TW503115B - New stabilized galenic formulations comprising an acid labile benzimidazole compound and its preparation - Google Patents
New stabilized galenic formulations comprising an acid labile benzimidazole compound and its preparation Download PDFInfo
- Publication number
- TW503115B TW503115B TW085100946A TW85100946A TW503115B TW 503115 B TW503115 B TW 503115B TW 085100946 A TW085100946 A TW 085100946A TW 85100946 A TW85100946 A TW 85100946A TW 503115 B TW503115 B TW 503115B
- Authority
- TW
- Taiwan
- Prior art keywords
- inert
- drug
- acid
- soluble polymer
- core
- Prior art date
Links
- -1 benzimidazole compound Chemical class 0.000 title claims abstract description 16
- 239000002253 acid Substances 0.000 title claims abstract description 10
- 239000000203 mixture Substances 0.000 title claims description 9
- 238000009472 formulation Methods 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title description 9
- 239000002702 enteric coating Substances 0.000 claims abstract description 16
- 238000009505 enteric coating Methods 0.000 claims abstract description 16
- 229920003169 water-soluble polymer Polymers 0.000 claims abstract description 10
- 239000004014 plasticizer Substances 0.000 claims abstract description 5
- 229920000642 polymer Polymers 0.000 claims abstract description 4
- 239000010410 layer Substances 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 16
- 239000003814 drug Substances 0.000 claims description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- 239000002671 adjuvant Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 230000002079 cooperative effect Effects 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 6
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 6
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 6
- 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 claims description 6
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 5
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 5
- 239000001069 triethyl citrate Substances 0.000 claims description 5
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 5
- 235000013769 triethyl citrate Nutrition 0.000 claims description 5
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 239000011248 coating agent Substances 0.000 claims description 4
- 238000000576 coating method Methods 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- BHIWKHZACMWKOJ-UHFFFAOYSA-N methyl isobutyrate Chemical compound COC(=O)C(C)C BHIWKHZACMWKOJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 2
- WDAXFOBOLVPGLV-UHFFFAOYSA-N isobutyric acid ethyl ester Natural products CCOC(=O)C(C)C WDAXFOBOLVPGLV-UHFFFAOYSA-N 0.000 claims description 2
- 229940126701 oral medication Drugs 0.000 claims 4
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 claims 1
- 239000003513 alkali Substances 0.000 claims 1
- 229940049706 benzodiazepine Drugs 0.000 claims 1
- 239000011247 coating layer Substances 0.000 claims 1
- 238000013329 compounding Methods 0.000 claims 1
- 239000013583 drug formulation Substances 0.000 claims 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
- 229940088594 vitamin Drugs 0.000 claims 1
- 229930003231 vitamin Natural products 0.000 claims 1
- 235000013343 vitamin Nutrition 0.000 claims 1
- 239000011782 vitamin Substances 0.000 claims 1
- 239000000454 talc Substances 0.000 abstract description 11
- 229910052623 talc Inorganic materials 0.000 abstract description 11
- 238000002955 isolation Methods 0.000 abstract 1
- 239000008203 oral pharmaceutical composition Substances 0.000 abstract 1
- 239000000049 pigment Substances 0.000 abstract 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 25
- 229960000381 omeprazole Drugs 0.000 description 13
- 229940089505 prilosec Drugs 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000006185 dispersion Substances 0.000 description 7
- 239000000835 fiber Substances 0.000 description 7
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 239000011521 glass Substances 0.000 description 5
- 239000008188 pellet Substances 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 3
- 230000004888 barrier function Effects 0.000 description 3
- HFACYLZERDEVSX-UHFFFAOYSA-N benzidine Chemical compound C1=CC(N)=CC=C1C1=CC=C(N)C=C1 HFACYLZERDEVSX-UHFFFAOYSA-N 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 239000000123 paper Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000004408 titanium dioxide Substances 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000002845 discoloration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010062532 Erosive duodenitis Diseases 0.000 description 1
- 206010063655 Erosive oesophagitis Diseases 0.000 description 1
- 206010017865 Gastritis erosive Diseases 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 201000008629 Zollinger-Ellison syndrome Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 150000003868 ammonium compounds Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229920001688 coating polymer Polymers 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 208000029493 gastroesophageal disease Diseases 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 150000007857 hydrazones Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940127554 medical product Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- DYIZHKNUQPHNJY-UHFFFAOYSA-N oxorhenium Chemical compound [Re]=O DYIZHKNUQPHNJY-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000000590 phytopharmaceutical Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229910003449 rhenium oxide Inorganic materials 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
五 、發明説明（ A7 B7 卜 本發明為含化學式 I 之 2[(2-pyridyl)methylsulphinyl]- 苯引木ΦΤ生物（以下稱苯引朵化合物）之新且穩定的口 服用藥。 ^3
10 15 20 經濟部中央標準局員工消費合作社印繁 化，式1中R1為氫、甲氧或二聚氟甲氧，r2為甲 3甲氧基’ 為甲氧基、2,2,2，·三氟乙氧基或3-甲氧 基丙氧基、R4為氫或或甲基。 本發明也包括製造該藥之方法及治療腸胃疾病之方 法.。 上述笨朵化合物對治療胃及十二指腸糜爛、胃食管 ’危病、食管糜爛、Zollinger-Ellison症候群及Η幽 ^根除都很有效。但是這些化合物的穩定性卻不隹。在固 狀毖時，它們很容易受到熱、潮濕、光線的影響。在水 洛液或懸膠體狀態時其穩定性會隨酸鹼值的降低而降低。 這些化合物的退化是由酸性反應化合物所催化。 含不耐酸化合物的藥劑必須包覆起來以免有效成份與 外面腸溶衣發生反應而導致有效成份的退化、不穩定及持 續褪色。 使用一阻礙層來防止藥劑因腸溶衣而造成退化為已知 之技術。然而以傳統方法使用傳統腸溶衣在不耐酸之苯引 本紙張尺度適财_(CNS)M規格(训幻97公瘦） (請先閱讀背面之注意事項再填寫本頁) i. 訂 503115 A7 B7_ 五、發明説明（） ^ 朵化合物上則不可行，因為有效成份會隨著時間而分解、 褪色、流失。已知技術將如US 4,786,505，US 5,232,706， EP237200, EP124495, US 5,385,739, EP519144 所敘述將 苯引朵化合物之驗鹽或驗反應化合物（氧化鍰、氫氧化物 5 或碳酸鹽、氫氧化鋁、鋁、鈣、鈉或碳酸鉀、磷酸鹽、棒 檬酸鹽、併合銘/鍰化合物、月桂基硫酸钟、氨基酸、 甲基-D-Ghxcamine等）加入腸溶衣製劑而部份解決了上述 穩定性問題，此驗反應化合物與苯引朵:化合物一起出現在 核體表面或裏面。一些發明者也使用驗反應化合物來構成 10 —第二隔離層以確保製劑的穩定性。值得注意的是在us 專利4,786,505號例一的表一中舉例說明了 一種沒有該種 鹼性化合物的製劑，在表三中我們可以看出此製劑的穩定 性較差。因此鹼性物質與苯引朵化合物之中性形態結合可 增進此有效化合物，尤其是固體時之穩定性。使用腸溶衣 15 也可改善穩定性。意即根據目前科技水準，在醫藥製劑中 加入鹼性物質對藥品長期儲存之穩定性來說是必須的。 根據本發明可得到化學式I之含苯引朵化合物之高穩 定性固體製劑。此種新植物製藥並不含鹼性反應化合物； 因此本發明之腸溶衣配方中並無鹼性反應化合物。令人驚 20 喜的是所獲得之新製劑的長期儲存穩定性已大幅提高，要 比現有已知的製劑高得很多，避免褪色及純度流失，因此 更適合用在醫藥上。 新配方特別地方在一個惰性糖/澱粉球狀核心，含化 學式I之苯引朵化合物混合物作為有效成份、水溶性惰性 -4- 本紙張尺度適用中國國家標準(CNS ) A4規格（210X297公釐) ' '" (請先閱讀背面之注意事項再填寫本頁) 1T- 經濟部中央標準局員工消費合作社印製 503115 A7 B7 五、發明説明（） 聚合體以及非鹼性反應藥品可接受辅藥的第一層塗在其 上，第二層隔離層由水溶性聚合體以及相容輔藥所組成。 最後一層則為腸溶衣。核心、處理條件及輔藥都經過選擇 以獲得各塗層所要求之覆蓋效率。 5 所製造出之新製劑不會在酸性之胃液中分解，而會在 中至鹼性情況下的小腸近端快速分解。以美國藥典所載方 法測試此製劑之抗酸性我們可以發現，經過2小時後苯 引朵仍完好無缺，只要將酸鹼值改變至6.8 ，30分鐘後 所有苯引朵物質都完全分解。 10 在流化床儀器中均勻的球狀惰性核體（根據美國藥典 組成）第一層被塗上含一層不耐酸的苯引朵化合物及一惰 性水溶性聚合體，例如羥基丙基甲基纖維素或羥基丙基纖 維素以及滑石。 第二層則為由一水溶性聚合體如羥基丙基甲基纖維素 15 或羥基丙基讖維素、滑石及一染料如二氧化鈦所組成。第 三及腸溶衣層由腸溶衣聚合體如共聚合異丁晞酸/異丁埽 酸甲基酯、一增塑劑如檸檬酸三乙酯或相似增塑劑、以及 滑石所組成。 經濟部中央標準局員工消費合作社印製 (請先閲讀背面之注意事項再填寫本頁) 塗抹物質使用水溶液或水分散系以傳統的流化床塗層 20 技術來進行。 可根據市面上之相對製劑服用同樣劑量的有效成份。 口服時最好服用含小粒之膠囊或壓縮成錠劑使用。 苯引朵的劑量為lmg至100mg/kg/天，根據醫師指 示可依病人不同的需求而調整。 -5- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 503115 A7 B7 五、發明説明（） 謹詳述本發明於下列例證中： 例一： 在3440克消除電離水中，436克的Omeprazole ( I; R! =OCH3，R2 =CH3，R3 =-OCH3，R4 =CH3 )、444 克的羥 5 基丙基甲基纖維素及118克的滑石被分散。 3010克的惰性均勻糖/澱粉球體（根據美國藥典組成）被 導入一流化床儀器，而先前所得的分散系被喷在這些球 體。噴完後，在塗第二層前球體須先乾燥。 在2365克的消除電離水中，355克的羥基丙基甲基 10 纖維素、43克的滑石及43克的二氧化鈦被分散，所得的 水分散系被噴在前一步驟所得的球體上。喷完後，在塗上 第三腸溶衣層前，球體須先乾燥。 在1890克的消除電離水中，1950克的異丁晞酸共聚 物（美國藥典C型水分散系）、98克的檸檬酸三乙酯及 15 98克的滑石被分散，所得之水分散系被噴在前一步驟所 得之球體上。在塗上最後之腸溶衣層後，球體（小丸）乾 燥了。 經濟部中央標準局員工消費合作社印繁 (請先閲讀背面之注意事項再填寫本頁) 所得到之小丸被儲存於一密封的聚乙晞袋中。這個袋 子則被放在一密封厚紙板纖維容器及密封之玻璃容器，再 20 進行所謂的加速情況，也就是40C及75%的相對濕度。 在此同時由從Prilosec® capsules(Merck/Astra註冊商標）所 得之小藥丸也同時進行同樣狀況。加速狀況試驗結果可在 表1，2,3中看到。很明顯的，它們的穩定性要比市面上的 產品好很多。 -6- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 503115 A7 B7 五、發明説明（) 表1 小藥丸之顏色 小藥丸容器（I)-纖維 開始 A 一個月 A 三個月 D J 小藥丸容器（I)-玻璃 A A B Prilosec®容器-纖維 A C F Prilosec®-玻璃 A A E 10 (讀先閱讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印製 A:白色B:粉紅白色C:暗棕色D:淡棕色E:棕色F:深棕色 表2 OMEPRAZOLE 純度1 2 15 開始 一個月 三個月 小藥丸容器（I)-纖維 99.5% 98.8% 52% 小藥丸容器（I)-玻璃 99.5% 98.7% 97.9%
Prilosec®容器-纖維 96.1% 85.2% 1% 1
Prilosec®-玻璃 96.1% 96.2% 1% 2 如HPLC分析，在1992年六月第四期之Pharmaeuropa 中有敘述。以直接區域百分比表示 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 503115 A7 B7 五、發明説明（） 表3 US分解試驗後OMEPRAZOLE恢復情形 一個月 三個月 小藥丸容器（I)-纖維 96.8% 9,2% 5 -^— 小藥丸容器（I)·玻璃 99.9% 73.8%
Prilosec⑧容器-纖維 21.3% «1%
Prilosec® •玻璃 . 84.5% «1% 10 例二： 在580克消除電離水中，75克的LansoprazoledRi =H， R2=CH3，R3 =2,2,2-三氟乙氧基 R4 =H)、70克的羥基 丙基甲基纖維素及18.5克的滑石被分散。 490克惰性均勻糖/澱粉球體被放在一流化床儀器， 15 前面所得之.分散系被喷在這些球體上。第二層與第三層腸 溶衣的處理過程與方法與例——樣。這兩種分散系的成份 如下： 第二層：350克的消除電離水、52克的羥基丙基甲 基纖維素、7克的滑石及7克的二氧化鈦。 經濟部中央標準局員工消費合作社印f (請先閱讀背面之注意事項再填寫本頁) 20 腸溶衣層：280克消除電離水、290克USP異丁烯 酸共聚物（C型水懸浮體）、13克擰檬酸三乙酯及13克的 滑石。 所得之小藥丸相當穩定，各種情況與例一所得之小藥 丸相似。 -8- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 503115 A7 B7 五、發明説明（） 生物製藥研究 (請先閱讀背面之注意事項再填寫本頁) 此研究之目的為調查此新發展之Omeprazole配方與 標準膠囊配方（Prilosec⑧；20mg)比較下其生物有效性及藥 效如何。 5 硬明膠膠囊内裝滿之Omeprazole處於植物製藥狀 態，根據例一，大約有20mg的Omeprazole。 此實驗為在24位健康的男女身上進行一個單一中 心、公開標籤、隨機雙向交換的研究。 受實驗者在接受治療前一天晚上八點向醫療單位報 10 到，直到服藥12小時後才離開醫院。受實驗者在接受劑 量前吃了份標準晚餐。 受實驗者在服藥同時亦喝入200ml的自來水。在服 藥前至少都已禁食超過10小時。 血漿中Omeprazole的濃度由有效之高壓液體層析法及紫 15 外線偵測來分析。（内部報告No. CPR 95-742 )。表為 血漿内Omeprazole濃度的平均值。 經濟部中央標準局員工消費合作社印繁 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 503115 A7 B7 五、發明説明（） 表4 下表為口服20mg之Omeprazole新配方膠囊與Prilosec®後 血漿濃度平均值(ng/ml) 時間（時） 新配方 Prilosec® 基準線 0.0 0.0 0.5 16.4 6.3 10 1.0 103.7 105.4 1.5 161.8 191.9 2.0 192.0 210.1 2.5 165.4 168.4 3.0 132.7 119.8 15 3.5 103.8 87.6 4.0 81.4 63.5 5.0 39.7 47.2 6.0 14.9 22.0 7.0 8.1 9.5 20 8.0 5.4 5.7 12.0 0.0 2.3 (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部中央標準局員工消費合作社印f -10-本紙張尺度適用中國國家標準（CNS ) A4規格（210X 297公釐） 503115
A B 經濟部中央標準局員工消費合作社印製 五、發明説明（）
Omeprazole的藥效結果與文獻中的結果比車交 (WildeMI，Mctavish Omeprazole在與酸相關疾病的藥理及 治療使用上的更新。Drugsl994, 48: 91-132)。在分別口服 入新配方及Prilosec®之後，Omeprazole半衰期之算術平 5 均數（SD)分別為0.9(0.4)以及1.1(0.7)小時。在服用新配 方及Prilosec後，Omeprazole之Tmax算術平均值分別為 2.3 (1.0)及2.0(1.1)小時。最大血漿濃度Cmax之等比中項 對應值為249(197)及241(174)ng/ml。而AUC所得之值則 分別為 434(440)及 486(436)ng h/m卜 10 Cmax與AUC的等比中項比率為1·03。這些比率的兩 邊90%信賴區間在0.80-1.25區間内。根據CPMP對生 物等量研究的指南，配方間的生物等量是（新配方與 Prilosec® )可被接受的。（參考資料：CPMP醫療產品功效 研究1991。 15 生物有效性與生物等量研究；Schulz HU，Steinijans VW。努力求取生物等量評估標準：回顧：夂⑶!!· Pharmacol.Ther. Toxicol. 1992,30) 因此根據本發明來調配Omeprazole膠囊即可獲得含 有相同數量細微有效化合物以及與Prilosec®具相同生物有 20 效性的配方。 -11- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） (請先閱讀背面之注意事項再填寫本頁)
Claims (1)
- 503115 A8 B8 C8 D8 六、申請專利範圍 1· 一種含化學式I中不耐酸苯引朵化合物的穩定口服 藥配方，經濟部智慧財產局員工消費合作社印製 10其中R!為氫、甲氧基或三氟甲氧基，R2為甲基或甲氧 基，R3為甲氧基、2,2,2，-三氟乙氧基或3-甲氧基丙氧基， 心為氫或甲基，其中包含有 (a) —核體由一惰性核心、不耐酸的苯引朵、惰性水 溶性聚合體及非鹼牲反應藥物可接受輔藥所組成； 15 0) —惰性層佈置於該核體上，係由一水溶性聚合體 及其它藥物可接受輔藥所組成； (c) 一外層佈置於該惰性層上，含有腸溶衣。 2·依據申請專利範園第1項所述之一種口服藥配方， 其中水溶性聚合體包含羥基丙基甲基纖維素或羥基丙基纖 20 維素。 3·依據申請專利範圍第1項所述之一種口服藥配方， 其中腸溶衣包含抗胃酸聚合體如共聚異丁婦酸/異丁婦酸 甲酯、一增塑劑如檸檬酸三乙酯、以及藥物可接受辅藥。 4.一含有化學式I中不耐酸苯引朵化合物作為有效成 25 份之穩定口服藥的調配過程，包括：調配一核體，由一惰 -12- ------------ (請先閱讀背面之注意事項再填寫本頁) 訂·- ·1· 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 503115 A8 B8 C8 D8 六、申請專利範圍 性核心及包覆層所構成，該包覆層包含不耐酸苯引朵、含 羥基丙基甲基纖維素或羥基丙基纖維素的惰性水溶性聚合 體及非鹼性反應藥物可接受輔藥；塗佈一惰性層於該核體 上，該惰性層包含含有羥基丙基甲基纖維素或羥基丙基纖 5 維素之惰性水溶性聚合體及其它藥物可接受輔藥；最後塗 佈一層腸溶衣於前一惰性層上，該腸溶衣包含含有抗胃酸 聚合體如共聚異丁晞酸/異丁烯酸甲基酯、增塑劑如擰檬 酸三乙酯及藥物可接受輔藥。 5.依據申請專利範圍第1項所述之一種口服藥配方， 10 係為一種植物配方之膠囊或藥片。 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -13- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）
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| SE9500478D0 (sv) * | 1995-02-09 | 1995-02-09 | Astra Ab | New pharmaceutical formulation and process |
| DE69631981T2 (de) * | 1995-09-21 | 2005-04-14 | Pharma Pass Ii Llc, Irvine | Lansoprazolhaltige Arzneizusammensetzung und Herstellungsverfahren |
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-
1995
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- 1995-04-27 US US08/429,689 patent/US5626875A/en not_active Expired - Lifetime
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- 1996-01-04 IL IL11667396A patent/IL116673A/xx not_active IP Right Cessation
- 1996-01-17 AR AR10105196A patent/AR002702A1/es not_active Application Discontinuation
- 1996-01-22 IN IN104CA1996 patent/IN186596B/en unknown
- 1996-01-26 PT PT96901349T patent/PT773025E/pt unknown
- 1996-01-26 HU HU9603014A patent/HU229219B1/hu not_active IP Right Cessation
- 1996-01-26 EP EP99116334A patent/EP0993830B1/en not_active Revoked
- 1996-01-26 PT PT99116334T patent/PT993830E/pt unknown
- 1996-01-26 DK DK96901349T patent/DK0773025T3/da active
- 1996-01-26 AU AU45403/96A patent/AU4540396A/en not_active Abandoned
- 1996-01-26 SI SI9630226T patent/SI0773025T1/xx unknown
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- 1996-01-26 WO PCT/ES1996/000013 patent/WO1996023500A1/es not_active Ceased
- 1996-01-26 SI SI9630710T patent/SI0993830T1/xx unknown
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- 1996-01-26 AT AT99116334T patent/ATE292967T1/de not_active IP Right Cessation
- 1996-01-26 DK DK99116334T patent/DK0993830T3/da active
- 1996-01-26 TW TW085100946A patent/TW503115B/zh not_active IP Right Cessation
- 1996-01-26 ES ES99116334T patent/ES2238796T3/es not_active Expired - Lifetime
- 1996-01-26 KR KR1019960704702A patent/KR100331290B1/ko not_active Expired - Fee Related
- 1996-01-26 AT AT96901349T patent/ATE193649T1/de not_active IP Right Cessation
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