WO2017041679A1 - Dispersion solide de tadalafil et d'excipients pharmaceutiques, et procédé de préparation de la dispersion solide - Google Patents

Dispersion solide de tadalafil et d'excipients pharmaceutiques, et procédé de préparation de la dispersion solide Download PDF

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WO2017041679A1
WO2017041679A1 PCT/CN2016/098094 CN2016098094W WO2017041679A1 WO 2017041679 A1 WO2017041679 A1 WO 2017041679A1 CN 2016098094 W CN2016098094 W CN 2016098094W WO 2017041679 A1 WO2017041679 A1 WO 2017041679A1
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tadalafil
solid dispersion
agent
amorphous
excipient
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PCT/CN2016/098094
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English (en)
Chinese (zh)
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张席妮
熊志刚
张三丰
资春鹏
王颖奇
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常州方楠医药技术有限公司
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Priority claimed from CN201510562080.4A external-priority patent/CN106491612A/zh
Priority claimed from CN201610440524.1A external-priority patent/CN107510695A/zh
Application filed by 常州方楠医药技术有限公司 filed Critical 常州方楠医药技术有限公司
Publication of WO2017041679A1 publication Critical patent/WO2017041679A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems

Definitions

  • 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.
  • 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.
  • Patent CN1045777 discloses a white needle crystal of tadalafil
  • Form I 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.
  • 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.
  • a new solid form of the drug is usually developed. Solid forms with better drug solubility and higher bioavailability are necessary.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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.
  • the characteristic peak of the tadalafil crystal is absent after subtracting the background peak of the carrier and the pharmaceutically acceptable excipient.
  • the organic vehicle is selected from a pharmaceutically acceptable polymer or copolymer.
  • 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.
  • 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:
  • the invention provides a preparation method of another solid dispersion of tadalafil and a medicinal adjuvant, comprising the following steps:
  • 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.
  • 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.
  • 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 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:
  • the present invention provides a process for the preparation of a pharmaceutical composition comprising a solid dispersion of tadalafil comprising the steps of:
  • the organic vehicle described in the step 1) is selected from a pharmaceutically acceptable polymer or copolymer.
  • 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.
  • 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.
  • 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.
  • 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-K ⁇ radiation, deducting the background peak of the medicinal excipient from the X-ray powder diffraction spectrum expressed by degree 2 ⁇ 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.
  • 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.
  • 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.
  • 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.
  • Example 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.
  • Example 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.
  • FIG. 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.
  • 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:
  • Scanning range: from 2.0 to 60.0 degrees;
  • Scan rate 60 degrees / minute.
  • tadalafil Any physical form of tadalafil can be used to prepare the amorphous tadalafil solid dispersion of the present invention.
  • Tadanafil (50 mg) and povidone K30 (100 mg) were dissolved in methanol (600 ⁇ l) 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.
  • Tatanafil (50 mg) and polyethylene glycol 4000 (200 mg) were dissolved in ethanol (600 ⁇ l) and water (600 ⁇ l), 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.
  • 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.
  • the solid dispersion 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.
  • Tadalafil (1 g) and hydroxypropylmethylcellulose E50 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.
  • 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.
  • 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.
  • Tadanafil 50 mg
  • polyacrylic resin Eudragit L100 100 mg
  • methanol 750 ⁇ l
  • 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.
  • Tadanafil 50 mg
  • polyacrylic resin Eudragit S100 5 mg
  • methanol 4 ml
  • ethyl acetate 1 ml
  • the mixture was stirred at -30 °C.
  • 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.
  • Tadanafil 50 mg
  • Carbopol Carbomer 940 50 mg
  • methanol 4 ml
  • tetrahydrofuran 1 ml
  • 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.
  • 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.
  • Tadanafil 50 mg
  • pregelatinized starch 100 mg
  • methanol 4 ml
  • water 1 ml
  • 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
  • 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.
  • Tadanafil 50 mg
  • sodium carboxymethylcellulose SCMC 500 mg
  • 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.
  • 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.
  • Tadalafil 50 mg
  • carboxymethylcellulose phthalate Agucoat CPD 5 g
  • 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.
  • a white solid a solid dispersion of amorphous tadalafil and carboxymethylcellulose phthalate Agucoat CPD.
  • 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.
  • Tadanafil (30 mg) and polyacrylic resin Eudragit E100 (30 mg) were dissolved in ethanol (600 ⁇ L), tetrahydrofuran (900 ⁇ L) and N,N-dimethylformamide (600 ⁇ L) 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.
  • X X
  • Tadalafil (30 mg) and collagen Peptan (300 mg) were dissolved in ethanol (600 ⁇ l), tetrahydrofuran (900 ⁇ l) and acetonitrile (600 ⁇ l), 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.
  • Tadalafil (30 mg) and gum Galactosol (300 mg) were dissolved in ethanol (600 ⁇ L) and tetrahydrofuran (900 ⁇ L), 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.
  • Tadanafil (30 mg) and carboxyacetic acid lactone (300 mg) were added to ethanol (750 ⁇ l) and water (750 ⁇ l), 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.
  • Tadanafil (30 mg) and ⁇ -cyclodextrin (30 mg) were added to methanol (300 ⁇ l) and water (300 ⁇ l), 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 ⁇ -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.
  • Tadanafil (30 mg) and sodium carboxymethylcellulose SCMC (30 mg) were added to methanol (300 ⁇ l) and water (60 ⁇ L), 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.
  • Tadanafil (5 mg) and polyethylene oxide Polyox WSR301 (60 mg) were added to methanol (300 ⁇ l) and water (60 ⁇ L), 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 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Tadalafil 50 mg
  • polyacrylic resin Eudragit L100 100 mg
  • microcrystalline cellulose 100 mg
  • 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.
  • Tadanafil 50 mg
  • polyacrylic resin Eudragit S100 5 mg
  • acetic acid 4 ml
  • ethyl acetate 1 ml
  • 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.
  • Tadanafil 50 mg
  • chitosan 500 mg
  • dimethylformamide 5 ml
  • 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.
  • Tadanafil 50 mg
  • carrageenan E407 500 mg
  • microcrystalline cellulose 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 tadalafil solid dispersion and microcrystalline cellulose, X-ray powder of the composition.
  • a white solid that is, a combination of an amorphous tadalafil solid dispersion and microcrystalline cellulose, X-ray powder of the composition.
  • 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.
  • Tadanafil 50 mg
  • chitosan 5 g
  • lactose 100 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.
  • 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.
  • the carrier was subtracted. And the characteristic peak of the crystalline form of tadalafil hydrochloride after the background peak of the medicinal excipient.
  • tadalafil (30 mg) and sodium carboxymethylcellulose SCMC (30 mg) to methanol (300 ⁇ l) and acetic acid (600 ⁇ l), 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.
  • the carrier was subtracted.
  • the background peak of the medicinal excipients has no characteristic peak of the amorphous state of Tada.
  • tadalafil (30 mg) and polyvinyl alcohol EG-40 (60 mg) to methanol (300 ⁇ l), 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • 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
  • 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
  • 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.
  • 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.
  • Example 78 of the present invention 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 ⁇ m 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.
  • 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.
  • 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%).

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Abstract

L'invention concerne une dispersion solide de tadalafil et d'excipients pharmaceutiques, et un procédé de préparation de la dispersion solide. Le tadalafil est sous forme amorphe. L'invention concerne également une composition pharmaceutique contenant la dispersion solide, et un procédé de préparation de la composition pharmaceutique. L'invention concerne également une utilisation de la dispersion solide dans la préparation d'un médicament pour traiter le dysfonctionnement érectile chez l'homme.
PCT/CN2016/098094 2015-09-07 2016-09-05 Dispersion solide de tadalafil et d'excipients pharmaceutiques, et procédé de préparation de la dispersion solide WO2017041679A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201510562080.4 2015-09-07
CN201510562080.4A CN106491612A (zh) 2015-09-07 2015-09-07 一种无定型他达那非与药用辅料的固体分散体及其制备方法
CN201610440524.1 2016-06-17
CN201610440524.1A CN107510695A (zh) 2016-06-17 2016-06-17 一种含有无定型他达拉非固体分散体的药用组合物及其制备方法

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Publication number Priority date Publication date Assignee Title
CN114028349A (zh) * 2021-10-12 2022-02-11 南京恒正药物研究院有限公司 一种他达拉非口崩片
CN114432241A (zh) * 2021-12-21 2022-05-06 上海奥全生物医药科技有限公司 一种快速分散的助悬组合物、制备方法及其应用
CN114569565A (zh) * 2022-04-21 2022-06-03 北京闪释科技有限公司 一种他达拉非冻干口崩片及制备方法
CN115154471A (zh) * 2022-08-12 2022-10-11 广东万年青制药股份有限公司 一种用于治疗勃起功能障碍及早泄的组合片及其制备方法

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CN101163704A (zh) * 2005-02-25 2008-04-16 特瓦制药工业有限公司 大粒径他达那非及其制备方法
CN102647978A (zh) * 2009-10-07 2012-08-22 力奇制药公司 包含溶解性差的活性成分和高支化聚合物的药物组合物

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Publication number Priority date Publication date Assignee Title
CN101163704A (zh) * 2005-02-25 2008-04-16 特瓦制药工业有限公司 大粒径他达那非及其制备方法
CN102647978A (zh) * 2009-10-07 2012-08-22 力奇制药公司 包含溶解性差的活性成分和高支化聚合物的药物组合物

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114028349A (zh) * 2021-10-12 2022-02-11 南京恒正药物研究院有限公司 一种他达拉非口崩片
CN114432241A (zh) * 2021-12-21 2022-05-06 上海奥全生物医药科技有限公司 一种快速分散的助悬组合物、制备方法及其应用
CN114432241B (zh) * 2021-12-21 2023-07-14 上海奥全生物医药科技有限公司 一种快速分散的助悬组合物、制备方法及其应用
CN114569565A (zh) * 2022-04-21 2022-06-03 北京闪释科技有限公司 一种他达拉非冻干口崩片及制备方法
CN115154471A (zh) * 2022-08-12 2022-10-11 广东万年青制药股份有限公司 一种用于治疗勃起功能障碍及早泄的组合片及其制备方法

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