WO2017036420A1 - 含沙库比曲和缬沙坦的药用组合物及其制备方法 - Google Patents

含沙库比曲和缬沙坦的药用组合物及其制备方法 Download PDF

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WO2017036420A1
WO2017036420A1 PCT/CN2016/098093 CN2016098093W WO2017036420A1 WO 2017036420 A1 WO2017036420 A1 WO 2017036420A1 CN 2016098093 W CN2016098093 W CN 2016098093W WO 2017036420 A1 WO2017036420 A1 WO 2017036420A1
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valsartan
pharmaceutically acceptable
acceptable salt
agent
pharmaceutical composition
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PCT/CN2016/098093
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English (en)
French (fr)
Inventor
张席妮
熊志刚
资春鹏
涂福荣
周涛
熊理查
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常州方楠医药技术有限公司
常州爱诺新睿医药技术有限公司
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Priority claimed from CN201510558821.1A external-priority patent/CN106491600A/zh
Priority claimed from CN201610436431.1A external-priority patent/CN107510653A/zh
Application filed by 常州方楠医药技术有限公司, 常州爱诺新睿医药技术有限公司 filed Critical 常州方楠医药技术有限公司
Publication of WO2017036420A1 publication Critical patent/WO2017036420A1/zh

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing a kubuqu and valsartan and a preparation method thereof, and to an amorphous shakubi sulphate, valsartan or a pharmaceutically acceptable thereof
  • Sacubitril chemical name (2S,4R)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)amino]-2-methylpentanoate
  • Valsartan chemical name N-pentanoyl-N-[[2'-(1H-tetrazolyl-5-yl)[1,1'-biphenyl]-4-yl]methyl] -L-valine, an angiotensin II receptor antagonist.
  • LCZ-696 is a trisodium salt hemipentate eutectic of Shakubi and valsartan, and its chemical name is [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-B Oxycarbonyl-1-butylcarbamoyl)propionic acid-(S)-3'-methyl-2'-(pentanoyl ⁇ 2"-(tetrazol-5-yl)biphenyl-4'-yl Methyl ⁇ amino)butyric acid]trisodium hemipentahydrate, trade name Entresto. This product was developed by Swiss Novartis on July 7, 2015 and approved by the US Food and Drug Administration (FDA) six weeks in advance.
  • FDA US Food and Drug Administration
  • LCZ-696 is a first innovative drug that acts on the neuroendocrine system of the heart in a variety of ways, which is the treatment of heart failure over the past 25 years. A great breakthrough in the field is expected to successfully shake the overall framework of heart failure treatment that has not been modified in the past 10 years.
  • CN102091330 A pharmaceutical composition comprising (I) an AT1-antagonist valsartan or a pharmaceutically acceptable salt thereof and (II) a NEP inhibitor or a pharmaceutically acceptable salt thereof, and comprising or not comprising a pharmaceutically acceptable carrier, For the treatment of a variety of diseases.
  • LCZ-696 is a dual-effect complex with covalent and non-covalent interactions between the two pharmaceutically active components, and non-covalent interactions including hydrogen. Bonds, van der Waals forces, ionic bonds, etc. Thus, the solid form of LCZ-696 is actually a solid composite in the form of a eutectic.
  • 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. Generally due to the order and periodicity of crystalline material molecules Arrangement, reducing the energy of the interaction between molecules, the energy is lower, while the molecules of the amorphous state are in a highly disordered state, the surface free energy of the substance is larger, and the molecules in the solid matter are more than the molecules in the crystalline solid matter. Higher energy, easier to disperse, increase its dissolution, and improve the bioavailability of the drug.
  • 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 pharmaceutical composition containing saponin and valsartan and a preparation method thereof, which can obtain an amorphous form of sulco or a pharmaceutically acceptable orally acceptable sulphate. a salt, valsartan or a combination thereof with a pharmaceutically acceptable salt and a pharmaceutically acceptable adjuvant, which increases the dissolution of the sulbac or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof
  • the preparation method 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 pharmaceutical composition comprising a sulbacb and a valsartan, the composition comprising a sirbe or a pharmaceutically acceptable salt thereof, valsartan or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant,
  • the ratio of the amount of the substance of the sulbacb or the pharmaceutically acceptable salt thereof to the valsartan or a pharmaceutically acceptable salt thereof is from 1:0.95 to 1.05, and the ratio of the total weight of the two to the weight of the pharmaceutically acceptable excipient Is 1:0.1 to 100, wherein the sir-fibrew or a pharmaceutically acceptable salt thereof, valsartan or a pharmaceutically acceptable salt thereof is in an amorphous state, and the X-ray of the composition In the powder diffraction spectrum, after subtracting the background peak of the pharmaceutical excipient, there is no characteristic peak of the crystal of the complex of the complex of the sulphate or its pharmaceutically acceptable salt, valsartan or its pharmaceutically acceptable salt.
  • 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 shakupit or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof, which comprises Shakubi Or a pharmaceutically acceptable salt thereof and a solid dispersion of valsartan or a pharmaceutically acceptable salt thereof with an organic vehicle, and at least one pharmaceutically acceptable adjuvant, shakupit or pharmaceutically acceptable thereof
  • the weight of the salt and valsartan or a pharmaceutically acceptable salt thereof is from 20% to 80% by weight based on the total weight of the solid dispersion, and the weight of the auxiliary material is from 0.1% to 80% by weight of the solid dispersion, wherein The kucurbit or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof are in an amorphous state, and the X-ray powder diffraction spectrum of the composition is deducted from the carrier and the pharmaceutically acceptable excipient After the background peak, there is no characteristic peak
  • 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 At least one of them.
  • the preparation method of the medicinal composition of the present invention for the combination of the sulphone and valsartan of the present invention comprises the following steps:
  • the present invention provides a method for preparing a composition of another sulco or a pharmaceutically acceptable salt thereof, valsartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant, comprising the steps of:
  • 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, and collagen.
  • the solvent in the step 1) is selected from the group consisting of alcohols having a carbon number of 12 or less, 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 composition in the present invention means a mixture, a composite, a copolymer, a coprecipitate, a eutectic, a composition, a solvate, and a hydrate.
  • the pharmaceutically acceptable pharmaceutical excipients and pharmaceutical preparation excipients in the present invention refer to excipients and additives used in the production of pharmaceuticals and formulation formulations, including excipients, propellants, solubilizers, solubilizers, emulsifiers, 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 , flocculants and deflocculants, antioxidants, adsorbents, filter aids, release retarders, etc.
  • the pharmaceutically acceptable salts in the present invention include sodium salts, potassium salts, lithium salts, calcium salts, magnesium salts and the like, and are preferably sodium salts and potassium salts.
  • a process for the preparation of a pharmaceutical composition comprising a solid dispersion of sirbe or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof, comprising the steps of:
  • the present invention provides a process for the preparation of a pharmaceutical composition comprising a solid dispersion of sirbe or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof, 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 in the step 1) is selected from the group consisting of alcohols having a carbon number of 12 or less, 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 present invention also provides a solid dispersion containing amorphous Shakupit or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable adjuvant
  • a solid dispersion containing amorphous Shakupit or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable adjuvant
  • a composition of the succinol or a pharmaceutically acceptable salt thereof, valsartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant of the present invention using Cu-K ⁇ radiation, X-ray powder expressed in degrees 2 ⁇
  • a characteristic peak of a crystalline state in which the background peak of the pharmaceutically acceptable excipient is degraded in the diffraction spectrum without the sirbecob or a pharmaceutically acceptable salt thereof, valsartan or a pharmaceutically acceptable salt thereof, and a combination thereof Kubbit or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof are in an amorphous state, and in the prior art, shakupit and valsartan trisodium salt hemipentahydrate are generally used.
  • the eutectic is LCZ-696, and no reports of its amorphous form have been reported.
  • the energy of the intermolecular interaction is reduced, and the energy is low, while the Shakubi, valsartan or its pharmaceutically acceptable salt of the present invention is indeterminate.
  • the molecule is highly disordered, the surface free energy of the substance is larger, the molecules in the solid matter have higher energy than the molecules in the crystalline solid matter, are more likely to disperse, increase the dissolution rate, and improve the shakubi ratio.
  • the present invention mixes Shakubis or a pharmaceutically acceptable salt thereof, valsartan or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant, and then uses a "solid dispersant" method to polymerize by a pharmaceutical excipient.
  • the body network structure blocks the drug molecules and inhibits the occurrence of crystallization, so that it remains dispersed and amorphous.
  • the invention adopts the medicinal excipients which are widely used, low in price and good in solubility, and the medicinal excipients are mixed with sabbit or a pharmaceutically acceptable salt thereof, valsartan or a pharmaceutically acceptable salt thereof, and evaporating Techniques such as spray drying, freeze drying and hot melt extrusion can provide an amorphous form of sirbe or its pharmaceutically acceptable salt, valsartan or a pharmaceutically acceptable salt thereof, adding to the composition of the present invention The stability of the amorphous form of sirbecob or its pharmaceutically acceptable salt, valsartan or a pharmaceutically acceptable salt thereof.
  • the invention selects a pharmaceutically widely used and inexpensive auxiliary material, and obtains a composition of sabbit or a pharmaceutically acceptable salt thereof, valsartan or a pharmaceutically acceptable salt thereof and a medicinal auxiliary, which is easy to develop.
  • the preparation method of the invention is not limited by the drying process, nor is it limited by the type of solvent and the amount of solvent, and is easy to operate, low in cost, easy to realize, and industrialized production can be realized.
  • composition of the amorphous Shakupit or the pharmaceutically acceptable salt thereof, the valsartan or the pharmaceutically acceptable salt thereof and the pharmaceutically acceptable adjuvant prepared by the present invention has high dispersibility and stability, and is prepared After the solid preparation, the disintegration can make the dispersion of the drug particles 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 composition of the succinol or the pharmaceutically acceptable salt thereof, the valsartan or the pharmaceutically acceptable salt thereof and the pharmaceutically acceptable auxiliary agent in the amorphous state of the present invention is not limited by the drying process, and It is easy to operate, low in cost, easy to implement, and can be industrially produced without being limited by the type of solvent and the amount of solvent.
  • composition of the amorphous form of Shakupit or the pharmaceutically acceptable salt thereof, valsartan or a pharmaceutically acceptable salt thereof and the pharmaceutically acceptable adjuvant prepared by the present invention under accelerated test conditions 40 ° C ⁇ 2 ° C, humidity 75% ⁇ 5%
  • the present invention will have broad application prospects.
  • Example 1 is an X-ray powder diffraction pattern of a composition of amorphous Shakubis, amorphous valsartan and povidone K30 of Example 1 of the present invention.
  • Example 2 is an X-ray powder diffraction pattern of a composition of an amorphous sandboxazone sodium salt, an amorphous valsartan disodium salt, and a polyacrylic resin Eudragit L100 according to Example 12 of the present invention.
  • Figure 3 is an X-ray powder diffraction pattern of a composition of amorphous Sarkuel sodium salt, amorphous valsartan disodium salt solid dispersion, and microcrystalline cellulose according to Example 51 of the present invention.
  • Figure 4 is an X-ray powder diffraction pattern of microcrystalline cellulose used in Example 51 of the present invention.
  • Figure 5 is an X-ray powder diffraction pattern of the composition of the amorphous Shakupit sodium salt, the amorphous valsartan disodium salt solid dispersion and the colloidal silica Aerosil 200 of Example 71 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.
  • Any physical form of sulbacb or a pharmaceutically acceptable salt thereof and valsartan or a pharmaceutically acceptable salt thereof can be used for the preparation of the amorphous Shakupit or the pharmaceutically acceptable salt thereof of the present invention. And a solid dispersion of valsartan or a pharmaceutically acceptable salt thereof.
  • composition of tanzan sodium salt and polyethylene glycol 8000 a composition of tanzan sodium salt and polyethylene glycol 8000, the X-ray powder diffraction pattern of the composition, after subtracting the background peak of the medicinal excipient, no LCZ-696, shakupitide sodium salt and valsartan Characteristic peak of the sodium salt crystal form.
  • Shakupit 411.5 mg
  • valsartan 435.5 mg
  • hydroxypropylmethylcellulose E50 0.2 g
  • the above solution was freeze-dried to obtain a white solid, that is, a composition of amorphous Shakupit, amorphous valsartan and hydroxypropylmethylcellulose E50, and the composition was deducted from the X-ray powder diffraction pattern.
  • a white solid that is, a composition of amorphous Shakupit, amorphous valsartan and hydroxypropylmethylcellulose E50
  • Shakubi (411.5 mg), valsartan (435.5 mg), ethanol (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 composition of amorphous Shakupit, amorphous valsartan and polyethylene glycol 10000, and the X-ray powder diffraction pattern of the composition is deducted from the pharmaceutical excipient After the background peak, there are no characteristic peaks of Shakubi and valsartan crystal forms.
  • LCZ-696 50 mg
  • polyacrylic resin Eudragit L100 100 mg
  • methanol 750 ⁇ l
  • the above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, i.e., a composition of amorphous sir-salt, amorphous valsartan and polyacrylic resin Eudragit L100, X-ray powder diffraction pattern of the composition
  • Fig. 2 it can be seen from Fig. 2 that the characteristics of the crystal form of LCZ-696, sacobiqu salt and valsartan disodium salt are not deducted from the background peak of the excipients in the X-ray powder diffraction pattern. peak.
  • LCZ-696 50 mg
  • polyacrylic resin Eudragit S100 5 mg
  • methanol 4 ml
  • water 1 ml
  • the above solution was slowly concentrated to dryness in a rotary evaporator to obtain a white solid, and a white solid was precipitated under stirring, that is, a composition of an amorphous shakupit, an amorphous valsartan and a polyacrylic resin Eudragit S100, the composition of which was In the X-ray powder diffraction pattern, there are no characteristic peaks of LCZ-696, shakupitide sodium salt and valsartan disodium salt crystal form after subtracting the background peak of the medicinal adjuvant.
  • the X-ray powder diffraction pattern of the composition has no characteristic peaks of LCZ-696, sulbactam sodium salt, and valsartan disodium salt crystal form after subtracting the background peak of the medicinal adjuvant.
  • LCZ-696 50 mg
  • high-branched cross-linked starch 50 mg
  • methanol 4 ml
  • water 1 ml
  • a white solid is obtained, and a white solid is precipitated under stirring, that is, a composition of amorphous amorphous Shakutia sodium salt, amorphous valsartan disodium salt and high-branched crosslinked starch, and the X-ray powder diffraction pattern of the composition is obtained.
  • deducting the background of pharmaceutical excipients There are no characteristic peaks of LCZ-696, Shakubite sodium salt and valsartan disodium salt crystal form after the peak.
  • LCZ-696 50 mg
  • sodium carboxymethylcellulose SCMC 500 mg
  • the above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, that is, a composition of an amorphous form of sulbactam sodium, an amorphous valsartan disodium salt and sodium carboxymethylcellulose SCMC, the composition In the X-ray powder diffraction pattern, there are no characteristic peaks of LCZ-696, shakupitide sodium salt and valsartan disodium salt crystal form after subtracting the background peak of the medicinal adjuvant.
  • LCZ-696 50 mg
  • carboxymethylcellulose phthalate Agucoat CPD 5 g
  • methanol 30 ml
  • the above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, that is, an amorphous form of sir-salt sodium salt, an amorphous valsartan disodium salt and a carboxymethyl fiber.
  • LCZ-696 50 mg
  • chitosan 5 g
  • methanol 50 ml
  • the above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, i.e., a composition of amorphous sulbactam sodium salt, amorphous valsartan disodium salt and chitosan, X-ray of the composition
  • a white solid i.e., a composition of amorphous sulbactam sodium salt, amorphous valsartan disodium salt and chitosan
  • X-ray of the composition In the powder diffraction pattern, after the background peak of the medicinal excipient was deducted, there were no characteristic peaks of the crystal form of LCZ-696, sacurbitium sodium salt and valsartan disodium salt.
  • LCZ-696 (30 mg) and polyacrylic resin Eudragit E100 (60 mg) were dissolved in ethanol (120 ⁇ L), tetrahydrofuran (120 ⁇ L) and N,N-dimethylformamide (60 ⁇ L). The mixture was heated to 50 ° C, stirred and dissolved, and the solution was cooled to 10 ° C to precipitate a white solid, which was filtered and dried to obtain a combination of amorphous Shakupit sodium salt, amorphous valsartan disodium salt and polyacrylic resin Eudragit E100.
  • X-ray powder diffraction pattern of the composition there is no characteristic peak of the crystal form of LCZ-696, shakupitide sodium salt and valsartan disodium salt after subtracting the background peak of the medicinal adjuvant.
  • LCZ-696 (30 mg) and gum Galactosol (300 mg) were dissolved in ethanol (600 ⁇ L) and water (600 ⁇ L) and heated to 50 ° C to dissolve. The above solution was concentrated to dryness in a rotary evaporator.
  • LCZ-696 (30 mg) and hydroxypropylmethylcellulose phthalate HPMCP (30 mg) were added to ethanol (750 ⁇ l) and water (750 ⁇ l), heated to 80 ° C and stirred to mix well.
  • the above solution was slowly concentrated to dryness in a rotary evaporator to give a white solid, that is, an amorphous form of sir-salt sodium salt, amorphous valsartan disodium salt and hydroxypropylmethylcellulose phthalate HPMCP.
  • composition in the X-ray powder diffraction pattern of the composition, has no characteristic peaks of the crystal form of LCZ-696, shakupitide sodium salt and valsartan disodium salt after subtracting the background peak of the medicinal adjuvant.
  • Shakubiqu (11.1 mg), valsartan (43.5 mg) and carboxyacetolactone (300 mg) were added to ethanol (750 ⁇ l) and water (750 ⁇ l), and heated to 80 ° C with stirring and homogenized.
  • the above solution was slowly concentrated in a rotary evaporator to remove the solvent to obtain a white solid, that is, a composition of amorphous Shakuqu, amorphous valsartan and carboxyacetolactone, in the X-ray powder diffraction pattern of the composition.
  • a white solid that is, a composition of amorphous Shakuqu, amorphous valsartan and carboxyacetolactone, in the X-ray powder diffraction pattern of the composition.
  • Shakubiqu (41.1 mg), valsartan (43.5 mg) and dextrin Maltrin M100 (300 mg) were added to ethanol (750 ⁇ l) and water (750 ⁇ l), heated to 80 ° C and stirred and mixed.
  • the above solution was slowly concentrated to dryness in a rotary evaporator to give a brown solid, that is, a composition of amorphous Shakuqu, amorphous valsartan and dextrin Maltrin M100, in the X-ray powder diffraction pattern of the composition.
  • a brown solid that is, a composition of amorphous Shakuqu, amorphous valsartan and dextrin Maltrin M100, in the X-ray powder diffraction pattern of the composition.
  • a white solid that is, a composition of an amorphous form of sulbactam sodium, an amorphous valsartan disodium salt, and a polyethylene oxide Polyox WSR301, the composition In the X-ray powder diffraction pattern, there are no characteristic peaks of LCZ-696, shakupitide sodium salt and valsartan disodium salt crystal form after subtracting the background peak of the medicinal adjuvant.
  • Example 37 Influential factors test of amorphous Shaku sulphate sodium salt, amorphous valsartan disodium salt and polyacrylic resin Eudragit L100 composition
  • MATERIALS The composition of the amorphous Shaku citrate sodium salt, the amorphous valsartan disodium salt and the polyacrylic resin Eudragit L100 obtained in Example 12
  • Table 1 illustrates: a combination of amorphous Shaku sulphate sodium salt, amorphous valsartan disodium salt and polyacrylic resin Eudragit L100, placed for 10 days, no significant change in related substances, no Shakubite sodium salt and strontium Crystallization of the sultan disodium salt.
  • Example 38 Accelerated Test of Amorphous Shaku Sorghum Sodium Salt, Amorphous Valsartan Disodium Salt and Polyacrylic Acid Resin Eudragit L100 Composition
  • MATERIALS The composition of the amorphous Shakusone sodium salt, the amorphous valsartan disodium salt and the polyacrylic resin Eudragit L100 obtained in Example 12.
  • Table 2 shows that the composition of the amorphous Shaku sulphate sodium salt, the amorphous valsartan disodium salt and the polyacrylic resin Eudragit L100 was placed under accelerated test conditions for 6 months, and the relevant substances showed no significant change, no sand reservoir. Crystallization of the sodium sulphate and valsartan disodium salt.
  • a composition of amorphous sandboxazone sodium salt, amorphous valsartan disodium salt and polyacrylic resin Eudragit L100 was prepared according to the method of Example 12.
  • LCZ-696 was prepared according to the method of Example 2 of the patent CN101098689.
  • Liquid A Take 16.6 ml of phosphoric acid, and add water to 100 ml to shake.
  • Liquid B 71.63 g of disodium hydrogen phosphate was taken, and water was added to dissolve it into 1000 ml. Take 72.5 ml of the above liquid A and 27.5 ml of the liquid B, and shake well to obtain.
  • Table 3 shows that the apparent solubility of the pharmaceutical compositions of the present invention at each pH value is significantly higher than the apparent solubility of the mixture of the crystalline form LCZ-696 and the polyacrylic resin Eudragit L100.
  • Shakubiqu (411.5 mg), valsartan (435.5 mg) and povidone K30 (10 g) were dissolved in ethanol (60 ml), heated to 60 ° C, stirred and dissolved, and then added with microcrystalline cellulose (50 mg). ).
  • the above solution was rapidly cooled to -10 ° C, a white solid was precipitated, filtered, and dried in vacuo to obtain a composition of amorphous Shakupit and valsartan solid dispersion and microcrystalline cellulose, the X-ray powder of the composition. After the background peak of the carrier and the medicinal excipient was subtracted from the diffraction pattern, there were no characteristic peaks of the Shakubi and valsartan crystal forms.
  • Shakubiqu (411.5 mg), valsartan (435.5 mg), ethanol (0.1 g) and polyethylene glycol 10000 (100 g) were heated to 240 ° 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 combination of amorphous Shakupit and valsartan solid dispersion and microcrystalline cellulose, the composition In the X-ray powder diffraction pattern, there are no characteristic peaks of the Shakubi and valsartan crystal forms after subtracting the background peaks of the carrier and the medicinal adjuvant.
  • the X-ray powder diffraction pattern of the pharmaceutical composition is free of the background peaks of the carrier and the medicinal excipients without the crystal form of the sulphate sodium salt and the valsartan disodium salt. Characteristic peak.
  • the X-ray powder diffraction pattern of microcrystalline cellulose is shown in Fig. 4.
  • Shakubi 50 mg
  • valsartan 51 mg
  • carrageenan E407 500 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 amorphous Shakut and valsartan solid dispersion and microcrystalline cellulose, the composition of which In the X-ray powder diffraction pattern, there are no characteristic peaks of the Shakubi and valsartan crystal forms after subtracting the background peaks of the carrier and the medicinal adjuvant.
  • Shakubi (30 mg), valsartan (31 mg) and collagen Peptan (300 mg) were dissolved in ethanol (600 ⁇ l), heated to 50 ° C, stirred and dissolved, and then microcrystalline cellulose was added (30 Mg). The solution was cooled to 10 ° C, a white solid precipitated, filtered, and dried to obtain a composition of amorphous Shakupit and valsartan and collagen Peptan.
  • the X-ray powder diffraction pattern of the composition was deducted from the carrier and There are no characteristic peaks of the Shakubi and valsartan crystal forms after the background peak of the medicinal excipients.
  • Example 76 Influencing Factors of Compositions of Solid Dispersions and Microcrystalline Cellulose of Amorphous Shaku Sorghum Salt and Valsartan Disodium Salt
  • MATERIALS The composition of the solid dispersion of the amorphous form of the sulphate and the valsartan disodium salt obtained in Example 51 and the microcrystalline cellulose
  • Table 4 illustrates that the composition of the solid dispersion of the amorphous sandboxing sodium valsarate salt and valsartan disodium salt of the present invention and the microcrystalline cellulose is placed under high temperature and high humidity conditions for 10 days, and the related substances are not significant. Change, no sulphate sodium salt and valsartan disodium salt crystallized.
  • Example 77 Accelerated stability test of a combination of a solid dispersion of amorphous sandboxet sodium salt and valsartan disodium salt and microcrystalline cellulose
  • MATERIALS The composition of the solid dispersion of the amorphous form of the sulphate and the valsartan disodium salt obtained in Example 51 and the microcrystalline cellulose
  • Table 5 shows that the combination of the solid dispersion of the amorphous Shaku sulphate and valsartan disodium salt and the microcrystalline cellulose was placed under accelerated test conditions for 6 months, and the relevant substances showed no significant change, no sand.
  • the kubitrol sodium salt and the valsartan disodium salt crystallized.
  • Example 78 Comparison of Apparent Solubility of Solid Dispersion and Microcrystalline Cellulose and Amorphous Solubility of LCZ-696 of Amorphous Shaku Sorghum Salt and Valsartan Disodium Salt
  • a composition of the solid dispersion of the amorphous sandboxazone and valsartan disodium salt of the present invention and microcrystalline cellulose was prepared according to the method of Example 51.
  • LCZ-696 was prepared according to the method of Example 2 of the patent CN101098689.
  • Example 51 of the present invention A sufficient amount of the pharmaceutical composition obtained in Example 51 of the present invention, a mixture of LCZ-696 and polyacrylic resin Eudragit L100 and microcrystalline cellulose (physical mixing, weight ratio of 1:1: 1) Add the diluted solution of the specified pH to the two conical flasks to prepare a supersaturated solution and seal tightly. Three samples were prepared in parallel for each pH dilution. The mixture was shaken for 12 hours in a constant temperature water bath shaker at 37 ° C ⁇ 0.5 ° C to dissolve it sufficiently to reach 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 6 shows that at each pH value, the apparent solubility of the composition of the amorphous Shaku sulphate salt, the amorphous valsartan disodium salt and the polyacrylic resin Eudragit L100 is significantly higher than that of the crystalline form. Apparent solubility of a mixture of LCZ-696 and polyacrylic resin Eudragit L100 and microcrystalline cellulose.
  • composition of the amorphous Shakubis or the pharmaceutically acceptable salt thereof, the amorphous valsartan or the pharmaceutically acceptable salt thereof and the pharmaceutically acceptable adjuvant of the present invention has a markedly increased dissolution and is more advantageous for improving the drug.
  • the bioavailability enables the drug to better exert its therapeutic effects on clinical diseases.
  • the amorphous substance maintains good physical stability and chemistry under accelerated test conditions (40 ° C ⁇ 2 ° C, humidity 75% ⁇ 5%). stability.

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Abstract

一种含沙库比曲和缬沙坦的药用组合物及其制备方法,该药用组合物还包括药用辅料,其中沙库比曲和缬沙坦均为无定型态,沙库比曲和缬沙坦可分别为其药学上可接受的盐。该药用组合物增加了沙库比曲和缬沙坦的溶出度。

Description

含沙库比曲和缬沙坦的药用组合物及其制备方法 技术领域
本发明属于药物制剂领域,具体涉及一种含沙库比曲和缬沙坦的药用组合物及其制备方法,还涉及一种含有无定型沙库比曲、缬沙坦或其药学上可接受的盐的固体分散体的药用组合物及其制备方法,以及该组合物治疗心血管疾病的用途。
背景技术
沙库比曲(Sacubitril),化学名为(2S,4R)-5-(联苯基-4-基)-4-[(3-羧基丙酰基)氨基]-2-甲基戊酸乙酯,是一种脑啡肽酶抑制剂。缬沙坦(Valsartan),化学名为N-戊酰基-N-[[2'-(1H-四氮唑-5-基)[1,1'-联苯]-4-基]甲基]-L-缬氨酸,是一种血管紧张素Ⅱ受体拮抗剂。
LCZ-696是沙库比曲和缬沙坦的三钠盐半五水合物共晶,化学名为[3-((1S,3R)-1-联苯-4-基甲基-3-乙氧基羰基-1-丁基氨甲酰基)丙酸-(S)-3’-甲基-2’-(戊酰基{2”-(四唑-5-基)联苯-4’-基甲基}氨基)丁酸]三钠半五水合物,商品名为Entresto。该产品是瑞士诺华公司开发的2015年7月7日提前6周获得美国食品和药品监管局(FDA)批准,用于射血分数降低的心力衰竭患者,降低心血管死亡和心衰住院风险。LCZ-696是一种首创新药,以多种方式作用于心脏的神经内分泌系统,该药是过去25年内心衰治疗领域的一个伟大突破,有望成功动摇过去10年未被修改的心衰治疗整体框架。
CN102091330一种包含(I)AT1-拮抗剂缬沙坦或其可药用盐和(II)NEP抑制剂或其可药用盐的组合并包含或不包含可药用载体的药物组合物,用于治疗多种疾病。CN101098689固体形式的[3-((1S,3R)-1-联苯-4-基甲基-3-乙氧基羰基-1-丁基氨甲酰基)丙酸-(S)-3’-甲基-2’-(戊酰基{2”-(四唑-5-基)联苯-4’-基甲基}氨基)丁酸]三钠半五水合物,并提供了单晶X-射线衍射和X-射线粉末衍射的参数。说明书指出,LCZ-696是一种具有双重作用的复合物,两种药物活性成分存在共价键和非共价相互作用,非共价相互作用包括氢键、范德华力和离子键等。因此,固体形式的LCZ-696实际上是以共晶形式存在的一种固体复合物。
药物的固体形态直接影响原料药的溶解速率、制剂的溶出度和生物利用度,为了提高药物的生物利用度,降低用量、降低毒副作用,通常会开发药物的新的固体形态,因此,开发该药物溶解性更好、生物利用度更高的固体形式就显得很有必要。
药物的固体形态除晶态外,还有无定型状态,药物的无定型状态作为固体物质的一种特殊形态,在药物制备中有着重要的用途。一般由于晶态物质分子的有序和周期性 排列,降低了分子间相互作用的能量,能量较低,而无定型态的分子处于高度无序状态,物质的表面自由能更大,固体物质中的分子较晶态固体物质中的分子有更高的能量,更容易分散,增加其溶出度,提高药物的生物利用度。无定型态药物不仅可以广泛应用于药物制剂中,而且可以通过多种技术手段和方法提高无定型态药物的稳定性,使之成为具有优良品质的药物。
由于LCZ-696在生物利用度方面的不足和无定型药物活性成分在药物制剂方面的良好的应用前景,寻找新的无定型沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐及其制备方法就显得十分必要。
发明内容
本发明的目的是提供一种含沙库比曲和缬沙坦的药用组合物及其制备方法,得到稳定性及分散性良好的无定型态的沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐与药用辅料的组合物,增加了沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的溶出度,其制备方法不受干燥过程的限制,也不受溶剂种类和溶剂量的限制,操作简便,成本低廉,易于实现,可实现工业化生产。
为了达到上述目的,本发明的技术方案如下:
一种含沙库比曲和缬沙坦的药用组合物,该组合物包含沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐与药用辅料,沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的物质的量的比为1:0.95~1.05,两者的总重量与药用辅料的重量之比为1:0.1~100,其中,所述的沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐为无定型态,所述组合物的X-射线粉末衍射光谱中,扣除药用辅料的背景峰后无沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐和二者的复合物的晶体的特征峰。
进一步,所述药用辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
优选地,所述的药用辅料选自羟丙甲基纤维素、羟丙基纤维素、聚维酮,聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、离子交换树脂和胶原蛋白中的至少一种。
进一步,本发明还提供了一种含有沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的固体分散体的药用组合物,其包含沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐与有机载体形成的固体分散体以及至少一种药学上可接受的辅料,沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的重量为固体分散体的总重量的20%-80%,辅料的重量为固体分散体的重量的0.1%~80%,其中,所述的沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐为无定型态,所述组合物的X-射线粉末衍射光谱中,扣除载体和药用辅料的背景峰后无沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐晶体的特征峰。
进一步,所述的有机载体选自药学上可接受的聚合物或共聚物。
优选地,所述的有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮,聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、离子交换树脂和胶原蛋白中的至少一种。
又,所述的药用制剂辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
本发明的含沙库比曲和缬沙坦的药用组合物沙库比曲的制备方法,包括如下步骤:
1)将沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐和药用辅料混合,加热至药用辅料熔融;其中,沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的物质的量的比为1:0.95~1.05,两者的总重量和药用辅料重量之比为1:0.1~100;
2)混合均匀后冷却,将混合物粉碎,得到无定型态的沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐与药用辅料的组合物。
本发明提供另一种沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐与药用辅料的组合物的制备方法,包括如下步骤:
1)将沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐和药用辅料在溶剂中混合,混合温度为-50~150℃,形成含沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐和药用辅料的溶液或悬浮液,其中,沙库比曲或其药学上可 接受的盐和缬沙坦或其药学上可接受的盐的物质的量的比为1:0.95~1.05,两者的总重量和药用辅料的重量之比为1:0.1~100,两者的总重量与溶剂的重量之比为1:0.1~1000;
2)除去步骤1)得到的溶液或悬浮液中的溶剂,得到无定型态的沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐与药用辅料的组合物。
进一步,上述两种制备方法中,所述药用辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
优选地,步骤1)中所述的药用辅料选自羟丙甲基纤维素、羟丙基纤维素、聚维酮,聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖和胶原蛋白中的至少一种。
又,上述溶液法制备方法中,步骤1)所述溶剂选自碳原子数在12以下的醇类、酚类、醚类、卤代烃、酮类、醛类、腈类、酰胺、砜、亚砜、羧酸和水中的至少一种,步骤2)除去溶剂的方法包括:蒸发、真空蒸发、喷雾干燥、冷冻干燥、热熔挤出、过滤、离心或搅拌薄膜干燥。
本发明中的组合物是指混合物、复合物、共聚物、共沉淀物、共晶、组合物、溶剂合物和水合物。
本发明中药学上可接受的药用辅料和药用制剂辅料是指生产药品和调配处方时使用的赋形剂和附加剂,包括赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂等。
本发明中所述药学上可接受的盐包括钠盐、钾盐、锂盐、钙盐和镁盐等,优选为钠盐和钾盐。
本发明含有沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的固体分散体的药用组合物的制备方法,包括如下步骤:
1)将沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐、至少一种有机载体和至少一种药用制剂辅料混合,加热至熔融,其中,沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的重量为固体分散体的总重量的20%-80%, 药用制剂辅料的重量为固体分散体的重量的0.1%~80%;
2)混合均匀后冷却,将得到的混合物粉碎,得到含无定型态的沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的固体分散体的药用组合物。
本发明提供另一种含有沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的固体分散体的药用组合物的制备方法,包括如下步骤:
1)将沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐、至少一种有机载体和至少一种药学上可接受的辅料在溶剂中混合,混合温度为-50~150℃,形成含沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐、有机载体和药用辅料的溶液或悬浮液,其中,沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐与溶剂的总重量比为0.001~100:1,沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的总重量为固体分散体的总重量的20%-80%,辅料的重量为固体分散体的重量的0.1%~80%;
2)除去步骤1)得到的溶液或悬浮液中的溶剂,得到含无定型态的沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的固体分散体的药用组合物。
进一步,上述两种制备方法中,步骤1)中所述的有机载体选自药学上可接受的聚合物或共聚物。
优选地,步骤1)中所述的有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮,聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖和胶原蛋白中的至少一种。
又,步骤1)中所述的药用制剂辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
再,上述溶液法制备方法中,步骤1)所述溶剂选自碳原子数在12以下的醇类、酚类、醚类、卤代烃、酮类、醛类、腈类、酰胺、砜、亚砜、羧酸和水中的至少一种,步骤2)除去溶剂的方法包括:蒸发、真空蒸发、喷雾干燥、冷冻干燥、热熔挤出、过滤、离心或搅拌薄膜干燥。
本发明还提供了一种含有无定型沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的固体分散体和至少一种药学上可接受的辅料的药用组合物用于制备治疗心血管疾病药物的用途,优选为制备治疗高血压和心力衰竭药物的用途。
本发明的沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐与药用辅料的组合物,使用Cu-Kα辐射,以度2θ表示的X-射线粉末衍射光谱中扣除药用辅料的背景峰无沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐和二者的复合物的结晶态的特征峰,表明沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐为无定型状态,而现有技术中一般使用沙库比曲和缬沙坦三钠盐半五水合物的共晶体即LCZ-696,未见其无定型态的报道。
一般由于晶态物质分子的有序和周期性排列,降低了分子间相互作用的能量,能量较低,而本发明的沙库比曲、缬沙坦或其药学上可接受的盐为无定型态,分子处于高度无序状态,物质的表面自由能更大,固体物质中的分子较晶态固体物质中的分子有更高的能量,更容易分散,增加其溶出度,提高沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐的生物利用度。
本发明将沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐和药用辅料混合均匀后,使用“固体分散剂”法,通过药用辅料的多聚体网状结构将药物分子阻隔,抑制结晶的发生,使其保持分散和无定型状态。本发明采用应用广泛、价格低廉、溶解性好的药用辅料,这些药用辅料与沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐混合,配合蒸发、喷雾干燥、冷冻干燥和热熔挤出等技术可以得到沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐的无定型形式,增加本发明的组合物中的沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐的无定型态的稳定性。
本发明选用在药学上应用广泛的、价格低廉的辅料,得到沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐与药用辅料的组合物,易于开发制剂配方,本发明的制备方法不受干燥过程的限制,也不受溶剂种类和溶剂量的限制,操作简便,成本低廉,易于实现,可实现工业化生产。
与现有技术相比,本发明的有益效果是:
1)本发明制备的无定型沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐与药用辅料的组合物具有高度分散性及稳定性,在制成固体制剂后,经过崩解可使药物粒子的分散程度更好,分散及溶出速度更快,有利于药物的吸收。因此,无定型状态药物的溶出度明显增加,更有利于机体对药物的吸收,提高药物的生物利用度,使药物能够更好地发挥临床疾病治疗作用。
2)本发明无定型状态的沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐与药用辅料的组合物的制备方法不受干燥过程的限制,也不受溶剂种类和溶剂量的限制,操作简便,成本低廉,易于实现,可实现工业化生产。
3)本发明制备的无定型状态的沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐与药用辅料的组合物在加速试验条件下(40℃±2℃,湿度75%±5%),能保持良好的物理稳定性和化学稳定性。因此,本发明将会有广阔的应用前景。
附图说明
图1为本发明实施例1的无定型沙库比曲、无定型缬沙坦和聚维酮K30的组合物的X-射线粉末衍射图。
图2为本发明实施例12的无定型沙库比曲钠盐、无定型缬沙坦二钠盐和聚丙烯酸树脂Eudragit L100的组合物的X-射线粉末衍射图。
图3为本发明实施例51的无定型沙库比曲钠盐、无定型缬沙坦二钠盐固体分散体和微晶纤维素的组合物的X-射线粉末衍射图。
图4为本发明实施例51中使用的微晶纤维素的X-射线粉末衍射图。
图5为本发明实施例71的无定型沙库比曲钠盐、无定型缬沙坦二钠盐固体分散体与胶态二氧化硅Aerosil 200的组合物的X-射线粉末衍射图。
具体实施方式
以下结合具体实施例对本发明作进一步说明,但本发明的保护范围不受以下实施例的限制。
本发明所述的X-射线粉末衍射图在Ultima IV X-射线衍射仪上采集。本发明所述的X-射线粉末衍射的方法参数如下:
X-射线粉末参数:Cu-Kα;
Figure PCTCN2016098093-appb-000001
:1.5418;
电压:40千伏;
电流:40毫安;
发散狭缝:自动;
扫描模式:连续;
扫描范围:自2.0至60.0度;
取样步长:0.0200度;
扫描速率:60度/分钟。
任何物理形式的沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐都可以用于制备本发明无定型的沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的固体分散体。
实施例1
将沙库比曲(411.5毫克)、缬沙坦(435.5毫克)和聚维酮K30(10克)溶于乙醇(60毫升),加热到60℃搅拌溶清。将上述溶液迅速降温到-10℃,析出白色固体,过滤,干燥,得到无定型沙库比曲、无定型缬沙坦与聚维酮K30的组合物,该组合物的X-射线粉末衍射图如图1所示,由图1可以看出,X-射线粉末衍射图中扣除药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例2
将沙库比曲钠盐(433.5毫克)、缬沙坦二钠盐(479.5毫克)和聚乙二醇4000(20克)溶于乙醇(60毫升)和水(60毫升)中,在-40℃下搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,得到无定型沙库比曲钠盐、无定型缬沙坦二钠盐与聚乙二醇4000的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例3
将沙库比曲钠盐(4.33克)、缬沙坦二钠盐(4.80克)和聚乙二醇8000(20克)加入水(300毫升)中,加热到60℃搅拌溶清。将上述溶液用JISL微型喷雾干燥机LSD-48干燥,维持进口温度60℃、出口温度50℃,收集出口物料,得到白色固体,进一步真空干燥得到无定型沙库比曲钠盐、无定型缬沙坦二钠盐与聚乙二醇8000的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例4
将沙库比曲(411.5毫克)、缬沙坦(435.5毫克)和羟丙甲基纤维素E50(0.2克)加到水(10毫升)中,加热到40℃搅拌溶清。将上述溶液冷冻干燥,得到白色固体,即无定型沙库比曲、无定型缬沙坦与羟丙甲基纤维素E50的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例5
将沙库比曲(411.5毫克)、缬沙坦(435.5毫克)和聚乙二醇8000(10克)加热到熔融,搅拌下迅速冷却到室温,得到白色固体。将上述固体粉碎,得到白色粉末状固体,即无定型沙库比曲、无定型缬沙坦与聚乙二醇8000的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例6
将沙库比曲(411.5毫克)、缬沙坦(435.5毫克)、乙醇(0.1克)和聚乙二醇10000(100克)加热到240℃,混合均匀,迅速冷却到室温,得到白色固体。将上述固体粉碎,得到白色粉末状固体,即无定型沙库比曲、无定型缬沙坦与聚乙二醇10000的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无沙库比曲、缬沙坦晶型的特征峰。
实施例7
将沙库比曲(411.5毫克)、缬沙坦(435.5毫克)、四氢呋喃(10克)、乙醇(20克)和脂质体(5克)的混合物加热到90℃,搅拌,混合均匀,真空蒸发除去溶剂,冷却到室温得到白色固体,即无定型沙库比曲、无定型缬沙坦与脂质体的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例8
将沙库比曲(411.5毫克)、缬沙坦(435.5毫克)、甲醇(20克)和甲基丙烯酸共聚物A型(4克)的混合物加热到50℃,搅拌,溶清,真空蒸发除去溶剂,冷却到室温得到白色固体,即无定型沙库比曲、无定型缬沙坦与甲基丙烯酸共聚物A型的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无沙库比曲、缬沙坦晶型的特征峰。
实施例9
将沙库比曲(411.5毫克)、缬沙坦(435.5毫克)、乙醇(20克)、四氢呋喃(10克)和乙基纤维素(2克)的混合物加热到30℃,搅拌,混合均匀,真空蒸发除去溶剂,冷却到室温得到白色固体,即无定型沙库比曲、无定型缬沙坦与乙基纤维素的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无沙库比曲、缬沙坦晶型的特征峰。
实施例10
将沙库比曲钠盐(433.5毫克)、缬沙坦二钠盐(479.5毫克)、甲醇(20克)和羟丙基纤维素SSL(5克)的混合物加热到30℃,搅拌溶清,真空蒸发除去溶剂,冷却到室温得到白色固体,即无定型沙库比曲钠盐、无定型缬沙坦二钠盐与羟丙基纤维素SSL的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例11
将沙库比曲(411.5毫克)、缬沙坦(435.5毫克)、甲醇(20克)、水(10克)和聚醋酸乙烯(4克)的混合物加热到30℃,搅拌溶清,真空蒸发除去溶剂,冷却到室温得到白色固体,即无定型沙库比曲、无定型缬沙坦与聚醋酸乙烯的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例12
将LCZ-696(50毫克)和聚丙烯酸树脂Eudragit L100(100毫克)加入到甲醇(750微升),室温下搅拌溶清。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲、无定型缬沙坦与聚丙烯酸树脂Eudragit L100的组合物,该组合物的X-射线粉末衍射图如图2所示,由图2可以看出,X-射线粉末衍射图中扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例13
将LCZ-696(50毫克)和聚丙烯酸树脂Eudragit S100(5毫克)加入到甲醇(4毫升)和水(1毫升),在-30℃下搅拌溶清。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,搅拌下析出白色固体,即无定型沙库比曲、无定型缬沙坦与聚丙烯酸树脂Eudragit S100的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例14
将沙库比曲(41.2毫克)、缬沙坦(45毫克)和聚羧乙烯Carbomer 940(100毫克)加入到甲醇(8毫升)和四氢呋喃(2毫升),在-30℃下搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,搅拌下析出白色固体,即无定型沙库比曲、无定型缬沙坦与聚羧乙烯Carbomer 940的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例15
将沙库比曲(41.2毫克)、缬沙坦(43.5毫克)、氢氧化钠(12毫克)和预胶化淀粉Pharma-Gel(100毫克)加入到甲醇(4毫升)和水(1毫升),室温下混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,搅拌下析出白色固体,即无定型沙库比曲钠盐、无定型缬沙坦二钠盐与Pharma-Gel预胶化淀粉的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐、缬沙坦二钠盐晶型的特征峰。
实施例16
将LCZ-696(50毫克)和高支链交联淀粉(50毫克)加入到甲醇(4毫升)和水(1毫升),室温下搅拌溶清,将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,搅拌下析出白色固体,即无定型无定型沙库比曲钠盐、无定型缬沙坦二钠盐与高支链交联淀粉的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景 峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例17
将LCZ-696(50毫克)和羧甲基纤维素钠SCMC(500毫克)加入到甲醇(5毫升),室温下搅拌溶清。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲钠盐、无定型缬沙坦二钠盐与羧甲基纤维素钠SCMC的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例18
将LCZ-696(50毫克)和几丁聚糖(500毫克)加入到乙醇(5毫升)和二甲基亚砜(1毫升)中,室温下搅拌溶清,将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲钠盐、无定型缬沙坦二钠盐与几丁聚糖的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无沙库比曲缬沙坦晶型的特征峰。
实施例19
将沙库比曲(43.5毫克)、缬沙坦(43.5毫克)、氢氧化钾(16.8毫克)和羧甲基淀粉钠Explotab(500毫克)加入到乙醇(5毫升)和水(2毫升)中,室温下搅拌混合均匀,将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲钾盐、无定型缬沙坦二钾盐与羧甲基淀粉钠Explotab的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无沙库比曲钾盐和缬沙坦二钾盐晶型的特征峰。
实施例20
将沙库比曲(41.1毫克)、缬沙坦(43.5毫克)和藻酸盐E401(500毫克)加入到乙醇(5毫升)中,室温下搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲、无定型缬沙坦与藻酸盐E401的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例21
将LCZ-696(50毫克)和羧甲基纤维素邻苯二甲酸酯Agucoat CPD(5克)悬浮于甲醇(30毫升)中,加热到50℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲钠盐、无定型缬沙坦二钠盐与羧甲基纤 维素邻苯二甲酸酯Agucoat CPD的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例22
将LCZ-696(50毫克)和卡拉胶E407(500毫克)悬浮于甲醇(30毫升),加热到50℃搅拌混合均匀,将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲钠盐、无定型缬沙坦二钠盐与卡拉胶E407的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例23
将LCZ-696(50毫克)和壳聚糖(5克)悬浮于甲醇(50毫升),加热到50℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲钠盐、无定型缬沙坦二钠盐与壳聚糖的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例24
将LCZ-696(30毫克)和聚丙烯酸树脂Eudragit E100(60毫克)溶于乙醇(120微升)、四氢呋喃(120微升)和N,N-二甲基甲酰胺(60微升)中,加热到50℃搅拌溶清,将上述溶液降温到10℃,析出白色固体,过滤,干燥,得到无定型沙库比曲钠盐、无定型缬沙坦二钠盐与聚丙烯酸树脂Eudragit E100的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例25
将沙库比曲(41.1毫克)、缬沙坦(43.5毫克)和胶原蛋白Peptan(100毫克)溶于乙醇(600微升)和乙腈(600微升)中,加热到50℃搅拌溶清。将上述溶液降温到-10℃,析出白色固体,过滤,干燥,得到无定型沙库比曲、无定型缬沙坦与胶原蛋白Peptan的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例26
将LCZ-696(30毫克)和树胶Galactosol(300毫克)溶于乙醇(600微升)和水(600微升)中,加热到50℃搅拌溶清。将上述溶液在旋转蒸发器中浓缩至干,得 到白色固体,即无定型沙库比曲钠盐、无定型缬沙坦二钠盐与树胶Galactosol的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例27
将LCZ-696(30毫克)和羟丙甲基纤维素邻苯二甲酸酯HPMCP(30毫克)加入到乙醇(750微升)和水(750微升),加热到80℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲钠盐、无定型缬沙坦二钠盐与羟丙甲基纤维素邻苯二甲酸酯HPMCP的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例28
将沙库比曲(41.1毫克)、缬沙坦(43.5毫克)和离子交换树脂Amberlite IRA400(600毫克)加入到水(6毫升),室温下搅拌混合均匀。将上述悬浮液过滤,得到棕色固体,即无定型沙库比曲、无定型缬沙坦与离子交换树脂Amberlite IRA400的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例29
将沙库比曲(41.1毫克)、缬沙坦(43.5毫克)和羧基乙酸内酯(300毫克)加入到乙醇(750微升)和水(750微升),加热到80℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂,得到白色固体,即无定型沙库比曲、无定型缬沙坦与羧基乙酸内酯的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例30
将沙库比曲(41.1毫克)、缬沙坦(43.5毫克)和糊精Maltrin M100(300毫克)加入到乙醇(750微升)和水(750微升),加热到80℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到棕色固体,即无定型沙库比曲、无定型缬沙坦与糊精Maltrin M100的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例31
将沙库比曲钠盐(43.5毫克)、缬沙坦二钠盐(47.9毫克)和羧甲基纤维素钠 SCMS(3毫克)加入到水(30毫升)中,加热到100℃搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲钠盐、无定型缬沙坦二钠盐与羧甲基纤维素钠SCMC的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例32
将沙库比曲钠盐(43.3毫克)、缬沙坦(47.9毫克)和β-环糊精(100毫克)加入到甲醇(300微升)和水(300微升),室温下搅拌溶清。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲钠盐、无定型缬沙坦二钠盐与β-环糊精的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、库区比钠盐和缬沙坦二钠盐晶型的特征峰。
实施例33
将沙库比曲钠盐(43.3毫克)、缬沙坦二钠盐(47.9毫克)和聚环氧乙烷Polyox WSR301(300毫克)加入到甲醇(300微升)和水(60微升),60℃下搅拌混合均匀。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲钠盐、无定型缬沙坦二钠盐与聚环氧乙烷Polyox WSR301的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例34
将沙库比曲钠盐(43.3毫克)、缬沙坦二钠盐(47.9毫克)和聚乙烯醇EG-40(90毫克)加入到甲醇(300微升)和水(60微升),60℃下搅拌溶清,将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲钠盐、无定型缬沙坦二钠盐与聚乙烯醇EG-40的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例35
将LCZ-696(50毫克)和羟丙甲基纤维素醋酸酯琥珀酸酯Agoat MG(2克)加入到乙醇(10毫升)和水(2毫升),80℃下搅拌混合均匀,将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲钠盐、无定型缬沙坦二钠盐与羟丙甲基纤维素醋酸酯琥珀酸酯Agoat MG的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例36
将LCZ-696(50毫克)和羧甲基乙基纤维素(2克)加入到乙醇(10毫升)和水(1毫升),80℃下搅拌混合均匀,将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲钠盐、无定型缬沙坦二钠盐与羧甲基乙基纤维素的组合物,该组合物的X-射线粉末衍射图中,扣除药用辅料的背景峰后无LCZ-696、沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例37:无定型沙库比曲钠盐、无定型缬沙坦二钠盐与聚丙烯酸树脂Eudragit L100组合物的影响因素试验
材料:实施例12所得无定型沙库比曲钠盐、无定型缬沙坦二钠盐与聚丙烯酸树脂Eudragit L100的组合物
表1:
Figure PCTCN2016098093-appb-000002
表1说明:无定型沙库比曲钠盐、无定型缬沙坦二钠盐与聚丙烯酸树脂Eudragit L100的组合物,放置10天,有关物质无显著改变,无沙库比曲钠盐和缬沙坦二钠盐的结晶析出。
实施例38:无定型沙库比曲钠盐、无定型缬沙坦二钠盐与聚丙烯酸树脂Eudragit L100组合物的加速试验
材料:实施例12所得无定型沙库比曲钠盐、无定型缬沙坦二钠盐与聚丙烯酸树脂Eudragit L100的组合物。
实验条件:温度40℃±2℃,湿度75%±5%,结果参见表2。
表2:
Figure PCTCN2016098093-appb-000003
Figure PCTCN2016098093-appb-000004
表2说明:无定型沙库比曲钠盐、无定型缬沙坦二钠盐与聚丙烯酸树脂Eudragit L100的组合物在加速试验条件下,放置6个月,有关物质无显著改变,无沙库比曲钠盐和缬沙坦二钠盐的结晶析出。
实施例39:沙库比曲和LCZ-696的表观溶解性的比较
无定型沙库比曲钠盐、无定型缬沙坦二钠盐与聚丙烯酸树脂Eudragit L100的组合物,根据实施例12的方法制备得到。LCZ-696,根据专利CN101098689的实施例2的方法制备得到。
表观溶解度的测定:分别称取足量无定型沙库比曲钠盐、无定型缬沙坦二钠盐与聚丙烯酸树脂Eudragit L100的组合物、LCZ-696与聚丙烯酸树脂Eudragit L100的混合物(物理混合,重量比为1:2)于两个具塞锥形瓶中,加入指定pH值的稀释液,配制成过饱和溶液,密封盖紧。每个pH稀释液中平行制备三份样品。置于37℃±0.5℃的恒温水浴摇床中振荡12小时,使其充分溶解以达到饱和。取上清液用0.45微米的微孔滤膜趁热过滤,并适当稀释,摇匀,分别注入液相色谱仪。以外标法计算三份平行样品在此pH缓冲液中的表观溶解度,取平均值,实验结果如表3所示。
各种pH值稀释液的配制:
(1)pH=1.0的稀释液:9毫升浓盐酸加水稀释至1000毫升。
(2)pH=2.0的稀释液:甲液:取磷酸16.6毫升,加水至100毫升摇匀。乙液: 取磷酸氢二钠71.63克,加水使溶解成1000毫升。取上述甲液72.5毫升与乙液27.5毫升混合,摇匀,即得。
(3)pH=3.0的稀释液:取冰醋酸50毫升,加水800毫升混合后,用氢氧化锂调节pH值至3.0,再加水稀释至1000毫升,即得。
(4)pH=4.5的稀释液:取醋酸铵7.7克,加水50毫升溶解后,加冰醋酸6毫升与适量的水使成100毫升,即得。
(5)pH=5.6的稀释液:取邻苯二甲酸氢钾10克,加水900毫升,搅拌使溶解,用氢氧化钠试液(必要时用稀盐酸)调节pH值至5.6,加水稀释至1000毫升,混匀,即得。
(6)pH=6.8的稀释液:取0.2摩尔/升的磷酸二氢钾溶液250毫升,加0.2摩尔/升的氢氧化钠溶液118毫升,用水稀释至1000毫升,摇匀,即得。
(7)pH=7.4的稀释液:取磷酸二氢钾1.36克,加0.l摩尔/升的氢氧化钠溶液79毫升,用水稀释至200毫升,即得。
表3:
Figure PCTCN2016098093-appb-000005
表3表明:在各个pH值下,本发明的药用组合物的表观溶解度明显高于晶型物LCZ-696与聚丙烯酸树脂Eudragit L100的混合物的表观溶解度。
实施例40
沙库比曲(411.5毫克)、缬沙坦(435.5毫克)和聚维酮K30(10克)溶于乙醇(60毫升),加热到60℃搅拌溶清,再加入微晶纤维素(50毫克)。将上述溶液迅速降温到-10℃,析出白色固体,过滤,真空干燥,得到无定型沙库比曲和缬沙坦固体分散体与微晶纤维素的组合物,该组合物的X-射线粉末衍射图中扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例41
将沙库比曲钠盐(433.5毫克)、缬沙坦二钠盐(479.5毫克)和聚乙二醇4000(20克)溶于乙醇(60毫升)和水(60毫升)中。在-40℃下搅拌混合均匀,再加入微晶纤维素(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲钠盐和缬沙坦二钠盐与微晶纤维素的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例42
将沙库比曲钠盐(4.33克)、缬沙坦二钠盐(4.80克)和聚乙二醇8000(10克)加入甲醇(300毫升)中,加热到60℃搅拌溶清,再加入交联羧甲基纤维素钠(0.1克)。将上述溶液用JISL微型喷雾干燥机LSD-48干燥,维持进口温度60℃、出口温度50℃,收集出口物料,得到白色固体,进一步真空干燥得到无定型沙库比曲钠盐和缬沙坦二钠盐的固体分散体与交联羧甲基纤维素钠的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例43
将沙库比曲(411.5毫克)、缬沙坦(435.5毫克)和羟丙甲基纤维素E50(0.2克)加到水(10毫升)中,加热到40℃搅拌溶清,再加入交联聚维酮(0.2克)。将上述溶液冷冻干燥,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与交联聚维酮的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例44
将沙库比曲(411.5毫克)、缬沙坦(435.5毫克)和聚乙二醇8000(5克)加热到熔融,搅拌下迅速冷却到室温,得到白色固体。将上述固体粉碎,得到白色粉末状固体,即无定型沙库比曲和缬沙坦固体分散体和甘露醇的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例45
将沙库比曲钠盐(1克)、缬沙坦二钠盐(1克)、甘露醇(0.1克)和聚乙二醇10000(10克)加热到240℃,混合均匀,迅速冷却到室温,得到白色固体。将上述固体粉碎,得到白色粉末状固体,即无定型沙库比曲钠盐和缬沙坦二钠盐的固体分散体与甘露醇的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景 峰后无沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例46
将沙库比曲(411.5毫克)、缬沙坦(435.5毫克)、乙醇(0.1克)和聚乙二醇10000(100克)加热到240℃,搅拌下混合均匀。再加入微晶纤维素(2克),搅拌均匀,真空蒸发除去溶剂,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与微晶纤维素的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例47
将沙库比曲(4.1克)、缬沙坦(4.3克)、甲醇(20克)和甲基丙烯酸共聚物A型(4克)的混合物加热到50℃,搅拌下溶清,再加入交联聚维酮(1克),真空蒸发除去溶剂,冷却到室温得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与交联聚维酮的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例48
将沙库比曲(4.1克)、缬沙坦(4.3克)、乙醇(20克)和乙基纤维素(2克)的混合物加热到30℃,搅拌,混合均匀,再加入硬脂酸镁(0.1克),真空蒸发除去溶剂,冷却到室温得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与硬脂酸镁的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例49
将沙库比曲(4.1克)、缬沙坦(4.3克)、甲醇(10克)、二氯甲烷(10克)和羟丙基纤维素SSL(4克)的混合物加热到30℃,搅拌溶清,再加入微晶纤维素(0.5克),真空蒸发除去溶剂,冷却到室温得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与微晶纤维素的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例50
将沙库比曲(1克)、缬沙坦(1.1克)、甲醇(20克)、二氯甲烷(10克)和聚醋酸乙烯(4克)的混合物加热到30℃,搅拌溶清,再加入微晶纤维素(0.5克)真空蒸发除去溶剂,冷却到室温得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与微晶纤维素的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的 背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例51
将沙库比曲钠盐(50毫克)、缬沙坦二钠盐(51毫克)和聚丙烯酸树脂Eudragit L100(100毫克)加入到甲醇(750微升),60℃下搅拌溶清,再加入微晶纤维素(100毫克)。将上述悬浮液迅速冷却至-10℃,析出白色固体。过滤、真空干燥,得到白色固体,即无定型沙库比曲钠盐和缬沙坦二钠盐的固体分散体与微晶纤维素的组合物,该组合物的X-射线粉末衍射图如图3所示,由图3可以看出,该药用组合物的X-射线粉末衍射图中扣除载体和药用辅料的背景峰后无沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。微晶纤维素的X-射线粉末衍射图如图4所示。
实施例52
将沙库比曲(50毫克)、缬沙坦(51毫克)和聚丙烯酸树脂Eudragit S100(5毫克)加入到甲醇(4毫升)和乙酸乙酯(1毫升),-30℃下搅拌溶清。在加入羧甲基淀粉钠(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与羧甲基淀粉钠的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例53
将沙库比曲(50毫克)、缬沙坦(51毫克)和聚羧乙烯Carbomer 940(50毫克)加入到甲醇(4毫升)和四氢呋喃(1毫升),30℃下搅拌混合均匀,再加入微晶纤维素(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与微晶纤维素的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例54
将沙库比曲(50毫克)、缬沙坦(51毫克)和预胶化淀粉Pharma-Gel(100毫克)加入到甲醇(4毫升)和水(1毫升),室温下混合均匀,再加入交联羧甲基纤维素钠(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与交联羧甲基纤维素钠的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例55
将沙库比曲(50毫克)、缬沙坦(51毫克)和高支链交联淀粉(50毫克)加入 到甲醇(4毫升)和水(1毫升),室温下搅拌溶清,再加入交联羧甲基纤维素钠(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无无定型沙库比曲和缬沙坦固体分散体与交联羧甲基纤维素钠的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例56
将沙库比曲(50毫克)、缬沙坦(51毫克)和羧甲基纤维素钠SCMC(500毫克)加入到二甲基亚砜(5毫升),室温下搅拌溶清,再加入交联羧甲基纤维素钠(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与交联羧甲基纤维素钠的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例57
将沙库比曲(50毫克)、缬沙坦(51毫克)和几丁聚糖(500毫克)加入到乙醇(5毫升),室温下搅拌溶清,再加入微晶纤维素(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与微晶纤维素的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例58
将沙库比曲(43.5毫克)、缬沙坦(43.5毫克)、氢氧化钾(16.8毫克)和羧甲基淀粉钠Explotab(500毫克)加入到乙醇(5毫升)和水(2毫升)中,室温下搅拌混合均匀,室温下搅拌混合均匀,再加入乳糖(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲钾盐和缬沙坦钾盐的固体分散体与乳糖的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲钾盐和缬沙坦钾盐晶型的特征峰。
实施例59
将沙库比曲(50毫克)、缬沙坦(51毫克)和藻酸盐E401(500毫克)加入到乙醇(5毫升),室温下搅拌混合均匀,在加入乳糖(10毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与乳糖的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例60
将沙库比曲(50毫克)、缬沙坦(51毫克)和羧甲基纤维素邻苯二甲酸酯Agucoat  CPD(0.5克)悬浮于甲醇(30毫升),加热到50℃搅拌混合均匀,再加入乳糖(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去大部分溶剂,过滤,干燥,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与乳糖的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例61
将沙库比曲(50毫克)、缬沙坦(51毫克)和卡拉胶E407(500毫克)悬浮于甲醇(30毫升),加热到50℃搅拌混合均匀,再加入微晶纤维素(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去大部分溶剂,过滤,干燥,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与微晶纤维素的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例62
将沙库比曲(50毫克)、缬沙坦(51毫克)和壳聚糖(5克)悬浮于甲醇(50毫升),加热到50℃搅拌混合均匀,再加入乳糖(100毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去大部分溶剂,过滤,干燥,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与乳糖的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例63
将沙库比曲(30毫克)、缬沙坦(31毫克)和聚丙烯酸树脂Eudragit E100(30毫克)溶于乙醇(600微升),加热到50℃搅拌溶清,再加入乳糖(30毫克)。将上述溶液降温到10℃,析出白色固体,过滤,干燥,得到无定型沙库比曲和缬沙坦固体分散体与乳糖的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例64
将沙库比曲(30毫克)、缬沙坦(31毫克)和胶原蛋白Peptan(300毫克)溶于乙醇(600微升),加热到50℃搅拌溶清,再加入微晶纤维素(30毫克)。将上述溶液降温到10℃,析出白色固体,过滤,干燥,得到无定型沙库比曲和缬沙坦与胶原蛋白Peptan的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例65
将沙库比曲(30毫克)、缬沙坦(31毫克)和树胶Galactosol(300毫克)溶于 乙醇(600微升)加热到50℃搅拌溶清,再加入微晶纤维素(30毫克)。将上述溶液降温到10℃,析出白色固体,过滤,干燥,得到无定型沙库比曲和缬沙坦固体分散体与微晶纤维素的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例66
将沙库比曲(30毫克)、缬沙坦(31毫克)和羟丙甲基纤维素邻苯二甲酸酯HPMCP(30毫克)加入到乙醇(750微升)和水(750微升),加热到80℃搅拌混合均匀,加入羧甲基纤维素钠(30毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂,得到白色固体,即无定型沙库比曲和缬沙坦与羧甲基纤维素钠的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例67
将沙库比曲(30毫克)、缬沙坦(31毫克)和羧基乙酸内酯(300毫克)加入到乙醇(750微升)和水(750微升),加热到80℃搅拌混合均匀,再加入乳糖(200毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与乳糖的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例68
将沙库比曲(30毫克)、缬沙坦(31毫克)和糊精Maltrin M100(300毫克)加入到乙醇(750微升)和水(750微升),加热到80℃搅拌混合均匀,再加入乳糖(200毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与乳糖的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例69
将沙库比曲(30毫克)、缬沙坦(31毫克)和羧甲基纤维素钠SCMS(3毫克)加入到水(30毫升),加热到100℃搅拌混合均匀,再加入微晶纤维素(30毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与微晶纤维素的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例70
将沙库比曲(30毫克)、缬沙坦(31毫克)和羧甲基纤维素钠SCMC(30毫克)加入到甲醇(300微升)和水(60微升),60℃下搅拌混合均匀,再加入微晶纤维素(60毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与微晶纤维素的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例71
将沙库比曲(5毫克)、缬沙坦(5毫克)和聚环氧乙烷Polyox WSR301(30毫克)加入到甲醇(300微升)和水(60微升),60℃下搅拌混合均匀,加入胶态二氧化硅Aerosil 200(20毫克)。将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与胶态二氧化硅Aerosil 200的组合物,该组合物的X-射线粉末衍射图如图5所示,X-射线粉末衍射图中扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例72
将沙库比曲(30毫克)、缬沙坦(31毫克)和聚乙烯醇EG-40(60毫克)加入到甲醇(300微升)和水(60微升),60℃下搅拌溶清,再加入乳糖(30毫克)将上述溶液在旋转蒸发器中缓慢浓缩除去溶剂,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与乳糖的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例73
将沙库比曲(50毫克)、缬沙坦(52毫克)和羟丙甲基纤维素醋酸酯琥珀酸酯Agoat MG(2克)加入到乙醇(10毫升)和水(2毫升),80℃下搅拌混合均匀,再加入微晶纤维素(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与微晶纤维素的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例74
将沙库比曲(50毫克)、缬沙坦(52毫克)和羧甲基乙基纤维素(2克)加入到乙醇(10毫升)和水(1毫升),80℃下搅拌混合均匀,再加入交联羧甲基纤维素钠(50毫克)。将上述溶液在旋转蒸发器中缓慢浓缩至干,得到白色固体,即无定型沙库比曲和缬沙坦固体分散体与交联羧甲基纤维素钠的组合物,该组合物的X-射线粉末衍射图中,扣除载体和药用辅料的背景峰后无沙库比曲和缬沙坦晶型的特征峰。
实施例75
将沙库比曲钠盐(5.0克)、缬沙坦二钠盐(5.2克)和聚维酮K30(10.2克)加入到乙醇(10毫升)和水(1毫升),80℃下搅拌溶清。将上述混合物在流化床中喷雾干燥,负载到微晶纤维素(10克)上,得到白色固体28.3克,即无沙库比曲和缬沙坦固体分散体与微晶纤维素的组合物。该组合物的X-射线粉末衍射图中扣除药用辅料的背景峰后无沙库比曲钠盐和缬沙坦二钠盐晶型的特征峰。
实施例76:无定型沙库比曲钠盐和缬沙坦二钠盐的固体分散体与微晶纤维素的组合物的影响因素试验
材料:实施例51所得无定型沙库比曲钠盐和缬沙坦二钠盐的固体分散体与微晶纤维素的组合物
表4:
Figure PCTCN2016098093-appb-000006
表4说明:本发明的无定型沙库比曲钠盐和缬沙坦二钠盐的固体分散体与微晶纤维素的组合物在高温、高湿条件下,放置10天,有关物质无显著改变,无沙库比曲钠盐和缬沙坦二钠盐结晶析出。
实施例77:无定型沙库比曲钠盐和缬沙坦二钠盐的固体分散体与微晶纤维素的组合物的加速稳定性实验
材料:实施例51所得无定型沙库比曲钠盐和缬沙坦二钠盐的固体分散体与微晶纤维素的组合物
实验条件:温度40℃±2℃,湿度75%±5%
表5:
Figure PCTCN2016098093-appb-000007
表5说明:无定型沙库比曲钠盐和缬沙坦二钠盐的固体分散体与微晶纤维素的组合物在加速试验条件下,放置6个月,有关物质无显著改变,无沙库比曲钠盐和缬沙坦二钠盐结晶析出。
实施例78:无定型沙库比曲钠盐和缬沙坦二钠盐的固体分散体与微晶纤维素的组合物和LCZ-696的表观溶解性的比较
本发明的无定型沙库比曲钠盐和缬沙坦二钠盐的固体分散体与微晶纤维素的组合物,根据实施例51的方法制备得到。LCZ-696,根据专利CN101098689的实施例2的方法制备得到。
表观溶解度的测定:分别称取足量本发明实施例51获得的药用组合物、LCZ-696与聚丙烯酸树脂Eudragit L100及微晶纤维素的混合物(物理混合,重量比为1:1:1)于两个具塞锥形瓶中,加入指定pH值的稀释液,配制成过饱和溶液,密封盖紧。每个pH稀释液中平行制备三份样品。置于37℃±0.5℃的恒温水浴摇床中振荡12小时,使其充分溶解以达到饱和。取上清液用0.45微米的微孔滤膜趁热过滤,并适当稀释,摇匀,分别注入液相色谱仪。以外标法计算三份平行样品在此pH缓冲液中的表观溶解度,取平均值。
各种pH值稀释液的配制:
(1)pH=1.0的稀释液:9毫升浓盐酸加水稀释至1000毫升。
(2)pH=2.0的稀释液:甲液:取磷酸16.6毫升,加水至100毫升摇匀。乙液:取磷酸氢二钠71.63克,加水使溶解成1000毫升。取上述甲液72.5毫升与乙液27.5毫升混合,摇匀,即得。
(3)pH=3.0的稀释液:取冰醋酸50毫升,加水800毫升混合后,用氢氧化锂调节pH值至3.0,再加水稀释至1000毫升,即得。
(4)pH=4.5的稀释液:取醋酸铵7.7克,加水50毫升溶解后,加冰醋酸6毫升与适量的水使成100毫升,即得。
(5)pH=5.6的稀释液:取邻苯二甲酸氢钾10克,加水900毫升,搅拌使溶解,用氢氧化钠试液(必要时用稀盐酸)调节pH值至5.6,加水稀释至1000毫升,混匀,即得。
(6)pH=6.8的稀释液:取0.2摩尔/升的磷酸二氢钾溶液250毫升,加0.2摩尔/升的氢氧化钠溶液118毫升,用水稀释至1000毫升,摇匀,即得。
(7)pH=7.4的稀释液:取磷酸二氢钾1.36克,加0.l摩尔/升的氢氧化钠溶液79毫升,用水稀释至200毫升,即得。
实验结果如表6所示:
Figure PCTCN2016098093-appb-000008
表6表明:在各个pH值下,无定型沙库比曲钠盐、无定型缬沙坦二钠盐与聚丙烯酸树脂Eudragit L100的组合物的表观溶解度的表观溶解度明显高于晶型物LCZ-696与聚丙烯酸树脂Eudragit L100及微晶纤维素的混合物的表观溶解度。
本发明的无定型沙库比曲或其药学上可接受的盐、无定型缬沙坦或其药学上可接受的盐与药用辅料的组合物,其溶出度明显增加,更有利于提高药物的生物利用度,使药物能够更好地发挥临床疾病治疗作用,该无定型物在加速试验条件下(40℃±2℃,湿度75%±5%),能保持良好的物理稳定性和化学稳定性。

Claims (24)

  1. 一种含沙库比曲和缬沙坦的药用组合物,其特征在于,所述组合物包含沙库比曲或其药学上可接受的盐,缬沙坦或其药学上可接受的盐,以及药用辅料,沙库比曲或其药学上可接受的盐与缬沙坦或其药学上可接受的盐的摩尔比为1:0.95~1.05,两者的总重量和药用辅料重量之比为1:0.1~100,其中,所述的沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐为无定型态,所述组合物的X-射线粉末衍射光谱中,扣除药用辅料的背景峰后无沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐和二者复合物的晶体特征峰。
  2. 根据权利要求1所述的含沙库比曲和缬沙坦的药用组合物,其特征在于,所述药用辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
  3. 根据权利要求1所述的含沙库比曲和缬沙坦的药用组合物,其特征在于,所述药用辅料选自羟丙甲基纤维素、羟丙基纤维素、聚维酮,聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、离子交换树脂和胶原蛋白中的至少一种。
  4. 根据权利要求1所述的含沙库比曲和缬沙坦的药用组合物,其特征在于,所述药用辅料中包含有机载体和药用制剂辅料,沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐与有机载体形成固体分散体,所述的固体分散体与药用制剂辅料形成组合物,沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的总重量为固体分散体重量的20-80%,药用制剂辅料的重量为固体分散体重量的0.1~80%。
  5. 根据权利要求4所述的含沙库比曲和缬沙坦的药用组合物,其特征在于,所述的有机载体选自药学上可接受的聚合物或共聚物。
  6. 根据权利要求4或5所述的含沙库比曲和缬沙坦的药用组合物,其特征在于,所述有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮,聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、 聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、离子交换树脂和胶原蛋白中的至少一种。
  7. 根据权利要求4所述的含沙库比曲和缬沙坦的药用组合物,其特征在于,所述药用制剂辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
  8. 如权利要求1所述的含沙库比曲和缬沙坦的药用组合物的制备方法,包括如下步骤:
    1)将沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐与药用辅料混合,加热至药用辅料熔融;其中,沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的物质的量的比为1:0.95~1.05,两者的总重量和药用辅料重量之比为1:0.1~100;
    2)混合均匀后冷却,将得到的混合物粉碎,得到无定型态的沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐与药用辅料的组合物。
  9. 据权利要求8所述的含沙库比曲和缬沙坦的药用组合物的制备方法沙库比曲,其特征在于,所述药用辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
  10. 根据权利要求8所述的含沙库比曲和缬沙坦的药用组合物的制备方法,其特征在于,所述的药用辅料选自羟丙甲基纤维素、羟丙基纤维素、聚维酮,聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖和胶原蛋白中的至少一种。
  11. 如权利要求1所述的含沙库比曲和缬沙坦的药用组合物的制备方法,包括如下步骤:
    1)将沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐和药用辅料 在溶剂中混合,混合温度为-50~150℃,形成含沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐和药用辅料的溶液或悬浮液,其中,沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的物质的量的比为1:0.95~1.05,两者的总重量和药用辅料的重量之比为1:0.1~100,两者的总重量与溶剂的重量之比为1:0.1~1000;
    2)除去步骤1)得到的溶液或悬浮液中的溶剂,得到无定型态的沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐与药用辅料的组合物。
  12. 根据权利要求11所述的含沙库比曲和缬沙坦的药用组合物的制备方法,其特征在于,所述药用辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
  13. 根据权利要求11所述的含沙库比曲和缬沙坦的药用组合物的制备方法,其特征在于,所述的药用辅料选自羟丙甲基纤维素、羟丙基纤维素、聚维酮,聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、离子交换树脂和胶原蛋白中的至少一种。
  14. 根据权利要求11所述的含沙库比曲和缬沙坦的药用组合物的制备方法,其特征在于,步骤1)所述溶剂选自碳原子数在12个以下的醇类、酚类、醚类、卤代烃、酮类、醛类、腈类、酰胺、砜、亚砜、羧酸和水中的至少一种;步骤2)除去溶剂的方法包括:蒸发、真空蒸发、喷雾干燥、冷冻干燥、热熔挤出、过滤、离心或搅拌薄膜干燥。
  15. 一种权利要求4所述的含沙库比曲和缬沙坦的药用组合物的制备方法,包括如下步骤:
    1)将沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐、至少一种有机载体和至少一种药学上可接受的药用制剂辅料混合,加热至熔融,其中,沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的总重量为固体分散体的总重量的20~80%,药用制剂辅料的重量为固体分散体的重量的0.1~80%;
    2)混合均匀后冷却,将得到的混合物粉碎,得到含无定型态的沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的固体分散体的药用组合物。
  16. 根据权利要求15所述的含沙库比曲和缬沙坦的药用组合物的制备方法,其特征在于,所述的有机载体选自药学上可接受聚合物或共聚物。
  17. 根据权利要求15或16所述的含沙库比曲和缬沙坦的药用组合物的制备方法,其特征在于,所述的有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮,聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖和胶原蛋白中的至少一种。
  18. 根据权利要求15所述的含沙库比曲和缬沙坦的药用组合物的制备方法,其特征在于,所述的药用制剂辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
  19. 一种权利要求4所述的含沙库比曲和缬沙坦的药用组合物的制备方法,包括如下步骤:
    1)将沙库比曲或其药学上可接受的盐、缬沙坦或其药学上可接受的盐、至少一种有机载体和至少一种药学上可接受的药用制剂辅料在溶剂中混合形成溶液或悬浮液,混合温度为-50~150℃,其中,沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐与溶剂的重量比为0.001~100:1,沙库比曲或其药学上可接受的盐和缬沙坦或其药学上可接受的盐的总重量为固体分散体的总重量的20~80%,药用制剂辅料的重量为固体分散体的重量的0.1~80%;
    2)除去步骤1)得到的溶液或悬浮液中的溶剂,得到所述药用组合物。
  20. 根据权利要求19所述的含沙库比曲和缬沙坦的药用组合物的制备方法,其特征在于,所述药用制剂辅料选自所述的有机载体选自药学上可接受的聚合物或共聚物。
  21. 根据权利要求18或19所述的含沙库比曲和缬沙坦的药用组合物的制备方法,其特征在于,所述的有机载体选自羟丙甲基纤维素、羟丙基纤维素、聚维酮,聚乙二醇、乙基纤维素、脂质体、甲基丙烯酸共聚物、聚醋酸乙烯、羧甲基乙基纤维素、羧甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素邻苯二甲酸酯、羟丙甲基纤维素醋酸酯琥珀酸酯、聚丙烯酸树脂、聚羧乙烯、藻酸盐、卡拉胶、羧基乙酸内酯、树胶、聚乙烯醇、预胶化淀粉、交联淀粉、羧甲基淀粉钠、糊精、聚环氧乙烷、壳聚糖、几丁聚糖、离子交换树脂和胶原蛋白中的至少一种。
  22. 根据权利要求19所述的含沙库比曲和缬沙坦的药用组合物的制备方法,其特征在 于,所述的药用制剂辅料选自赋形剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、黏合剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、稀释剂、絮凝剂与反絮凝剂、抗氧剂、吸附剂、助滤剂、释放阻滞剂中的至少一种。
  23. 根据权利要求19所述的含沙库比曲和缬沙坦的药用组合物的制备方法,其特征在于,步骤1)所述溶剂选自碳原子数在12个以下的醇类、酚类、醚类、卤代烃、酮类、醛类、腈类、酰胺、砜、亚砜、羧酸和水中的至少一种;步骤2)除去溶剂的方法包括:蒸发、真空蒸发、喷雾干燥、冷冻干燥、热熔挤出、过滤、离心或搅拌薄膜干燥。
  24. 如权利要求1或4的含沙库比曲和缬沙坦的药用组合物在用于制备治疗心血管疾病药物中的用途,优选为制备治疗高血压和心力衰竭药物的用途。
PCT/CN2016/098093 2015-09-06 2016-09-05 含沙库比曲和缬沙坦的药用组合物及其制备方法 WO2017036420A1 (zh)

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WO2018069833A1 (en) 2016-10-10 2018-04-19 Laurus Labs Limited Stable amorphous form of sacubitril valsartan trisodium complex and processes for preparation thereof
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WO2018069937A1 (en) * 2016-10-13 2018-04-19 Mylan Laboratories Limited Solid dispersions of trisodium sacubitril valsartan and process for the preparation thereof
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WO2020039394A1 (en) 2018-08-24 2020-02-27 Novartis Ag New drug combinations
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EP4088715A1 (en) 2021-05-14 2022-11-16 KRKA, d.d., Novo mesto Pharmaceutical formulation of valsartan and sacubitril
CN116059331A (zh) * 2022-12-14 2023-05-05 佛山市正典生物技术有限公司 一种助悬剂颗粒及其制备方法和用途
CN116059331B (zh) * 2022-12-14 2023-09-19 佛山市正典生物技术有限公司 一种助悬剂颗粒及其制备方法和用途

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