KR19990087387A - 미졸라스틴을 함유하는 서방성 약학적 제제물 - Google Patents
미졸라스틴을 함유하는 서방성 약학적 제제물 Download PDFInfo
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- KR19990087387A KR19990087387A KR1019980706802A KR19980706802A KR19990087387A KR 19990087387 A KR19990087387 A KR 19990087387A KR 1019980706802 A KR1019980706802 A KR 1019980706802A KR 19980706802 A KR19980706802 A KR 19980706802A KR 19990087387 A KR19990087387 A KR 19990087387A
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- Prior art keywords
- acid
- sustained
- mizolastine
- release pharmaceutical
- release
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- PVLJETXTTWAYEW-UHFFFAOYSA-N Mizolastine Chemical compound N=1C=CC(=O)NC=1N(C)C(CC1)CCN1C1=NC2=CC=CC=C2N1CC1=CC=C(F)C=C1 PVLJETXTTWAYEW-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 229960001144 mizolastine Drugs 0.000 title claims abstract description 26
- 238000013268 sustained release Methods 0.000 title claims abstract description 12
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 6
- 150000007524 organic acids Chemical class 0.000 claims abstract description 9
- 239000011159 matrix material Substances 0.000 claims abstract description 6
- 239000007939 sustained release tablet Substances 0.000 claims abstract description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 17
- 239000003826 tablet Substances 0.000 claims description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 239000004359 castor oil Substances 0.000 claims description 3
- 235000019438 castor oil Nutrition 0.000 claims description 3
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 239000001361 adipic acid Substances 0.000 claims description 2
- 235000011037 adipic acid Nutrition 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 150000004668 long chain fatty acids Chemical class 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 150000004667 medium chain fatty acids Chemical class 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 235000011044 succinic acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 150000003626 triacylglycerols Chemical class 0.000 claims description 2
- 239000000203 mixture Substances 0.000 description 18
- 238000009472 formulation Methods 0.000 description 16
- 238000004090 dissolution Methods 0.000 description 11
- 239000007903 gelatin capsule Substances 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- -1 behenic acid Chemical class 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000008119 colloidal silica Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 235000021357 Behenic acid Nutrition 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 201000004624 Dermatitis Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000000543 Histamine Receptors Human genes 0.000 description 1
- 108010002059 Histamine Receptors Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 208000028004 allergic respiratory disease Diseases 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 229940116226 behenic acid Drugs 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 206010015907 eye allergy Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 201000004335 respiratory allergy Diseases 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/14—Decongestants or antiallergics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
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- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pulmonology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Immunology (AREA)
- Ophthalmology & Optometry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
미졸라스틴을 함유하고 지방매트릭스 및 유기산과 조합된 미졸라스틴을 포함하는 서방성 정제로 이루어진 코어를 포함하는 것을 특징으로 하고, 상기 정제는 피복되는 서방성 약학적 제제물이 개시된다.
Description
미졸라스틴은 유럽특허 EP 0,217,700에 설명되어있다.
미졸라스틴은 H1히스타민 수용체에 결합되어 생체외 및 생체내 비만세포의 과립감소를 억제한다. 그러므로 미졸라스틴은 호흡기알레르기, 피부알레르기나 눈(眼)알레르기 그리고 여러 가지 알레르기성 발현의 치료를 위해 사용될 수 있다.
미졸라스틴을 함유하는 속효성 제제물의 경구투여동안, 혈장에서 높은 피크의 존재와 관련된 바람직하지 않은 진정효과가 나타났다.
따라서 생물학적 이용율(bioavailability)을 감소시키지않고 혈장에서 낮은 피크를 얻을 수 있도록 유효성분방출의 프로파일을 갖는 경구투여를 위한 제제물을 찾아내는 것이 필요했다.
본 발명은 유효성분으로서 2-[[1-[1-[(4-플루오로페닐)메틸]-1H-벤즈이미다졸-2-일]피페리드-4-일]메틸아미노]-피리미딘-4-올이나 2-[[1-[1-[(4-플루오로페닐)메틸]-1H-벤즈이미다졸-2-일]피페리드-4-일]메틸아미노]-피리미딘-4(1H)-온, 또는 미졸라스틴(mizolastine)을 함유하는 신규의 서방성 약학적 제제물에 관한 것이다.
도 1은 본발명에 따른 제제물로 얻은 용해 프로파일,
도 2는 본발명에 따른 제제물과 동일하나 L-타르타르산을 함유하지 않은 제제물로 얻은 용해 프로파일,
도 3은 본발명의 약학적 제제물의 혈장용해 속도론을 젤라틴 캡슐제와 비교한 것을 도시한다.
본 출원회사는 미졸라스틴의 용해속도론의 연구에 기초하여 그러한 제제물을 연구했다. 그 이유는 미졸라스틴이 물에서는 가용성이 작지만(중성pH에서 13mg/l) 산성pH에서는 더욱 더 가용성(pH 3에서 11g/l)인 약염기(pK 5.6)이기 때문이다; 우선 젤라틴캡슐은 pH 2의 용해매질에서 30분에 걸쳐 미졸라스틴 100%를 방출한 반면에 pH 6.8에서는 단지 40%만이 용해되었다.
더욱이 본 발명에 따른 서방성 약학적 형상물로부터의 미졸라스틴의 방출은 위장관에서 pH의 차이에 영향받을 필요가 없었다.
본 발명의 목적은 용해프로파일이 다음과 같은 미졸라스틴함유 제제물을 제안하는 것이다:
- 1시간이내에 미졸라스틴 약 30 내지 70%가 용해되고,
- 3 내지 5시간이내에 미졸라스틴 100%가 용해되고, 그리고
- pH-비의존적 프로파일.
본 출원회사는 지방매트릭스 및 유기산과 조합된 미졸라스틴을 함유하는 서방성 정제로 형성된 코어를 포함하는 정제를 제시했고, 빛으로 인한 생성물의 분해를 방지하기위해 피복된 상기 정제는 전적으로 적절하다.
본 발명에 따른 정제는 1mg 내지 25mg의 미졸라스틴을 함유한다. 이 투여량은 미졸라스틴 0.5 내지 12중량%의 농도에 대응한다.
지방매트릭스는 수소화 피마자유, 수소화 레시틴, 또는 예를 들어 베헨산같은 C12-C28지방산같은 장쇄지방산, 또는 예를 들어 C8-C18지방산같은 중쇄지방산으로 에스테르화된 트리글리세리드로 만든다.
바람직하게는 2이상의 pK를 갖는 유기산은 라세미화합물 또는 이성질체의 형태로 말레산, 타르타르산, 말산, 푸마르산, 락트산, 시트르산, 아디프산 및 숙신산으로부터 선택된다. 본 발명에 따라 특히 바람직한 산은 L-타르타르산이다.
미졸라스틴과 유기산사이의 중량비는 0.3 내지 1이어야한다. L-타르타르산에 대해 이 비는 바람직하게는 0.5이다.
정제는 유효성분을 사용한 과립화로 제조되고, 이 약제는 지방매트릭스, 유기산 그리고 예를 들어 락토스, 마니톨 및 당 또는 유사 당-알콜, 미정질 셀룰로스, 녹말, 인산칼슘 및 황산칼슘, 폴리비돈(polyvidone), 그리고 히드록시프로필 셀룰로스, 히드록시프로필메틸셀룰로스 또는 메틸셀룰로스같은 치환셀룰로스이다.
과립화는, 예를 들어 물이나 알콜의 존재하에, 습윤상(wet phase)으로 실행할 수 있거나, 또는 융합이나 성형으로 행할 수 있다. 과립화단계는 임의로 제외할 수 있고 정제는 미졸라스틴과 부형제의 혼합물의 직접정제화로 제조된다.
무수 콜로이드성 실리카와 스테아르산마그네슘을 얻어진 과립에 첨가하고 그 혼합물을 정제화했다. 그 다음에 유동공기상(fluidized-air bed)이 있는 기계나 피복 터빈에서 피복액으로 분무함으로써 정제를 피복막으로 덮는다.
하기하는 실시예는 본 발명을 제한하지않고 설명한다:
정제
%(중량)
미졸라스틴 4.8
수소화 피마자유 12.0
락토스 60.0
미정질 셀룰로스 9.6
L-타르타르산 9.6
폴리비돈 2.9
무수 콜로이드성 실리카 0.2
스테아르산마그네슘 0.9
정제수 충분한 양
총계 100.0
피복물
메틸히드록시프로필셀룰로스 74.0
이산화티타늄(E171) 18.5
프로필렌 글리콜 7.5
정제수 충분한 양
총계 100.0
본 발명에 따른 제제물로 얻은 용해프로파일을 도 1에 도시했다.
이 프로파일은 1시간 이내에 약 50% 용해된 생성물, 3 내지 5시간 이내에 약 100% 용해된 생성물을 제시하고, pH에 대해 비의존적이다.
본 발명의 제제물과 동일하나 L-타르타르산을 함유하지 않은 제제물로 얻은 용해프로파일을 도 2에 도시했다.
미졸라스틴 10mg을 함유하는 본발명에 따른 약학적 형상물의 혈장용해속도론을 단독경구투여 후에 건강한 지원자에 대해 연구하고, 미졸라스틴 10mg을 함유하는 표준 속효성 젤라틴캡슐과 비교했다.
표 1은 속도론파라미터를 표시하고 도 3은 혈장용해속도론곡선을 표시하고, 이들은 각각의 제제물로 얻었다; 본 발명에 따른 약학적 형상물로 얻은 혈장용해속도론은 생물학적 이용율을 잃지않고 혈장내의 피크를 방지하는 것을 가능하게 한다.
또한 본 발명에 따른 약학적 형상물의 혈장 용해 속도론을 L-타르타르산이 없는 동일한 제제물과 비교하여 연구했다.
연구는 미졸라스틴 10mg을 함유하는 본 발명에 따른 정제 또는 L-타르타르산이 없는 동일한 정제의 단독 경구투여 후에 12명의 건강한 지원자에 대해 행했다.
표 2는 L-타르타르산을 함유하지 않는 제제물의 생물학적 이용율이 L-타르타르산을 함유하는 본 발명에 따른 제제물로 관측된 생물학적 이용율의 43%만 나타내는 것을 증명한다. Cmax값과 AUC값(0-∞)은 L-타르타르산을 함유하는 제제물이 전혀 함유하지 않는 것보다 각각 1.5 및 2배이다.
게다가 L-타르타르산이 있는 제제물에 대해 최소-최대 변화지수가 훨씬 낮고, 이것은 방출에서 균일성이 큰 것을 암시한다.
| 제제물 | Tmax(h) | Cmax(ng/ml) | t1/2β(h) | AUC(0-∞)(ng.ml-1.h) | Frel |
| 젤라틴캡슐최소-최대 | 0.9 | 398.4±22.7 | 14.8±1.5 | 1481±96 | |
| 0.5-1.5 | 202-529 | 6.7±33.1 | 1092-2717 | ||
| 정제최소-최대 | 1.4 | 234.2±13.7 | 14.5±1.2 | 1406.1±119 | 0.962 |
| 0.5-2.5 | 154-393 | 6.7-26.4 | 775-2458 | ||
| 통계학상의 비교 | NS | p<0.001 | NS | NS |
| 제제물 | Tmax(h) | Cmax(ng/ml) | t1/2β(h) | AUC(0-∞)(ng.ml-1.h) | AUC(0-∞)(ng.ml-1.h) | Frel |
| L-타르타르산함유최소-최대 | 1.00 | 243.7±12.7 | 13.1±1.2 | 1327±117 | 1444±125 | |
| 0.75-2.5 | 166.5-314.1 | 5.9±19.4 | 734-1878 | 773-2011 | ||
| L-타르타르산함유최소-최대 | 0.75 | 147.0±28.8 | 12.9±1.1 | 601±134 | 635±139 | 0.43±0.08 |
| 0.5-2.5 | 4.5-285.4 | 5.1-17.6 | 27-1347 | 38-1397 | 0.03-0.87 | |
| 통계학상의 비교 | NS | p<0.05 | NS | p<0.01 | p<0.01 |
결과 전체로서 본 발명에 따른 제제물이 다음 특성을 가지는 것을 증명한다:
- pH-비의존적 용해프로파일,
- 혈장에서 높은 피크를 방지하는 생체내 방출,
- 속효성 제제물에 비해 감소되지 않은 생물학적 이용율,
- 혈장 용해 속도론결과의 낮은 변화성.
Claims (7)
- 미졸라스틴을 함유하는 서방성 약학적 제제물에 있어서, 지방매트릭스 및 유기산과 조합된 미졸라스틴을 함유하는 서방성 정제로 형성된 코어를 포함하고, 상기 정제는 피복되는 것을 특징으로 하는 서방성 약학적 제제물.
- 제 1 항에 있어서, 미졸라스틴과 유기산 사이의 중량비는 0.3 내지 1인 것을 특징으로 하는 서방성 약학적 제제물.
- 제 1 항 또는 제 2 항에 있어서, 지방매트릭스는 수소화 피마자유, 수소화 레시틴, 장쇄 지방산, 또는 중쇄 지방산으로 에스테르화된 트리글리세리드로 제조되는 것을 특징으로 하는 서방성 약학적 제제물.
- 제 1 항 내지 제 3 항중 어느 한 항에 있어서, 유기산은 라세미화합물 또는 이성질체의 형태로 말레산, 타르타르산, 말산, 푸마르산, 락트산, 시트르산, 아디프산 및 숙신산으로부터 선택되는 것을 특징으로 하는 서방성 약학적 제제물.
- 제 1 항 내지 제 4 항중 어느 한 항에 있어서, 유기산은 L-타르타르산인 것을 특징으로 하는 서방성 약학적 제제물.
- 제 5 항에 있어서, 미졸라스틴과 L-타르타르산 사이의 비는 0.5인 것을 특징으로 하는 서방성 약학적 제제물.
- 제 1 항 내지 제 6 항중 어느 한 항에 있어서, 미졸라스틴 1 내지 25mg을 함유하는 것을 특징으로 하는 서방성 약학적 제제물.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9602662A FR2745500B1 (fr) | 1996-03-04 | 1996-03-04 | Formulations pharmaceutiques a liberation prolongee contenant de la mizolastine |
| FR96/2662 | 1996-03-04 |
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| KR19990087387A true KR19990087387A (ko) | 1999-12-27 |
| KR100369888B1 KR100369888B1 (ko) | 2003-05-17 |
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| KR10-1998-0706802A Expired - Lifetime KR100369888B1 (ko) | 1996-03-04 | 1997-02-28 | 미졸라스틴을함유하는서방성약학적제제물 |
Country Status (34)
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| US (2) | US6165507A (ko) |
| EP (1) | EP0906101B1 (ko) |
| JP (2) | JP2000512617A (ko) |
| KR (1) | KR100369888B1 (ko) |
| CN (1) | CN1112929C (ko) |
| AR (1) | AR006082A1 (ko) |
| AT (1) | ATE219365T1 (ko) |
| AU (1) | AU725494B2 (ko) |
| BG (1) | BG63451B1 (ko) |
| BR (1) | BR9707827A (ko) |
| CA (1) | CA2247405C (ko) |
| CO (1) | CO4780020A1 (ko) |
| CY (1) | CY2293B1 (ko) |
| CZ (1) | CZ291418B6 (ko) |
| DE (1) | DE69713505T2 (ko) |
| DK (1) | DK0906101T3 (ko) |
| EE (1) | EE03511B1 (ko) |
| ES (1) | ES2177942T3 (ko) |
| FR (1) | FR2745500B1 (ko) |
| HU (1) | HU227472B1 (ko) |
| IL (1) | IL126050A (ko) |
| IN (1) | IN187739B (ko) |
| NO (1) | NO315841B1 (ko) |
| NZ (1) | NZ331947A (ko) |
| OA (1) | OA10854A (ko) |
| PL (1) | PL189813B1 (ko) |
| PT (1) | PT906101E (ko) |
| RU (1) | RU2173997C2 (ko) |
| SK (1) | SK282112B6 (ko) |
| TR (1) | TR199801574T2 (ko) |
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| UA (1) | UA49004C2 (ko) |
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Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH10101564A (ja) * | 1996-09-27 | 1998-04-21 | Mitsubishi Chem Corp | 鼻炎予防及び／又は治療剤 |
| JP2002087960A (ja) * | 2000-07-14 | 2002-03-27 | Toyama Chem Co Ltd | 徐放性錠剤 |
| DK1322158T3 (da) * | 2000-10-02 | 2012-11-19 | Usv Ltd | Farmaceutiske præparater med langvarig frigivelse, som indeholder metformin, og fremgangsmåde til fremstilling deraf |
| US7052706B2 (en) | 2001-06-08 | 2006-05-30 | Nostrum Pharmaceuticals, Inc. | Control release formulation containing a hydrophobic material as the sustained release agent |
| US20030181488A1 (en) | 2002-03-07 | 2003-09-25 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof |
| EP1599189A4 (en) * | 2003-03-04 | 2009-07-01 | Nostrum Pharmaceuticals Inc | FORMULATION WITH CONTROLLED RELEASE AND WITH WATER-REPELLENT MATERIAL AS A MEANS FOR DELAYED RELEASE |
| DE10337697A1 (de) * | 2003-08-16 | 2005-03-24 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Tablette enthaltend 3-[(2-{[4-(Hexyloxycarbonylamino-imino-methyl)-phenyl-amino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionsäure-ethylester oder dessen Salze |
| GEP20146166B (en) | 2008-07-28 | 2014-09-25 | Takeda Pharmaceuticals Co | Pharmaceutical composition |
| JP5744412B2 (ja) * | 2010-03-26 | 2015-07-08 | テバ製薬株式会社 | フロセミド製剤 |
| US20140179712A1 (en) | 2012-12-21 | 2014-06-26 | Astrazeneca Ab | Pharmaceutical formulation of n-[5-[2-(3,5-dimethoxyphenyl)ethyl]-2h-pyrazol-3-yl]-4-[(3r,5s)-3,5-dimethylpiperazin-1-yl]benzamide |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4364945A (en) * | 1979-12-13 | 1982-12-21 | Whittle Barry J | Nasal composition for relieving nasal distress |
| US4421736A (en) * | 1982-05-20 | 1983-12-20 | Merrel Dow Pharmaceuticals Inc. | Sustained release diethylpropion compositions |
| US4590062A (en) * | 1984-04-16 | 1986-05-20 | Tech Trade Corp. | Dry direct compression compositions for controlled release dosage forms |
| FR2587029B1 (fr) * | 1985-09-11 | 1987-10-30 | Synthelabo | Derives de benzimidazole, leur preparation et leur application en therapeutique |
| JPH0776172B2 (ja) * | 1986-04-16 | 1995-08-16 | 藤沢薬品工業株式会社 | マトリツクス錠 |
| JPS62283926A (ja) * | 1986-06-02 | 1987-12-09 | Nippon Chemiphar Co Ltd | 塩酸ニカルジピン持続性組成物 |
| EP0269383A3 (en) * | 1986-11-21 | 1990-05-02 | A.H. Robins Company, Incorporated | 1-Aryloxy-4-[(4-aryl)-1-piperazinyl]-2-butanols useful as antiallergy agents |
| DE3812799A1 (de) * | 1988-04-16 | 1989-10-26 | Sanol Arznei Schwarz Gmbh | Oral zu verabreichende pharmazeutische zubereitung mit kontrollierter wirkstofffreisetzung und verfahren zu deren herstellung |
| JP3195391B2 (ja) * | 1991-11-14 | 2001-08-06 | エスエス製薬株式会社 | 徐放性トラピジル錠 |
| RU2015975C1 (ru) * | 1992-02-13 | 1994-07-15 | Пятигорский фармацевтический институт | Производные 4-оксо-1,4-дигидропиримидина, обладающие антиаллергической и иммунотропной активностью |
| US5686105A (en) * | 1993-10-19 | 1997-11-11 | The Procter & Gamble Company | Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery |
| IT1264696B1 (it) * | 1993-07-09 | 1996-10-04 | Applied Pharma Res | Forme farmaceutiche destinate alla somministrazione orale in grado di rilasciare sostanze attive a velocita' controllata e differenziata |
| JPH07112932A (ja) * | 1993-08-27 | 1995-05-02 | Mitsui Toatsu Chem Inc | 徐放性医薬製剤 |
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1996
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1997
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1998
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- 1998-09-02 NO NO19984035A patent/NO315841B1/no not_active IP Right Cessation
- 1998-09-04 OA OA9800160A patent/OA10854A/fr unknown
- 1998-09-18 NZ NZ331947A patent/NZ331947A/xx not_active IP Right Cessation
-
2002
- 2002-08-26 CY CY0200052A patent/CY2293B1/xx unknown
-
2005
- 2005-01-03 US US11/027,680 patent/US20050202089A1/en not_active Abandoned
-
2007
- 2007-03-05 JP JP2007054262A patent/JP2007182451A/ja active Pending
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