmellose Sodium (100 mg). The above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, i.e., a composition of a non-determined tadalafil solid dispersion and croscarmellose sodium, X-ray powder diffraction of the composition. In the figure, there is no characteristic peak of the amorphous form after deducting the background peak of the carrier and the medicinal adjuvant.

Example 58

Add tadalafil (50 mg) and sodium carboxymethylcellulose SCMC (500 mg) to dimethyl sulfoxide (5 ml), dissolve at room temperature, and add croscarmellose sodium. (100 mg). The above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, i.e., a combination of an amorphous tadanafil solid dispersion and croscarmellose sodium, the X-ray powder diffraction pattern of the composition. In the absence of the background peak of the carrier and the medicinal excipient, there is no characteristic peak of the amorphous form.

Example 59

Tadanafil (50 mg) and chitosan (500 mg) were added to dimethylformamide (5 ml), and the solution was dissolved by stirring at room temperature, followed by addition of microcrystalline cellulose (50 mg). The above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, that is, a combination of an amorphous tadalafil solid dispersion and microcrystalline cellulose. The X-ray powder diffraction pattern of the composition was subtracted from the carrier. And the background peak of the medicinal excipients has no characteristic peak of the amorphous state of Tada.

Example 60

Add tadalafil (50 mg) and sodium carboxymethyl starch Explotab (500 mg) to dimethylacetamide (5 ml), mix well at room temperature, and add lactose (100 mg). The above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, a combination of an amorphous tadanafil solid dispersion and lactose. The X-ray powder diffraction pattern of the composition was deducted from the carrier and medicinal. After the background peak of the excipient, there is no amorphous characteristic peak of Tada.

Example 61

Add tadalafil (50 mg) and alginate E401 (500 mg) to methanol (5 ml), mix well at room temperature, and add lactose (10 mg). The above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, a combination of an amorphous tadanafil solid dispersion and lactose. The X-ray powder diffraction pattern of the composition was deducted from the carrier and medicinal. After the background peak of the excipient, there is no amorphous characteristic peak of Tada.

Example 62

Add tadalafil (50 mg) and carboxymethylcellulose phthalate Agucoat CPD (0.5 g) in methanol (30 ml), heat to 50 ° C, mix well, then add lactose (50 mg) ). The above solution was slowly concentrated in a rotary evaporator to remove most of the solvent, filtered and dried to give a white solid, that is, a combination of an amorphous tadanafil solid dispersion and lactose, in an X-ray powder diffraction pattern of the composition. After deducting the background peak of the carrier and the medicinal excipient, there is no characteristic peak of the amorphous form.

Example 63

Tadanafil (50 mg) and carrageenan E407 (500 mg) were suspended in methanol (30 ml), heated to 50 ° C, stirred and mixed, and then microcrystalline cellulose (50 mg) was added. The above solution was slowly concentrated in a rotary evaporator to remove most of the solvent, filtered and dried to give a white solid, that is, a combination of an amorphous tadalafil solid dispersion and microcrystalline cellulose, X-ray powder of the composition. In the diffraction pattern, after subtracting the background peak of the carrier and the medicinal excipient, there is no characteristic peak of the amorphous state of Tada.

Example 64

Tadanafil (50 mg) and chitosan (5 g) were suspended in methanol (50 ml), heated to 50 ° C, stirred and mixed, and then lactose (100 mg) was added. The above solution was slowly concentrated in a rotary evaporator to remove most of the solvent, filtered and dried to give a white solid, that is, a combination of an amorphous tadanafil solid dispersion and lactose, in an X-ray powder diffraction pattern of the composition. After deducting the background peak of the carrier and the medicinal excipient, there is no characteristic peak of the amorphous form.

Example 65

Dissolve tadalafil (30 mg) and polyacrylic resin Eudragit E100 (30 mg) in N,N-dimethylformamide (600 μl), heat to 50 ° C, stir and dissolve, then add lactose (30 Mg). The solution was cooled to 10 ° C, a white solid was precipitated, filtered, and dried to obtain a composition of an amorphous tadalafil solid dispersion and lactose. In the X-ray powder diffraction pattern of the composition, the carrier and the medicinal excipient were subtracted. After the background peak, there is no amorphous characteristic peak of Tata.

Example 66

Add tadalafil (30 mg) and collagen Peptan (300 mg) in acetic acid (900 μl) and acetonitrile (600 μl), heat to 50 ° C, stir and dissolve, then add microcrystalline cellulose (30 Mg). The solution was cooled to 10 ° C, a white solid was precipitated, filtered, and dried to obtain a composition of amorphous tadalafil and collagen Peptan. The X-ray powder diffraction pattern of the composition was deducted from the carrier and the medicinal excipient. There is no amorphous characteristic peak of the Tatana after the background peak.

Example 67

Add tadalafil (30 mg) and gum Galactosol (300 mg) in tetrahydrofuran (900 μl) and methanol (600 μl), heat to 50 ° C, stir to dissolve, and add microcrystalline cellulose (30 mg). ). The solution was cooled to 10 ° C, a white solid was precipitated, filtered, and dried to obtain a composition of an amorphous tadalafil solid dispersion and microcrystalline cellulose. The X-ray powder diffraction pattern of the composition was deducted from the carrier and There is no characteristic peak of the amorphous form of the medicinal excipient after the background peak.

Example 68

Add tadalafil (30 mg) and hydroxypropylmethylcellulose phthalate HPMCP (30 mg) to ethanol (750 μl) and acetic acid (750 μl), heat to 80 ° C and mix. Uniformly, sodium carboxymethylcellulose (30 mg) was added. The solution was slowly concentrated in a rotary evaporator to remove the solvent to give a white solid, that is, a combination of amorphous tadalafil and sodium carboxymethylcellulose. The X-ray powder diffraction pattern of the composition was subtracted from the carrier and There is no characteristic peak of the amorphous form of the medicinal excipient after the background peak.

Example 69

Add tadalafil (30 mg) and carboxyacetic acid lactone (300 mg) to ethanol (750 μl) and dimethylformamide (750 μl), heat to 80 ° C, mix well, then add lactose (200 mg). The solution is slowly concentrated in a rotary evaporator to remove the solvent to give a white solid, a combination of an amorphous tadalafil solid dispersion and lactose. The X-ray powder diffraction pattern of the composition is deducted from the carrier and medicinal. After the background peak of the excipient, there is no amorphous characteristic peak of Tada.

Example 70

Add tadalafil (30 mg) and dextrin Maltrin M100 (300 mg) to ethanol (750 μl) and acetic acid (750 μl), heat to 80 ° C, mix well, then add lactose (200 mg) . The solution is slowly concentrated in a rotary evaporator to remove the solvent to give a white solid, a combination of an amorphous tadalafil solid dispersion and lactose. The X-ray powder diffraction pattern of the composition is deducted from the carrier and medicinal. After the background peak of the excipient, there is no amorphous characteristic peak of Tada.

Example 71

Tadanafil (30 mg) and sodium carboxymethylcellulose SCMS (3 mg) were added to tetrahydrofuran (30 ml), heated to 100 ° C, stirred and mixed, and then microcrystalline cellulose (30 mg) was added. The above solution was slowly concentrated in a rotary evaporator to remove the solvent to obtain a white solid, that is, a composition of an amorphous tadalafil solid dispersion and microcrystalline cellulose. In the X-ray powder diffraction pattern of the composition, the carrier was subtracted. And the characteristic peak of the crystalline form of tadalafil hydrochloride after the background peak of the medicinal excipient.

Example 72

Add tadalafil (30 mg) and sodium carboxymethylcellulose SCMC (30 mg) to methanol (300 μl) and acetic acid (600 μl), mix well at 70 ° C, and add microcrystalline fiber. Vegetarian (60 mg). The above solution was slowly concentrated in a rotary evaporator to remove the solvent to obtain a white solid, that is, a composition of an amorphous tadalafil solid dispersion and microcrystalline cellulose. In the X-ray powder diffraction pattern of the composition, the carrier was subtracted. And the background peak of the medicinal excipients has no characteristic peak of the amorphous state of Tada.

Example 73

Add tadalafil (5 mg) and polyethylene oxide Polyox WSR301 (30 mg) to methanol (300 μl) and tetrahydrofuran (600 μl), mix well at 60 ° C, add colloidal dioxide Silicon Aerosil 200 (20 mg). The above solution was slowly concentrated in a rotary evaporator to remove the solvent to give a white solid, that is, a combination of an amorphous tadanafil solid dispersion and colloidal silica Aerosil 200, the X-ray powder diffraction pattern of the composition was as As shown in Fig. 5, it can be seen from Fig. 5 that the X-ray powder diffraction pattern deducts the characteristic peak of the amorphous form after deducting the background peak of the carrier and the pharmaceutically acceptable excipient.

Example 74

Add tadalafil (30 mg) and polyvinyl alcohol EG-40 (60 mg) to methanol (300 μl), stir and dissolve at 60 ° C, and add lactose (30 mg) to spin the solution. The solvent was slowly concentrated to remove the solvent to obtain a white solid, that is, a combination of an amorphous tadalafil solid dispersion and lactose. The X-ray powder diffraction pattern of the composition was subtracted from the background peak of the carrier and the pharmaceutically acceptable excipient. He is the amorphous peak of the amorphous type.

Example 75

Add tadalafil (50 mg) and hydroxypropylmethylcellulose acetate succinate Agoat MG (2 g) to ethanol (10 ml) and tetrahydrofuran (2 ml), mix well at 80 ° C, then Microcrystalline cellulose (50 mg) was added. The above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, that is, a combination of an amorphous tadalafil solid dispersion and microcrystalline cellulose. The X-ray powder diffraction pattern of the composition was subtracted from the carrier. And the background peak of the medicinal excipients has no characteristic peak of the amorphous state of Tada.

Example 76

Add tadalafil (50 mg) and carboxymethylethylcellulose (2 g) to ethanol (10 ml) and acetic acid (1 ml), mix well at 80 ° C, then add cross-linked carboxymethyl Cellulose sodium (50 mg). The above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, i.e., a combination of an amorphous tadanafil solid dispersion and croscarmellose sodium, the X-ray powder diffraction pattern of the composition. In the absence of the background peak of the carrier and the medicinal excipient, there is no characteristic peak of the amorphous form.

Example 77

Tadanafil (10 g) and hydroxypropylcellulose HPC SSL (20 g) were added to ethanol (30 ml) and acetone (30 ml), and the mixture was stirred at room temperature. The above mixture was spray dried in a fluidized bed and loaded onto microcrystalline cellulose (20 g) to give 47.3 g of a white solid, i.e., amorphous tadalafil, hydroxypropylcellulose HPC SSL and microcrystalline cellulose. In the composition, the loading ratio of the active ingredient was 20.8%. The X-ray powder diffraction pattern of the composition deducted the characteristic peak of the amorphous form after deducting the background peak of the pharmaceutical excipient.

Example 78

Tadanafil (10 g) and hydroxypropylcellulose HPC SSL (10 g) were added to methanol (30 ml) and acetone (30 ml), and the mixture was stirred at room temperature. The above mixture was spray dried in a fluidized bed and loaded onto lactose monohydrate (20 g) to give a white solid 37.4 g, a combination of amorphous tadalafil, hydroxypropylcellulose HPCSSL and lactose monohydrate. The loading ratio of the active ingredient was 26.1%. The X-ray powder diffraction pattern of the composition deducted the characteristic peak of the amorphous form after deducting the background peak of the pharmaceutical excipient.

Example 79

Tadanafil (10 g) and hydroxypropylcellulose HPC SSL (10 g) were added to methanol (40 ml) and acetone (40 ml), and the mixture was stirred at room temperature. The above mixture was spray dried in a fluidized bed and loaded onto lactose monohydrate (20 g) to give a white solid, 37.3 g, a combination of amorphous tadalafil, hydroxypropylcellulose HPCSSL and lactose monohydrate. The loading ratio of the active ingredient was 25.9%. The X-ray powder diffraction pattern of the composition deducted the characteristic peak of the amorphous form after deducting the background peak of the pharmaceutical excipient.

Example 80

Tadanafil (10 g) and hydroxypropylcellulose HPC SSL (10 g) were added to methanol (40 ml) and acetone (40 ml), and the mixture was stirred at room temperature. The above mixture was spray dried in a fluidized bed and loaded onto microcrystalline cellulose (20 g) to give a white solid 37.0 g, ie, amorphous tadalafil, hydroxypropylcellulose HPC SSL and microcrystalline cellulose. In the composition, the loading ratio of the active ingredient was 26.1%. The X-ray powder diffraction pattern of the composition deducted the characteristic peak of the amorphous form after deducting the background peak of the pharmaceutical excipient.

Example 81: Influencing Factors Test of Composition of Amorphous Tadalafil Solid Dispersion and Microcrystalline Cellulose

Material: The composition of the amorphous tadalafil solid dispersion obtained in Example 53 and microcrystalline cellulose.

See Table 4 for the results.

Table 4:

Table 4 shows that the composition containing the amorphous tadalafil solid dispersion and the microcrystalline cellulose was allowed to stand under high temperature and high humidity conditions for 10 days, and there was no significant change in the related substance, and no statin was precipitated.

Example 82: Accelerated Stability Experiment of a Composition of Amorphous Tadalafil Solid Dispersion and Microcrystalline Cellulose

Materials: The composition of the amorphous tadalafil solid dispersion obtained in Example 80 and microcrystalline cellulose

Experimental conditions: temperature 40 ° C ± 2 ° C, humidity 75% ± 5%

table 5:

Table 5 shows that the composition containing the amorphous tadalafil solid dispersion and the microcrystalline cellulose was allowed to stand for 6 months under accelerated test conditions, and there was no significant change in the related substance, and no statin was precipitated.

Example 83: Influential factors test of a combination of amorphous tadalafil solid dispersion and lactose monohydrate

Materials: The composition of the amorphous tadalafil solid dispersion obtained in Example 78 and lactose monohydrate.

See Table 6 for the results.

Table 6:

Table 6 shows that the composition containing the amorphous tadalafil solid dispersion and lactose monohydrate was allowed to stand under high temperature and high humidity conditions for 10 days, and there was no significant change in the related substances, and no statin was precipitated.

Example 84: Accelerated stability test of a combination of an amorphous tadalafil solid dispersion and lactose monohydrate

Materials: The composition of the amorphous tadalafil solid dispersion obtained in Example 78 and lactose monohydrate

Experimental conditions: temperature 40 ° C ± 2 ° C, humidity 75% ± 5%

Table 7:

Table 7 shows that the composition containing the amorphous tadalafil solid dispersion and lactose monohydrate was allowed to stand for 6 months under accelerated test conditions, and there was no significant change in the relevant substance, and no statin was precipitated.

Example 85: Determination of apparent solubility

The apparent solubility of the composition of the present invention containing a degnafil solid dispersion and a mixture of the Tatatan amorphous material was compared.

The measurement objects were respectively: the composition obtained in Example 78 of the present invention; a mixture of Tardana amorphous forms (which is a Tardana amorphous form (Form I), hydroxypropyl cellulose HPC SSL, and lactose monohydrate After physical mixing, heavy The ratio is 1:1:2. Among them, the Tana amorphous form (Form I) was prepared according to the method of Example 95 of Patent CN 1045777 and micronized to D90 = 8.4 μm.

Determination of Apparent Solubility: A sufficient amount of the composition obtained in Example 78 of the present invention and the above-mentioned mixture of the above-mentioned Tartana amorphous form were weighed and placed in two stoppered Erlenmeyer flasks, and a diluent of a specified pH was added. , formulated as a supersaturated solution, sealed tightly. Three samples were prepared in parallel for each pH dilution. It was shaken in a constant temperature water bath shaker at 37 ° C ± 0.5 ° C for 12 h to fully dissolve to achieve saturation. The supernatant was filtered with a 0.45 μm microporous membrane, diluted appropriately, shaken, and injected into the liquid chromatograph. The apparent solubility of the three parallel samples in this pH buffer was calculated by external standard method and averaged.

Preparation of various pH dilutions:

(1) Diluent of pH = 1.0: 9 ml of concentrated hydrochloric acid was diluted with water to 1000 ml.

(2) Diluent of pH=2.0: Liquid A: Take 16.6 ml of phosphoric acid, and add water to 100 ml to shake. Solution B: Take 71.63 g of disodium hydrogen phosphate and dissolve it into 1000 ml with water. Take 72.5 ml of the above liquid A and 27.5 ml of the liquid B, and shake well to obtain.

(3) Diluent of pH=3.0: 50 ml of glacial acetic acid, 800 ml of water was added, and the p H value was adjusted to 3.0 with lithium hydroxide, and then diluted with water to 1000 ml.

(4) Diluent of pH=4.5: Take 7.7 g of ammonium acetate, add 50 ml of water to dissolve, add 6 ml of glacial acetic acid and make an appropriate amount of water to make 100 ml.

(5) Dilution solution with pH=5.6: Take 10 g of potassium hydrogen phthalate, add 900 ml of water, stir to dissolve, adjust the pH to 5.6 with sodium hydroxide test solution (diluted hydrochloric acid if necessary), dilute with water until 1000 ml, mix well, that is.

(6) Dilution solution of pH=6.8: Take 250 ml of a 0.2 mol/L potassium dihydrogen phosphate solution, add 118 ml of a 0.2 mol/L sodium hydroxide solution, dilute to 1000 ml with water, and shake well.

(7) Diluent of pH=7.4: Take 1.36 g of potassium dihydrogen phosphate, add 0.1 mol/l

79 ml of sodium hydroxide solution, diluted to 200 ml with water, is obtained.

The experimental results are shown in Table 8:

Table 8:

Table 8 shows that at each pH value, the apparent solubility of the apparent solubility of the amorphous solid dispersion of tadalafil and the lactose monohydrate is significantly higher than the apparent appearance of the mixture of Form I. Solubility.

The composition of the present invention containing the amorphous tadalafil solid dispersion and the medicinal excipient has a significantly increased dissolution rate, is more beneficial to improving the bioavailability of the drug, and enables the drug to better exert the therapeutic effect of the clinical disease. The amorphous material maintains good physical and chemical stability under accelerated test conditions (40 ± 2 ° C, humidity 75% ± 5%).

Claims (24)

A solid dispersion containing tadalafil and a pharmaceutically acceptable excipient, characterized in that the solid dispersion has a weight ratio of tadalafil to a pharmaceutically acceptable excipient of 1:0.1 to 100, wherein The tadalafil is in an amorphous state, and the X-ray powder diffraction spectrum of the solid dispersion deducts the characteristic peak of the tadalafil crystal after subtracting the background peak of the medicinal adjuvant. The solid dispersion containing tadalafil and a pharmaceutically acceptable adjuvant according to claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of excipients, propellants, solubilizers, solubilizers, emulsifiers, colorants , adhesives, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesion Agent, integrator, penetration enhancer, pH adjuster, buffer, plasticizer, surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculation And at least one of a deflocculating agent, an antioxidant, an adsorbent, a filter aid, and a release retarder. The solid dispersion containing tadalafil and a pharmaceutically acceptable adjuvant according to claim 1, wherein the pharmaceutically acceptable adjuvant is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, povidone, and poly Ethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl methyl cellulose Phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinized starch, cross At least one of a combination of starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, chitosan, and collagen. A pharmaceutical composition comprising a solid dispersion of tadalafil characterized by the formation of a solid dispersion of tadalafil with an organic vehicle, said solid dispersion forming a composition with a pharmaceutical formulation excipient, Tada The weight of the non-weight is 20-80% of the total weight of the solid dispersion, and the weight of the pharmaceutical preparation excipient is 0.1-80% by weight of the solid dispersion, wherein the tadalafil is an amorphous state. In the X-ray powder diffraction spectrum of the composition, the characteristic peak of the tadalafil crystal is absent after subtracting the background peak of the organic vehicle and the pharmaceutically acceptable adjuvant. A pharmaceutical composition comprising a tadalafil solid dispersion according to claim 4, wherein the organic vehicle is selected from pharmaceutically acceptable polymers or copolymers. A pharmaceutical composition comprising an amorphous tadalafil solid dispersion according to claim 4 or 5, wherein the organic vehicle is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyv. Ketone, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl methyl Cellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinization At least one of starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, chitosan, ion exchange resin, and collagen. A pharmaceutical composition comprising a tadalafil solid dispersion according to claim 4, wherein said The pharmaceutical preparation auxiliary is selected from the group consisting of excipients, propellants, solubilizers, solubilizers, emulsifiers, colorants, binders, disintegrators, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, Glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, anti-adhesives, integrators, penetration enhancers, pH adjusters, buffers, plasticizers, surfactants, hair At least one of a foaming agent, an antifoaming agent, a thickener, an inclusion agent, a moisturizing agent, an absorbent, a diluent, a flocculating agent and a deflocculating agent, an antioxidant, an adsorbent, a filter aid, and a release retardant . A method of preparing a solid dispersion of tadalafil and a pharmaceutical excipient according to claim 1, comprising the steps of: 1) mixing tadalafil with a medicinal adjuvant, heating until the medicinal adjuvant melts; wherein the weight ratio of tadalafil to the medicinal adjuvant is 1:0.1-100; 2) After mixing and cooling, the obtained mixture was pulverized to obtain a solid dispersion of an amorphous form of tadalafil and a pharmaceutically acceptable adjuvant. The method for preparing a solid dispersion of tadalafil and a pharmaceutical excipient according to claim 8, wherein the excipient is selected from the group consisting of an excipient, a propellant, a solubilizer, a solubilizer, an emulsifier, Colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, Anti-adhesive, integrator, penetration enhancer, pH adjuster, buffer, plasticizer, surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, thinner At least one of a flocculating agent and a deflocculating agent, an antioxidant, an adsorbent, a filter aid, and a release retarder. The method for preparing a solid dispersion of tadalafil and a pharmaceutical excipient according to claim 8, wherein the pharmaceutical excipient is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyv. Ketone, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl methyl Cellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinization At least one of starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, chitosan, and collagen. A method of preparing a solid dispersion of tadalafil and a pharmaceutical excipient according to claim 1, comprising the steps of: 1) mixing tadalafil with a medicinal adjuvant in a solvent at a mixing temperature of -50 to 150 ° C to form a solution or suspension containing tadalafil and a pharmaceutical excipient, wherein tadalafil and a solvent are used. The weight ratio is 0.001 to 100:1, and the weight ratio of tadalafil to the medicinal excipient is 1:0.1 to 100; 2) The solvent in the solution or suspension obtained in the step 1) is removed to obtain a solid dispersion of the amorphous form of tadalafil and a pharmaceutically acceptable adjuvant. The method for preparing a solid dispersion of tadalafil and a medicinal adjuvant according to claim 11, wherein the pharmaceutically acceptable excipient is selected from the group consisting of an excipient, a propellant, a solubilizer, a co-solvent, an emulsifier, Colorant, sticky Mixture, disintegrant, filler, lubricant, wetting agent, osmotic pressure regulator, stabilizer, glidant, flavoring agent, preservative, suspending agent, coating material, fragrance, anti-adhesive agent, Integrating agent, penetration enhancer, pH adjuster, buffer, plasticizer, surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, diluent, flocculant and At least one of a deflocculating agent, an antioxidant, an adsorbent, a filter aid, and a release retarder. The method for preparing a solid dispersion of tadalafil and a pharmaceutical excipient according to claim 11, wherein the pharmaceutical excipient is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyv. Ketone, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl methyl Cellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pregelatinization At least one of starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, chitosan, and collagen. The method for preparing a solid dispersion of tadalafil and a medicinal adjuvant according to claim 11, wherein the solvent in the step 1) is selected from the group consisting of alcohols having less than 12 carbon atoms, phenols and ethers. At least one of a halogenated hydrocarbon, a ketone, an aldehyde, a nitrile, an amide, a sulfone, a sulfoxide, a carboxylic acid, and water; and the step 2) the solvent is removed by evaporation, vacuum evaporation, spray drying, freeze drying , hot melt extrusion, filtration, centrifugation or stirring film drying. A method of preparing a pharmaceutical composition comprising a tadalafil solid dispersion according to claim 4, comprising the steps of: 1) heating a mixture of tadalafil, at least one organic vehicle and at least one pharmaceutical preparation auxiliary, wherein the weight of tadalafil is 20 to 80% by weight based on the total weight of the solid dispersion. The weight of the preparation auxiliary is 0.1 to 80% by weight of the solid dispersion; 2) The mixture was uniformly cooled, and the resulting mixture was pulverized to obtain a pharmaceutical composition containing an amorphous form of the tadalafil solid dispersion. A process for the preparation of a pharmaceutical composition comprising a tadalafil solid dispersion according to claim 15, wherein the organic vehicle is selected from pharmaceutically acceptable polymers or copolymers. The method for preparing a pharmaceutical composition comprising a tadalafil solid dispersion according to claim 15 or 16, wherein the organic vehicle is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, Povidone, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl Methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pre- At least one of gelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, chitosan, and collagen. The method for preparing a pharmaceutical composition containing a tadalafil solid dispersion according to claim 15, wherein the pharmaceutical preparation excipient is selected from the group consisting of an excipient, a propellant, a solubilizer, a solubilizing agent, and an emulsion. Agent Toners, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances, Anti-adhesive, integrator, penetration enhancer, pH adjuster, buffer, plasticizer, surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, thinner At least one of a flocculating agent and a deflocculating agent, an antioxidant, an adsorbent, a filter aid, and a release retarder. A method of preparing a pharmaceutical composition comprising a tadalafil solid dispersion according to claim 4, comprising the steps of: 1) mixing tadalafil, at least one organic vehicle and at least one pharmaceutical preparation auxiliary in a solvent at a mixing temperature of -50 to 150 ° C to form a solution containing tadalafil, an organic vehicle and a pharmaceutically acceptable adjuvant. Or a suspension wherein the weight ratio of tadalafil to the solvent is from 0.001 to 100:1, the weight of tadalafil is from 20 to 80% by weight based on the total weight of the solid dispersion, and the weight of the auxiliary material is the weight of the solid dispersion. 0.1 to 80%; 2) The solvent in the solution or suspension obtained in the step 1) is removed to obtain a pharmaceutical composition of the amorphous form of tadalafil. A method of preparing a pharmaceutical composition comprising a tadalafil solid dispersion according to claim 19, wherein the organic vehicle is selected from the group consisting of pharmaceutically acceptable polymers or copolymers. The method for preparing a pharmaceutical composition containing a tadalafil solid dispersion according to claim 19 or 20, wherein the organic vehicle is selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, Povidone, polyethylene glycol, ethyl cellulose, liposome, methacrylic acid copolymer, polyvinyl acetate, carboxymethyl ethyl cellulose, carboxymethyl cellulose phthalate, hydroxypropyl Methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyacrylic resin, carboxyvinyl, alginate, carrageenan, carboxyacetolactone, gum, polyvinyl alcohol, pre- At least one of gelatinized starch, crosslinked starch, sodium carboxymethyl starch, dextrin, polyethylene oxide, chitosan, chitosan, and collagen. The method for preparing a pharmaceutical composition containing a tadalafil solid dispersion according to claim 19, wherein the pharmaceutical adjuvant is selected from the group consisting of an excipient, a propellant, a solubilizer, a solubilizer, and an emulsifier , colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, coating materials, fragrances , anti-adhesive, integrator, penetration enhancer, pH adjuster, buffer, plasticizer, surfactant, foaming agent, antifoaming agent, thickener, inclusion agent, moisturizer, absorbent, dilution At least one of a agent, a flocculating agent and a deflocculating agent, an antioxidant, an adsorbent, a filter aid, and a release retardant. The method for preparing a pharmaceutical composition containing a tadalafil solid dispersion according to claim 19, wherein the solvent of the step 1) is selected from the group consisting of alcohols having 12 or less carbon atoms, phenols, and ethers. At least one of a halogenated hydrocarbon, a ketone, an aldehyde, a nitrile, an amide, a sulfone, a sulfoxide, a carboxylic acid, and water; and the step 2) the solvent is removed by evaporation, vacuum evaporation, spray drying, freeze drying , hot melt extrusion, filtration, centrifugation or stirring film drying. A solid dispersion containing tadalafil and a pharmaceutically acceptable adjuvant according to claim 1 for the treatment of male erectile dysfunction In the use of drugs.

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