WO2018190451A1 - Composition pharmaceutique contenant un bloqueur du récepteur de l'angiotensine - Google Patents

Composition pharmaceutique contenant un bloqueur du récepteur de l'angiotensine Download PDF

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Publication number
WO2018190451A1
WO2018190451A1 PCT/KR2017/004224 KR2017004224W WO2018190451A1 WO 2018190451 A1 WO2018190451 A1 WO 2018190451A1 KR 2017004224 W KR2017004224 W KR 2017004224W WO 2018190451 A1 WO2018190451 A1 WO 2018190451A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
polymer
dispersant
angiotensin receptor
dielectric constant
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PCT/KR2017/004224
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English (en)
Korean (ko)
Inventor
오동호
채보람
박명신
송세현
손세일
Original Assignee
대원제약주식회사
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Application filed by 대원제약주식회사 filed Critical 대원제약주식회사
Priority to CN201780001612.4A priority Critical patent/CN109152765A/zh
Publication of WO2018190451A1 publication Critical patent/WO2018190451A1/fr

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    • 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
    • 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
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • 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
    • A61K9/1664—Compounds of unknown constitution, e.g. material from plants or animals

Definitions

  • the present invention relates to pharmaceutical compositions comprising one or more selected from angiotensin receptor blockers (ARBs), isomers thereof, pharmaceutically acceptable salts, or prodrugs thereof. More specifically, the present invention relates to pharmaceutical compositions having improved bioavailability and improved methods of improving the solubility and dissolution rate of angiotensin receptor antagonists.
  • ARBs angiotensin receptor blockers
  • Angiotensin receptor antagonists such as valsartan and telmisartan, are poorly soluble drugs, which have low solubility in water and a large change in solubility according to pH, resulting in large absorption deviations between individuals and low bioavailability (BA). there is a problem.
  • Valsartan and telmisartan have a BA of about 25% and 42-58% when administered orally, valsartan reduces BA by about 40% by food, and telmisartan reduces BA by about 20% by food.
  • AUC's CV coefficient of variation
  • valsartan reduces BA by about 40% by food
  • telmisartan reduces BA by about 20% by food.
  • AUC's CV coefficient of variation
  • telmisartan coefficient of variation
  • the CV of AUC was increased to 24% by the intravenous administration of telmisartan 40 mg, whereas the oral dose of telmisartan was increased to 47% by oral administration of the same amount of telmisartan. It is known.
  • US 2008/0113936 discloses a process of dissolving valsartan in organic solvents such as ethanol and ethyl acetate, dispersing mannitol, and the like, and then solidifying the same by drying under reduced pressure.
  • Korean Unexamined Patent Application Publication No. KR2010-0083047 attempts to solubilize valsartan, an angiotensin receptor antagonist, by using an organic solvent and to improve the dissolution rate at low pH by adding a surfactant, and ethanol, methanol, acetone, Methylenedichloride is mentioned.
  • the present invention is to increase the absorption rate in vivo by improving the solubility and dissolution rate of the active ingredient in the pharmaceutical composition comprising an angiotensin receptor antagonist.
  • the present invention provides an angiotensin receptor antagonist, an isomer thereof, a pharmaceutically acceptable salt, or a prodrug thereof as an active ingredient; Dispersants having a dielectric constant of 20 or less; And a dissolution aid.
  • the pharmaceutical composition comprising an angiotensin receptor antagonist can increase the bioavailability by improving the solubility and dissolution rate of the active ingredient.
  • Figure 1 shows the dissolution test results of Experimental Example 3.
  • FIG. 1 shows the dissolution test results of Experimental Example 4.
  • FIG. 3 shows the dissolution test results of Experimental Example 5.
  • FIG. 5 shows the dissolution test results of Experimental Example 7.
  • Figure 6 shows the dissolution test results of Experimental Example 8.
  • the present invention provides an angiotensin receptor antagonist, an isomer thereof, a pharmaceutically acceptable salt, or a prodrug thereof as an active ingredient; Dispersants having a dielectric constant of 20 or less; And it relates to a pharmaceutical composition comprising a dissolution aid. It is preferable that the composition of this invention further contains 1 or more types of polymers.
  • the angiotensin receptor antagonist is valsartan, telmisartan, losartan, candesartan, eprosartan, olmesartan, olmesartan, irbesartan May be selected from irbesartan or fimasartan.
  • Dielectric constant is an indicator of the polarity of a material and is measured as the charge capacity between two electrodes. Dielectric constants are generally classified as polarity if they are 50 or more, and non-polar substances are classified as 1-20. [Anaesthesia 2001; 56: 965-979.
  • the dispersant having a dielectric constant of 20 or less used in the present invention is selected from the group consisting of vegetable or animal oils, triglycerides, glyceryl fatty acid esters, fatty acid esters, polyethylene glycol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof. One or more may be selected.
  • the dispersant having a dielectric constant of 20 or less may be used at 0.05 to 5 parts by weight based on 1 part by weight of the active ingredient.
  • the dissolution aid is polyethylene sorbate, polyethylene sorbate derivatives, macrogol glyceride fatty acid esters, polyoxyl castor oils, polyoxyl stearate, ethylene glycol esters, polyethylene glycol, glycerin, fatty acids, soybean oil, palm oil, triglycol One or more selected from the group consisting of serides and mixtures thereof.
  • the dissolution aid may be used in 0.1 ⁇ 10.0 parts by weight relative to 1 part by weight of the active ingredient.
  • the polymer is a cellulose derivative such as poloxamer, hypromellose, hypromellose acetate succinate, hypromellose phthalate, hydroxypropyl cellulose, methacrylate polymer, polyvinylpyrrolidone, polyvinyl Polyvinyl derivatives and mixtures thereof, such as alcohols and polyvinylacetates, polyethylene glycol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymers, tocopherols and derivatives thereof and mixtures thereof and one or more thereof.
  • the polymer may be used in an amount of 0.05 to 5.0 parts by weight based on 1 part by weight of the active ingredient.
  • the pharmaceutical composition of the present invention may be prepared by mixing an angiotensin receptor antagonist, an isomer thereof, a pharmaceutically acceptable salt thereof, or a prodrug thereof as a dispersant and a dispersing agent having a dielectric constant of 20 or less as an active ingredient. If necessary, the method may further include mixing one or more polymers.
  • the pharmaceutical composition thus prepared may have a viscosity and may be liquid or semisolid.
  • the obtained pharmaceutical composition may be prepared in a solid phase through a powdering or granulating step.
  • powdering or granulation can be carried out by adsorption, wet granulation, dry granulation, melt granulation, spray drying, freeze drying, fluidized bed drying, evaporation drying or coprecipitation.
  • the solidifying agent used in the adsorption method, wet granulation method or dry granulation method may be at least one selected from the group consisting of sugars, silicates, cellulose and its derivatives and povidone and its derivatives.
  • the pharmaceutical composition according to the invention may preferably be formulated in a formulation such as tablets, capsules and the like.
  • the pharmaceutical composition of the present invention may further include pharmaceutically acceptable excipients, diluents, binders, disintegrants, glidants and the like.
  • the main component was dispersed in the dispersant.
  • the main component was added to the mixture of the dispersant and the dissolution aid, and mixed until the main component was completely dispersed.
  • the mixture of the dispersant and the dissolution aid was warmed, the polymer was added and mixed and cooled, and then the main component was added and mixed until the main component was completely dispersed.
  • compositions of Examples 1 to 4 and Comparative Examples 1 and 2 prepared above were added at 320 mg of valsartan, respectively, at 24 ° C. and 200 rpm. Shake for hours (VS-8480, Vision Scientific Co.). Each sample was centrifuged at 13,000 rpm for 10 minutes to filter the supernatant with a 0.45 ⁇ m filter, and then analyzed for solubility. The analysis was performed with reference to USP 40 Valsartan tablets assay. The analysis conditions were as follows.
  • the alkalizing agent was first mixed with the dispersant and the dissolution aid, and the polymer was added and mixed in a heated state. After cooling the mixed solution in which the polymer was completely mixed, the main component was added and mixed until the main component was completely dispersed.
  • compositions of Examples 5 to 8 and Comparative Examples 3 to 4 prepared above were added at 80 mg of telmisartan, respectively, at 25 ° C. and 200 rpm. Shake for 24 hours (VS-8480, Vision Scientific Co.). Each sample was centrifuged at 13,000 rpm for 10 minutes to filter the supernatant with a 0.45 ⁇ m filter, and then analyzed for solubility. The analysis was performed with reference to USP 40 Telmisartan Tablets Assay, and the analysis conditions are as follows.
  • test was performed according to USP 40 dissolution apparatus 2 (paddle method) using a pH 1.2 eluate (1st KEPCO dissolution test), which showed a low dissolution rate of valsartan, and the dissolution test solution was analyzed according to the analysis conditions of Experimental Example 1. . Test conditions are as follows, and the dissolution test of the following Experimental Examples 4 to 10 was also carried out in the same manner as in Experimental Example 3.
  • Dispersant screening results is the same as FIG. As a result, it was found that the dissolution rate was high when the dispersant having a dielectric constant of 20 or less was used.
  • Dispersant use range results is the same as FIG. As a result, even when a small amount of dispersant having a dielectric constant of 20 or less was used, it was found that the dissolution rate was high compared with the comparative example.
  • Dissolution aid screening results is the same as FIG. As a result, it was found that the dissolution rate was high when the dissolution aid was used.
  • Dissolution aid use range results is shown in FIG. As a result, it was found that the dissolution rate was high even when a small amount of the dissolution aid was used.
  • Examples 36 to 42 were prepared in the composition of Table 9 below.
  • the granules of the examples were prepared by mixing a main component, a dispersant, a dissolution aid, and a polymer, and wet granules from the mixture using water and a solidifying agent.
  • the granules of the comparative example were also prepared by wet granulation using water and a solidifying agent.
  • Tablets were prepared by mixing and tableting magnesium stearate with the granules of Examples 59 to 62, which were used as Examples 63 to 66.
  • the granules of Examples were prepared by mixing a solid component and a mixture of a main component, a dispersing agent, a dissolution aid, a polymer, and a solidifying agent without using a separate bonding liquid by using a high shear mixer having excellent shearing force.
  • Granules of a comparative example were also prepared without using a separate binding solution.
  • Tablets were prepared by mixing magnesium stearate with the granules of Examples 67 to 73 and then tableting the tablets.
  • compositions described in Table 15 were administered orally to 6-8 week old Sprague Dawley rats (250-280 g), and blood was collected 10 times into the orbital vein for 24 h including Initial. Biosamples were analyzed using LC-MS / MS and the relative bioavailability compared to the raw materials was evaluated.
  • the pharmaceutical composition according to the present invention greatly improved the solubility, dissolution rate and bioavailability.

Abstract

L'invention concerne : une composition pharmaceutique contenant un ou plusieurs éléments choisis parmi un bloqueur du récepteur de l'angiotensine (ARB), un isomère de celui-ci, un sel pharmaceutiquement acceptable de celui-ci, ou un promédicament de celui-ci et ayant une biodisponibilité améliorée par l'amélioration de la solubilité et de la vitesse de dissolution de l'ARB; et son procédé de préparation.
PCT/KR2017/004224 2017-04-12 2017-04-20 Composition pharmaceutique contenant un bloqueur du récepteur de l'angiotensine WO2018190451A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201780001612.4A CN109152765A (zh) 2017-04-12 2017-04-20 包含血管紧张素受体拮抗剂的药剂学组合物

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KR1020170047314A KR101920628B1 (ko) 2017-04-12 2017-04-12 안지오텐신 수용체 길항제를 포함하는 약제학적 조성물
KR10-2017-0047314 2017-04-12

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WO2018190451A1 true WO2018190451A1 (fr) 2018-10-18

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Publication number Priority date Publication date Assignee Title
KR102406616B1 (ko) * 2019-12-19 2022-06-10 대원제약주식회사 안지오텐신 수용체 길항제를 포함하는 약제학적 조성물 및 이의 제조방법

Citations (6)

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Publication number Priority date Publication date Assignee Title
KR20090086281A (ko) * 2006-12-05 2009-08-11 노파르티스 아게 발사르탄의 마이크로에멀젼 투여 형태 및 이의 제조 방법
KR20100083047A (ko) * 2009-01-12 2010-07-21 한국유나이티드제약 주식회사 생체이용률이 향상된 발사르탄을 포함하는 약제학적 조성물
KR20110015650A (ko) * 2008-06-03 2011-02-16 노파르티스 아게 발사르탄의 펄스형 방출
KR20110103928A (ko) * 2008-04-29 2011-09-21 한올바이오파마주식회사 안지오텐신-ⅱ-수용체 차단제를 포함하는 약제학적 제제
KR20150053760A (ko) * 2012-09-06 2015-05-18 한국콜마주식회사 발사르탄 함유 고형 경구제형 및 그 제조방법
KR20170020479A (ko) * 2014-06-19 2017-02-22 솔루랄 파마 에이피에스 친유성 화합물의 고형 경구 투여 형태

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20090086281A (ko) * 2006-12-05 2009-08-11 노파르티스 아게 발사르탄의 마이크로에멀젼 투여 형태 및 이의 제조 방법
KR20110103928A (ko) * 2008-04-29 2011-09-21 한올바이오파마주식회사 안지오텐신-ⅱ-수용체 차단제를 포함하는 약제학적 제제
KR20110015650A (ko) * 2008-06-03 2011-02-16 노파르티스 아게 발사르탄의 펄스형 방출
KR20100083047A (ko) * 2009-01-12 2010-07-21 한국유나이티드제약 주식회사 생체이용률이 향상된 발사르탄을 포함하는 약제학적 조성물
KR20150053760A (ko) * 2012-09-06 2015-05-18 한국콜마주식회사 발사르탄 함유 고형 경구제형 및 그 제조방법
KR20170020479A (ko) * 2014-06-19 2017-02-22 솔루랄 파마 에이피에스 친유성 화합물의 고형 경구 투여 형태

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KR101920628B1 (ko) 2018-11-22
KR20180115379A (ko) 2018-10-23
CN109152765A (zh) 2019-01-04

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