KR20180101307A - An oral sustained-release tablet comprising tianeptine or pharmaceutically acceptable salts thereof - Google Patents
An oral sustained-release tablet comprising tianeptine or pharmaceutically acceptable salts thereof Download PDFInfo
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- KR20180101307A KR20180101307A KR1020180105295A KR20180105295A KR20180101307A KR 20180101307 A KR20180101307 A KR 20180101307A KR 1020180105295 A KR1020180105295 A KR 1020180105295A KR 20180105295 A KR20180105295 A KR 20180105295A KR 20180101307 A KR20180101307 A KR 20180101307A
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- South Korea
- Prior art keywords
- sustained
- release
- tablet
- layer
- sodium
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Links
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 30
- 150000003839 salts Chemical class 0.000 title claims abstract description 5
- JICJBGPOMZQUBB-UHFFFAOYSA-N 7-[(3-chloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2]thiazepin-11-yl)amino]heptanoic acid Chemical compound O=S1(=O)N(C)C2=CC=CC=C2C(NCCCCCCC(O)=O)C2=CC=C(Cl)C=C21 JICJBGPOMZQUBB-UHFFFAOYSA-N 0.000 title description 13
- 229960005138 tianeptine Drugs 0.000 title description 13
- 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 claims abstract description 24
- 239000011734 sodium Substances 0.000 claims abstract description 24
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 24
- 238000013268 sustained release Methods 0.000 claims description 97
- 239000012730 sustained-release form Substances 0.000 claims description 97
- 239000010410 layer Substances 0.000 claims description 96
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- 239000003814 drug Substances 0.000 claims description 81
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- 238000004090 dissolution Methods 0.000 claims description 22
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- 239000000203 mixture Substances 0.000 claims description 22
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 21
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 17
- 239000012792 core layer Substances 0.000 claims description 16
- 238000012360 testing method Methods 0.000 claims description 13
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- 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
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- 239000004480 active ingredient Substances 0.000 claims 1
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 38
- 235000019359 magnesium stearate Nutrition 0.000 description 19
- 230000006399 behavior Effects 0.000 description 15
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- ZLBSUOGMZDXYKE-UHFFFAOYSA-M sodium;7-[(3-chloro-6-methyl-5,5-dioxo-11h-benzo[c][2,1]benzothiazepin-11-yl)amino]heptanoate Chemical compound [Na+].O=S1(=O)N(C)C2=CC=CC=C2C(NCCCCCCC([O-])=O)C2=CC=C(Cl)C=C21 ZLBSUOGMZDXYKE-UHFFFAOYSA-M 0.000 description 12
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000001103 potassium chloride Substances 0.000 description 6
- 235000011164 potassium chloride Nutrition 0.000 description 6
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
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- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 4
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 4
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- 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 3
- 229930195725 Mannitol Natural products 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
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- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000002356 single layer Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 229920003169 water-soluble polymer Polymers 0.000 description 3
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 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
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
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- 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
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
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- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
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- 230000036772 blood pressure Effects 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 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
- 150000001720 carbohydrates Chemical class 0.000 description 1
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- RKTYLMNFRDHKIL-UHFFFAOYSA-N copper;5,10,15,20-tetraphenylporphyrin-22,24-diide Chemical compound [Cu+2].C1=CC(C(=C2C=CC([N-]2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3[N-]2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 RKTYLMNFRDHKIL-UHFFFAOYSA-N 0.000 description 1
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- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
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- 229940057948 magnesium stearate Drugs 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
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- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
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- 239000005720 sucrose Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
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- 231100000419 toxicity Toxicity 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
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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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
-
- 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
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Medicinal Preparation (AREA)
Abstract
본 발명은 티아넵틴 및 이의 약제학적으로 허용되는 염을 포함하는 경구투여용 서방성 정제에 관한 것으로, 보다 상세하게는 티아넵틴 나트륨을 1일 1회 복용하도록 하기 위한 서방성 정제에 관한 것이다.The present invention relates to a sustained-release tablet for oral administration comprising tianeptin and a pharmaceutically acceptable salt thereof, and more particularly to a sustained-release tablet for taking tianaptin sodium once a day.
Description
본 발명은 티아넵틴 또는 이의 약제학적으로 허용되는 염을 포함하는 서방성 정제에 관한 것으로, 보다 상세하게는 주성분인 티아넵틴 나트륨(이하 티아넵틴이라 한다)37.5mg을 1일 1회 복용하기 위해 제조되는 서방성 정제에 관한 것이다. The present invention relates to a sustained-release tablet containing tianaptin or a pharmaceutically acceptable salt thereof, and more particularly, to a tablet containing 37.5 mg of thiacenepine sodium (hereinafter referred to as " tianepentin " ≪ / RTI >
대한민국 등록특허 10-0464180호에서는 티아넵틴에 다양한 부가염의 합성 방법에 관한 내용을 공개하고 있다.Korean Patent Registration No. 10-0464180 discloses a method for synthesizing various addition salts to tianaptin.
미국 등록특허 5,888,542호에서는 티아넵틴을 1일 1회 복용하기 위한 서방성 매트릭스 정제에 관한 것으로 1일 1회 가능 복용량을 12.5mg에서 50mg범위라고 공개하고 있으며 1일 1회 복용양을 50mg로 한 서방성 정제를 개시하고 있다. U.S. Patent No. 5,888,542 discloses a sustained-release matrix tablet for once-a-day dosing of tianeptine, which discloses that the dose can be administered once a day from 12.5 mg to 50 mg, and has a dose of 50 mg per day Sexual < / RTI >
British Journal of Psychiatry (1992), 160, 66-71에서는 티아넵틴이 1일 3회 제형으로 복용되며 평균 37.5mg/day를 복용할 수 있다는 내용을 개시하고 있다.The British Journal of Psychiatry (1992), 160, 66-71, discloses that tianeptine is taken three times a day as a dosage form and can take an average of 37.5 mg / day.
주성분으로서 티아넵틴 12.5mg을 1일 3회 복용한 임상시험 관련 문헌들이 다수 보고되고 있다. 동물 모델에서는 1일 티아넵틴 복용량이 12.5mg에서 최대 300mg에 걸쳐서 복용할 수 있다는 것이 밝혀졌으며 이것은 어디까지나 동물을 대상으로 한 실험한 결과이기 때문에 사람을 대상으로 했을 때에는 추가적인 임상시험이 반드시 필요하며 대부분 임상시험에서는 티아넵틴 1일 복용량이 25mg에서 50mg에 걸쳐서 수행되었다. 그러나, 일반적으로 속방형 정제의 경우 혈중농도가 짧은 시간에 최대치에 도달한 이후에 급격히 혈중농도가 감소하는 단점이 존재하며 이러한 현상을 기초로 하여 원하지 않은 부작용이 발생될 수 있는 가능성이 존재한다. 티아넵틴 약물의 분포반감기는 0.7시간, 배설반감기는 2.5시간으로서 매우 짧은 것이 특징이다 (Clinical Neuropharmacology, 11, 2, S90-S96). 이렇게 약물의 반감기가 매우 짧은 경우, 혈중약물 농도가 높을 때는 독성이 나타나고 약물농도가 최소 치료농도 밑으로 떨어질 때는 약효가 없어지는 단점이 있다. 또한 반감기가 짧은 약물의 경우 최소효능농도(Minimum Effective Concentration;MCM)이하로 떨어지는 속도가 빠르기 때문에 치료영역내의 혈중농도로 유지시켜주기 위해서는 약물의 복용횟수를 늘려야만 한다. 이 경우에 투여간 약물농도 변동폭이 줄어들어서 치료적인 관점에서는 유리하지만 약을 자주 복용해야만 하므로 환자에게는 불편하고 약물투여의 순응도가 나빠질 수 있다. A number of reports have been reported on clinical trials in which 12.5 mg of tianeptine was used as the main ingredient three times a day. In animal models, it has been shown that the dose of tianeptine per day can be taken from 12.5 mg up to 300 mg, and this is an experimental result for animals only, so additional clinical studies are necessary for human subjects In clinical trials, tianeptine daily doses were performed from 25 mg to 50 mg. However, in general, in the case of rapid-acting tablets, there is a disadvantage that the blood concentration rapidly decreases after reaching the maximum value in a short time, and there is a possibility that undesired side effects may occur based on this phenomenon. The half-life of tianaptin is 0.7 hour and the excretion half-life is 2.5 hours (Clinical Neuropharmacology, 11, 2, S90-S96). When the half-life of the drug is very short, toxicity occurs when the concentration of the drug in the blood is high, and when the drug concentration falls below the minimum therapeutic concentration, the drug has a disadvantage. In addition, for drugs with short half-lives, the rate of decline to below the Minimum Effective Concentration (MCM) is high. Therefore, in order to maintain the blood concentration in the therapeutic area, the number of drug use must be increased. In this case, the fluctuation of the drug concentration between doses is reduced, which is advantageous from a therapeutic point of view, but since the drug should be taken frequently, it may be uncomfortable for the patient and adherence to the drug administration may deteriorate.
혈중농도를 지속적으로 유지시키기 위해서는 정제로부터 약물의 방출 속도가 지속적으로 일정하게 방출되도록 하는 것이 가장 이상적이다. 미국 등록특허 5,888,542호에서는 일반적으로 이용되는 수용성 고분자인 HPMC를 이용하여 티아넵틴을 서방화 시킨 내용이 보고되고 있으며 이 문헌에서는 1회 단위 복용량을 50mg로 한 서방성 정제를 개발하였다. 이 문헌에서는 기존에 12.5mg을 포함하는 속방형 정제를 1일 3회 복용하게 될 때의 용량인 37.5mg을 포함하는 서방정이 아닌 50mg을 포함하는 1일 1회 복용 서방정으로 연구되었다. 이 문헌을 토대로 하더라도 속방정 1일 3회 복용한 총약물양을 기준으로 유효 치료 혈중농도에 동등하도록 1일 1회 복용하는 서방정으로 개량하는 것이 매우 어려운 일인 것을 알 수 있다. 또한, 이 문헌의 경우 복용량이 50mg로서 속방정 3회 복용량인 37.5mg보다 높아서 식사 전, 식사 후에 약물을 복용했을 때의 혈중 약물 농도의 변동 폭이 더 커질 수 있고 이 경우 혈중약물농도가 치료영역을 벗어날 가능성이 있으며, 약물의 burst가 발생될 시에는 부작용이 발생될 가능성도 존재한다.In order to keep the blood concentration constant, it is ideal to have a constant and constant release rate of the drug from the tablet. US Pat. No. 5,888,542 reports the release of tianaptin using a commonly used water-soluble polymer, HPMC. In this document, a sustained-release tablet was prepared in which the unit dose was 50 mg once. In this document, a single daily dose of 50 mg was studied in a sustained-release formulation containing 37.5 mg of the fast-acting tablets containing 12.5 mg, which is the dose of 3 tablets per day. Based on this document, it can be seen that it is very difficult to improve the blood pressure to the same level as the effective treatment blood concentration based on the total amount of drug taken three times a day, once per day. In addition, in this document, the dosage is 50 mg, which is higher than the dose of 37.5 mg, which is the dose of 3 times fasting, so that the fluctuation range of the drug concentration in the blood when the drug is taken before and after the meal may become larger. There is a possibility that side effects may occur when a drug burst occurs.
따라서, 본연구자들은 티아넵틴을 사람을 대상으로 하여 1일 1회 복용량으로 37.5mg을 지속적 방출을 통해서 유효 혈중농도로 유지시키고자 한 노력끝에 본 발명이 완성되게 되었다. 일반적으로 1일 3회 복용하는 속방정과 본 발명에서 개발하고자 하는 1일 1회 복용 서방정의 혈중약물농도 변수중에서 Cmax와 AUC의 경우 식약청에서 고시하는 동등성 범위내에 위치하는 것이 바람직하다. 2009년 8월 18일에 개정된 식품의약품안전청 고시 제2009-67호의 생물학적 동등성 시험 기준에서는 비교하고자 하는 약물간의 비교평가항목치를 로그변환하여 통계처리하였을 때, 로그변환한 평균치의 차의 90% 신뢰구간이 log0.8에서 log1.25 이내일 경우 두 약물이 동등하다고 나타내고 있다. 따라서, 본 발명에서는 속방정과 서방정과의 동등성을 비교하기 위해 약물동력학적 변수인 Cmax와 AUC를 가지고 비교하였다.Therefore, the present inventors completed the present invention after endeavoring to maintain the effective blood concentration of 37.5 mg of tianeptine at a dose of once per day for a human being through sustained release. In general, it is preferable that the Cmax and the AUC among the blood drug concentration variables of the slow-release tablet to be taken three times a day and the one-dose once-daily tablet to be developed in the present invention are within the equivalence range notified by the KFDA. In the bioequivalence test standard of the Korea Food and Drug Administration Notice No. 2009-67, amended on August 18, 2009, when the comparative evaluation items to be compared were log-transformed and statistically processed, 90% confidence If the interval is between log0.8 and log1.25, the two drugs are equivalent. Therefore, in the present invention, the pharmacokinetic parameters Cmax and AUC were compared in order to compare the equilibrium between fasting and slowing.
1일 1회 복용되는 서방성 제형에 대한 연구가 다른 약물들에서도 많이 시도 되었으며 약물마다 생체이용률과 물리화학적 성질이 다르기 때문에 1일 3회 복용하던 약물과의 생물학적 동등성을 확보하기 위한 서방성 정제의 생체외 약물 용출률이 약물마다 다르고 신규 서방성 제형 연구에 있어서는 목표로 삼고자 하는 용출거동을 설정하기 어렵다. 특히, 티아넵틴의 경우 1일 1회 복용하는 서방성 제형을 개발하기 위해서는 서방정의 용출률이 특정시간에서 전체 100% 용출률 대비 일정비율부분 이상이어야만이 기존에 1일 3회 복용하던 속방정과의 생물학적 동등성을 확보할 수 있다는 것을 발견하여 본 발명에 이르게 되었다. 즉, 본 발명에서는, 티아넵틴 37.5mg을 포함하는 1일 1회 투여가능한 다양한 형태의 서방성 정제를 개시하며, 특히, 티아넵틴 12.5mg을 포함하는 기존의 1일 3회 투여 정제와 생물학적 동등성을 확보하기 위하여 초기의 약물방출거동이 제어된 서방성 정제가 개시된다.Studies on sustained-release formulations, which are taken once a day, have been extensively studied in other drugs, and since bioavailability and physico-chemical properties of each drug are different, a sustained-release tablet to ensure bioequivalence with drugs taken three times a day In vitro drug dissolution rates vary from drug to drug, and it is difficult to establish the dissolution behavior to be targeted in the new sustained release formulation study. In particular, in the case of tianeptine, in order to develop a sustained-release preparation to be taken once a day, the dissolution rate of the sustained-release tablet should be at least a certain percentage of the total dissolution rate at a specific time, And it is possible to secure equivalence, leading to the present invention. That is, the present invention discloses various types of sustained-release tablets that can be administered once a day, including 37.5 mg of tianeptine, and specifically, a method of administering a sustained- A sustained-release tablet in which the initial drug release behavior is controlled is disclosed.
본 발명에서 개시하는 다양한 형태의 서방성 정제에는 단층정을 비롯하여 이중정, 삼중정 및 사중정등의 다층정, 또한 핵정 등이 포함된다. The sustained release tablets of various types disclosed in the present invention include single layer tablets, multi-layer tablets such as double tablets, triplet tablets and tetragonal tablets, as well as a core tablet.
본 발명에 의한 단층정은, 수용성 서방성 고분자와 약물, 그리고, 결합제, 붕해제를 비롯한 약제학적으로 허용가능한 임의의 부형제를 균일하게 혼합한 후 타정해서 제조되는 매트릭스 정제로서, 고분자의 종류 및 배합량에 의해서 약물의 용출률이 효과적으로 조절되는 특성을 갖는다. 구체적으로는, 전혼합 또는 후혼합과정에서 약물과 혼합되는 수용성 서방성 고분자의 양을 증가시키는 경우 보다 오랜 시간동안 용출률을 제어하는 것이 가능하며, 매트릭스 정제 투여후 최대 24시간에 걸쳐서 서방성 방출을 달성할 수 있다.The single-layer tablet according to the present invention is a matrix tablet prepared by uniformly mixing a water-soluble sustained-release polymer, a drug, and a pharmaceutically acceptable excipient including a binder, a disintegrant, and the like, The dissolution rate of the drug is effectively controlled. Specifically, it is possible to control the dissolution rate over a longer period of time than when the amount of the water-soluble sustained-release polymer to be mixed with the drug is increased during the pre-mixing or post-mixing, and the sustained release Can be achieved.
이중정의 경우 두가지 방법으로 제조할 수 있다. 첫번째는 1차층에 약물일부와 수용성 서방성 고분자로 구성하고 2차층에 나머지약물과 속방형 부형제로 구성되게 할 수 있다. 두번째는 1차층에 전체약물과 수용성 서방성 고분자로 구성하고 2차층에 수용성 고분자로 구성되는 차단층을 위치시켜서 제조할 수 있다. 이중정에서 각층에 약제학적으로 허용가능한 부형제를 배합하여 약물의 용출이 조절가능하다. 유핵정의 경우 코어층과 외층으로 구성된다. 코어층에는 약물이 존재하고 여기에 속방성 부형제 또는 수용성 서방성 고분자들이 배합가능하다. 외층의 경우 필요에 따라서 전체약물중 일부를 이동시켜 배합할 수 있으며 수용성 서방성 고분자 또는 약제학적 허용가능한 부형제들로 구성가능하다. 코어층의 과립을 먼저 타정하여 정제를 제조하고 이 코어층 정제를 외층의 과립이 완전히 둘러쌓이도록 타정하여 유핵정을 제조하게 된다. 삼중정의 경우 총 3개의 층으로 구성되며 1차층과 3차층에 수용성 서방성 고분자와 추가적으로 약제학적 허용가능한 부형제들로 구성되게 되며 2차층에 전체약물을 포함하는 속방층을 위치시켜 제조할 수 있다. 이러한 삼중정제에서 다양한 약물 방출 거동을 얻도록 하기 위하여 1차와 3차층에 모두에 전체약물중 일부 이동시키거나 또는 한개의 서방층에 약물 일부를 이동시켜 제조가능하다. 또한 1차층과 3차층에 서방성고분자들로만 구성되게 하고 2차층에는 전체약물을 포함하는 속방층으로 삼중정제를 제조한 후에 매질에 따른 균일한 용출률을 얻고 다양한 용출 거동을 얻도록 하기 위해서 약물을 포함하는 코팅층을 추가로 도입할 수 있다. 사중정의 경우에는 상기에서 공개한 삼중정제의 특징적 구조에서 추가로 약물 일부를 포함하는 속방형 과립을 위치시켜서 총 4개의 층이 존재하는 사중정제를 제조할 수 있다. In the case of double definition, two methods can be used. The first may be composed of a drug moiety and a water soluble sustained-release polymer in the first layer and the remaining drug and the fast-acting excipient in the second layer. The second can be prepared by forming the whole drug and the water-soluble sustained-release polymer on the first layer and placing the barrier layer composed of the water-soluble polymer on the second layer. Dissolution of the drug can be controlled by mixing a pharmaceutically acceptable excipient in each layer in the dill. In the case of a pressed core, it is composed of a core layer and an outer layer. Drugs are present in the core layer and immediate release excipients or water soluble sustained release polymers can be incorporated therein. In the case of the outer layer, a part of the whole drug can be mixed and dispensed as needed, and it can be composed of a water-soluble sustained-release polymer or pharmaceutically acceptable excipients. The granules of the core layer are first kneaded to prepare tablets, and the core layer tablets are kneaded so that the granules of the outer layer are completely enclosed to produce a press-coated tablet. It is composed of three layers in total, and consists of water-soluble sustained-release polymers in the first layer and the third layer, and additionally pharmaceutically acceptable excipients, and can be manufactured by placing the immediate layer containing the whole drug in the second layer. In order to obtain various drug release behaviors in such a triple tablet, it is possible to transfer some of the whole drug to both the primary and the tertiary layer, or to transfer a part of the drug to one sustained layer. In addition, triple tablets are prepared from the first layer and the third layer only by the sustained-release polymer containing the whole drug in the second layer, and then the drug is contained to obtain a uniform dissolution rate according to the medium and to obtain various dissolution behavior Can be additionally introduced. In the case of quadruple definition, quadruple tablets having a total of four layers can be prepared by disposing the rapid-acting granules containing a part of the drug in the characteristic structure of the triplet tablet disclosed above.
본 발명에서 이용가능한 수용성 서방성 고분자로는 폴리에칠렌옥사이드, 히드록시프로필메칠셀룰로오스, 카보머, 카르복시메칠셀룰로오스, 히드록시프로필셀룰로오스, 히드록시에칠셀룰로오스 및 폴리비닐알콜로 이루어지는 군으로부터 선택 가능하다. The water-soluble sustained-release polymer usable in the present invention may be selected from the group consisting of polyethylene oxide, hydroxypropylmethylcellulose, carbohydrates, carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose and polyvinylalcohol.
또한, 본 발명에서 이용가능한 약제학적 허용가능한 부형제로는 유당, 덱스트로스, 수크로스, 덱스트레이트, 만니톨, 소르비톨, 자일리톨, 염화나트륨, 염화칼륨, 염화마그네슘, 인산수소칼슘, 인산칼슘, 구연산, 미결정셀룰로오스, 코포비돈, 폴리비닐피롤리돈, 전분글리콜산나트륨, 크로스카멜로오스나트륨, 크로스포비돈, 저치환도 히드록시프로필셀룰로오스, 부틸히드록시톨루엔, 부틸히드록시아니솔, 글리세릴베헤네이트, 스테아린산마그네슘, 스테아린산, 스테아릴푸마르산나트륨, 경질무수규산등이 있으며 약물을 서방화하고자 이용하는 수용성 서방성 고분자와 함께 혼합될 수 있다. In addition, pharmaceutically acceptable excipients usable in the present invention include lactose, dextrose, sucrose, dextrates, mannitol, sorbitol, xylitol, sodium chloride, potassium chloride, magnesium chloride, calcium hydrogen phosphate, calcium phosphate, citric acid, microcrystalline cellulose, Sodium carboxymethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxypropylcellulose, butylhydroxytoluene, butylhydroxyanisole, glyceryl behenate, magnesium stearate, stearic acid , Sodium stearyl fumarate, light anhydrous silicic acid, and the like, and may be mixed together with a water-soluble sustained-release polymer used to release the drug.
다른 한편, 본 발명에서는 약리학적 활성물질과 약제학적으로 허용 가능한 부형제를 선택적으로 혼합후 과립화하여 타정물을 제조하는 단계와 각 타정물을 차례로 타정하는 단계로 이루어진 제조방법을 제공한다. 타정물은 통상의 방법에 의해서 제조되며 혼합물은 혼합기를 사용하여 혼합한 다음 단층정 타정기, 핵정타정기 또는 다층정 타정기를 사용하여 타정하여 경구용 서방성 정제를 제조할 수 있다. According to another aspect of the present invention, there is provided a method for manufacturing a tablet, comprising the steps of selectively mixing a pharmacologically active substance with a pharmaceutically acceptable excipient and then granulating the mixture to form a tablet, and sequentially tabletting the tablet. The preparations can be prepared by conventional methods, and the mixture can be mixed using a mixer and then tableted using a single-layer tablet machine, a tablet press machine or a multi-layer tablet machine to produce an oral sustained-release tablet.
본 발명에 따른 경구용 티아넵틴 서방성 정제는 수용성 서방성 고분자를 이용하여 효율적으로 생체외에서 약물을 24시간까지 조절할 수 있음을 확인하였다. 생체외 결과를 기초로 생체내 약물 농도 비교 시험결과에서 볼 수 있듯이 1일 3회 복용한 대조약의 혈중약물 농도와 1일 1회 복용한 서방성 정제의 Cmax와 AUC가 동등성 범위내에 있는 것으로 보아서 본 발명의 서방성 정제가 복용횟수를 줄이면서 장시간 유효한 혈중농도로 유지될 수 있는 장점을 갖는 것을 확인하였다.The sustained-release thiaertin tablet for oral use according to the present invention was found to be capable of efficiently controlling the drug in vitro for up to 24 hours by using a water-soluble sustained-release polymer. Based on the in vitro results, as shown in the results of the in vivo drug concentration comparison, the blood drug concentration of the reference drug administered three times a day and the C max and the AUC of the sustained-release tablet once a day are within the equivalence range As a result, it was confirmed that the sustained-release tablet of the present invention has an advantage of being able to be maintained at an effective blood concentration for a long time while reducing the number of doses.
도 1은 실시예 1 내지 5의 용출시험 결과를 나타낸 것이다.
도 2는 실시예 6 내지 8의 용출시험 결과를 나타낸 것이다.
도 3은 실시예 9 내지 11의 용출시험 결과를 나타낸 것이다.
도 4는 실시예 12 내지 14의 용출시험 결과를 나타낸 것이다.
도 5는 실시예 15 내지 18의 용출시험 결과를 나타낸 것이다.
도 6은 실시예 19의 용출시험 결과를 나타낸 것이다.
도 7는 실시예 9 내지 실시예 11 및 대조약과의 시간에 따른 혈중약물 농도 곡선을 나타낸 것이다.Fig. 1 shows the dissolution test results of Examples 1 to 5. Fig.
Fig. 2 shows the dissolution test results of Examples 6 to 8. Fig.
Fig. 3 shows the dissolution test results of Examples 9 to 11. Fig.
Fig. 4 shows the dissolution test results of Examples 12 to 14. Fig.
Fig. 5 shows the dissolution test results of Examples 15 to 18. Fig.
Fig. 6 shows the dissolution test results of Example 19. Fig.
Figure 7 shows blood drug concentration curves over time with Examples 9-11 and the reference drug.
이하, 본 발명을 하기 실시예에 의하여 더욱 상세하게 설명하고자 한다. 다만 하기 실시예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 범위가 이들만으로 한정되는 것은 아니다. Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
<실시예1 내지 5>≪ Examples 1 to 5 >
하기 표 1와 같은 성분비에 따라 각 층별 혼합물을 제조하고 직경 9.0mm 원형 다이에 차례로 충전하여 유압프레스를 사용하여 6MPa 압력을 가하여 삼중정제를 타정하였다.The mixture for each layer was prepared according to the composition ratios shown in Table 1 below, filled in a circular die having a diameter of 9.0 mm in a row, and pressed at a pressure of 6 MPa using a hydraulic press.
<실시예6 내지 8>≪ Examples 6 to 8 >
수용성 서방성 고분자가 위치하는 1차, 3차층의 물성을 변화시키기 위하여 실시예 7은 수용성 서방성 고분자인 PEO 700만을 95%v/v에탄올을 서방성 고분자 중량대비 20w/w%를 결합액으로서 이용하여 습식과립하였으며 실시예 8은 소수성 부형제로서 대표 물질인 미결정셀룰로오스를 배합하였다. In order to change the physical properties of the primary and tertiary layers in which the water-soluble sustained-release polymer is located, in Example 7, only water-soluble sustained-release polymer PEO 700 was mixed with 95% v / v ethanol in an amount of 20 w / w% , And wet granulation was carried out. In Example 8, microcrystalline cellulose as a representative hydrophobic excipient was blended.
(DC: Direct compression, 직타법/ WG: Wet-granulation, 습식과립법)(DC: Direct compression, WG: Wet-granulation, wet granulation)
상기 표 2와 같은 성분비에 따라 각 층별 혼합물을 제조하고 직경 9.0mm 원형 다이에 차례로 충전하여 유압프레스를 사용하여 6MPa 압력으로 삼중정제를 타정하였다.According to the composition ratios shown in Table 2, each layer mixture was prepared and filled in a round die having a diameter of 9.0 mm in a row, and the triple tablet was compressed at a pressure of 6 MPa using a hydraulic press.
<실시예 9 내지 11>≪ Examples 9 to 11 &
하기 표 3와 같은 성분비에 따라 각 층별 혼합물을 제조하고 직경 9.0mm 원형 다이에 차례로 충전하여 유압프레스를 사용하여 6MPa 압력으로 사중정제를 타정하였다. The mixture for each layer was prepared according to the composition ratios as shown in Table 3 below, filled in a circular die having a diameter of 9.0 mm in a row, and quadrupled at a pressure of 6 MPa using a hydraulic press.
<실시예12 내지 14>≪ Examples 12 to 14 >
수용성 서방성 고분자인 HPMC를 이용하여 1일 1회 복용량으로서 티아넵틴 37.5mg을 포함하는 서방정제를 제조하였다.A sustained release preparation containing 37.5 mg of tianeptine was prepared as a once-a-day dose using HPMC, a water-soluble sustained-release polymer.
상기와 같은 성분비에 의해 과립을 제조하여 9mm직경의 원형 다이에 9MPa의 힘으로 유압프레스를 이용하여 타정하였다.The granules were prepared according to the above-mentioned composition ratios, and pressed into a circular die having a diameter of 9 mm at a force of 9 MPa using a hydraulic press.
<실시예15>≪ Example 15 >
수용성 서방성 고분자인 HPMC를 이용하여 1일 1회 복용량으로서 티아넵틴 37.5mg을 포함하는 경구투여용 티아넵틴 서방성 이중정제를 제조하였다.A sustained-release double-tablet of tiaertin for oral administration containing 37.5 mg of tianeptine as a once-a-day dose was prepared using HPMC as a water-soluble sustained-release polymer.
초기에 약물의 급격한 방출 현상을 막기위하여 약물을 포함하는 서방성 1차층 반대편에 수용성 고분자로 추가로 차단층을 구성하여 약물의 방출 속도를 조절하고자 하였다. In order to prevent the rapid release of the drug in the early stage, the release rate of the drug was controlled by forming a further barrier layer as a water-soluble polymer on the opposite side of the slow release primary layer containing the drug.
상기와 같은 성분비에 의하여 각 층별 과립을 제조하여 9mm직경의 원형 다이에 예압없이 6MPa의 힘으로 유압프레스를 이용하여 타정하였다.The granules of each layer were prepared according to the composition ratios as described above, and pressed into a circular die having a diameter of 9 mm using a hydraulic press with a force of 6 MPa without a preload.
<실시예16>≪ Example 16 >
수용성 서방성 고분자인 HPMC를 이용하여 티아넵틴 29.5mg을 포함하는 1차층 서방성 과립을 제조한 후에 다양한 용출거동을 얻도록 하기 위하여 티아넵틴 8.0mg을 2차층 속방층에 위치시켜 1회 전체 복용량이 37.5mg인 경구투여용 티아넵틴 서방성 이중정을 제조하였다. In order to obtain various dissolution behavior after preparing the first layer sustained-release granules containing 29.5 mg of tianeptin using HPMC as a water-soluble sustained-release polymer, 8.0 mg of tianaptin was placed in the secondary layer and the total dose 37.5 mg of tiarethin for oral administration was prepared.
상기와 같은 성분비에 의하여 각 층별 과립을 제조하여 9mm직경의 원형 다이에 예압없이 6MPa의 힘으로 유압프레스를 이용하여 타정하였다.The granules of each layer were prepared according to the composition ratios as described above, and pressed into a circular die having a diameter of 9 mm using a hydraulic press with a force of 6 MPa without a preload.
<실시예 17>≪ Example 17 >
수용성 서방성 고분자인 HPMC를 이용하여 약물을 포함하는 서방성 코어층을 제조한 후에 정제당 전체약물중 일정비율의 약물을 포함하는 속방성 외층이 구성되도록 하는 유핵정을 제조하였다. A sustained release core layer containing a drug was prepared by using a water soluble sustained release polymer, HPMC, and then a core tablet was prepared so as to form a quick release outer layer containing a certain percentage of drugs per tablet.
상기와 같은 성분비에 의하여 각층별 과립을 제조하여 7mm 직경의 원형 다이에 코어층 과립을 10MPa의 힘으로 유압프레스를 이용하여 코어층을 미리 타정한다. 9mm 직경의 원형 다이에 외층 과립물 일부를 넣고 미리 타정된 코어층 정제가 중심에 위치하도록 넣은 후에 나머지 외층을 넣어서 6MPa의 힘으로 유압프레스를 이용하여 타정하였다.The granules for each layer are prepared according to the composition ratios as described above, and the core layer granules are pre-compressed using a hydraulic press with a force of 10 MPa on a circular die having a diameter of 7 mm. A portion of the outer layer granules was placed in a circular die having a diameter of 9 mm, and the tablets of the core layer, which had been previously tableted, were placed so as to be positioned at the center, and then the remaining outer layer was inserted and pressed with a hydraulic press at a force of 6 MPa.
<실시예 18>≪ Example 18 >
약물을 포함하는 속방형 코어층을 제조한 후에 수용성 서방성 고분자가 외층에 위치하도록 구성되는 유핵정을 제조하였다. After preparing a fast core layer containing a drug, a core tablet was prepared so that a water soluble sustained-release polymer was located in the outer layer.
상기와 같은 성분비에 의하여 각층별 과립을 제조하여 6mm 직경의 원형 다이에 코어층 과립을 4MPa의 힘으로 유압프레스를 이용하여 코어층을 타정한 다. 9mm 직경의 원형 다이에 외층 과립물 일부를 넣고 미리 타정된 코어층 정제가 중심에 위치하도록 넣은 후에 나머지 외층을 넣어서 6MPa의 힘으로 유압프레스를 이용하여 타정하였다.The core layer granules were pressed on a circular die having a diameter of 6 mm by using a hydraulic press with a force of 4 MPa to fix the core layer. A portion of the outer layer granules was placed in a circular die having a diameter of 9 mm, and the tablets of the core layer, which had been previously tableted, were placed so as to be positioned at the center, and then the remaining outer layer was inserted and pressed with a hydraulic press at a force of 6 MPa.
<실시예 19>≪ Example 19 >
다양한 약물 용출 거동을 얻도록 하기 위해서 서방성 정제에서 코팅층을 도입하고 이 코팅층에 일정비율의 티아넵틴이 존재하도록 하였다. 티아넵틴이 서방성 정제에 코팅될 수 있는지 여부를 확인하기 위해서 수용성 서방성 고분자인 HPMC 90SH 100,000와 Mannitol 300DC를 3:1로 혼합하여 1정당 200mg인 서방성 Placebo 정제를 제조하여 이 정제 표면에 티아넵틴이 균일하게 부착되는지 여부를 확인하였다 .To obtain a variety of drug elution behaviors, a coating layer was introduced in a sustained-release tablet and a certain percentage of tianeptine was present in the coating layer. In order to confirm whether thianaptin can be coated on the sustained-release tablet, a sustained-release placebo tablet of 200 mg per tablet was prepared by mixing a water-soluble sustained-release polymer such as HPMC 90SH 100,000 and Mannitol 300DC in a ratio of 3: 1, It was confirmed whether or not the neptin was uniformly adhered.
표9와 같은 코팅 처방조성으로 코팅액을 조제 후 함량균일성 및 용출거동을 평가하였다. 먼저 증류수에 티아넵틴을 완전히 용해시킨 후에 Pharmacoat 606을 증류수에 넣고 완전히 용해 시킨다. 그 후에 PEG 6,000을 완전 용해시키고 SLS를 첨가하여 완전 용해시킨다. 가장 마지막으로 TiO2를 분산시켜서 코팅액 제조를 완료한다. 이렇게 제조된 코팅액을 모델명 SFC-30FN Hi-Coater (Sejong Pharmatech. Co., LTD)를 이용하여 미리 타정한 서방성 Placebo 정제 표면에 코팅하여 티아넵틴 약물 코팅을 완료하였다.The uniformity and the dissolution behavior of the coating were evaluated after preparing the coating solution with the coating formulation as shown in Table 9. First, completely dissolve thiaminethine in distilled water, then add Pharmacoat 606 in distilled water and completely dissolve. Thereafter, PEG 6,000 is completely dissolved and SLS is added to dissolve completely. Finally, TiO 2 is dispersed to complete the coating solution preparation. The thus-prepared coating solution was coated on the surface of the tablets which had been previously tableted using a model name SFC-30FN Hi-Coater (Sejong Pharmatech Co., LTD) to complete the coating of thiacenepine drug.
<실험예 1> 티아넵틴을 포함하는 코팅층의 함량균일성 시험<Experimental Example 1> Content uniformity test of coating layer containing tianeptin
실시예19를 통해 코팅된 티아넵틴의 함량균일성을 평가하였다. 티아넵틴이 코팅된 서방성 정제를 100% 메탄올을 이용하여 정제를 완전히 붕해시켜 약물을 추출하였다. 이렇게 코팅막이 완전히 붕해되었을 경우, 별도의 희석과정 없이 코팅층에 존재하는 티아넵틴의 함량균일성을 비교하였다. The content uniformity of the coated thianaphene was evaluated through Example 19. The sustained-release tablets coated with tianaptin were completely disintegrated with 100% methanol to extract the drug. When the coating was completely disintegrated, the uniformity of tianaptin content in the coating layer was compared without further dilution.
티아넵틴이 코팅된 정제의 질량 표준편차와 코팅된 티아넵틴의 함량 표준편차가 각각 4.0와 4.3으로 유사한 값을 보이는 것으로 보아서 서방정제 표면에 티아넵틴이 균일하게 분산되어 코팅되었음을 확인할 수 있었다.The mass standard deviation of the tablet coated with tianaptin and the standard deviation of the content of coated tianeptine were 4.0 and 4.3, respectively, indicating that tianeptin was uniformly dispersed on the surface of the sustained release tablet.
<실험예 2><Experimental Example 2>
용출시험상기 실시예들에 대한 용출시험을 pH 6.8 인산염 완충액(대한약전, 붕해시험법 제2액) 900mL에서 대한약전 용출시험법 제 2법에 따라 37.5℃, 100rpm에서 실시하였다. 도 1의 실시예 1에서 5의 결과를 비교하면 서방성 고분자인 PEO 700만의 양이 적을수록 더 빠른 용출을 보이고 있다. 도2의 실시예 6에서 8을 비교하면 서방성 고분자인 PEO 700만을 직타로 이용한 실시예 6에 비해서 습식과립화하여 PEO 700만의 입도를 증가시킨 실시예 7와 친수성 PEO 700만에 소수성 부형제인 미결정셀룰로오스를 배합한 실시예 8이 초기용출이 더 빠른 것을 확인할 수 있었다. 도 3의 실시예 9에서 11의 경우에는 표3에서 1차층에서 3차층까지는 서방층으로 구성되며 4차층은 속방층으로 구성되어 있고 4차층의 구성이 실시예 9에서 11까지가 동일하기 때문에 초기 용출률이 동일하게 발생된 이후에 서방층의 PEO의 양과 PEO와 소수성 부형제의 배합유무에 따라서 12시간에서의 용출률 기준으로 실시예9는 90%, 실시예10은 81%, 실시예 11은 71%의 용출률을 각각 보이고 있다. 도 4는 실시예 12에서 14의 용출거동을 나타낸 것이며 수용성 서방성 고분자인 HPMC를 이용하였을 때에도 티아넵틴의 약물 용출률을 효율적으로 조절가능함을 확인하였다. 도 5는 실시예 15에서 18까지의 용출거동을 나타낸 것이다. 실시예 15와 16은 이중정의 용출거동을 나타낸 것이며 실시예 17와 18은 유핵정의 용출거동을 나타낸 것이다. 이 용출거동을 통해서 서방성 정제내부에서 구조상 약물이 어느곳에 위치하는지 여부와 구조적으로 어떠한 차이가 있는지에 따라서 다양한 용출거동을 얻을 수 있었으며 20시간까지 조절된 약물방출거동을 얻을 수 있었다. 도 6은 티아넵틴을 포함하는 코팅층의 용출률을 확인한 그림이다. 5분안에 약95%, 10분안에 100%의 용출률을 보이고 있다. 이 결과를 통해 서방성 정제표면에 코팅된 티아넵틴의 양만큼 초기용출률을 조절할 수 있음을 확인하였다. Elution test The dissolution test for the above Examples was carried out in 900 mL of pH 6.8 phosphate buffer solution (Kagaku Kogyo, Disintegration Test Method 2) at 37.5 캜 and 100 rpm in accordance with
<실험예 3> 생체내 약물 농도 비교 시험<Experimental Example 3> In vivo drug concentration comparison test
1일 1회 복용하도록 설계된 표3의 실시예 9내지 11의 정제와 1일 3회 복용하는 대조약 스타브론정과의 시간에 따른 생체내약물농도 거동을 비교하고자 하였다. 대조약 1개의 군과 시험약(실시예9~11) 3개의 군으로 총 4개의 군으로 나누어 각 군별 개체수 10으로 평가하였다. 도 7은 4개 군의 시간에 따른 혈중 약물농도 곡선을 나타내고 있다. 하기의 표11은 각 군별 Cmax와 AUC의 기하평균값을 기준으로 비교한 표이다. To compare the drug concentration behavior in vivo with time of tablets of Examples 9 to 11 of Table 3 designed to be taken once a day and the control drug Stavron's tablet to be taken three times a day. The control group was divided into four groups, one group and the test group (Examples 9 to 11). FIG. 7 shows blood drug concentration curves of the four groups over time. Table 11 below is a table comparing the geometric mean values of C max and AUC for each group.
Cmax 기준으로는 실시예 9~11 모두 동등성 범위내에 존재하지만 AUC기준으로 비교했을 때에는 12시간에서의 용출률 기준으로 실시예9는 약 90%, 실시예 10은 약 80%, 실시예 11은 약 70%의 용출률을 갖으며 용출률이 약 70%인 실시예 11의 경우에만 동등성 범위에서 벗어나는 것으로 보아서 12시간에서 용출률이 70% 이상, 바람직하게는 12시간에서 용출률이 75% 이상되어야 한다는 것을 발견할 수 있었다. 이 결과를 통해서 24시간 동안 티아넵틴이 생체내외에서 효과적으로 제어되고 있었으며 식약청이 고시한 생물학적 동등성 기준 범위내에 실시예9와 실시예 10의 Cmax와 AUC가 존재하기 때문에 1일 1회 제형으로서 이용가능함을 확인할 수 있었다.On the basis of Cmax, all of Examples 9 to 11 are within the equivalence range, but when compared on the AUC basis, about 90% of Example 9, about 80% of Example 9, and about 70% of Example 11, % And a dissolution rate of 70% or more, preferably 12 hours or more at 75%, it is found that the dissolution rate should be 75% or more at 12 hours. there was. These results indicate that tianaptin was effectively controlled in vitro and in vivo for 24 hours, and since the Cmax and AUC of Examples 9 and 10 exist within the range of the biological equivalency notified by the KFDA, they can be used as a formulation once a day I could confirm.
본 발명에 따른 경구용 티아넵틴 서방성 정제는 수용성 서방성 고분자를 이용하여 효율적으로 생체외에서 약물을 24시간까지 조절할 수 있다.The sustained-release thiaertin tablet for oral use according to the present invention can efficiently control the drug for 24 hours in vitro using a water-soluble sustained-release polymer.
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| US5888542A (en) | 1996-04-24 | 1999-03-30 | Adir Et Compagnie | Matrix tablet allowing the prolonged release of the sodium salt of tianeptine after administration by the oral route |
| KR100464180B1 (en) | 2000-03-31 | 2004-12-31 | 르 라보레또레 쎄르비에르 | NEW PROCESS FOR THE PREPARATION OF 11-AMINO-3-CHLORO-6,11-DIHYDRO-5,5-DIOXO-6-METHYL-DIBENZO[c,f][1,2]THIAZEPINE AND APPLICATION TO THE SYNTHESIS OF TIANEPTINE |
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| US5888542A (en) | 1996-04-24 | 1999-03-30 | Adir Et Compagnie | Matrix tablet allowing the prolonged release of the sodium salt of tianeptine after administration by the oral route |
| KR100464180B1 (en) | 2000-03-31 | 2004-12-31 | 르 라보레또레 쎄르비에르 | NEW PROCESS FOR THE PREPARATION OF 11-AMINO-3-CHLORO-6,11-DIHYDRO-5,5-DIOXO-6-METHYL-DIBENZO[c,f][1,2]THIAZEPINE AND APPLICATION TO THE SYNTHESIS OF TIANEPTINE |
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