TW201834643A - Pharmaceutical formulation containing itopride hydrochloride and having immediate and sustained release properties - Google Patents
Pharmaceutical formulation containing itopride hydrochloride and having immediate and sustained release properties Download PDFInfo
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Abstract
Description
本申請案主張於2017年2月20日在大韓民國提出申請之韓國專利申請案第10-2017-0022040號之優先權，此韓國專利申請案之揭示內容以引用之方式併入本文。本揭示案係關於一種包含鹽酸依托必利的藥物製劑，更具體而言係關於一種能夠經由每日一次給藥來改善藥物順應性且同時提供快速鎮痛效果的藥物製劑。The present application claims priority to Korean Patent Application No. 10-2017-0022040, filed on Jan. 20,,,,,,,,,,,,,,,,, The present disclosure relates to a pharmaceutical preparation comprising etoriride hydrochloride, and more particularly to a pharmaceutical preparation capable of improving drug compliance via a once-a-day administration while providing a rapid analgesic effect.
鹽酸依托必利（N-[[4-[2-(二甲基胺基)乙氧基]苯基]甲基]-3,4-二甲氧基苯甲醯胺鹽酸鹽）係一種藉由抑制乙醯膽鹼酯酶及多巴胺D2受體來增加乙醯膽鹼的量的藥物。乙醯膽鹼促進胃腸道之蠕動，從而治療由功能性消化不良引起的胃腸道症狀，諸如腹脹、上腹痛、厭食、胸痛及嘔吐。此藥物適合長期用藥，因為它幾乎不展現用以改善胃腸道功能的外周選擇性多巴胺D2拮抗劑多潘立酮的副作用，諸如男性女乳症、泌乳等。 Ettoride hydrochloride (N-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-3,4-dimethoxybenzamide hydrochloride) is a kind A drug that increases the amount of acetylcholine by inhibiting the acetylcholinesterase and the dopamine D2 receptor. Acetylcholine promotes peristalsis of the gastrointestinal tract, thereby treating gastrointestinal symptoms caused by functional dyspepsia, such as bloating, upper abdominal pain, anorexia, chest pain, and vomiting. This drug is suitable for long-term use because it hardly exhibits side effects of the peripherally selective dopamine D2 antagonist domperidone, which is used to improve gastrointestinal function, such as male breast milk, lactation and the like.
在口服鹽酸依托必利（N-[[4-(2-二甲基胺基乙氧基)苯基]甲基]-3,4-二甲氧基苯甲醯胺）後，起效時間為30分鐘內，在約0.5至1.5小時內達到最高血液濃度，且持續時間為約12小時。眾所周知，在口服依托必利後，約80%經由排尿排出（消除），且***率（半衰期）為約6小時。Onset time after oral administration of etorride hydrochloride (N-[[4-(2-dimethylaminoethoxy)phenyl]methyl]-3,4-dimethoxybenzamide) The highest blood concentration was reached in about 0.5 to 1.5 hours in 30 minutes and lasted for about 12 hours. It is well known that after oral administration of etomiride, about 80% is excreted (eliminated) via urination, and the excretion rate (half-life) is about 6 hours.
消化功能差的患者需要長期用藥，因為症狀時常由於壓力而出現。然而，由於尚未開發每日一次給藥的製劑，長時間服用依托必利的患者可能在藥物教示及藥物順應性方面發現不便。Patients with poor digestion require long-term medication because symptoms often occur due to stress. However, patients who take etotopril for a long time may find inconvenience in drug teaching and drug compliance because they have not yet developed a once-daily dosing formulation.
為了避免每日服藥3次的不便，已努力開發每日一次給藥的製劑。然而，使用一般緩釋製劑難以迅速緩解疼痛。In order to avoid the inconvenience of taking the medicine 3 times a day, efforts have been made to develop a preparation for once-daily administration. However, it is difficult to quickly relieve pain using a general sustained release preparation.
技術問題technical problem
本揭示案係針對提供一種包含鹽酸依托必利且同時具有速釋和緩釋性質之藥物製劑。The present disclosure is directed to providing a pharmaceutical formulation comprising etopride hydrochloride with both immediate and sustained release properties.
本揭示案亦針對提供包含速釋部分與緩釋部分的藥物製劑，此藥物製劑可因藥物緩釋而經由每日一次給藥來改善藥物順應性，同時提供快速鎮痛效果。The present disclosure is also directed to providing a pharmaceutical preparation comprising an immediate release portion and a sustained release portion which can be improved in drug compliance by once-daily administration due to sustained release of the drug, while providing a rapid analgesic effect.
本揭示案可減少由於在初期階段釋放過量藥物而可能發生的副作用。 技術方案The present disclosure can reduce side effects that may occur due to the release of excess drug at an early stage. Technical solutions
本揭示案係關於一種包含依托必利或依托必利之醫藥學上可接受之鹽（具體而言，鹽酸依托必利）作為活性成分的藥物製劑，並且提供了在初期階段展示出優異功效且同時經由每日一次給藥提供改善的藥物順應性的藥物製劑。The present disclosure relates to a pharmaceutical preparation comprising an pharmaceutically acceptable salt of etidride or etopride (specifically, etopride hydrochloride) as an active ingredient, and provides excellent efficacy at the initial stage and simultaneously A pharmaceutical formulation that provides improved drug compliance via once-daily dosing.
本揭示案係關於一種依托必利或其醫藥學上可接受之鹽的口服製劑，其中依托必利在治療消化系統病症方面非常有用。更具體而言，本揭示案提供了具有改善藥物順應性的口服藥物製劑，因為可每日服藥一次，因為依托必利或其醫藥學上可接受之鹽以恆定速率釋放24小時。The present disclosure relates to an oral formulation of etodoride or a pharmaceutically acceptable salt thereof, wherein it is very useful in treating digestive disorders. More specifically, the present disclosure provides oral pharmaceutical preparations with improved drug compliance, as the drug can be administered once a day because it is released at a constant rate for 24 hours with etomiride or a pharmaceutically acceptable salt thereof.
本揭示案提供了包含依托必利或依托必利之醫藥學上可接受之鹽的製劑，具體而言包含鹽酸依托必利的藥物製劑，此藥物製劑以恆定速率提供藥物的持續釋放，同時在初期階段展示出優異功效。The present disclosure provides a formulation comprising a pharmaceutically acceptable salt of etoriride or etopride, in particular a pharmaceutical formulation comprising etofride hydrochloride, which provides sustained release of the drug at a constant rate, while at the beginning The stage shows excellent results.
依托必利之醫藥學上可接受之鹽可為例如酸加成鹽、四級銨鹽等。酸加成鹽可為無機酸鹽，諸如鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硫酸鹽、磷酸鹽等，或有機酸鹽，諸如草酸鹽、順丁烯二酸鹽、反丁烯二酸鹽、乳酸鹽、蘋果酸鹽、琥珀酸鹽、酒石酸鹽、苯甲酸鹽、甲磺酸鹽、檸檬酸鹽等，且四級銨鹽可為低級烷基鹵化物，諸如甲基碘、甲基溴、乙基碘、乙基溴等，或低級烷基磺酸酯，諸如甲磺酸甲酯、甲磺酸乙酯等，低級烷基芳基磺酸酯，諸如對甲苯磺酸甲酯等。具體而言，可使用鹽酸依托必利。為了藉由一起包括速釋部分與緩釋部分而在初期階段提供緩釋以及優異的功效，可使用鹽酸依托必利。The pharmaceutically acceptable salt of etodoride may be, for example, an acid addition salt, a quaternary ammonium salt or the like. The acid addition salt may be a mineral acid salt such as a hydrochloride, a hydrobromide, a hydroiodide, a sulfate, a phosphate or the like, or an organic acid salt such as an oxalate, maleate or the like. Butenedioate, lactate, malate, succinate, tartrate, benzoate, methanesulfonate, citrate, etc., and the quaternary ammonium salt can be a lower alkyl halide, such as a Base iodine, methyl bromide, ethyl iodide, ethyl bromide, etc., or lower alkyl sulfonate, such as methyl methanesulfonate, ethyl methanesulfonate, etc., lower alkyl aryl sulfonate, such as p-toluene Methyl sulfonate and the like. Specifically, itopride hydrochloride can be used. In order to provide sustained release and excellent efficacy at an initial stage by including an immediate release portion and a sustained release portion together, it is possible to use itopride hydrochloride.
本揭示案可提供一種藥物製劑，此藥物製劑同時包含：(a)緩釋部分，包含：依托必利或其醫藥學上可接受之鹽；緩釋聚合物；CO2 源；有機酸；及醫藥學上可接受之填充劑（稀釋劑）；以及(b)速釋部分，包含：依托必利或其醫藥學上可接受之鹽；及醫藥學上可接受之填充劑（稀釋劑）。The present disclosure may provide a pharmaceutical preparation comprising: (a) a sustained release portion comprising: etofride or a pharmaceutically acceptable salt thereof; a sustained release polymer; a CO 2 source; an organic acid; A pharmaceutically acceptable filler (diluent); and (b) an immediate release portion comprising: etodoride or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable filler (diluent).
具體而言，可將鹽酸依托必利用作依托必利或依托必利之醫藥學上可接受之鹽。In particular, hydrochloric acid can be used as a pharmaceutically acceptable salt of etoriride or etoride.
本揭示案之發明人已研製一種藥物製劑，此藥物製劑提供依托必利或其醫藥學上可接受之鹽的緩釋，同時經由每日僅一次給藥來提供快速效果，並且發明人已完成本揭示案。The inventors of the present disclosure have developed a pharmaceutical preparation which provides sustained release of etomiride or a pharmaceutically acceptable salt thereof while providing a rapid effect by only one administration per day, and the inventors have completed This disclosure.
本揭示案中所使用之術語「緩釋部分」可理解為在投藥給人體後允許藥物緩慢溶解及以持續方式釋放的部分。The term "sustained release portion" as used in the present disclosure is understood to mean a portion which allows the drug to be slowly dissolved and released in a sustained manner after administration to a human.
本揭示案中所使用之術語「速釋部分」可理解為在投藥給人體後允許藥物快速釋放的部分。The term "immediate release portion" as used in the present disclosure is understood to mean a portion that allows rapid release of a drug after administration to a human.
作為本揭示案之緩釋部分，緩釋聚合物可用來有效控制具有非常高的水溶性的鹽酸依托必利之釋放。緩釋聚合物係指用以長時間緩慢釋放藥物的材料，並且可使用本領域中所使用之任何緩釋聚合物而無限制。具體而言，可使用選自由羥丙基甲基纖維素、羥丙基纖維素及聚乙烯吡咯酮組成之群組中的一者或更多者作為緩釋聚合物。更具體而言，可使用羥丙基甲基纖維素(hydroxypropyl methyl cellulose; HPMC)。進一步更具體而言，與羥丙基甲基纖維素相同，可使用羥丙基甲基纖維素2910、羥丙基甲基纖維素2208或其混合物。具體而言，羥丙基甲基纖維素可用於本揭示案之製劑中，因為它取決於pH展示出很小的黏度或釋放模式變化。羥丙基甲基纖維素可具有100-100,000 cPs之黏度以形成藥物釋放基質。具體而言，可使用具有5,000-30,000 cPs之平均黏度的HPMC。根據美國藥典(United States Pharmacopeia; USP)使用20℃的2重量%水溶液量測黏度。As a sustained release portion of the present disclosure, a sustained release polymer can be used to effectively control the release of etopride hydrochloride having a very high water solubility. The sustained release polymer means a material for slowly releasing the drug for a long period of time, and any sustained release polymer used in the art can be used without limitation. Specifically, one or more selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvinylpyrrolidone can be used as the sustained-release polymer. More specifically, hydroxypropyl methyl cellulose (HPMC) can be used. Further more specifically, as with hydroxypropyl methylcellulose, hydroxypropylmethylcellulose 2910, hydroxypropylmethylcellulose 2208 or a mixture thereof can be used. In particular, hydroxypropyl methylcellulose can be used in the formulations of the present disclosure because it exhibits little viscosity or release mode change depending on the pH. The hydroxypropyl methylcellulose may have a viscosity of from 100 to 100,000 cPs to form a drug release matrix. Specifically, HPMC having an average viscosity of 5,000 to 30,000 cPs can be used. Viscosity was measured according to the United States Pharmacopeia (USP) using a 2% by weight aqueous solution at 20 °C.
考慮到由於使用CO2 源與有機酸而發生起泡，可使用上文所描述之聚合物，因為藥物釋放受起泡的影響較小，且黏度並未顯著變化。In view of the occurrence of foaming due to the use of a source of CO 2 and an organic acid, the polymer described above can be used because the release of the drug is less affected by foaming and the viscosity does not change significantly.
以緩釋部分之總重量計，包含在緩釋部分中的緩釋聚合物可以10重量%至40重量%的量包含，具體而言15重量%至35重量%，更具體而言17重量%至30重量%，進一步更具體而言20重量%至29重量%，甚至更具體而言26重量%至28重量%。當考慮到藥物之緩釋、緩釋部分中的起泡等時，此範圍可為期望的。在此範圍內，可實現藥物緩釋而無需過度延遲藥物釋放。The sustained-release polymer contained in the sustained-release portion may be contained in an amount of 10% by weight to 40% by weight, based on the total weight of the sustained-release portion, specifically 15% by weight to 35% by weight, more specifically 17% by weight. Up to 30% by weight, further more specifically 20% to 29% by weight, even more specifically 26% to 28% by weight. This range may be desirable when considering the sustained release of the drug, foaming in the sustained release portion, and the like. Within this range, sustained release of the drug can be achieved without unduly delaying drug release.
本揭示案之製劑進一步包含緩釋部分中的CO2 源與有機酸。作為CO2 源，考慮到與本揭示案之藥物的相容性、優異的起泡、最小化的pH變化等，可使用選自碳酸鈉、碳酸鉀、碳酸氫鈉及碳酸氫鉀的一者或更多者。具體而言，考慮到本揭示案之目的，可使用碳酸氫鈉。以緩釋部分之總重量計，CO2 源可以1重量%至10重量%的量包含，具體而言3重量%至8重量%，更具體而言4重量%至7重量%。The formulation of the present disclosure further comprises a source of CO 2 and an organic acid in the sustained release portion. As the CO 2 source, one selected from the group consisting of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate can be used in consideration of compatibility with the drug of the present disclosure, excellent foaming, minimized pH change, and the like. Or more. In particular, sodium bicarbonate can be used for the purposes of this disclosure. The CO 2 source may be included in an amount of from 1% by weight to 10% by weight, based on the total weight of the sustained-release portion, specifically from 3% by weight to 8% by weight, more specifically from 4% by weight to 7% by weight.
作為有機酸，可使用選自由草酸、順丁烯二酸、反丁烯二酸、乳酸、蘋果酸、琥珀酸、酒石酸、苯甲酸、甲磺酸及檸檬酸組成之群組中的一者或更多者，此有機酸可藉由與CO2 源一起使用來產生氣泡。具體而言，考慮到本揭示案之目的，可使用檸檬酸。以緩釋部分之總重量計，有機酸可以1重量%至10重量%的量包含，具體而言3重量%至8重量%，更具體而言4重量%至7重量%。As the organic acid, one selected from the group consisting of oxalic acid, maleic acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, benzoic acid, methanesulfonic acid, and citric acid may be used. Further, this organic acid can be generated by using it with a CO 2 source. In particular, citric acid can be used for the purposes of this disclosure. The organic acid may be included in an amount of from 1% by weight to 10% by weight, based on the total weight of the sustained-release portion, specifically from 3% by weight to 8% by weight, more specifically from 4% by weight to 7% by weight.
在本揭示案之示例性實施例中，包含在緩釋部分中的CO2 源與有機酸之CO2 源：有機酸重量比可為1:0.1-10，具體而言1:0.5-5。The weight ratio of the organic acid may be 1:: 0.1 to 10, particularly 1: In this example, the sustained-release part containing CO 2 in the CO 2 source and an organic acid source in an exemplary embodiment of the present disclosure 0.5-5.
CO2 源與有機酸可使藥物漂浮在胃液中，並且由此可允許藥物長時間停留在胃腸道中。當CO2 源與有機酸之含量處於上述範圍內時，可實現極佳的漂浮效果。此外，對於在膠囊中包含兩個或更多個片劑的製劑，當CO2 源與有機酸之比率處於上述範圍內時，可預期優異的漂浮效果與緩釋效果。The CO 2 source and the organic acid can cause the drug to float in the gastric fluid, and thereby allow the drug to stay in the gastrointestinal tract for a long time. When the content of the CO 2 source and the organic acid is in the above range, an excellent floating effect can be achieved. Further, for the preparation containing two or more tablets in the capsule, when the ratio of the CO 2 source to the organic acid is within the above range, an excellent floating effect and a sustained release effect can be expected.
本揭示案之發明人已辨識，包含依托必利或其醫藥學上可接受之鹽的本發明之製劑可長時間停留在胃腸道中，因為此製劑包含CO2 源與有機酸。The inventors of the present disclosure have recognized that the formulation of the present invention comprising etomiride or a pharmaceutically acceptable salt thereof can remain in the gastrointestinal tract for a long time because the formulation comprises a source of CO 2 and an organic acid.
作為填充劑，可使用選自由微晶纖維素、乳糖、澱粉、甘露醇、葡萄糖、山梨糖醇、糊精及蔗糖組成之群組中的一者或更多者，但不限於此。As the filler, one or more selected from the group consisting of microcrystalline cellulose, lactose, starch, mannitol, glucose, sorbitol, dextrin, and sucrose may be used, but is not limited thereto.
緩釋部分可進一步包含潤滑劑。The sustained release portion may further comprise a lubricant.
潤滑劑用以改善製劑之成形性。舉例而言，可使用選自由輕質無水矽酸、二氧化矽、滑石粉、硬脂酸、硬脂酸鎂或其混合物組成之群組中的一者或更多者，但不限於此。Lubricants are used to improve the formability of the formulation. For example, one or more selected from the group consisting of light anhydrous citric acid, cerium oxide, talc, stearic acid, magnesium stearate or a mixture thereof may be used, but is not limited thereto.
除了依托必利或其醫藥學上可接受之鹽以外，緩釋部分可進一步包含防止製劑氧化的抗氧化劑、加味劑、防腐劑、芳香劑、甜味劑、著色劑、pH調節劑及黏度控制劑。In addition to etodoride or a pharmaceutically acceptable salt thereof, the sustained release portion may further comprise an antioxidant, an odorant, a preservative, a fragrance, a sweetener, a colorant, a pH adjuster, and a viscosity control for preventing oxidation of the preparation. Agent.
本揭示案之製劑之速釋部分可包含：依托必利或依托必利之醫藥學上可接受之鹽；以及醫藥學上可接受之填充劑。速釋部分可進一步包含崩解劑、潤滑劑等。The immediate release portion of the formulation of the present disclosure may comprise: a pharmaceutically acceptable salt of etidride or etopride; and a pharmaceutically acceptable filler. The immediate release portion may further contain a disintegrant, a lubricant, and the like.
崩解劑、潤滑劑等可以均勻分散在速釋部分中的形式存在。A disintegrant, a lubricant, or the like may be present in a form uniformly dispersed in the immediate release portion.
舉例而言，可使用選自由交聯之羧甲基纖維素鈉、羥甲基纖維素鈣、羥甲基纖維素鈉、交聯聚乙烯吡咯酮、澱粉、共聚乙烯吡咯酮及低取代羥丙基纖維素組成之群組中的一者或更多者作為崩解劑。具體而言，可使用交聯之羥甲基纖維素鈉。For example, a sodium carboxymethylcellulose selected from the group consisting of crosslinked carboxymethylcellulose sodium, hydroxymethylcellulose calcium, sodium carboxymethylcellulose, crosslinked polyvinylpyrrolidone, starch, copolyvinylpyrrolidone, and low substituted hydroxypropyl can be used. One or more of the group of base cellulose compositions acts as a disintegrant. Specifically, crosslinked hydroxymethylcellulose sodium can be used.
包含在速釋部分中的填充劑與包含在緩釋部分中的填充劑可為相同或不同的。The filler contained in the immediate release portion may be the same as or different from the filler contained in the sustained release portion.
本揭示案提供使用胃滯留藥物遞送系統的口服製劑，此口服製劑同時包含：(a)緩釋部分，包含：依托必利或其醫藥學上可接受之鹽作為活性成分；緩釋聚合物；CO2 源；有機酸；及醫藥學上可接受之填充劑；以及(b)速釋部分，包含：依托必利或其醫藥學上可接受之鹽；及醫藥學上可接受之填充劑。口服製劑同時具有緩釋部分與速釋部分。具體而言，緩釋部分與速釋部分可獨立地以彼此分離的形式存在於膠囊中。緩釋部分與速釋部分兩者可為顆粒或片劑形式，或緩釋部分與速釋部分中僅一者可為片劑形式。具體而言，緩釋部分與速釋部分兩者皆可為片劑形式。The present disclosure provides an oral preparation using a gastric retention drug delivery system, the oral preparation comprising: (a) a sustained release portion comprising: etoiride or a pharmaceutically acceptable salt thereof as an active ingredient; a sustained release polymer; a CO 2 source; an organic acid; and a pharmaceutically acceptable filler; and (b) an immediate release portion comprising: etodoride or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable filler. The oral preparation has both a sustained release portion and an immediate release portion. Specifically, the sustained release portion and the immediate release portion may be independently present in the capsule in a form separated from each other. Both the sustained release portion and the immediate release portion may be in the form of granules or tablets, or only one of the sustained release portion and the immediate release portion may be in the form of a tablet. Specifically, both the sustained release portion and the immediate release portion may be in the form of a tablet.
當膠囊中的速釋部分與緩釋部分兩者皆為片劑形式時，胃液中可能良好地發生起泡，並且可預期緩釋。具體而言，緩釋部分與速釋部分兩者皆可為片劑形式。When both the immediate release portion and the sustained release portion of the capsule are in the form of tablets, foaming may occur well in the gastric juice, and sustained release may be expected. Specifically, both the sustained release portion and the immediate release portion may be in the form of a tablet.
具體而言，製劑可包含鹽酸依托必利作為活性成分。包含在緩釋部分(a)中的鹽酸依托必利之含量可比包含在速釋部分(b)中的鹽酸依托必利之含量高3倍至5倍，具體而言高3.5倍至4.5倍。具體而言，包含在緩釋部分(a)中的鹽酸依托必利之含量可為包含在速釋部分(b)中的鹽酸依托必利之重量的4倍。在此範圍內，可實現允許每日一次給藥的緩釋，同時提供快速效果。Specifically, the preparation may contain etodoride hydrochloride as an active ingredient. The content of etopride hydrochloride contained in the sustained-release portion (a) may be 3 to 5 times higher than the content of etopride hydrochloride contained in the immediate release portion (b), specifically 3.5 to 4.5 times higher. Specifically, the content of etopride hydrochloride contained in the sustained-release portion (a) may be 4 times the weight of the etotopril hydrochloride contained in the immediate release portion (b). Within this range, sustained release allowing one administration per day can be achieved while providing a rapid effect.
藉由以例如片劑形式配製速釋部分與緩釋部分，可將包含本揭示案之緩釋部分與速釋部分的製劑提供為口服投藥形式。舉例而言，可將其提供為硬膠囊製劑，其中將緩釋部分與速釋部分混合在一起。The formulation comprising the sustained release portion and the immediate release portion of the present disclosure can be provided in an oral administration form by formulating the immediate release portion and the sustained release portion, for example, in the form of a tablet. For example, it can be provided as a hard capsule preparation in which a sustained release portion and an immediate release portion are mixed together.
在示例性實施例中，本揭示案提供一種用於每日一次口服投藥的藥物製劑，此藥物製劑包含： (a)緩釋部分，包含：以緩釋部分之總重量計，40重量%至70重量%之鹽酸依托必利；17重量%至30重量%之羥丙基甲基纖維素；10重量%至25重量%之微晶纖維素、乳糖、澱粉、磷酸一氫鈣或其混合物作為填充劑；1重量%至10重量%之碳酸鈉、碳酸鉀、碳酸氫鈉、碳酸氫鉀或其混合物作為CO2 源；1重量%至10重量%之草酸、順丁烯二酸、反丁烯二酸、蘋果酸、酒石酸、檸檬酸、苯甲酸或其混合物作為有機酸；及0.1重量%至5重量%之硬脂酸鎂、硬脂酸、輕質無水矽酸或其混合物作為潤滑劑；以及 (b)速釋部分，包含：以速釋部分之總重量計，30重量%至60重量%之鹽酸依托必利；20重量%至45重量%之微晶纖維素、乳糖、澱粉、磷酸一氫鈣或其混合物作為填充劑；18重量%至30重量%之交聯之羥甲基纖維素鈉；及0.1重量%至5重量%之輕質無水矽酸、硬脂酸鎂、硬脂酸或其混合物作為潤滑劑。In an exemplary embodiment, the present disclosure provides a pharmaceutical preparation for oral administration once a day, the pharmaceutical preparation comprising: (a) a sustained release portion comprising: 40% by weight to the total weight of the sustained release portion 70% by weight of etotopril hydrochloride; 17% by weight to 30% by weight of hydroxypropylmethylcellulose; 10% by weight to 25% by weight of microcrystalline cellulose, lactose, starch, calcium monohydrogen phosphate or a mixture thereof Filler; 1% by weight to 10% by weight of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or a mixture thereof as a source of CO 2 ; 1% by weight to 10% by weight of oxalic acid, maleic acid, counter-butyl Adipic acid, malic acid, tartaric acid, citric acid, benzoic acid or a mixture thereof as an organic acid; and 0.1% by weight to 5% by weight of magnesium stearate, stearic acid, light anhydrous citric acid or a mixture thereof as a lubricant And (b) an immediate release portion comprising: from 30% by weight to 60% by weight, based on the total weight of the immediate release portion, of etotopril; 20% by weight to 45% by weight of microcrystalline cellulose, lactose, starch, Calcium monohydrogen phosphate or a mixture thereof as a filler; 18% to 30% by weight of crosslinked hydroxy Sodium carboxymethyl cellulose; and 0.1% to 5% by weight of light anhydrous silicate, magnesium stearate, stearic acid or mixtures thereof as a lubricant.
具體而言，本揭示案提供一種用於每日一次口服投藥的藥物製劑，此藥物製劑包含： (a)緩釋部分，包含：以緩釋部分之總重量計，45重量%至60重量%之鹽酸依托必利；20重量%至25重量%之羥丙基甲基纖維素；12重量%至20重量%之微晶纖維素、乳糖、澱粉、磷酸一氫鈣或其混合物作為填充劑；3.5重量%至8重量%之碳酸鈉、碳酸鉀、碳酸氫鈉、碳酸氫鉀或其混合物作為CO2 源；3重量%至6重量%之草酸、順丁烯二酸、反丁烯二酸、蘋果酸、酒石酸、檸檬酸、苯甲酸或其混合物作為有機酸；及0.5重量%至3重量%之硬脂酸鎂、硬脂酸、輕質無水矽酸或其混合物作為潤滑劑；以及 (b)速釋部分，包含：以速釋部分之總重量計，35重量%至50重量%之鹽酸依托必利；25重量%至40重量%之微晶纖維素、乳糖、澱粉、磷酸一氫鈣或其混合物作為填充劑；20重量%至28重量%之交聯之羥甲基纖維素鈉；及0.5重量%至2重量%之輕質無水矽酸、硬脂酸鎂、硬脂酸或其混合物作為潤滑劑。In particular, the present disclosure provides a pharmaceutical preparation for oral administration once a day, the pharmaceutical preparation comprising: (a) a sustained release portion comprising: 45% to 60% by weight based on the total weight of the sustained release portion Etotopril hydrochloride; 20% to 25% by weight of hydroxypropyl methylcellulose; 12% to 20% by weight of microcrystalline cellulose, lactose, starch, monohydrogen phosphate or a mixture thereof as a filler; 3.5% to 8% by weight of sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate or a mixture thereof as a source of CO 2 ; 3 to 6% by weight of oxalic acid, maleic acid, fumaric acid , malic acid, tartaric acid, citric acid, benzoic acid or a mixture thereof as an organic acid; and 0.5% by weight to 3% by weight of magnesium stearate, stearic acid, light anhydrous citric acid or a mixture thereof as a lubricant; b) an immediate release portion comprising: 35 to 50% by weight of etodoride hydrochloride, based on the total weight of the immediate release portion; 25% to 40% by weight of microcrystalline cellulose, lactose, starch, monohydrogen phosphate Calcium or a mixture thereof as a filler; 20% to 28% by weight of crosslinked hydroxymethyl fibers Sodium; and 0.5 wt% to 2% by weight of light anhydrous silicate, magnesium stearate, stearic acid or mixtures thereof as a lubricant.
在本揭示案之特定示例性實施例中，緩釋部分可包含至少兩個片劑，例如2、3、4、5、6個或更多個片劑。更具體而言，緩釋部分可由2個片劑組成。In certain exemplary embodiments of the present disclosure, the sustained release portion may comprise at least two tablets, such as 2, 3, 4, 5, 6 or more tablets. More specifically, the sustained release portion may consist of 2 tablets.
具體而言，本揭示案之製劑可為包含兩個分離的片劑作為緩釋部分與一個片劑作為速釋部分的硬膠囊製劑。Specifically, the preparation of the present disclosure may be a hard capsule preparation comprising two separate tablets as a sustained release portion and one tablet as an immediate release portion.
緩釋部分(a)可包含兩個片劑，每個片劑包含55-65 mg之鹽酸依托必利，且速釋部分(b)可包含20-40 mg之鹽酸依托必利。The sustained release portion (a) may comprise two tablets, each tablet containing 55-65 mg of etopride hydrochloride, and the immediate release portion (b) may comprise 20-40 mg of etopride hydrochloride.
在另一示例性實施例中，本揭示案可提供一種用於製備包含依托必利或其醫藥學上可接受之鹽作為活性成分的製劑的方法。In another exemplary embodiment, the present disclosure may provide a method for preparing a formulation comprising etoriride or a pharmaceutically acceptable salt thereof as an active ingredient.
在示例性實施例中，此方法可包括： (S1)將緩釋部分製備成片劑之步驟，此緩釋部分包含依托必利或其醫藥學上可接受之鹽、緩釋聚合物、CO2 源、有機酸及醫藥學上可接受之填充劑； (S2)將速釋部分製備成片劑之步驟，此速釋部分包含依托必利或其醫藥學上可接受之鹽及醫藥學上可接受之填充劑；以及 (S3)製備製劑之步驟，此製劑包含片劑緩釋部分與速釋部分，其中分離且獨立地填充緩釋部分與速釋部分。In an exemplary embodiment, the method may comprise: (S1) the step of preparing the sustained-release portion into a tablet, the sustained-release portion comprising etomiride or a pharmaceutically acceptable salt thereof, a sustained-release polymer, CO 2 source, organic acid and pharmaceutically acceptable filler; (S2) a step of preparing the immediate release portion into tablets, the immediate release portion comprising etoriride or a pharmaceutically acceptable salt thereof and medicinal An acceptable filler; and (S3) a step of preparing a formulation comprising a tablet sustained release portion and an immediate release portion, wherein the sustained release portion and the immediate release portion are separately and independently filled.
用於製備片劑的方法並未特別限制，且可使用本領域熟習技術者常用的任何方法。The method for preparing the tablet is not particularly limited, and any method commonly used by those skilled in the art can be used.
在將緩釋部分製備成片劑之步驟(S1)中，可將緩釋部分製備成至少兩個片劑。In the step (S1) of preparing the sustained-release portion into a tablet, the sustained-release portion may be prepared into at least two tablets.
在製備製劑之步驟(S3)中，製劑並未特別限制。製劑可具體而言為膠囊製劑，更具體而言為硬膠囊製劑。In the step (S3) of preparing the preparation, the preparation is not particularly limited. The formulation may in particular be a capsule formulation, more specifically a hard capsule formulation.
在示例性實施例中，本揭示案提供一種用於每日一次口服投藥的製劑，此製劑包含鹽酸依托必利作為活性成分，從而允許同時自基質聚合物速釋鹽酸依托必利以及緩釋鹽酸依托必利。In an exemplary embodiment, the present disclosure provides a formulation for oral administration once daily, which comprises etofride hydrochloride as an active ingredient, thereby allowing simultaneous release of etopride hydrochloride and sustained release hydrochloric acid from a matrix polymer. Relying on Tony.
製劑可具有以下溶解曲線。The formulation may have the following dissolution profile.
可將製劑提供為每日一次口服投藥的製劑，並且在使用900 mL之pH 1.2緩衝液作為溶解介質在50 rpm之攪拌槳旋轉速度下量測時，製劑中的鹽酸依托必利之溶解率可為30分鐘內15%至40%，3小時內41%至70%，且9小時內80%或更高。The preparation may be provided as a preparation for oral administration once a day, and when 900 mL of pH 1.2 buffer is used as a dissolution medium and measured at a stirring paddle rotation speed of 50 rpm, the dissolution rate of etoride hydrochloride in the preparation may be 15% to 40% in 30 minutes, 41% to 70% in 3 hours, and 80% or higher in 9 hours.
當實施根據本揭示案的溶解測試時，上述條件及其他特定條件應遵守韓國藥典、美國藥典或其他國際標準。When carrying out the dissolution test according to the present disclosure, the above conditions and other specific conditions are to comply with the Korean Pharmacopoeia, the United States Pharmacopoeia or other international standards.
作為調查製劑之藥物溶解曲線及藥物動力學來研究藥物（依托必利或其醫藥學上可接受之鹽）在人體內的效果的結果，已證實依托必利或其醫藥學上可接受之鹽的藥物動力學取決於活體外溶解模式而變化，並且在活體內實現優異的藥理活性及生物利用率。As a result of investigating the drug dissolution profile and pharmacokinetics of the formulation to study the effect of the drug (etoride or its pharmaceutically acceptable salt) in the human body, it has been confirmed that it is a pharmaceutically acceptable salt thereof. The pharmacokinetics vary depending on the in vitro dissolution pattern and achieve excellent pharmacological activity and bioavailability in vivo.
本揭示案中所使用之術語「T最大 」係指達到最大血漿濃度的時間（至峰值血漿濃度的時間），且意謂從投予本揭示案之藥物製劑直到藥物（鹽酸依托必利）之血漿濃度變成最大之間的時間。As used in this disclosure the term "T max" means time to maximum plasma concentration (time to peak plasma concentration), and the means from the administration of the present case discloses a pharmaceutical formulation until the drug (hydrochloride relying cisapride) of The plasma concentration becomes the time between the maximum.
本揭示案中所使用之術語「C最大 」係指最大血漿濃度且意謂在投予本揭示案之藥物製劑後藥物（鹽酸依托必利）之最大血漿濃度。As used in this disclosure the term "C Maximum" means maximum plasma concentration of the drug and the means (relying cisapride hydrochloride) after administration of the present case discloses a pharmaceutical formulation of the maximum plasma concentration.
本揭示案中所使用之術語「AUC」係指血漿濃度-時間曲線下的面積。在藥物動力學中，術語「AUC」係指藉由繪製有益藥劑（藥物或活性成分）之血清濃度對比從投藥開始直到投藥開始後的時間「t」之間的時間來獲得的曲線下面積。通常，AUC為貫穿整個投藥期間的曲線下面積。AUC可藉由分析受試者之血清樣本來獲得。The term "AUC" as used in this disclosure refers to the area under the plasma concentration-time curve. In pharmacokinetics, the term "AUC" refers to the area under the curve obtained by plotting the serum concentration of a beneficial agent (drug or active ingredient) versus the time from the start of administration until the time "t" after the start of administration. Typically, the AUC is the area under the curve throughout the entire administration period. AUC can be obtained by analyzing a serum sample of a subject.
本揭示案之藥物製劑（其包含依托必利或其醫藥學上可接受之鹽）確保了藥物之速釋與藥物之緩釋兩者，速釋允許足量的藥物在初期階段快速地暴露，而緩釋相當於3次用藥。亦即，本揭示案提供了一種用於口服投藥的製劑，此製劑展示出速釋與緩釋之效果。在投予製劑後，經由依托必利或其醫藥學上可接受之鹽的非常高的初始釋放速率，實現對足量藥物的暴露，亦即，C最大 增加，至峰值血漿濃度的時間減少，以及初始AUC增加。The pharmaceutical preparation of the present disclosure, which comprises etomiride or a pharmaceutically acceptable salt thereof, ensures both immediate release of the drug and sustained release of the drug, and immediate release allows a sufficient amount of the drug to be rapidly exposed at an early stage, Slow release is equivalent to 3 doses. That is, the present disclosure provides a preparation for oral administration which exhibits an immediate release and sustained release effect. After administration of the formulation, exposure to a sufficient amount of drug is achieved via a very high initial release rate of etoride or a pharmaceutically acceptable salt thereof, that is, a maximum increase in C and a decrease in the time to peak plasma concentration, And the initial AUC increase.
與現有製劑需要每日三次投藥不同，本揭示案之製劑可經由每日一次口服投藥方便服藥。 有利效果Unlike the existing preparations which require three times a day, the preparation of the present disclosure can be conveniently administered by oral administration once a day. Favorable effect
根據本揭示案的藥物製劑具有優良的藥物便利性，因為可每日用藥一次。The pharmaceutical preparation according to the present disclosure has excellent drug convenience because it can be administered once a day.
當投藥給人體時，本揭示案之藥物製劑可實現速釋和緩釋效果兩者。When administered to a human, the pharmaceutical preparation of the present disclosure can achieve both immediate release and sustained release effects.
本揭示案之製劑可減少由血液濃度快速增加引起的副作用。The formulations of the present disclosure can reduce side effects caused by a rapid increase in blood concentration.
最佳模式Best mode
在下文中，將參照隨附圖式詳細描述本揭示案之較佳實施例。在描述之前，應理解，本說明書及隨附申請專利範圍中所使用之術語不應視為限於通用及詞典含義，而是在允許發明人為了最佳解釋而適當定義術語的原則基礎上基於與本揭示案之技術態樣相對應的含義與概念來解讀。因此，本文所提出之描述僅僅為出於說明目的之較佳實例，而不意欲限制本揭示案之範疇，因此應理解，可在不脫離本揭示案之範疇的情況下實施其他等效物及修改。DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, preferred embodiments of the present disclosure will be described in detail with reference to the accompanying drawings. Before the description, it should be understood that the terms used in the specification and the accompanying claims should not be construed as limited to the general and dictionary meanings, but rather based on the principle that the inventor is allowed to define the terms appropriately for the best explanation. The meaning and concept of the technical aspects of this disclosure are interpreted. Therefore, the descriptions of the present invention are intended to be illustrative only, and are not intended to limit the scope of the disclosure, and it is understood that other equivalents may be implemented without departing from the scope of the disclosure. modify.
＜API之製備＞- 化合物名稱：N-[[4-[2-(二甲基胺基)乙氧基]苯基]甲基]-3,4-二甲氧基苯甲醯胺鹽酸鹽，C2 0H27 ClN2 O4 。 - 分子量(M.W.)：394.89。 - 溶解性：溶於水(≧48 mg/mL)、甲醇或乙酸。<Preparation of API> - Compound name: N-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-3,4-dimethoxybenzamide hydrochloride, C 2 0H 27 ClN 2 O 4 . - Molecular weight (MW): 394.89. - Solubility: soluble in water (≧48 mg/mL), methanol or acetic acid.
＜製備實例1＞顆粒型膠囊<Preparation Example 1> Granular capsule
1.處方（批號：P01）1. Prescription (batch number: P01)
將150 mg之鹽酸依托必利製備成具有以下組合物的硬膠囊製劑。150 mg of etotopril hydrochloride was prepared into a hard capsule preparation having the following composition.
表1
將鹽酸依托必利及微晶纖維素混合，並經由30目篩篩分。與此分開地，將白糖、聚乙烯吡咯酮及聚山梨醇酯80溶於80%乙醇中用作黏合劑溶液。將鹽酸依托必利混合物添加至黏合劑溶液，並製備成濕顆粒。使用擠壓機擠出濕顆粒。使用滾圓機將擠出顆粒滾圓。將滾圓的顆粒在60℃的乾燥器中乾燥4小時。將乾燥產物添加至流化床處理器並使用塗覆溶液實施緩釋包衣，在此塗覆溶液中使乙基纖維素、檸檬酸三乙酯及滑石粉溶解並分散在80%乙醇中。Etotopril hydrochloride and microcrystalline cellulose were mixed and sieved through a 30 mesh sieve. Separately, white sugar, polyvinylpyrrolidone and polysorbate 80 were dissolved in 80% ethanol for use as a binder solution. The ittoride hydrochloride mixture was added to the binder solution and prepared into wet granules. The wet granules were extruded using an extruder. The extruded pellets were rounded using a spheronizer. The spheronized granules were dried in a drier at 60 ° C for 4 hours. The dried product was added to a fluidized bed processor and a sustained release coating was carried out using the coating solution, in which ethyl cellulose, triethyl citrate and talc were dissolved and dispersed in 80% ethanol.
第2圖繪示包含根據製備實例1所製備之依托必利顆粒的膠囊製劑。Fig. 2 is a view showing a capsule preparation containing the etofride particles prepared according to Preparation Example 1.
2.特性2. Characteristics
(1) 溶解率(1) Dissolution rate
溶解率係藉由攪拌槳測試法在pH 1.2及50 rpm下量測。The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.
結果展示於第3圖及表2中。The results are shown in Figure 3 and Table 2.
表2
與可商購之Ganaton相比，緩釋是可能的，並且在約4至5小時處實現80%或更高之溶解率。Sustained release is possible compared to commercially available Ganaton, and a dissolution rate of 80% or higher is achieved at about 4 to 5 hours.
(2) 藥物動力學參數(2) Pharmacokinetic parameters
表3
製備實例1中所製備之製劑展示出比可商購之Ganaton更高的生物利用率。低AUC（曲線下面積）及C最大 （最大濃度）可能是因為顆粒之表面上的水不溶性塗層並未漂浮在胃腸道中。The formulation prepared in Preparation Example 1 exhibited a higher bioavailability than the commercially available Ganaton. Low AUC (area under the curve) and Cmax (maximum concentration) may be because the water insoluble coating on the surface of the particles does not float in the gastrointestinal tract.
為解決此問題，使用親水性聚合物及CO2 源將顆粒變成迷你片劑，同時減小顆粒密度及增加漂浮及黏附到胃腸道黏膜的時間。To solve this problem, the hydrophilic polymer and the CO 2 source are used to convert the particles into mini-tablets while reducing the particle density and increasing the time of floating and adhering to the gastrointestinal mucosa.
＜製備實例2＞迷你片劑型膠囊<Preparation Example 2> Mini tablet type capsule
1.處方（批號：M02-1）1. Prescription (batch number: M02-1)
將150 mg之鹽酸依托必利製備成包含約2 mm大小之迷你片劑的硬膠囊製劑，具有以下組合物。150 mg of etotopril hydrochloride was prepared as a hard capsule preparation containing mini tablets of about 2 mm size, with the following composition.
表4
將鹽酸依托必利、微晶纖維素及羥丙甲纖維素混合，經由30目篩篩分，使用80%乙醇製備成濕顆粒，並隨後在60℃的乾燥器中乾燥4小時。將乾燥產物製備成18目顆粒，並隨後藉由添加硬脂酸鎂使用旋轉壓片機來製備成片劑。將製備的迷你片劑裝入膠囊中。Ettoride hydrochloride, microcrystalline cellulose, and hypromellose were mixed, sieved through a 30 mesh sieve, wet granules were prepared using 80% ethanol, and then dried in a drier at 60 ° C for 4 hours. The dried product was prepared into 18-mesh granules, and then prepared into tablets by the use of a rotary tableting machine by adding magnesium stearate. The prepared mini tablets were placed in capsules.
第6圖繪示包含根據製備實例2所製備之依托必利迷你片劑的膠囊製劑。Fig. 6 is a view showing a capsule preparation comprising an etalride mini tablet prepared according to Preparation Example 2.
2.特性2. Characteristics
(1)溶解率(1) Dissolution rate
溶解率係藉由攪拌槳測試法在pH 1.2及50 rpm下量測。The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.
結果展示於第7圖及表5中。The results are shown in Figure 7 and Table 5.
表5
儘管與可商購之Ganaton相比，製備實例2的緩釋是可能的，但由於高初始釋放速率，製備實例2難以用作控釋製劑。Although the sustained release of Preparation Example 2 was possible as compared with the commercially available Ganaton, Preparation Example 2 was difficult to use as a controlled release preparation due to a high initial release rate.
(2)藥物動力學參數(2) Pharmacokinetic parameters
表6展示製備實例2的藥物動力學參數。Table 6 shows the pharmacokinetic parameters of Preparation Example 2.
表6
可看出，與可商購之Ganaton相比，製備實例2同時展示出較高的AUC（曲線下面積）及C最大 （最大濃度）值。此可能是由於製劑之漂浮與膨脹。As can be seen, compared to the commercially available Ganaton, Preparation Example 2 while demonstrating higher AUC (area under the curve) and Maximum C (maximum concentration) values. This may be due to the floating and swelling of the formulation.
＜製備實例3＞迷你片劑型膠囊<Preparation Example 3> Mini tablet type capsule
1.處方（批號：M02-2）1. Prescription (batch number: M02-2)
將150 mg之鹽酸依托必利製備成包含約2 mm大小之迷你片劑的硬膠囊製劑，具有以下組合物。150 mg of etotopril hydrochloride was prepared as a hard capsule preparation containing mini tablets of about 2 mm size, with the following composition.
表7
將鹽酸依托必利、棕櫚基硬脂酸甘油酯及羥丙甲纖維素混合，並經由30目篩篩分。使用流化床處理器將混合物加熱至80℃或更高。在熔化、冷卻及隨後製備成30目顆粒後，使用80%乙醇將混合物製備成濕顆粒，並隨後在60℃的乾燥器中乾燥4小時。將乾燥產物製備成18目顆粒，並隨後藉由添加碳酸氫鈉及硬脂酸鎂使用旋轉壓片機來製備成片劑。將製備的迷你片劑裝入膠囊中。Etotopril hydrochloride, palmityl stearin and hypromellose were mixed and sieved through a 30 mesh sieve. The mixture was heated to 80 ° C or higher using a fluidized bed processor. After melting, cooling and subsequent preparation into 30-mesh particles, the mixture was prepared into wet granules using 80% ethanol, and then dried in a drier at 60 ° C for 4 hours. The dried product was prepared into 18-mesh granules, and then prepared into tablets by the use of a rotary tableting machine by adding sodium hydrogencarbonate and magnesium stearate. The prepared mini tablets were placed in capsules.
第6圖繪示包含根據製備實例3所製備之依托必利迷你片劑的膠囊製劑。Fig. 6 is a view showing a capsule preparation comprising an etalride mini tablet prepared according to Preparation Example 3.
2.特性2. Characteristics
(1)溶解率(1) Dissolution rate
溶解率係藉由攪拌槳測試法在pH 1.2及50 rpm下量測。The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.
結果展示於第10圖及表8中。The results are shown in Figure 10 and Table 8.
表8
與Ganaton相比，觀察到在溶解率方面沒有顯著差異。No significant difference in dissolution rate was observed compared to Ganaton.
(2)藥物動力學參數(2) Pharmacokinetic parameters
表9展示製備實例3的藥物動力學參數。Table 9 shows the pharmacokinetic parameters of Preparation Example 3.
表9
已證實AUC及C最大 的增加。此可能是由於使用了幫助製劑膨脹及漂浮的成分。然而，由於使用了許多添加劑，難以將片劑裝入膠囊中，且生產率下降。另外，製備實例3中使用的脂質對迷你片劑製劑之生產率或經濟效率產生不利影響。The largest increase in AUC and C has been confirmed. This may be due to the use of ingredients that help the formulation swell and float. However, since many additives are used, it is difficult to put a tablet into a capsule, and productivity is lowered. In addition, the lipids used in the preparation of Example 3 adversely affected the productivity or economic efficiency of the mini tablet formulation.
＜製備實例4＞ SR片劑型膠囊<Preparation Example 4> SR tablet type capsule
1.處方（批號：T03-1）1. Prescription (batch number: T03-1)
將150 mg之鹽酸依托必利製備成三個SR片劑，並裝入膠囊製劑中。150 mg of etotopril hydrochloride was prepared into three SR tablets and filled into capsule preparations.
表10
將鹽酸依托必利、微晶纖維素、羥丙甲纖維素及聚乙烯吡咯酮混合，經由30目篩篩分，使用80%乙醇製備成濕顆粒，並隨後在60℃的乾燥器中乾燥4小時。將乾燥產物製備成18目顆粒，並隨後藉由添加硬脂酸鎂使用旋轉壓片機來製備成片劑。Etotopril hydrochloride, microcrystalline cellulose, hypromellose and polyvinylpyrrolidone were mixed, sieved through a 30 mesh sieve, prepared into wet granules using 80% ethanol, and then dried in a dryer at 60 ° C. 4 hour. The dried product was prepared into 18-mesh granules, and then prepared into tablets by the use of a rotary tableting machine by adding magnesium stearate.
將製備的片劑裝入膠囊中。The prepared tablets were filled into capsules.
第13圖繪示包含根據製備實例4所製備之三個依托必利SR片劑的膠囊製劑。Figure 13 is a view showing a capsule preparation containing three etopride SR tablets prepared according to Preparation Example 4.
2.特性2. Characteristics
(1)溶解率(1) Dissolution rate
溶解率係藉由攪拌槳測試法在pH 1.2及50 rpm下量測。The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.
結果展示於第14圖及表11中。已證實溶解率的下降。The results are shown in Figure 14 and Table 11. A decrease in the dissolution rate has been confirmed.
表11
(2)藥物動力學參數(2) Pharmacokinetic parameters
表12展示製備實例4的藥物動力學參數。Table 12 shows the pharmacokinetic parameters of Preparation Example 4.
表12
據信，由於非常低的溶解率，BE（生物等效性）將為低的。It is believed that BE (bioequivalence) will be low due to very low dissolution rates.
＜製備實例5＞ SR片劑型膠囊<Preparation Example 5> SR tablet type capsule
1.處方（批號：T03-2）1. Prescription (batch number: T03-2)
將150 mg之鹽酸依托必利製備成三個SR片劑，並裝入膠囊製劑中。150 mg of etotopril hydrochloride was prepared into three SR tablets and filled into capsule preparations.
表13
將鹽酸依托必利、微晶纖維素、羥丙甲纖維素及乳糖混合，經由30目篩篩分，使用80%乙醇製備成濕顆粒，並隨後在60℃的乾燥器中乾燥4小時。將乾燥產物製備成18目顆粒，並隨後藉由添加碳酸氫鈉及硬脂酸鎂使用旋轉壓片機來製備成片劑。將製備的片劑裝入膠囊中。Etotopril hydrochloride, microcrystalline cellulose, hypromellose and lactose were mixed, sieved through a 30 mesh sieve, wet granules were prepared using 80% ethanol, and then dried in a drier at 60 ° C for 4 hours. The dried product was prepared into 18-mesh granules, and then prepared into tablets by the use of a rotary tableting machine by adding sodium hydrogencarbonate and magnesium stearate. The prepared tablets were filled into capsules.
第13圖繪示包含根據製備實例5所製備之三個依托必利SR片劑的膠囊製劑。Fig. 13 is a view showing a capsule preparation comprising three etopride SR tablets prepared according to Preparation Example 5.
2.特性2. Characteristics
(1)溶解率(1) Dissolution rate
溶解率係藉由攪拌槳測試法在pH 1.2及50 rpm下量測。The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.
結果展示於第14圖及表14中。The results are shown in Figure 14 and Table 14.
表14
(2)藥物動力學參數(2) Pharmacokinetic parameters
表15展示製備實例5的藥物動力學參數。Table 15 shows the pharmacokinetic parameters of Preparation Example 5.
表15
與製備實例4相比，製備實例5之製劑展示出增加的溶解率及略微增加的生物利用率。The formulation of Preparation Example 5 exhibited an increased dissolution rate and a slightly increased bioavailability compared to Preparation Example 4.
＜製備實例6＞ SR片劑型膠囊<Preparation Example 6> SR tablet type capsule
1.處方（批號：T03-3）1. Prescription (batch number: T03-3)
將150 mg之鹽酸依托必利製備成三個SR片劑，並裝入膠囊製劑中。用與製備實例5中相同的方法製備製劑。150 mg of etotopril hydrochloride was prepared into three SR tablets and filled into capsule preparations. The preparation was prepared in the same manner as in Preparation Example 5.
表16
第13圖繪示包含根據製備實例6所製備之三個依托必利SR片劑的膠囊製劑。Fig. 13 is a view showing a capsule preparation comprising three etopride SR tablets prepared according to Preparation Example 6.
2.特性2. Characteristics
(1)溶解率(1) Dissolution rate
溶解率係藉由攪拌槳測試法在pH 1.2及50 rpm下量測。The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.
結果展示於第20圖及表17中。The results are shown in Figure 20 and Table 17.
表17
與製備實例3相比，已證實溶解率的下降。A decrease in the dissolution rate was confirmed as compared with Preparation Example 3.
(2)藥物動力學參數(2) Pharmacokinetic parameters
表18展示製備實例6的藥物動力學參數。Table 18 shows the pharmacokinetic parameters of Preparation Example 6.
表18
儘管製備實例6之製劑展示出溶解率下降，但AUC值接近目標值。速釋製劑被認為可改善C最大 。Although the preparation of Preparation Example 6 exhibited a decrease in the dissolution rate, the AUC value was close to the target value. Immediate release formulations are believed to improve Cmax .
＜製備實例7＞ IR與SR片劑型膠囊<Preparation Example 7> IR and SR tablet type capsules
1.處方（批號：T04-1）1. Prescription (batch number: T04-1)
將150 mg之鹽酸依托必利製備成兩個SR片劑及一個IR片劑，並裝入膠囊製劑中。在下表中，SR部分的含量為兩個片劑的總含量。150 mg of etotopril hydrochloride was prepared into two SR tablets and one IR tablet and filled into a capsule preparation. In the table below, the content of the SR portion is the total content of the two tablets.
表19
將鹽酸依托必利、微晶纖維素及羥丙甲纖維素、乳糖混合，經由30目篩篩分，使用80%乙醇製備成濕顆粒，並隨後在60℃的乾燥器中乾燥4小時。將乾燥產物製備成18目顆粒，並隨後藉由添加碳酸氫鈉及硬脂酸鎂使用旋轉壓片機來製備成兩個緩釋片劑。Etotopril hydrochloride, microcrystalline cellulose and hypromellose, lactose were mixed, sieved through a 30 mesh sieve, wet granules were prepared using 80% ethanol, and then dried in a drier at 60 ° C for 4 hours. The dried product was prepared into 18-mesh granules, and then two sustained-release tablets were prepared by adding a sodium hydrogencarbonate and magnesium stearate using a rotary tableting machine.
將鹽酸依托必利、微晶纖維素、乳糖、交聯之羧甲基纖維素鈉及輕質無水矽酸混合，經由30目篩篩分，使用80%乙醇製備成濕顆粒，並隨後在60℃的乾燥器中乾燥4小時。將乾燥產物製備成18目顆粒，並隨後藉由添加硬脂酸鎂使用旋轉壓片機來製備成片劑。將製備的速釋片劑與緩釋片劑一起裝入膠囊中。Ettoride hydrochloride, microcrystalline cellulose, lactose, crosslinked sodium carboxymethylcellulose and light anhydrous citric acid were mixed, sieved through a 30 mesh sieve, and wet granules were prepared using 80% ethanol, and then at 60 Dry in a desiccator at °C for 4 hours. The dried product was prepared into 18-mesh granules, and then prepared into tablets by the use of a rotary tableting machine by adding magnesium stearate. The prepared immediate release tablet is filled into a capsule together with the sustained release tablet.
第23圖繪示包含根據製備實例7所製備之兩個依托必利SR片劑及一個IR片劑的膠囊製劑。Figure 23 is a view showing a capsule preparation comprising two etopride SR tablets and an IR tablet prepared according to Preparation Example 7.
2.特性2. Characteristics
(1)溶解率(1) Dissolution rate
溶解率係藉由攪拌槳測試法在pH 1.2及50 rpm下量測。The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.
結果展示於第24圖及表20中。The results are shown in Figure 24 and Table 20.
表20
(2)藥物動力學參數(2) Pharmacokinetic parameters
表21展示製備實例7的藥物動力學參數。Table 21 shows the pharmacokinetic parameters of Preparation Example 7.
表21
已發現，儘管實現相當的C最大 ，但由於在胃腸道中的停留時間減少，AUC減小。It has been found, although quite achieve the maximum C, but due to reduced residence time in the gastrointestinal tract, AUC decreased.
＜製備實例8＞ IR與SR片劑型膠囊<Preparation Example 8> IR and SR tablet type capsules
1.處方（批號：T04-2）1. Prescription (batch number: T04-2)
將150 mg之鹽酸依托必利製備成兩個SR片劑及一個IR片劑，並裝入膠囊製劑中。在下表中，SR部分的含量為兩個片劑的總含量。150 mg of etotopril hydrochloride was prepared into two SR tablets and one IR tablet and filled into a capsule preparation. In the table below, the content of the SR portion is the total content of the two tablets.
表22
將鹽酸依托必利、微晶纖維素及羥丙甲纖維素、乳糖混合，經由30目篩篩分，使用80%乙醇製備成濕顆粒，並隨後在60℃的乾燥器中乾燥4小時。將乾燥產物製備成18目顆粒，並隨後藉由添加碳酸氫鈉及硬脂酸鎂使用旋轉壓片機來製備成兩個緩釋片劑。Etotopril hydrochloride, microcrystalline cellulose and hypromellose, lactose were mixed, sieved through a 30 mesh sieve, wet granules were prepared using 80% ethanol, and then dried in a drier at 60 ° C for 4 hours. The dried product was prepared into 18-mesh granules, and then two sustained-release tablets were prepared by adding a sodium hydrogencarbonate and magnesium stearate using a rotary tableting machine.
將鹽酸依托必利、羥丙甲纖維素、微晶纖維素、乳糖、交聯之羧甲基纖維素鈉及碳酸氫鈉混合，經由30目篩篩分，使用80%乙醇製備成濕顆粒，並隨後在60℃的乾燥器中乾燥4小時。將乾燥產物製備成18目顆粒，藉由添加硬脂酸鎂使用旋轉壓片機來製備成片劑。將製備的速釋片劑與緩釋片劑一起裝入膠囊中。Ettoride hydrochloride, hypromellose hydrochloride, microcrystalline cellulose, lactose, crosslinked sodium carboxymethylcellulose and sodium hydrogencarbonate were mixed, sieved through a 30 mesh sieve, and wet granules were prepared using 80% ethanol. And then dried in a drier at 60 ° C for 4 hours. The dried product was prepared into 18-mesh pellets, which were prepared into tablets by the addition of magnesium stearate using a rotary tableting machine. The prepared immediate release tablet is filled into a capsule together with the sustained release tablet.
第23圖繪示包含根據製備實例8所製備之兩個依托必利SR片劑及一個IR片劑的膠囊製劑。Figure 23 is a view showing a capsule preparation comprising two etopride SR tablets and an IR tablet prepared according to Preparation Example 8.
2.特性2. Characteristics
(1)溶解率(1) Dissolution rate
溶解率係藉由攪拌槳測試法在pH 1.2及50 rpm下量測。The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.
結果展示於第28圖及表23中。The results are shown in Figure 28 and Table 23.
表23
(2)藥物動力學參數(2) Pharmacokinetic parameters
表24展示製備實例8的藥物動力學參數。Table 24 shows the pharmacokinetic parameters of Preparation Example 8.
表24
已證實，AUC增加，但C最大 減小。It has been shown to increase the AUC, but C maximum reduction.
＜製備實例9＞ IR與SR片劑型膠囊<Preparation Example 9> IR and SR tablet type capsules
1.處方（批號T04-3）1. Prescription (batch number T04-3)
將150 mg之鹽酸依托必利製備成兩個SR片劑及一個IR片劑，並裝入膠囊製劑中。在下表中，SR部分的含量為兩個片劑的總含量。150 mg of etotopril hydrochloride was prepared into two SR tablets and one IR tablet and filled into a capsule preparation. In the table below, the content of the SR portion is the total content of the two tablets.
表25
將鹽酸依托必利、微晶纖維素、羥丙甲纖維素、甘露醇及乳糖混合，經由30目篩篩分，使用80%乙醇製備成濕顆粒，並隨後在60℃的乾燥器中乾燥4小時。將乾燥產物製備成18目顆粒，並隨後藉由添加碳酸氫鈉及硬脂酸鎂使用旋轉壓片機來製備成兩個緩釋片劑。Etotopril hydrochloride, microcrystalline cellulose, hypromellose, mannitol and lactose were mixed, sieved through a 30 mesh sieve, wet granules were prepared using 80% ethanol, and then dried in a dryer at 60 ° C. 4 hour. The dried product was prepared into 18-mesh granules, and then two sustained-release tablets were prepared by adding a sodium hydrogencarbonate and magnesium stearate using a rotary tableting machine.
將鹽酸依托必利、羥丙甲纖維素、微晶纖維素、乳糖、交聯之羧甲基纖維素鈉、碳酸氫鈉及輕質無水矽酸混合，經由30目篩篩分，使用80%乙醇製備成濕顆粒，並隨後在60℃的乾燥器中乾燥4小時。將乾燥產物製備成18目顆粒，並隨後藉由添加硬脂酸鎂使用旋轉壓片機來製備成片劑。將製備的速釋片劑與緩釋片劑一起裝入膠囊中。Etoopril hydrochloride, hypromellose hydrochloride, microcrystalline cellulose, lactose, cross-linked sodium carboxymethylcellulose, sodium hydrogencarbonate and light anhydrous citric acid, sieved through a 30 mesh sieve, using 80% Ethanol was prepared into wet granules and then dried in a drier at 60 ° C for 4 hours. The dried product was prepared into 18-mesh granules, and then prepared into tablets by the use of a rotary tableting machine by adding magnesium stearate. The prepared immediate release tablet is filled into a capsule together with the sustained release tablet.
第36圖繪示包含根據製備實例9所製備之兩個SR片劑及一個IR片劑的膠囊製劑。Figure 36 is a view showing a capsule preparation comprising two SR tablets and one IR tablet prepared according to Preparation Example 9.
2.特性2. Characteristics
(1)溶解率(1) Dissolution rate
溶解率係藉由攪拌槳測試法在pH 1.2及50 rpm下量測。The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.
結果展示於第37圖及表26中。The results are shown in Figure 37 and Table 26.
表26
(2)藥物動力學參數(2) Pharmacokinetic parameters
表27展示製備實例9的藥物動力學參數。Table 27 shows the pharmacokinetic parameters of Preparation Example 9.
表27
儘管製備了各種製劑，但沒有展示出令人滿意的AUC及C最大 結果。Although various formulations were prepared, satisfactory AUC and C maximum results were not exhibited.
＜製備實例10＞ IR與SR片劑型膠囊<Preparation Example 10> IR and SR tablet type capsules
1.處方（批號：T05）1. Prescription (batch number: T05)
將150 mg之鹽酸依托必利製備成兩個SR片劑及一個IR片劑，並裝入膠囊製劑中。在下表中，SR部分的含量為兩個片劑的總含量。150 mg of etotopril hydrochloride was prepared into two SR tablets and one IR tablet and filled into a capsule preparation. In the table below, the content of the SR portion is the total content of the two tablets.
表28
將鹽酸依托必利、微晶纖維素及羥丙甲纖維素、乳糖混合，經由30目篩篩分，使用80%乙醇製備成濕顆粒，並隨後在60℃的乾燥器中乾燥4小時。將乾燥產物製備成18目顆粒，並隨後藉由添加碳酸氫鈉及硬脂酸鎂使用旋轉壓片機來製備成兩個緩釋片劑。Etotopril hydrochloride, microcrystalline cellulose and hypromellose, lactose were mixed, sieved through a 30 mesh sieve, wet granules were prepared using 80% ethanol, and then dried in a drier at 60 ° C for 4 hours. The dried product was prepared into 18-mesh granules, and then two sustained-release tablets were prepared by adding a sodium hydrogencarbonate and magnesium stearate using a rotary tableting machine.
將鹽酸依托必利、微晶纖維素、乳糖、交聯之羧甲基纖維素鈉及輕質無水矽酸混合，經由30目篩篩分，使用80%乙醇製備成濕顆粒，並隨後在60℃的乾燥器中乾燥4小時。將乾燥產物製備成18目顆粒，並隨後藉由添加硬脂酸鎂使用旋轉壓片機來製備成片劑。將製備的速釋片劑與緩釋片劑一起裝入膠囊中。Ettoride hydrochloride, microcrystalline cellulose, lactose, crosslinked sodium carboxymethylcellulose and light anhydrous citric acid were mixed, sieved through a 30 mesh sieve, and wet granules were prepared using 80% ethanol, and then at 60 Dry in a desiccator at °C for 4 hours. The dried product was prepared into 18-mesh granules, and then prepared into tablets by the use of a rotary tableting machine by adding magnesium stearate. The prepared immediate release tablet is filled into a capsule together with the sustained release tablet.
第36圖繪示包含根據製備實例10所製備之兩個依托必利SR片劑及一個IR片劑的膠囊製劑。Figure 36 is a view showing a capsule preparation comprising two etopride SR tablets and an IR tablet prepared according to Preparation Example 10.
2.特性2. Characteristics
(1)溶解率(1) Dissolution rate
溶解率係藉由攪拌槳測試法在pH 1.2及50 rpm下量測。The dissolution rate was measured by a paddle test at pH 1.2 and 50 rpm.
結果展示於第37圖及表29中。The results are shown in Figure 37 and Table 29.
表29
(2) 藥物動力學參數(2) Pharmacokinetic parameters
表20展示製備實例10的藥物動力學參數。Table 20 shows the pharmacokinetic parameters of Preparation Example 10.
表30
根據製備實例10所製備之膠囊製劑展示出令人滿意的AUC及C最大 。據信，此結果係因為製劑之漂浮及藥物在胃腸道中的停留時間增加。The capsule formulations exhibit satisfactory prepared in Preparation Example 10 AUC and C of the maximum. This result is believed to be due to the floating of the formulation and the increased residence time of the drug in the gastrointestinal tract.
＜製劑穩定性＞<Formulation stability>
針對製備實例10之製劑實施穩定性測試。A stability test was carried out for the preparation of Preparation Example 10.
表31
從表31可看出，3個月的穩定性並未受到影響。 行業適用性As can be seen from Table 31, the stability of 3 months was not affected. Industry applicability
本揭示案提供一種包含鹽酸依托必利的藥物製劑。The present disclosure provides a pharmaceutical preparation comprising etoriride hydrochloride.
本揭示案係關於一種能夠經由每日一次投藥來改善藥物順應性且同時提供快速鎮痛效果的藥物製劑。The present disclosure relates to a pharmaceutical preparation capable of improving drug compliance via a once-daily administration while providing a rapid analgesic effect.
無no
第1圖繪示開發本揭示案之製劑之過程。 0.8-mm SR聚合物包衣顆粒→2-mm迷你片劑→三個緩釋片劑→包含兩個速釋片劑及一個緩釋片劑的膠囊製劑。Figure 1 depicts the process of developing a formulation of the present disclosure. 0.8-mm SR polymer coated granules → 2-mm mini tablets → three sustained release tablets → capsule preparations comprising two immediate release tablets and one sustained release tablet.
第2圖繪示在開發鹽酸依托必利膠囊製劑之過程中製備的顆粒型膠囊。Figure 2 is a diagram showing the granule capsules prepared during the development of the formulation of the etoride hydrochloride capsule.
第3圖繪示比較P01與可商購之Ganaton的溶解率之結果。Figure 3 depicts the results of comparing the dissolution rates of P01 with commercially available Ganaton.
第4圖繪示調查製備實例1中的介質中的漂浮或膨脹程度之結果。顆粒展示出既不漂浮也不膨脹。Fig. 4 is a graph showing the results of investigating the degree of floating or swelling in the medium in Preparation Example 1. The particles show neither floating nor swelling.
第5圖繪示比較P01與可商購之Ganaton的PK結果之結果。Figure 5 depicts the results of comparing the PK results of P01 with commercially available Ganaton.
第6圖繪示在開發鹽酸依托必利膠囊製劑之過程中製備的迷你片劑膠囊製劑。Figure 6 depicts a mini tablet capsule formulation prepared during the development of a formulation of the etoride hydrochloride capsule.
第7圖繪示比較M02-1與可商購之Ganaton的溶解率之結果。Figure 7 is a graph showing the results of comparing the dissolution rates of M02-1 with commercially available Ganaton.
第8圖繪示調查製備實例2中的介質中的漂浮或膨脹程度之結果。已觀察到製備的迷你片劑漂浮至介質之上部並膨脹。 -2-mm迷你片劑。 -溶解模式：緩釋。 -親水性聚合物基質類型（+CO2 源）。 -漂浮與膨脹(O)。Fig. 8 is a graph showing the results of investigating the degree of floating or swelling in the medium in Preparation Example 2. It has been observed that the prepared mini tablets float to the upper part of the medium and swell. -2-mm mini tablets. - Dissolution mode: sustained release. - Hydrophilic polymer matrix type (+CO 2 source). - Floating and expanding (O).
第9圖繪示比較M02-1與可商購之Ganaton的PK結果之結果。Figure 9 is a graph showing the results of comparing the PK results of M02-1 with commercially available Ganaton.
第10圖繪示比較M02-2與M02-1及可商購之Ganaton的溶解率之結果。Figure 10 shows the results of comparing the dissolution rates of M02-2 with M02-1 and commercially available Ganaton.
第11圖繪示調查介質中的M02-2之漂浮或膨脹程度之結果。已觀察到製備的迷你片劑部分漂浮至介質之上部並膨脹。 -2-mm迷你片劑 -溶解模式：緩釋。 -親水性聚合物基質類型（+CO2 源+脂質）。 -漂浮(D)與膨脹(O)。Figure 11 shows the results of the degree of floating or swelling of M02-2 in the investigation medium. It has been observed that the prepared mini tablet portion floats to the upper portion of the medium and expands. -2-mm mini tablet - dissolution mode: sustained release. - Hydrophilic polymer matrix type (+CO 2 source + lipid). - Floating (D) and expanding (O).
第12圖繪示比較M02-2與可商購之Ganaton的PK結果之結果。Figure 12 depicts the results of comparing the PK results of M02-2 with commercially available Ganaton.
第13圖繪示在開發依托必利150-mg製劑之過程中製備的包含三個鹽酸依托必利50-mg片劑的膠囊製劑。Figure 13 depicts a capsule formulation comprising three etopride hydrochloride 50-mg tablets prepared during the development of the etoride 150-mg formulation.
第14圖繪示比較T03-1與可商購之Ganaton的溶解率之結果。Figure 14 depicts the results of comparing the dissolution rates of T03-1 with commercially available Ganaton.
第15圖繪示調查介質中的T03-1之漂浮或膨脹程度之結果。已觀察到製備的片劑漂浮至介質之上部並膨脹。 -親水性聚合物+CO2 源。 -緩釋片劑。 -漂浮與膨脹(O)。Figure 15 is a graph showing the results of the degree of floating or swelling of T03-1 in the investigation medium. It has been observed that the prepared tablets float to the upper part of the medium and swell. - a hydrophilic polymer + CO 2 source. - Sustained release tablets. - Floating and expanding (O).
第16圖繪示比較T03-1與可商購之Ganaton的PK結果之結果。Figure 16 depicts the results of comparing the PK results of T03-1 with commercially available Ganaton.
第17圖繪示比較T02-2與T02-1及可商購之Ganaton的溶解率之結果。Figure 17 depicts the results of comparing the dissolution rates of T02-2 with T02-1 and commercially available Ganaton.
第18圖繪示調查介質中的T03-2之漂浮或膨脹程度之結果。已觀察到製備的片劑漂浮至介質之上部並膨脹。 -與T03-1相比溶解率增加。 -親水性聚合物+CO2 源。 -緩釋片劑。 -漂浮與膨脹(O)。Figure 18 shows the results of the degree of floating or swelling of T03-2 in the investigation medium. It has been observed that the prepared tablets float to the upper part of the medium and swell. - Increased dissolution rate compared to T03-1. - a hydrophilic polymer + CO 2 source. - Sustained release tablets. - Floating and expanding (O).
第19圖繪示比較T03-2與可商購之Ganaton的PK結果之結果。Figure 19 depicts the results of comparing the PK results of T03-2 with commercially available Ganaton.
第20圖繪示比較T03-3與T03-1、T03-2及可商購之Ganaton的溶解率之結果。Figure 20 depicts the results of comparing the dissolution rates of T03-3 with T03-1, T03-2 and commercially available Ganaton.
第21圖繪示調查介質中的T03-3之漂浮或膨脹程度之結果。已觀察到製備的片劑漂浮至介質之上部並膨脹。 -為了使漂浮及膨脹的效果最大化，使用更多親水性聚合物及CO2 源。作為結果，與T03-2相比，溶解率下降。 -緩釋片劑。 -漂浮與膨脹(O)。Figure 21 shows the results of the degree of floating or swelling of T03-3 in the investigation medium. It has been observed that the prepared tablets float to the upper part of the medium and swell. - In order to maximize the effect of floating and expansion, more hydrophilic polymers and CO 2 sources are used. As a result, the dissolution rate was lowered as compared with T03-2. - Sustained release tablets. - Floating and expanding (O).
第22圖繪示比較T03-3與可商購之Ganaton的PK結果之結果。Figure 22 depicts the results of comparing the PK results of T03-3 with commercially available Ganaton.
第23圖繪示在開發依托必利150-mg製劑之過程中製備的包含兩個緩釋鹽酸依托必利50-mg片劑及一個速釋鹽酸依托必利50-mg片劑的膠囊製劑。Figure 23 depicts a capsule formulation comprising two sustained release etopride hydrochloride 50-mg tablets and one immediate release etoopril 50-mg tablet prepared during the development of the etoride 150-mg formulation.
第24圖繪示比較T04-1與可商購之Ganaton的溶解率之結果。Figure 24 depicts the results of comparing the dissolution rates of T04-1 with commercially available Ganaton.
第25圖繪示T04-1之溶解率。比較速釋部分與緩釋部分之溶解率。Figure 25 shows the dissolution rate of T04-1. Compare the dissolution rate of the immediate release portion and the sustained release portion.
第26圖繪示調查介質中的T04-1之漂浮或膨脹程度之結果。製備的片劑之速釋部分既不漂浮也不膨脹。已觀察到緩釋部分漂浮至介質之上部並膨脹。 IR部分：漂浮(X)，膨脹(X)。 SR部分：漂浮與膨脹(O)。 依托必利API比率：IR 50 mg，SR 100 mg。Figure 26 is a graph showing the results of the degree of floating or swelling of T04-1 in the investigation medium. The immediate release portion of the prepared tablet neither floats nor swells. It has been observed that the sustained release portion floats to the upper portion of the medium and expands. IR part: floating (X), swelling (X). SR part: floating and expanding (O). Ettopril API ratio: IR 50 mg, SR 100 mg.
第27圖繪示比較T04-1與可商購之Ganaton的PK結果之結果。Figure 27 depicts the results of comparing the PK results of T04-1 with commercially available Ganaton.
第28圖繪示比較T04-2與T04-1及可商購之Ganaton的溶解率之結果。Figure 28 shows the results of comparing the dissolution rates of T04-2 with T04-1 and commercially available Ganaton.
第29圖繪示T04-2之溶解率。比較速釋部分與緩釋部分之溶解率。Figure 29 shows the dissolution rate of T04-2. Compare the dissolution rate of the immediate release portion and the sustained release portion.
第30圖繪示調查介質中的T04-2之漂浮或膨脹程度之結果。速釋部分與緩釋部分兩者皆漂浮至介質之上部。Figure 30 shows the results of the degree of floating or swelling of T04-2 in the investigation medium. Both the immediate release portion and the sustained release portion float to the upper portion of the medium.
第31圖繪示比較T04-2與可商購之Ganaton的PK結果之結果。Figure 31 is a graph showing the results of comparing the PK results of T04-2 with commercially available Ganaton.
第32圖繪示比較T04-3與T04-1、T04-2及可商購之Ganaton的溶解率之結果。Figure 32 is a graph showing the results of comparing the dissolution rates of T04-3 with T04-1, T04-2 and commercially available Ganaton.
第33圖繪示T04-3之溶解率。比較速釋部分與緩釋部分之溶解率。Figure 33 shows the dissolution rate of T04-3. Compare the dissolution rate of the immediate release portion and the sustained release portion.
第34圖繪示調查介質中的T04-3之漂浮或膨脹程度之結果。已觀察到，速釋部分並未漂浮，而緩釋部分漂浮至介質之上部並膨脹。Figure 34 is a graph showing the results of the degree of floating or swelling of T04-3 in the investigation medium. It has been observed that the immediate release portion does not float, and the sustained release portion floats to the upper portion of the medium and expands.
第35圖繪示比較T04-3與可商購之Ganaton的PK結果之結果。Figure 35 depicts the results of comparing the PK results of T04-3 with commercially available Ganaton.
第36圖繪示根據示例性實施例的依托必利150-mg製劑。膠囊製劑包含兩個緩釋鹽酸依托必利60-mg片劑及一個速釋鹽酸依托必利30-mg片劑。Figure 36 depicts an etofride 150-mg formulation in accordance with an exemplary embodiment. The capsule preparation comprises two sustained-release etoride hydrochloride 60-mg tablets and one immediate release etoride hydrochloride 30-mg tablet.
第37圖繪示比較根據本揭示案之示例性實施例的依托必利150-mg製劑(T05)與可商購之Ganaton、T04-1、T04-2及T04-3的溶解率之結果。Figure 37 is a graph showing the results of comparing the dissolution rates of the etopride 150-mg formulation (T05) with commercially available Ganaton, T04-1, T04-2 and T04-3 according to an exemplary embodiment of the present disclosure.
第38圖繪示T05之溶解率。比較速釋部分與緩釋部分之溶解率。Figure 38 shows the dissolution rate of T05. Compare the dissolution rate of the immediate release portion and the sustained release portion.
第39圖繪示調查介質中的T05之漂浮或膨脹程度之結果。已觀察到，T05之速釋部分並未漂浮，而緩釋部分漂浮至介質之上部並膨脹。Figure 39 is a graph showing the results of the degree of floating or swelling of T05 in the investigation medium. It has been observed that the immediate release portion of T05 does not float, and the sustained release portion floats to the upper portion of the medium and expands.
第40圖繪示比較T05與可商購之Ganaton的PK結果之結果。Figure 40 depicts the results of comparing the P05 results of T05 with commercially available Ganaton.
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW107105604A TW201834643A (en) | 2017-02-20 | 2018-02-14 | Pharmaceutical formulation containing itopride hydrochloride and having immediate and sustained release properties |
Country Status (3)
| Country | Link |
|---|---|
| KR (1) | KR20180096530A (en) |
| TW (1) | TW201834643A (en) |
| WO (1) | WO2018151580A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2021107333A (en) * | 2019-12-27 | 2021-07-29 | 小林製薬株式会社 | Oral pharmaceutical composition |
| CN115844847B (en) * | 2022-11-17 | 2023-09-01 | 云南永安制药有限公司 | Itopride hydrochloride preparation and preparation method thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7374779B2 (en) * | 1999-02-26 | 2008-05-20 | Lipocine, Inc. | Pharmaceutical formulations and systems for improved absorption and multistage release of active agents |
| KR100762847B1 (en) * | 2006-01-27 | 2007-10-04 | 씨제이 주식회사 | Multiple unit type sustained release oral formulation and process for the preparation thereof |
| WO2010020098A1 (en) * | 2008-08-18 | 2010-02-25 | 北京天衡药物研究院 | Gastric retention drug delivery system, preparation method and use thereof |
| WO2011049309A2 (en) * | 2009-10-09 | 2011-04-28 | 영진약품공업 주식회사 | Pharmaceutical composition with both immediate and extended release characteristics |
| KR101270751B1 (en) * | 2010-05-06 | 2013-06-07 | (주)비씨월드제약 | Composition for the gastric retention and controlled release of therapeutic agents |
| KR101882946B1 (en) * | 2015-06-26 | 2018-08-24 | 한국유나이티드제약 주식회사 | Combination formulation comprising mosapride and rabeprazole |
-
2018
- 2018-02-14 TW TW107105604A patent/TW201834643A/en unknown
- 2018-02-20 WO PCT/KR2018/002079 patent/WO2018151580A1/en active Application Filing
- 2018-02-20 KR KR1020180019966A patent/KR20180096530A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2018151580A1 (en) | 2018-08-23 |
| KR20180096530A (en) | 2018-08-29 |
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