WO2019107989A1 - Dispersion solide comprenant du fimasartan - Google Patents

Dispersion solide comprenant du fimasartan Download PDF

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WO2019107989A1
WO2019107989A1 PCT/KR2018/015004 KR2018015004W WO2019107989A1 WO 2019107989 A1 WO2019107989 A1 WO 2019107989A1 KR 2018015004 W KR2018015004 W KR 2018015004W WO 2019107989 A1 WO2019107989 A1 WO 2019107989A1
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solid dispersion
pharmaceutically acceptable
salt
acid
potassium
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PCT/KR2018/015004
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English (en)
Korean (ko)
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신동철
김명식
서성미
황용연
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보령제약 주식회사
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Priority to CN201880076540.4A priority Critical patent/CN111417386A/zh
Publication of WO2019107989A1 publication Critical patent/WO2019107989A1/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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K31/41—Heterocyclic 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
    • 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
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof; And a solid dispersion comprising a pharmaceutically acceptable substrate.
  • the solid dispersion according to the present invention improves the bioavailability by increasing the solubility and increasing the elution of the Pimacartan.
  • the physicochemical properties of the drug also play an important role in the efficacy of the drug.
  • the drug dissolution rate between the preparations may be large and the dissolution rate may be low due to low solubility.
  • Pimassartan is a hypertensive drug that is an angiotensin II receptor antagonist.
  • Kanabra is available in three doses, 30, 60 and 120 mg under the trade name, and its main ingredient is Pimassartan potassium salt.
  • Patent Document 1 International Patent Publication No. WO999-055681
  • It is an object of the present invention to provide a pharmaceutical composition comprising fimasartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof; And a pharmaceutically acceptable substrate. ≪ Desc / Clms Page number 2 >
  • An object of the present invention is to provide a pharmaceutical composition comprising the solid dispersion and a pharmaceutically acceptable additive.
  • the present invention relates to a fimasartan represented by the following general formula (1), a pharmaceutically acceptable salt, a hydrate or a solvate thereof; And a pharmaceutically acceptable substrate.
  • the solid dispersion means that a fimasartan, a pharmaceutically acceptable salt, a hydrate or a solvate thereof is dispersed in a pharmaceutically acceptable substrate, and the amount of the phimacartan
  • the distribution form of fimasartan, its pharmaceutically acceptable salt, hydrate or solvate thereof may be dispersed in the form of small particles or very small particles and may be dispersed in molecular units.
  • the solid dispersion according to the present invention improves the bioavailability by increasing the solubility and increasing the elution of the Pimacartan.
  • the solubility as a poorly soluble drug was so low that formulation was not easy and bioavailability was not sufficiently high. Therefore, in order to exhibit a sufficient therapeutic effect through oral administration, the content of the phimassartan must be high in the preparation. As a result, the convenience of the patient's medication is deteriorated. In view of this, Has come.
  • Pimassartan, a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the present invention; And a pharmaceutically acceptable substrate are excellent in physicochemical and pharmacological properties required for drugs such as solubility or bioavailability, exhibit physical properties superior to those of conventional Picalsartan potassium salt preparations and are more easily formulated And the convenience of medication can be improved.
  • the substrate is not limited as long as it is pharmaceutically acceptable and can form a solid dispersion, that is, can dissolve or disperse the castor oil.
  • the polymeric excipient or Non-polymeric excipients are examples of the polymeric excipients.
  • the pharmaceutically acceptable substrate is a polymeric excipient.
  • the polymeric excipient is selected from the group consisting of hydroxyalkylmethylcellulose (e.g., hydroxypropylmethylcellulose), hydroxyalkylcellulose (e. G., Hydroxypropylcellulose or hydroxyethylcellulose) , Carboxymethylcellulose, sodium carboxymethylcellulose, ethylcellulose, cellulose succinate (for example, hydroxypropylmethylcellulose acetate succinate), cellulose phthalate (for example, hydroxypropylmethylcellulose phthalate), polymethacrylate (For example, Eudragit TM), polyhydroxyalkyl acrylates, polyhydroxyalkyl methacrylates, polyacrylates, polyvinyl alcohols, polyvinyl pyrrolidone, vinyl pyrrolidone / Vinyl acetate copolymer, crospovidone, polyalkylene glycol (e.g., One or two kinds selected from the group consisting of polyethylene glycol, polyethylene oxide, poloxamer, polyvinyl acetate
  • the pharmaceutically acceptable substrate is selected from the group consisting of hydroxypropylmethylcellulose (HPMC), polyvinylalcohol (PVA), hydroxypropylcellulose (HPC), and polymethacrylate One or two or more.
  • the polymethacrylate is eudragit EPO.
  • the pharmaceutically acceptable substrate is a non-polymeric excipient.
  • the non-polymeric excipient may be a sugar and / or sugar alcohols and / or a cyclodextrin.
  • sucrose, lactose, fructose, maltose, raffinose, sorbitol, lactitol, mannitol, maltitol, erythritol, traceol, adonitol, arabitol, pisilitol, dulcitol, inositol But are not limited to, halose, isomalt, inulin, maltodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether cyclodextrin or mixtures thereof.
  • the palmasaltan, a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable substrate are included in a weight ratio of 1: 0.1 to 1:10.
  • the pharmaceutically acceptable salt of Pimassartan may mean a salt commonly used in the pharmaceutical industry.
  • the pharmaceutically acceptable salt of Pimassartan may be selected from the group consisting of inorganic ion salts, inorganic acid salts, organic acid salts, sulfonic acid salts, amino acid salts and amine salts.
  • inorganic ion salts prepared from calcium, potassium, sodium and magnesium, inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid and sulfuric acid and the like, acetic acid, trifluoroacetic acid, , Succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, Organic acid salts prepared from malic acid, malic acid, malic acid, malic acid, malic acid, malic acid, pamoic acid, pantothenic acid, succinic acid, tartaric acid and the like, methanesulfonic acid, ethanesulfonic acid, ethanesulfonic acid, benzenesulfonic
  • the hydrates of the castazatins of the present invention or pharmaceutically acceptable salts thereof may contain stoichiometric or non-stoichiometric amounts of water that are bound by non-covalent intermolecular forces.
  • the hydrate may contain at least 1 equivalent, i. E. 1 to 5 equivalents of water, based on 1 equivalent of Pimacartan or a salt thereof.
  • Solvates of the palmatalkine or pharmaceutically acceptable salts thereof of the present invention may include stoichiometric or non-stoichiometric amounts of solvent bound by intermolecular forces.
  • the Pimassartan, a pharmaceutically acceptable salt, a hydrate or a solvate thereof is selected from the group consisting of Pimassartan free base, Pimassartan potassium, Pimassartan potassium trihydrate, Pimassartan potassium monohydrate, Toluenesulfonic acid salt, and toluenesulfonic acid ammonium salt.
  • the pharmaceutically acceptable salt of the palmatheartan may be potassium palmitate, pimacartan toluenesulfonate or piramassaitane ammonia salt.
  • the pharmaceutically acceptable hydrate of the salt of Pimasartan or Pimacartan may be Pimassartan potassium monohydrate or Pimassalant calcium trihydrate.
  • the solid dispersion of the present invention can be produced by a conventional method for producing a solid dispersion.
  • solid dispersions comprising Pimacartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof and a pharmaceutically acceptable substrate may be prepared using a fluid bed granulator, It is not limited.
  • a solution comprising Pimacartan, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, and a pharmaceutically acceptable substrate may be mixed with a pharmaceutically acceptable additive such as mannitol, dicalcium phosphate, starch glyconanic acid Sodium mixed powder to prepare a solid dispersion.
  • a pharmaceutically acceptable additive such as mannitol, dicalcium phosphate, starch glyconanic acid Sodium mixed powder to prepare a solid dispersion.
  • a pharmaceutical composition for preventing or treating an angiotensin II receptor-related disease comprising the above-mentioned solid dispersion and a pharmaceutically acceptable additive.
  • the Pimacartan, a pharmaceutically acceptable salt, a hydrate or a solvate thereof contained in the solid dispersion acts as an angiotensin II receptor inhibitor.
  • the pharmaceutically acceptable additive may be contained in the solid dispersion and may be separately provided from the solid dispersion to form a pharmaceutical composition.
  • Such pharmacologically acceptable is physiologically acceptable and is generally administered to humans without the usual occurrence of gastrointestinal disorders, allergic reactions such as dizziness, or similar reactions, It can mean to use.
  • the pharmaceutically acceptable excipient may be a carrier, an excipient, an extender, an antioxidant, a buffer, a filler, an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a suspending agent, a surfactant and an antiseptic agent.
  • the additive may be selected from the group consisting of lactose, dextrose, calcium silicate, corn starch, sodium starch glycolate, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate , Calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, sodium starch glycolate, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, methylhydroxybenzoate, Glycols, ethers (e.g., polyethylene glycol 400), oils such as glycerin, glycerin, glycerin, glycerin, glycerin, Fatty acids, fatty acid esters, glycerides or mixtures thereof.
  • additives which may be included in the compositions according to the present invention are not limited
  • the pharmaceutical composition of the present invention may be formulated according to a conventional method, and may be prepared into an oral preparation or a parenteral administration preparation, and preferably it may be an oral administration preparation.
  • the pharmaceutical preparations for oral administration may be solid preparations such as tablets, pills, powders, granules and capsules, or liquid preparations such as suspensions, solutions, emulsions and syrups, More preferably, it may be a tablet.
  • the pharmaceutical composition is a formulation of granules, capsules or tablets.
  • the above granules, capsules or tablets can be produced by a usual production method.
  • the tablets are prepared by a direct tableting method in which the above-mentioned solid dispersion is mixed with a pharmaceutically acceptable additive, or tablets are prepared by dry granulation after preparing granules .
  • a pharmaceutically acceptable additive may be the same as those mentioned above, and examples thereof include mannitol, croscarmellose sodium, and magnesium stearate.
  • the solid dispersion according to the present invention is excellent in physicochemical properties required for formulation such as processability as a formulation. Therefore, when formulating into the form of tablets or capsules, tablets or capsules with uniform pharmacological effects can be produced, and there is no problem that the pharmacological effect is lowered during the formulation process. Therefore, it is possible to economically produce an agent having a superior pharmacological effect and a uniform pharmacological effect.
  • the content of the additive contained in the pharmaceutical composition is not particularly limited and may be appropriately controlled within the range of contents used for usual formulation.
  • the pharmaceutical composition may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically), and the dose may be appropriately determined depending on the body weight, age, sex, The range may vary depending on the condition, diet, time of administration, method of administration, duration or interval of administration, excretion rate, sickness specificity, nature of the preparation, severity of the disease and the like.
  • the angiotensin II receptor-related disease is selected from the group consisting of stroke, stroke, stroke, cerebral infarction, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, diabetes, obesity, hyperlipidemia, coronary artery disease, angina pectoris, myocardial infarction, , Heart failure, and inflammation.
  • the pharmaceutical composition comprises the above-mentioned Pimacartan, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof; And a pharmacologically acceptable substrate, and other pharmacologically active substances in addition to the solid dispersion.
  • the pharmacologically active substance may have the same pharmacological activity as the castazate, its pharmaceutically acceptable salt, its hydrate or solvate, or may have other pharmacological activity.
  • the other pharmacologically active substances contained in the pharmaceutical composition may be selected from the group consisting of therapeutic agents for hyperlipidemia such as amlodipine, lercardipine, nicardipine, simvastatin, atorvastatin, pravastatin and rosuvastatin, metformin, hydrochlorothiazide, cytarglyptin, Or a pharmaceutically acceptable salt thereof, or a mixture of these, for the treatment of diabetes such as lipid, lignin, linagliptin, saxagliptin, teneligliptin, anagliptin, meloglyptin, twotogliptin, gemigliptin, More preferably amlodipine, rosuvastatin, atorvastatin, hydrochlorothiazide, cytarglyptin, bilagogliptin, linagliptin, and pharmaceutically acceptable salts thereof or a mixture thereof.
  • the pharmaceutical composition of the present invention can be used alone, for improving, alleviating, treating or preventing angiotensin II receptor-related progression, or in combination with methods using surgery, hormone therapy, drug therapy and biological response modifiers.
  • the solid dispersion may be used for the preparation of a medicament for the prevention or treatment of the angiotensin II receptor-related diseases.
  • a method for preventing or treating a stroke, stroke, stroke, cerebral infarction, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, diabetes, obesity, hyperlipidemia, coronary artery disease , Angina pectoris, myocardial infarction, hypertension, heart failure or inflammation it is also possible to provide a method for preventing or treating a stroke, stroke, stroke, cerebral infarction, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, diabetes, obesity, hyperlipidemia, coronary artery disease , Angina pectoris, myocardial infarction, hypertension, heart failure or inflammation.
  • a method for inhibiting the activation of angiotensin II receptor comprising administering a therapeutically effective amount of the solid dispersion.
  • Fimasartan a pharmaceutically acceptable salt, hydrate or solvate thereof, according to the present invention.
  • a pharmaceutically acceptable substrate increase the solubility of the Pimacartan and increase the elution to improve bioavailability.
  • Fig. 1 is a graph comparing drug dissolution rates of the solid dispersion prepared in Examples 1, 4, 5 and 6 and potassium succinate potassium trihydrate at pH 1.2.
  • Fig. 1 is a graph comparing drug dissolution rates of the solid dispersion prepared in Examples 1, 4, 5 and 6 and potassium succinate potassium trihydrate at pH 1.2.
  • FIG. 2 is a graph comparing drug dissolution rates of the solid dispersion prepared in Examples 2, 3 and 7 and the respective dissolution rates of Pima saccharan Toluene Sulfonate, Pima Sartan Ammonia Salt and Pima Sartan Free Base in the form of Pima Sartan salt at pH 1.2 to be.
  • Fig. 3 is a graph comparing drug dissolution rates of the solid dispersion prepared in Examples 1, 4, 5 and 6 and potassium palmitate potassium trihydrate at pH 4.0.
  • FIG. 4 is a graph comparing the dissolution rates of the solid dispersions prepared in Examples 2, 3 and 7, and the dissolution ratios of the respective salts of Pima saccharan Toluene Sulfonate, Pima Sartan Ammonia Salt and Pima Sartan Free Base at pH 4.0 to be.
  • Fig. 5 is a graph comparing the tablets containing the solid dispersion of Example 8 with 60 mg of cannabin, a comparative preparation, at pH 1.2.
  • Fig. 6 is a chart comparing the tablets containing the solid dispersion of Example 8 with 60 mg of cannabin, a comparative agent, at pH 4.0.
  • a solution of 0.4 kg of potassium palmitate trihydrate and 0.2 kg of HPMC in a mixture of 1.0 kg of purified water and 1.0 kg of ethanol was prepared. This solution was sprayed onto a powder bed of 0.4 kg of a mixture of mannitol, dicalcium phosphate and sodium starch glycolate at 50 to 60 ⁇ ⁇ using a fluidized bed granulator. This was dried to obtain a powder, which was sieved (0.8 mm) to prepare a solid dispersion.
  • a solution of 0.5 kg of phimersartan toluene sulfonic acid and 0.2 kg of HPMC in a mixture of 0.4 kg of purified water and 1.0 kg of methanol was prepared. This solution was sprayed onto a powder bed of 0.4 kg of a mixture of mannitol, dicalcium phosphate and sodium starch glycolate at 50 to 60 ⁇ ⁇ using a fluidized bed granulator. This was dried to obtain a powder, which was sieved (0.8 mm) to prepare a solid dispersion.
  • a solution of 0.3 kg of Pimersartan ammonia and 0.2 kg of HPMC in a mixture of 0.5 kg of purified water and 2.1 kg of methanol was prepared. This solution was sprayed onto a powder bed of 0.4 kg of a mixture of mannitol, dicalcium phosphate and sodium starch glycolate at 50 to 60 ⁇ ⁇ using a fluidized bed granulator. This was dried to obtain a powder, which was sieved (0.8 mm) to prepare a solid dispersion.
  • a solution of 0.4 kg of potassium palmitate trihydrate and 0.2 kg of HPMC in a mixture of 1.2 kg of purified water and 1.2 kg of ethanol was prepared. This solution was sprayed onto a powder bed of 0.4 kg of a mixture of mannitol, dicalcium phosphate and sodium starch glycolate at 50 to 60 ⁇ ⁇ using a fluidized bed granulator. This was dried to obtain a powder, which was sieved (0.8 mm) to prepare a solid dispersion.
  • a solution of 0.4 kg of potassium palmitate trihydrate and 0.2 kg of PVA in a mixture of 1.8 kg of purified water and 1.2 kg of ethanol was prepared. This solution was sprayed onto a powder bed of 0.4 kg of a mixture of mannitol, dicalcium phosphate and sodium starch glycolate at 50 to 60 ⁇ ⁇ using a fluidized bed granulator. This was dried to obtain a powder, which was sieved (0.8 mm) to prepare a solid dispersion.
  • a solution of 0.4 kg of potassium palmitate trihydrate and 0.2 kg of HPC in a mixture of 0.4 kg of purified water and 1.5 kg of methanol was prepared. This solution was sprayed onto a powder bed of 0.4 kg of a mixture of mannitol, dicalcium phosphate and sodium starch glycolate at 50 to 60 ⁇ ⁇ using a fluidized bed granulator. This was dried to obtain a powder, which was sieved (0.8 mm) to prepare a solid dispersion.
  • a solution of 0.3 kg of Pimersartan free base and 0.1 kg of HPC in a mixture of 2.0 kg of acetone and 0.5 kg of methanol was prepared. This solution was sprayed onto a powder bed of 0.3 kg of a mixture of mannitol, dicalcium phosphate and sodium starch glycolate at 50 to 60 ° C using a fluidized bed granulator. This was dried to obtain a powder, which was sieved (0.8 mm) to prepare a solid dispersion.
  • the solid dispersions prepared in Examples 1 to 7 can be used as they are or can be further formulated into, for example, granules, capsules or tablet formulations.
  • Example 1 The solid dispersion of Example 1 was compounded with 121 g of mannitol, 14 g of croscarmellose sodium and 3 g of magnesium stearate. The above-mentioned easily-pressurized combination was compressed into tablets containing 30 mg and 60 mg as potassium palmitate potassium in a one-shot type tabletting machine.
  • Example 2 The solid dispersion of Example 2 was compounded with 104 g of mannitol, 14 g of croscarmellose sodium and 3 g of magnesium stearate. The above-mentioned easily-pressurized combination was compressed into tablets containing 30 mg and 60 mg as potassium palmitate potassium in a one-shot type tabletting machine.
  • Example 3 The solid dispersion of Example 3 was compounded with 123 g of mannitol, 14 g of croscarmellose sodium and 3 g of magnesium stearate. The above-mentioned easily-pressurized combination was compressed into tablets containing 30 mg and 60 mg as potassium palmitate potassium in a one-shot type tabletting machine.
  • Example 4 The solid dispersion of Example 4 was compounded with 120 g of mannitol, 14 g of croscarmellose sodium and 3 g of magnesium stearate. The above-mentioned easily-pressurized combination was compressed into tablets containing 30 mg and 60 mg as potassium palmitate potassium in a one-shot type tabletting machine.
  • Example 12 Pima Saltan potassium Trihydrate and Of PVA solid The dispersion Preparation of tablets containing
  • Example 5 The solid dispersion of Example 5 was compounded with 120 g of mannitol, 14 g of croscarmellose sodium and 3 g of magnesium stearate. The above-mentioned easily-pressurized combination was compressed into tablets containing 30 mg and 60 mg as potassium palmitate potassium in a one-shot type tabletting machine.
  • Example 13 Pima Saltan potassium Trihydrate and HPC solid The dispersion Preparation of tablets containing
  • Example 6 The solid dispersion of Example 6 was compounded with 120 g of mannitol, 14 g of croscarmellose sodium and 3 g of magnesium stearate. The above-mentioned easily-pressurized combination was compressed into tablets containing 30 mg and 60 mg as potassium palmitate potassium in a one-shot type tabletting machine.
  • Example 14 Pima Saltan Free base HPC solid The dispersion Preparation of tablets containing
  • Example 7 The solid dispersion of Example 7 was compounded with 124 g of mannitol, 14 g of croscarmellose sodium and 3 g of magnesium stearate. The above-mentioned easily-pressurized combination was compressed into tablets containing 30 mg and 60 mg as potassium palmitate potassium in a one-shot type tabletting machine.
  • the tablets containing the solid dispersions prepared in Examples 8 to 14 may be further film-coated to protect them from light and moisture.
  • Drug dissolution rates of the novel solid dispersion formulations of Examples 1 to 7 were tested using paddle method Apparatus 2 in the dissolution test of KP (KP) at paddle speeds of 37 ⁇ 0.5 ° C and 75 rpm.
  • the first disintegration test solution (pH 1.2) and 500 ml sodium acetate buffer (pH 4.0) were used as the dissolution medium.
  • a solid dispersion in an amount corresponding to 240 mg as potassium palmitate potassium was placed in each vessel.
  • a test sample was withdrawn through the filter during the dissolution and the dissolved amount of the drug was analyzed by HPLC.
  • Fig. 1 is a graph comparing drug dissolution rates of the solid dispersion prepared in Examples 1, 4, 5 and 6 and potassium succinate potassium trihydrate at pH 1.2.
  • Fig. 1 is a graph comparing drug dissolution rates of the solid dispersion prepared in Examples 1, 4, 5 and 6 and potassium succinate potassium trihydrate at pH 1.2.
  • FIG. 2 is a graph comparing drug dissolution rates of the solid dispersion prepared in Examples 2, 3 and 7 and the respective dissolution rates of Pima saccharan Toluene Sulfonate, Pima Sartan Ammonia Salt and Pima Sartan Free Base in the form of Pima Sartan salt at pH 1.2 to be.
  • the novel pharmaceutical compositions of the present invention dissolve close to 100% solubility (0.45 mg / ml at 37 ⁇ ⁇ ) Level was dissolved within 30 minutes and maintained above a certain level for 1 hour.
  • the solubility of the solid dispersion according to the present invention is increased to 1.5 to 24 times as compared to that of Pimeticartan, its salt or its hydrate, and the drug solution of the solid dispersion according to the present invention.
  • Fig. 3 is a graph comparing drug dissolution rates of the solid dispersion prepared in Examples 1, 4, 5 and 6 and potassium palmitate potassium trihydrate at pH 4.0.
  • FIG. 4 is a graph comparing the dissolution rates of the solid dispersions prepared in Examples 2, 3 and 7, and the dissolution ratios of the respective salts of Pima saccharan Toluene Sulfonate, Pima Sartan Ammonia Salt and Pima Sartan Free Base at pH 4.0 to be.
  • FIGS. 3 and 4 show that the poor solubility (less than 0.01 mg / ml at 37 ° C.) of the salt of Pimacartan or its salt in the medium can be confirmed, and the low solubility of the solid dispersion according to the present invention It can be confirmed that the improvement is made.
  • the solubility of the solid dispersion according to the present invention is significantly increased to a level of 10 to 64 times as compared to the salt solution of Pimersartan or its salt and the drug solution of the solid dispersion according to the present invention.
  • the solubility of the solid dispersion according to the present invention was increased up to 1 hour.
  • the solid dispersion according to the present invention was able to form a supersaturated solution with a high dissolution rate and a high dissolution rate, and it was confirmed that the supersaturated solution had excellent stability to maintain solubility of the supersaturated solution.
  • the solid dispersion according to the present invention can be expected to achieve excellent water absorption, bioavailability and efficacy.
  • the dissolution test of the pharmaceutical composition of Example 8 was carried out using the paddle method apparatus 2 in the dissolution test of KP (KP) at a paddle speed of 37 ⁇ 0.5 ° C. and 50 rpm.
  • the first disintegration test solution (pH 1.2) and the sodium acetate buffer (pH 4.0) (900 mL) were used as dissolution media.
  • One tablet of the equivalent of 60 mg as potassium palmitate potassium was inserted into the container.
  • a test sample was withdrawn through the filter during elution and the dissolved amount of the drug was analyzed by HPLC.
  • the comparative preparation is a tablet containing 60 mg of potasartan potassium salt as a commercially available cannabis (trade name).
  • Fig. 5 is a graph comparing the tablets containing the solid dispersion of Example 8 with 60 mg of cannabin, a comparative preparation, at pH 1.2.
  • Fig. 6 is a chart comparing the tablets containing the solid dispersion of Example 8 with 60 mg of cannabin, a comparative agent, at pH 4.0.
  • the dosage of the comparative and test agents was an amount corresponding to 30 mg as the potassium salt potassium salt per individual.
  • Blood samples collected immediately before the drug administration, at 0, 10, 20, 30, 1, 2, 3, 4, 6, 8 and 12 hours after the administration of the blood sample were centrifuged (About 5 minutes), then transferred to a suitably labeled vial and stored frozen (-20 ° C) until analysis of the drug.
  • Plasma samples for drug concentration were analyzed by LC / MS / MS and the pharmacokinetic parameters were calculated and reported in Table 3.
  • the tablets of Example 8 showed a 2.4-fold increase in Cmax and a 1.7-fold increase in AUC, respectively, as compared to the comparative product Kanabu (registered trademark).
  • the solid dispersion according to the present invention improved drug absorption and bioavailability.

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Abstract

La présente invention concerne une dispersion solide comprenant : du fimasartan, un sel pharmaceutiquement acceptable de celui-ci ou un hydrate ou un solvate de celui-ci ; et un substrat pharmaceutiquement acceptable. La dispersion solide selon la présente invention augmente la solubilité du fimasartan, augmente son élution et améliore ainsi sa biodisponibilité.
PCT/KR2018/015004 2017-11-30 2018-11-29 Dispersion solide comprenant du fimasartan WO2019107989A1 (fr)

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KR10-2017-0163588 2017-11-30

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TW201924661A (zh) 2019-07-01
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KR20190064208A (ko) 2019-06-10

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