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WO2012159552A1 - Composition pharmaceutique solide contenant un dérivé de benzimidazole - Google Patents

Composition pharmaceutique solide contenant un dérivé de benzimidazole Download PDF

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Publication number
WO2012159552A1
WO2012159552A1 PCT/CN2012/075716 CN2012075716W WO2012159552A1 WO 2012159552 A1 WO2012159552 A1 WO 2012159552A1 CN 2012075716 W CN2012075716 W CN 2012075716W WO 2012159552 A1 WO2012159552 A1 WO 2012159552A1
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WIPO (PCT)
Prior art keywords
sodium
composition
pharmaceutical composition
azilsartan
dissolution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2012/075716
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English (en)
Chinese (zh)
Inventor
徐坚
周晓堂
宋阳
刘晓枫
张春红
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Hengrui Medicine Co Ltd
Original Assignee
Jiangsu Hengrui Medicine Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CN2011101392355A external-priority patent/CN102793681A/zh
Priority claimed from CN 201110144722 external-priority patent/CN102793697A/zh
Priority claimed from CN2011101620224A external-priority patent/CN102824343A/zh
Application filed by Jiangsu Hengrui Medicine Co Ltd filed Critical Jiangsu Hengrui Medicine Co Ltd
Priority to CN201280002761.XA priority Critical patent/CN103096878B/zh
Priority to JP2014511719A priority patent/JP2014515359A/ja
Priority to KR1020137032234A priority patent/KR20140030237A/ko
Priority to HK13110090.3A priority patent/HK1182638B/xx
Publication of WO2012159552A1 publication Critical patent/WO2012159552A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • Solid pharmaceutical composition comprising benzimidazole derivatives
  • the present invention relates to a solid pharmaceutical composition for improving drug dissolution and/or stability, a process for the preparation thereof, and use for the preparation of an antihypertensive drug. Background technique
  • Circulatory diseases also known as cardiovascular diseases, refer to the heart, blood vessels, and diseases of the nervous system that regulate blood circulation. The most common cause of heart disease and high blood pressure. Circulatory diseases are common diseases, especially in medical diseases. Heart disease often persists, affecting life and labor, and the mortality rate is high. With the control of infectious diseases, cardiovascular disease is more prominent in the causes of death. Circulatory diseases can be divided into two major categories: congenital and acquired. Congenital cardiovascular disease is caused by abnormal development of the heart's large blood vessels during the fetal period. Acquired cardiovascular disease, such as coronary heart disease, rheumatic heart disease, high blood pressure and high blood pressure heart disease.
  • Angiotensin II causes vasoconstriction through the angiotensin II receptor on the cell membrane and raises blood pressure.
  • the angiotensin II receptor antagonist can be an effective drug for treating diseases of the circulatory system such as hypertension.
  • the renin-angiotensin system together with the aldosterone system, participates in the control of systemic blood pressure, body fluid volume, electrolyte balance, etc. in the homeostasis.
  • angiotensin II which has potent vasoconstriction, raises blood pressure through the angiotensin II receptor located on the cell membrane, the relationship between renin-angiotensin and hypertension has been revealed, thereby, An antagonist of angiotensin II has been used to treat angiotensin-induced hypertension.
  • drugs having angiotensin-antagonism activity have been administered by oral administration as a preferred chemical structure for strongly expressing angiotensin II antagonistic activity, and it is known that an acid group such as tetrazole is present on a biphenyl side chain.
  • JP-A-5-271228 describes a compound in which the acid group on the biphenyl side chain is 5-oxo-4,5-dihydro-1,2,4-dioxa-3-yl, orally It shows long-term and intense angiotensin II antagonistic activity and antihypertensive activity after administration. Further, W003/047573 describes that the benimipro derivative described in JP-A-5-271228 has insulin sensitizing activity in addition to angiotensin II receptor antagonistic activity.
  • Azisartan (English name Azilsartan) is an angiotensin-receptor antagonist drug in the development of hypertension that selectively blocks the binding of angiotensin II to vascular smooth muscle ATI receptors. Blocking the vasoconstrictor of angiotensin II, which is often used to treat hypertension, is also the only angiotensin II receptor antagonist (sartan) drug in the terminal clinical stage.
  • compositions need to be effective, safe and stable.
  • effectiveness, safety and stability of a pharmaceutical product are not only closely related to the effectiveness and safety of the medicinal ingredient itself, but also by the preparation of the pharmacy.
  • the effects of properties, such as the stability of the medicinal ingredients in the formulation, and the dissolution characteristics of the drug from the formulation are all important. For example, even if the formulation satisfies a certain level of quality immediately after preparation, if the medicinal ingredient in the formulation decomposes over time, the formulation is problematic depending on the effectiveness and safety of the drug product.
  • dissolution characteristics of the drug from the formulation when the drug is too slow to dissolve from the formulation, the drug may not reach an effective concentration in the blood and may not achieve the desired effect. When the drug is dissolved too fast, it may cause a rapid increase in blood drug concentration in the body, and the risk of side effects may also increase.
  • the method of improving the stability of the medicinal ingredient in the preparation it is known to add a pH adjusting agent, and only the method of using fumaric acid and sodium hydroxide, or monosodium fumarate as a stabilizer is disclosed in the patent document CN101677961A.
  • the active ingredient is azisartan potassium salt.
  • the patent document claims to improve the dissolution of the drug, but the specific embodiment given is a dissolution test at a high pH (pH 6.8), which fails to demonstrate its dissolution advantage in the human environment. The dissolution of the pharmaceutical composition provided by this patent application under low pH conditions was measured, and it was found that the improvement effect was very limited.
  • CN101528262A discloses a solid pharmaceutical composition comprising a medicinal active ingredient, a low-melting oily substance and a low-viscosity binder, and an improved dissolution property of a pharmaceutical preparation comprising a solid dosage form containing a low-melting oily substance, wherein the pharmaceutical active ingredient is improved,
  • the specific implementations given are all dissolution tests at high pH (pH 6.8), which have failed to demonstrate their dissolution advantages in the human environment.
  • the dissolution of the pharmaceutical composition provided by this patent application under low pH conditions was measured, and it was found that the improvement effect was very limited. Summary of the invention
  • It is an object of the present invention to provide a solid pharmaceutical composition comprising a compound represented by the formula (I), which is characterized in that it is capable of being adjusted
  • R 1 is a monocyclic nitrogen-containing heterocyclic group having a hydrogen atom deprotonated, R 2 is a carboxyl group, and R 3 is a lower alkyl group, and preferably the compound of the formula (I) is azilsartan;
  • the amount of dissolution adjustment is from 5% to 100%, preferably from 10% to 90%.
  • the amount of adjustment is an amount of increase or decrease, and the degree of dissolution is a dissolution rate in the dissolution medium of ⁇ ⁇ 1 to 10, preferably a pH of 4 to 8.
  • the inactive ingredient may be present on the surface of the pharmaceutical composition or dispersed within the pharmaceutical composition.
  • the inventors were consciously surprised to find that the addition of a co-solvent can improve the dissolution of azilsartan.
  • the co-solvent is selected from the group consisting of sodium carbonate, sodium hydrogencarbonate, calcium hydrogen phosphate, magnesium carbonate, magnesium hydroxide and the like, and sodium carbonate and sodium hydrogencarbonate are preferred.
  • the cosolvent is added in an amount of from 0.01% to 20%, preferably from 0.01% to 10% by weight based on the total weight of the solid pharmaceutical composition.
  • Some stabilizers can improve the stability of solid pharmaceutical compositions such as maleic acid and sodium hydroxide, fumaric acid and sodium hydroxide, citric acid and sodium hydroxide, tartaric acid and sodium hydroxide, and maleic acid.
  • Sodium, monosodium fumarate, sodium tartrate, monosodium citrate, propyl gallate, ethylenediaminetetraacetic acid, disodium edetate, butylated hydroxyanisole, sodium sulfite, sodium bisulfite, sodium metabisulfite And/or ascorbic acid preferably maleic acid with sodium hydroxide, fumaric acid and sodium hydroxide, citric acid and sodium hydroxide, monosodium maleate, monosodium fumarate and/or monosodium citrate.
  • the stabilizer is added in an amount of from 0.01% to 20%, preferably from 0.01% to 10%, based on the total weight of the solid pharmaceutical composition.
  • azilsartan has a particle diameter d (0.5) of between 1 and 50 ⁇ m, and d (0.9) is less than or equal to 150 ⁇ m; preferably d (0.5) between 1 and 20 ⁇ m, d (0.9) is less than or equal to 80 ⁇ m; more preferably d (0.5) is between 1-10 ⁇ m, d (0.9) is less than or equal to 40 ⁇ m; most preferably d (0.5) is at Between 5 ⁇ , d (0.9) is less than or equal to 15 ⁇ .
  • Azilsartan has good dissolution at high ⁇ (such as ⁇ 6.8), but it has poor dissolution at low ⁇ (such as ⁇ 4.5).
  • ⁇ ⁇ value is about 4-7. The inventors have surprisingly found that the treatment of azilsartan to the above particle size range can effectively improve its dissolution at low ⁇ .
  • the solid pharmaceutical composition further comprises polyethylene glycol, preferably PEG 4000 or PEG 6000, more preferably PEG 6000.
  • polyethylene glycol preferably PEG 4000 or PEG 6000, more preferably PEG 6000.
  • the content of the polyethylene glycol is not particularly limited, and in a further preferred embodiment of the invention, it is from 0.01% to 20%, preferably from 0.01% to 10% by weight based on the total mass of the composition.
  • the solid pharmaceutical composition further comprises citric acid, sodium citrate, or a mixture thereof.
  • citric acid, sodium citrate, or mixtures thereof can substantially increase the bioavailability of azilsartan.
  • the content of the citric acid, sodium citrate, or a mixture thereof is not particularly limited, and in a further preferred embodiment of the present invention, it is from 0.01% to 20%, preferably from 0.01% to 10%, based on the total amount of the composition.
  • the solid pharmaceutical composition further comprises a penetration enhancer selected from the group consisting of sodium dodecyl sulfate (SDS), sodium lauryl sarcosinate, Poloxamer, Tween, Span, polyoxyethylene hydrogenated castor oil, castor oil polyoxyl ester; poloxamer can be poloxamer 188, poloxamer 407; Tween can be Tween 20 Tween 60 and Tween 80.
  • SDS sodium dodecyl sulfate
  • Poloxamer Poloxamer
  • Tween Span
  • poloxamer can be poloxamer 188, poloxamer 407
  • Tween can be Tween 20 Tween 60 and Tween 80.
  • the addition of a penetration enhancer improves the absorption of azilsartan in the body and also increases its bioavailability.
  • the content of the penetration enhancer is not particularly limited, and in
  • the compound of the formula (I) is encapsulated in a hole structure of a cyclodextrin and a derivative thereof, wherein the cyclodextrin and a derivative thereof are selected from the group consisting of ⁇ -cyclodextrin.
  • Another object of the present invention is a method of preparing the pharmaceutical composition, characterized in that
  • the compound represented by (I) is dispersed and/or embedded in each component of the composition to form a solid composition.
  • Another object of the present invention is to provide a use of the pharmaceutical composition for the preparation of a medicament for treating diseases of the circulatory system, which is preferably hypertension.
  • the sodium cellulose (16 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve. To the whole granules, 3.3 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 7.0 mm punch to obtain a plain tablet having the following composition.
  • composition of the preparation (per 159.6mg)
  • Azilsartan (64 g) was mixed with ⁇ -cyclodextrin (384 g) uniformly, added with 768 g of water, ground for 6 h to a semi-solid state, and dried under reduced pressure at 40 ° C to give a solid.
  • the obtained solid was washed with an appropriate amount of water and methanol, and dried under reduced pressure to give a clath.
  • Take appropriate amount of inclusion complex (containing azilsartan 32g), mix with mannitol (100g), microcrystalline cellulose (15g), croscarmellose sodium (8g), using 5% hydroxypropyl fiber
  • the aqueous solution of the solution is a binder, granulation, fluidized bed drying, and a 1.0 mm sieve. To the whole granules, 3.3 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 10.0 mm punch to obtain a plain tablet having the following composition.
  • Azisartan inclusion complex 216mg (containing azilsartan 32mg)
  • aqueous cellulose solution was a binder, granulated, fluidized bed dried, and 1.0 mm sieve granules. To the granules after the granules, 3 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 7.0 mm punch to obtain a plain tablet having the following composition.
  • composition of the preparation (per 156mg)
  • Azilsartan (64g), with mannitol (90g), microcrystalline cellulose (90g), cross-linked carboxymethyl fiber Sodium (15g) and sodium carbonate (40g) were mixed uniformly, and 3 g of magnesium stearate was added and mixed well.
  • the resulting mixture was tableted by a 7.0 mm punch to obtain a plain tablet having the following composition.
  • composition of the preparation (per 151mg)
  • Azisartan 64g
  • mannitol 90g
  • microcrystalline cellulose 90g
  • croscarmellose sodium 15g
  • sodium lauryl sulfate 40g
  • the aqueous solution of % hydroxypropylcellulose was used as a binder, granulated, fluidized bed drying, and 1.0 mm sieve granules.
  • 3 g of magnesium stearate was added to the granules after the granules, and the mixture was uniformly mixed.
  • the resulting mixture was tableted by a 7.0 mm punch to obtain a plain tablet having the following composition.
  • composition of the preparation (per 155mg)
  • Azisartan 64g
  • mannitol 90g
  • microcrystalline cellulose 90g
  • croscarmellose sodium 15g
  • 5% hydroxypropyl cellulose solution including 2.5 % citric acid, 0.83% sodium hydroxide
  • Azisartan 64g
  • mannitol 90g
  • microcrystalline cellulose 90g
  • croscarmellose sodium 15g
  • 5% hydroxypropyl cellulose solution including 2.5 % maleic acid, 0.83% sodium hydroxide
  • To the whole granules 3 g of magnesium stearate was added and mixed well.
  • the resulting mixture was tableted by a 7.0 mm punch to obtain a tablet having the following composition.
  • Azisartan 64g
  • mannitol 90g
  • microcrystalline cellulose 90g
  • croscarmellose sodium 15g
  • 5% hydroxypropyl cellulose solution including 2.5 % fumaric acid, 0.83% sodium hydroxide
  • Azisartan 64g
  • mannitol 90g
  • microcrystalline cellulose 90g
  • croscarmellose sodium 15g
  • 5% hydroxypropyl cellulose solution including 2.5 % fumaric acid, 0.83% sodium hydroxide
  • To the whole granules 3 g of magnesium stearate was added and mixed well. The resulting mixture was tableted through a 9.0 mm punch to obtain a plain tablet.
  • the methacrylic acid copolymer type A and the methacrylic acid copolymer type B were dissolved in 95% ethanol, continuously stirred until completely dissolved, and slowly added, stirring was continued until dissolution, and it was used.
  • the talc powder and triethyl citrate were added to the remaining aqueous ethanol solution, and after mixing, they were homogenized for 10 minutes, and then slowly added to the copolymer solution, and stirring was continued for 30 minutes.
  • the tablet was placed in a high-efficiency coating pan for coating to obtain a coated tablet of the following composition.
  • composition of the coating layer (per 332.9mg)
  • Methacrylic acid copolymer type A 2.48mg
  • Methacrylic acid copolymer type B 7.44mg
  • Azisartan 64g
  • mannitol 90g
  • microcrystalline cellulose 90g
  • croscarmellose sodium 15g
  • 5% hydroxypropyl cellulose solution including 2.5 % fumaric acid, 0.83% sodium hydroxide
  • 3 g of magnesium stearate was added to the granules after the granules, and the mixture was uniformly mixed.
  • the resulting mixture was tableted through a 10.0 mm punch to obtain a plain tablet.
  • the methacrylic acid copolymer type A and the methacrylic acid copolymer type B were dissolved in 95% ethanol, continuously stirred until completely dissolved, and slowly added, stirring was continued until dissolution, and it was used. Add talc powder and triethyl citrate to the remaining ethanol water The solution, after mixing, was homogenized for 10 minutes and then slowly added to the copolymer solution, and stirring was continued for 30 minutes. The tablet was placed in a high-efficiency coating pan for coating to obtain a coated tablet of the following composition.
  • composition of the coating layer (per 320.2mg)
  • Methacrylic acid copolymer type B 1.98mg
  • Azisartan (64 g), methacrylic acid copolymer type A (18.65 g), methacrylic acid copolymer type B (55.95 g), magnesium stearate (1.4 g) were uniformly mixed, and the resulting mixture was washed through 7.0 mm. The head was pressed to obtain a plain tablet having the following composition.
  • Methacrylic acid copolymer type A 18.65mg
  • Methacrylic acid copolymer type B 55.95mg
  • Azisartan (64 g), calcium hydrogen phosphate (67.6:), pregelatinized starch (7 g), magnesium stearate (1.4 g) were uniformly mixed, and the resulting mixture was passed through a 7.0 mm punch to obtain a pigment having the following composition. sheet.
  • Azilsartan (64 g) was mixed with hydroxypropyl- ⁇ -cyclodextrin (256 g) uniformly, and 512 g of water was added thereto, and the mixture was ground for 6 hours to a semi-solid state, and dried under reduced pressure at 40 ° C to obtain a solid.
  • the obtained solid was washed with an appropriate amount of water and methanol, and dried under reduced pressure to give a clath.
  • composition of the preparation (per 290 mg)
  • Azilsartan inclusion complex 161mg (containing azilsartan 32mg) mannitol lOOmg
  • Sodium methylcellulose (20 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve. To the whole granules, 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 8.0 mm punch to obtain a plain tablet having the following composition.
  • Sodium methylcellulose (20 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve.
  • 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was compressed by a 8.0 mm punch.
  • Sodium methylcellulose (20 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve. To the whole granules, 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 8.0 mm punch to obtain a plain tablet having the following composition.
  • Sodium methylcellulose (20 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose (containing polyethylene glycol 6000) was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve. To the whole granules, 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 8.0 mm punch to obtain a plain tablet having the following composition.
  • composition of the preparation per 205.5mg
  • Sodium methylcellulose (20 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve.
  • 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was compressed by a 8.0 mm punch.
  • Sodium methylcellulose (20 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose (containing citric acid/sodium citrate) was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve was granulated. To the whole granules, 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 8.0 mm punch to obtain a plain tablet having the following composition.
  • Sodium methylcellulose (20 g) was uniformly mixed, and a 5% aqueous solution of hydroxypropylcellulose (containing poloxamer 188) was used as a binder, granulated, fluidized bed drying, and a 1.0 mm sieve. To the whole granules, 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed. The resulting mixture was tableted by a 8.0 mm punch to obtain a plain tablet having the following composition.
  • Azisartan (64 g) using a 60 mesh sieve was mixed with mannitol (200 g) and microcrystalline cellulose (30 g of croscarmellose sodium (16 g) uniformly, using a hydroxypropylcellulose aqueous solution. Adhesive, granulation, fluidized bed drying, 1.0 mm sieve granules. 3.3 g of magnesium stearate was added to the granules after granulation, and the mixture was uniformly mixed. The resulting mixture was tableted by a 7.0 mm punch to obtain the following composition. Tablets.
  • composition of the preparation (per 159.6mg)
  • the aqueous cellulose solution (containing polyethylene glycol 6000) was used as a binder, granulated, fluidized bed drying, and 1.0 mm sieve granules.
  • 4.0 g of magnesium stearate was added, and the mixture was uniformly mixed.
  • the resulting mixture was tableted by a 8.0 mm punch to obtain a plain tablet having the following composition.
  • composition of the preparation per 205.5mg
  • Example 1 The drug dissolution behavior evaluation conditions of the tablets obtained in Example 1 and Comparative Example 1 were as follows: Dissolution medium: pH 4.5 acetate buffer + 5% sodium lauryl sulfate, pH 6.8 phosphate buffer dissolution medium Volume: 900ml
  • Dissolution method According to the Chinese Pharmacopoeia 2010 dissolution test method, the second method of dissolution measurement (ie, paddle method) was selected, and the rotation speed was 50 rpm.
  • the dissolution profile was determined by HPLC as shown in Figure 1.
  • Example 2 The drug dissolution behavior evaluation conditions of the tablets obtained in Example 2 and Comparative Example 1 were as follows: Dissolution medium: pH 4.5 acetate buffer + 5% sodium lauryl sulfate
  • Dissolution medium volume 900ml
  • Dissolution method According to the Chinese Pharmacopoeia 2010 dissolution test method, the second method of dissolution measurement (ie, paddle method) was selected, and the rotation speed was 50 rpm.
  • the dissolution profile was determined by HPLC as shown in Fig. 2.
  • Example 2 and Comparative Example 1 were moisture-proof packaged, and placed at 40 ° C and 60 ° C, respectively, and sampled at 7 days and 14 days, respectively, and the amount of decomposition products was measured by HPLC method. See Table 2.
  • Example 3 The drug dissolution behavior evaluation conditions of the tablets obtained in Example 3 and Comparative Example 1 were as follows: Dissolution medium: ⁇ 4.5 acetate buffer, ⁇ 4.5 acetate buffer + 5% sodium dodecyl sulfate dissolution Media volume: 900ml
  • Dissolution method According to the Chinese Pharmacopoeia 2010 dissolution test method, the second method of dissolution measurement (ie, paddle method) was selected, and the rotation speed was 50 rpm.
  • the dissolution profile was determined by HPLC as shown in Fig. 3.
  • Example 7 As shown in Figure 3, the use of sodium carbonate as a co-solvent significantly improved the dissolution behavior of azilsartan under these conditions.
  • Experimental example 6 The plain tablets obtained in Example 7 and Comparative Example 1 were moisture-proof packaged and placed at 40 ° C and 60 ° C respectively, and sampled at 7 days and 14 days, respectively, and the amount of decomposition products was measured by HPLC method. See Table 3.
  • the plain tablets obtained in Examples 19 and 20 and Comparative Examples 5 and 6 were moisture-proof packaged and placed at 60 ° C, respectively, and sampled at 7 days and 14 days, respectively, and the amount of decomposition products was measured by HPLC method. See Table 5.
  • Example 3 The evaluation conditions of the drug dissolution behavior of the tablets obtained in Example 3 and Comparative Examples 1 and 2 were as follows: Dissolution medium: pH 4.5 acetate buffer + 5% sodium lauryl sulfate, pH 6.8 phosphate buffer Dissolution medium volume: 900ml
  • Dissolution method According to the Chinese Pharmacopoeia 2010 dissolution test method, the second method of dissolution measurement (ie, paddle method) was selected, and the rotation speed was 50 rpm.
  • the dissolution profile was determined by HPLC as shown in Fig. 4.
  • Dissolution medium pH 4.5 acetate buffer + 5% sodium lauryl sulfate
  • Dissolution medium volume 900ml
  • Dissolution method According to the Chinese Pharmacopoeia 2010 dissolution test method, the second method of dissolution measurement (ie, paddle method) was selected, and the rotation speed was 50 rpm.
  • the dissolution profile is shown in Figure 5.
  • Examples 20 and 21 were performed on human pharmacokinetic studies, respectively. After 40 mg orally on an empty stomach, the Cmax and AUC of Example 20 were 4025 ng/ml and 26968 ng/ml*h, respectively, and the Cmax and AUC of Example 21 were 4436 ng/ml and 36895 ng/ml*h, respectively.
  • the AUC of Example 21 (which is 1.37 times that of Example 20, shows that the addition of citric acid/sodium citrate improves the bioavailability of the formulation.
  • Experimental Example 12 Examples 20 and 22 were performed on human pharmacokinetic studies, respectively.
  • Example 20 After 40 mg orally on an empty stomach, the Cmax and AUC of Example 20 were 4025 ng/ml and 26968 ng/ml*h, respectively, and the Cmax and AUC of Example 22 were 4559 ng/ml and 37725 ng/ml*h, respectively.
  • the AUC of Example 22 (which is 1.40 times that of Example 20, shows that the addition of Poloxamer 188 improves the bioavailability of the formulation.

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Abstract

L'invention porte sur une composition pharmaceutique solide contenant un dérivé de benzimidazole et sur son procédé de préparation, ladite composition pharmaceutique solide étant utilisée pour ajuster les degrés de dissolution d'un médicament et/ou améliorer sa stabilité, et sur ses utilisations dans la préparation de médicaments pour le traitement de maladies de la circulation.
PCT/CN2012/075716 2011-05-23 2012-05-18 Composition pharmaceutique solide contenant un dérivé de benzimidazole Ceased WO2012159552A1 (fr)

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CN201280002761.XA CN103096878B (zh) 2011-05-23 2012-05-18 包含苯并咪唑衍生物的固体药物组合物
JP2014511719A JP2014515359A (ja) 2011-05-23 2012-05-18 ベンズイミダゾール誘導体を含む固形医薬組成物
KR1020137032234A KR20140030237A (ko) 2011-05-23 2012-05-18 벤즈이미다졸 유도체를 함유하는 고체 약제학적 조성물
HK13110090.3A HK1182638B (en) 2011-05-23 2012-05-18 Solid pharmaceutical composition containing benzimidazole derivative

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CN2011101392355A CN102793681A (zh) 2011-05-23 2011-05-23 包含苯并咪唑衍生物的固体药物组合物
CN201110144722.0 2011-05-26
CN 201110144722 CN102793697A (zh) 2011-05-26 2011-05-26 包含苯并咪唑衍生物的固体药物组合物
CN2011101620224A CN102824343A (zh) 2011-06-16 2011-06-16 包含苯并咪唑衍生物的固体药物组合物
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JP6081376B2 (ja) * 2011-12-28 2017-02-15 ニプロ株式会社 アンギオテンシンｉｉ拮抗作用を有する化合物を含有する固形医薬組成物
JP6883401B2 (ja) * 2015-11-16 2021-06-09 エルメッド株式会社 アジルサルタン含有錠剤及び錠剤におけるアジルサルタンの安定化方法
JP6808515B2 (ja) * 2016-02-12 2021-01-06 エルメッド株式会社 アジルサルタン含有湿製錠剤及びその製造方法
JP6293850B1 (ja) * 2016-11-14 2018-03-14 エルメッド エーザイ株式会社 医薬組成物におけるアジルサルタンの速やかな溶出性を維持し、かつ安定化する方法
JP6895779B2 (ja) * 2017-03-17 2021-06-30 東和薬品株式会社 アジルサルタン含有固形医薬組成物
WO2019130277A1 (fr) * 2017-12-30 2019-07-04 Lupin Limited Formulations pharmaceutiques d'azilsartan médoxomil
JP2020111545A (ja) * 2019-01-15 2020-07-27 ダイト株式会社 アジルサルタン含有組成物
IN202021028444A (fr) * 2020-07-03 2022-01-28
KR20240147572A (ko) * 2023-03-31 2024-10-08 (주)셀트리온 아질사르탄을 포함하는 고혈압 치료용 약학 조성물

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