TWI488658B - Method for improvement of elution - Google Patents

Method for improvement of elution Download PDF

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TWI488658B
TWI488658B TW096149678A TW96149678A TWI488658B TW I488658 B TWI488658 B TW I488658B TW 096149678 A TW096149678 A TW 096149678A TW 96149678 A TW96149678 A TW 96149678A TW I488658 B TWI488658 B TW I488658B
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layer
acid
ingot
olmesartan medoxomil
adipine
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TW200835525A (en
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Ikumasa Ohno
Ryoichi Hayakawa
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Daiichi Sankyo Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Description

溶出性之改善方法Method for improving dissolution

本發明係關於含有奧美沙坦酯(olmesartan medoxomil)及阿折地平(azelnidipine)之固形製劑之溶出性改善方法。The present invention relates to a method for improving the dissolution properties of a solid preparation containing olmesartan medoxomil and azelnidipine.

現今，廣泛使用血管收縮素II受體拮抗劑及鈣離子通道拮抗劑作為高血壓症或心臟病等治療或預防用之醫藥。為腎素-血管收縮素系之抑制藥的血管收縮素II受體拮抗劑對腎素依賴性之高血壓症特別有效，顯示出對於心血管或腎臟障礙之保護作用。又，由於鈣離子通道拮抗劑除了具有血管擴張作用外又具有鈉利尿作用，對於體液儲存性(腎素非依賴性)之高血壓症亦有效。因此，若併用血管收縮素Ⅱ受體拮抗劑與鈣離子通道拮抗劑，由於除了有來自血管收縮素II受體拮抗劑之腎素-血管收縮素系之抑制效果外，加上來自鈣離子通道拮抗劑之血管平滑肌的鈣離子通道拮抗作用及二次性鈉***作用，同時抑制複數種高血壓成因成為可能，而期待顯示不管病因為何之安定且充分的高血壓症之治療或預防效果。Nowadays, angiotensin II receptor antagonists and calcium channel antagonists are widely used as medicines for the treatment or prevention of hypertension or heart disease. Angiotensin II receptor antagonists, which are inhibitors of the renin-angiotensin system, are particularly effective against renin-dependent hypertension and exhibit protective effects against cardiovascular or renal disorders. Further, since the calcium ion channel antagonist has a sodium diuretic action in addition to the vasodilating action, it is also effective for humoral storage (renin-independent) hypertension. Therefore, if an angiotensin II receptor antagonist and a calcium channel antagonist are used in combination, the inhibitory effect of the renin-angiotensin system from the angiotensin II receptor antagonist is added, and the calcium ion channel is added. The calcium channel antagonism and secondary sodium excretion of the vascular smooth muscle of the antagonist are possible, and it is possible to suppress the cause of a plurality of hypertension, and it is expected to show the therapeutic or preventive effect of hypertension regardless of the stability and sufficient condition of the disease.

(5-甲基-2-酮基-1,3-二氧戊環-4-基)甲基4-(1-羥基-1-甲基乙基)-2-丙基-1-[2'-(1H-四唑-5-基)聯苯基-4-基甲基]咪唑-5-羧酸酯(以下，稱為奧美沙坦酯)為優異的血管收縮素II受體拮抗劑，已知作為高血壓症及心臟病等治療或預防用之醫藥為有用的(日本專利第2082519號公報、 美國專利第5,616,599號公報)。(5-Methyl-2-keto-1,3-1,3-dioxolan-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2 '-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazol-5-carboxylate (hereinafter referred to as olmesartan medoxomil) is an excellent angiotensin II receptor antagonist It is known to be useful as a medicine for treatment or prevention such as hypertension and heart disease (Japanese Patent No. 2082519, U.S. Patent No. 5,616,599).

奧美沙坦酯已有以Olmetec®(註冊商標)錠被販售，含有有效成分奧美沙坦酯5mg、10mg、20mg或40mg，及含有作為添加物之低取代度羥丙基纖維素、羥丙基纖維素、結晶纖維素、乳糖、硬脂酸鎂。Olmesartan medoxomil has been sold as an Olmetec® (registered trademark) ingot containing the active ingredient olmesartan medoxomil 5 mg, 10 mg, 20 mg or 40 mg, and contains low-substituted hydroxypropyl cellulose as an additive, hydroxypropyl Cellulose, crystalline cellulose, lactose, magnesium stearate.

又，(±)-2-胺基-1,4-二氫-6-甲基-4-(3-硝基苯基)-3,5-吡啶二羧酸3-(1-二苯基甲基吖丁啶-3-基)酯5-異丙基酯(以下稱為阿折地平)，為優異的鈣離子通道拮抗劑，已知作為高血壓症及心臟病等治療或預防用之醫藥為有用的(日本專利第1666755號公報、美國專利第4,772,596號公報)。Further, (±)-2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-(1-diphenyl Methyl azetidin-3-yl)ester 5-isopropyl ester (hereinafter referred to as adipine) is an excellent calcium channel antagonist and is known for use as a treatment or prevention for hypertension and heart disease. The medicine is useful (Japanese Patent No. 1666755, and U.S. Patent No. 4,772,596).

阿折地平已有以Calblock®(註冊商標)錠被販售，含 有有效成分阿折地平8mg或16mg，及含有作為添加物之D-甘露糖醇、羧甲基纖維素鈣、低取代度羥丙基纖維素、碳酸氫鈉、聚山梨酸酯80、偏矽酸鋁酸鎂、輕質矽酸酐、羥丙基纖維素、滑石、硬脂酸鎂。Adipine has been sold as Calblock® (registered trademark) ingots, including There is an active ingredient adipine in 8mg or 16mg, and contains as an additive D-mannitol, calcium carboxymethylcellulose, low-substituted hydroxypropyl cellulose, sodium bicarbonate, polysorbate 80, hemiplegia Magnesium aluminate, light phthalic anhydride, hydroxypropyl cellulose, talc, magnesium stearate.

於先前技術中，組合奧美沙坦酯及阿折地平之醫藥為已知(國際公開第2004/067003號小冊)，但並未知悉本發明之含有奧美沙坦酯及阿折地平之固形製劑之溶出性改善方法。In the prior art, a combination of olmesartan medoxomil and adipine is known (International Publication No. 2004/067003), but the solid preparation containing olmesartan medoxomil and adipine is not known. The dissolution improvement method.

專利文獻1：日本專利第2082519號公報(美國專利第5,616,599號公報) 專利文獻2：日本專利第1666755號公報(美國專利第4,772,596號公報) 專利文獻3：國際公開第2004/067003號小冊。Patent Document 1: Japanese Patent No. 2082519 (U.S. Patent No. 5,616,599) Patent Document 2: Japanese Patent No. 1666755 (U.S. Patent No. 4,772,596) Patent Document 3: International Publication No. 2004/067003 booklet.

本發明之課題係提供含有奧美沙坦酯及阿折地平之固形製劑之溶出性改善方法。An object of the present invention is to provide a method for improving the dissolution property of a solid preparation containing olmesartan medoxomil and aflatabine.

近年來，高血壓患者有併用含合併症治療之藥劑的複數種藥劑的傾向，此被指摘為成為血壓控制不良之一個原因的可能性。由於一旦服用的藥劑數多，服藥順從性會降低，為了實現確實的血壓控制，認為企求患者服藥順從性之提升為重要的。血管收縮素II受體拮抗劑之奧美沙坦酯與鈣離子通道拮抗劑之阿折地平，由於可期待有更確實的高血壓治療效果之組合而於醫療場所中被廣泛併用，為使 患者之服藥順從性提升，強烈地冀望兩藥劑之調配劑之開發。In recent years, patients with hypertension have a tendency to use a plurality of drugs containing a drug for treatment of comorbidities, which is considered to be a cause of poor blood pressure control. Since the dose of medication once taken is reduced, the compliance of the medication will be lowered. In order to achieve accurate blood pressure control, it is considered important to improve the patient's compliance with medication. Omethacillin, an angiotensin II receptor antagonist, and adipine, a calcium channel antagonist, are widely used in medical facilities because they can be expected to have a more effective combination of therapeutic effects of hypertension. The patient's medication compliance improved, and the development of the two agents was strongly expected.

一般而言開發含有2種類藥劑之固形製劑(調配劑)時，經常於任一方單劑之處方上，再追加另一方有效成分的處方或使用二層錠者。然而，含有奧美沙坦酯及阿折地平的固形製劑中，Olmetec®(註冊商標)錠、Calblock®(註冊商標)錠之處方作為基礎的場合，已知隨著時間奧美沙坦酯之溶出性會變低。In general, when a solid preparation (mixture) containing two types of pharmaceuticals is developed, it is often necessary to add a prescription for the other active ingredient or a two-layer tablet to a single dose. However, in the solid preparation containing olmesartan medoxomil and adipine, the dissolution of olmesartan medoxomil over time is known as the basis of the Olmetec® (registered trademark) ingot and Calblock® (registered trademark) ingot. Will become lower.

本發明者們為解決上述課題致力研究的結果，發現經由將製劑中各別有效成分分離調配，又將對兩主藥為不活性的層夾入成為三層錠，使隨時間之奧美沙坦酯溶出性的降低被改善，遂而完成本發明。As a result of intensive research to solve the above problems, the present inventors have found that by separating and dissolving the respective active ingredients in the preparation, a layer in which the two main drugs are inactive is sandwiched into a three-layer ingot to make olmesartan over time. The reduction in ester elution property is improved, and the present invention has been completed.

本發明為提供含有奧美沙坦酯及阿折地平之固形製劑(特別是高血壓症之預防或治療用製劑)之奧美沙坦酯之溶出性改善方法、製造前述固形製劑(特別是高血壓症之預防或治療用製劑)用之奧美沙坦酯及阿折地平之使用、將含有奧美沙坦酯及阿折地平之藥理學上有效量之前述固形製劑投與溫血動物(特別是人類)之預防或治療疾病(特別是高血壓症)的方法。The present invention provides a method for improving the dissolution of olmesartan medoxomil containing a solid preparation of olmesartan medoxomil and aflatabine (particularly a preparation for prevention or treatment of hypertension), and the manufacture of the aforementioned solid preparation (especially hypertension) For the prophylactic or therapeutic use), the use of olmesartan medoxomil and adipine in a pharmacologically effective amount of the aforementioned solid preparation containing olmesartan medoxomil and adipine is administered to a warm-blooded animal (especially human) A method of preventing or treating a disease, particularly hypertension.

亦即，本發明提供：(1)一種固形製劑之溶出性改善方法，其含有奧美沙坦酯及阿折地平；(2)(1)中記載之方法，其特徵為奧美沙坦酯及 阿折地平以互不接觸的方式分離調配；(3)(1)或(2)中記載之方法，其中固形製劑為錠劑之形態；(4)(3)中記載之方法，其中錠劑為多層錠；(5)(4)中記載之方法，其中多層錠為三層錠，第1層含有奧美沙坦酯，夾著中間層的另一層含有阿折地平；(6)(4)中記載之方法，多層錠為由內核與中間層與外層構成的有核錠，其中內核含有奧美沙坦酯，外層含有阿折地平；(7)(4)中記載之方法，多層錠為內核、中間層、外層構成的有核錠，其中內核含有阿折地平，外層含有奧美沙坦酯；(8)(5)至(7)中任一項記載之方法，其中中間層含有賦形劑；(9)(8)中記載之方法，其中賦形劑為選自乳糖、結晶纖維素、輕質矽酸酐組成之群之1或2種以上；(10)(1)至(9)中任一項記載之方法，其係用於改善奧美沙坦酯之溶出性；(11)(1)至(10)中任一項記載之方法，其係用於治療或預防高血壓症等。That is, the present invention provides: (1) a method for improving the dissolution property of a solid preparation comprising olmesartan medoxomil and adipine; (2) (1), characterized by olmesartan medoxomil and (3) The method described in (1) or (2), wherein the solid preparation is in the form of a tablet; (4) the method described in (3), wherein the tablet is in the form of a tablet; The method described in (5) (4), wherein the multi-layer ingot is a three-layer ingot, the first layer contains olmesartan medoxomil, and the other layer sandwiching the intermediate layer contains abdipine; (6) (4) In the method described, the multi-layer ingot is a core ingot composed of an inner core and an intermediate layer and an outer layer, wherein the inner core contains olmesartan medoxomil and the outer layer contains adipine; the method described in (7) (4), the multi-layer ingot is a core a core ingot comprising an intermediate layer and an outer layer, wherein the inner layer contains adedipine, and the outer layer contains olmesartan medoxomil; (8) the method according to any one of (5) to (7), wherein the intermediate layer contains an excipient (9) The method according to (8), wherein the excipient is one or more selected from the group consisting of lactose, crystalline cellulose, and light phthalic anhydride; (10) (1) to (9) The method according to any one of the aspects of the invention, wherein the method of any one of (1) to (10), which is used for the treatment or prevention of hypertension or the like.

依據本發明，提供含有奧美沙坦酯及阿折地平之固形製劑之溶出性改善方法成為可能。According to the present invention, it is possible to provide a dissolution improving method comprising a solid preparation of olmesartan medoxomil and adipine.

實施發明之最佳形態Best form for implementing the invention

本發明之固形製劑之有效成分為奧美沙坦酯與阿折地平。The active ingredient of the solid preparation of the present invention is olmesartan medoxomil and adipine.

本發明之固形製劑中有效成分之一的奧美沙坦酯可依據日本專利第2082519號公報(美國專利第5,616,599號公報)等記載之方法而容易地製造。The olmesartan medoxomil which is one of the active ingredients in the solid preparation of the present invention can be easily produced by the method described in Japanese Patent No. 2082519 (U.S. Patent No. 5,616,599).

本發明之固形製劑中有效成分之一者的阿折地平可依據日本專利第1666755號公報(美國專利第4,772,596號公報)等記載之方法容易地製造。阿折地平可形成酸加成鹽，此等酸加成鹽亦包含於本發明。阿折地平之酸加成鹽之酸部分，只要可與阿折地平形成酸加成鹽的酸者即可未特別限定，作為如此之酸，可列舉例如鹽酸、氫溴酸、氫碘酸、硫酸、硝酸、磷酸、乙酸、草酸、丙二酸、富馬酸、馬來酸、酒石酸、琥珀酸、檸檬酸、甲磺酸、苯磺酸、對甲苯磺酸、或萘磺酸，較佳為鹽酸、氫溴酸、硫酸、磷酸、富馬酸、酒石酸、檸檬酸、甲磺酸、苯磺酸、對甲苯磺酸、或萘磺酸，更佳為氫溴酸、檸檬酸、甲磺酸、苯磺酸、對甲苯磺酸、或萘磺酸，再更佳為氫溴酸、甲磺酸、或對甲苯磺酸，又更佳為氫溴酸或甲磺酸，最佳為氫溴酸。Adesodipine, which is one of the active ingredients in the solid preparation of the present invention, can be easily produced by the method described in Japanese Patent No. 1666755 (U.S. Patent No. 4,772,596). Adipine can form acid addition salts, and such acid addition salts are also included in the present invention. The acid portion of the adipine acid addition salt is not particularly limited as long as it can form an acid addition salt with adipine, and examples of such an acid include hydrochloric acid, hydrobromic acid, and hydroiodic acid. Sulfuric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, malonic acid, fumaric acid, maleic acid, tartaric acid, succinic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid, preferably Is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, tartaric acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid, more preferably hydrobromic acid, citric acid, methanesulfonic acid Acid, benzenesulfonic acid, p-toluenesulfonic acid, or naphthalenesulfonic acid, more preferably hydrobromic acid, methanesulfonic acid, or p-toluenesulfonic acid, more preferably hydrobromic acid or methanesulfonic acid, most preferably hydrogen Bromo acid.

本發明中所謂「溶出性改善」，係指於安定性試驗(60℃及/或40℃75%相對濕度、及/或25℃60%相對濕度)改善固形製劑中奧美沙坦酯溶出性之降低現象，較佳為安定性試驗後，檢體之溶出試驗中奧美沙坦酯之30分鐘後之溶出率 為75%以上，較佳為80%以上，更佳為85%以上。The term "improvement in dissolution" in the present invention means improving the dissolution of olmesartan medoxomil in a solid preparation in a stability test (60 ° C and/or 40 ° C 75% relative humidity, and/or 25 ° C 60% relative humidity). The phenomenon of lowering the phenomenon, preferably after 30 minutes after the stability test, the dissolution rate of olmesartan medoxomil in the dissolution test of the sample It is 75% or more, preferably 80% or more, more preferably 85% or more.

本發明之固形製劑之溶出性，依據日局一般試驗法之溶出試驗法第2法(槳攪法(paddle method))測定。例如，漿攪回轉數每分鐘75次回轉，使用日局第2液(JP-2、pH6.8)900mL作為試驗液，經由採取試驗開始30分鐘後之試驗液，使用0.45μm孔徑之膜過濾器過濾，濾液使用高速液體色層分析定量，可算出奧美沙坦酯之溶出率。The dissolution property of the solid preparation of the present invention is measured in accordance with the second method of the dissolution test method (paddle method) of the general test method of the Japanese office. For example, the number of revolutions of the slurry is 75 rotations per minute, and 900 mL of the second liquid (JP-2, pH 6.8) is used as the test liquid, and the test liquid after 30 minutes from the start of the test is used, and the membrane is filtered using a pore size of 0.45 μm. The filtrate was filtered and the filtrate was quantified using high-speed liquid chromatography to calculate the dissolution rate of olmesartan medoxomil.

作為本發明之「固形製劑」，可列舉例如錠劑(含舌下錠、口腔內崩壞錠)、膠囊劑(含軟膠囊、微膠囊)、顆粒劑、細粒劑、散劑、丸劑、舌片劑等，較佳為錠劑。Examples of the "solid preparation" of the present invention include a tablet (including a sublingual tablet, an orally disintegrating ingot), a capsule (including a soft capsule, a microcapsule), a granule, a fine granule, a powder, a pill, and a tongue. A tablet or the like is preferably a tablet.

本發明中所謂之「多層錠」，係指數種類處方成分分階段以層狀堆積而壓縮成形，納入同一劑形內之錠劑(積層錠)，較佳為具有兩主藥以含有不活性的添加劑之中間層分離的奧美沙坦酯層及阿折地平層之三層所構成的錠劑。再者，奧美沙坦酯層及/或阿折地平層之外側上可有追加之層。此等追加的層可為美觀的目的，亦可為藥劑味遮蔽、含有其他有效成分之目的。In the present invention, the "multilayer ingot" is a type of index component which is formed by laminating in layers and compressed and formed into a tablet (layered ingot) in the same dosage form, preferably having two main drugs to contain inactive A tablet composed of an olmesartan medoxorate layer separated by an intermediate layer of the additive and three layers of an adipine layer. Further, an additional layer may be present on the outer side of the olmesartan medoxomil layer and/or the adipine layer. These additional layers may be aesthetically pleasing, or may be intended to mask the medicinal taste and contain other active ingredients.

本發明中所謂之「三層錠」，為含有一方之有效成分的第1層、含有不活性的添加劑之第2層(中間層)及含有另一方有效成分之第3層所構成的積層錠。藉由中間層可迴避藥物間之直接接觸，而改善溶出性。The "three-layer ingot" in the present invention is a laminated layer composed of a first layer containing one active ingredient, a second layer containing an inactive additive (intermediate layer), and a third layer containing the other active ingredient. . The dissolution can be improved by avoiding direct contact between the drugs by the intermediate layer.

本發明中所謂之「有核錠」，為以含有另一方藥物之外層包覆含有一方之藥物的內核之錠劑，該內核與外層可相接，又作為回避藥物間之直接接觸的目的，可設置以高分 子或糖被覆該內核之中間層。The "nuclear ingot" in the present invention is a tablet containing a core containing a drug of the other side, and the core is connected to the outer layer, and serves as a direct contact between drugs. Can be set to high scores The child or sugar covers the middle layer of the kernel.

作為中間層中使用的不活性添加劑，只要與有效成分不反應之添加劑即可未特別限定，可列舉作為通常賦形劑使用之添加劑等。作為如此之添加劑，可列舉例如乳糖、乳糖(造粒粉末)、白糖、葡萄糖、甘露糖醇或山梨糖醇等糖衍生物；玉米澱粉、馬鈴薯澱粉、α-澱粉或糊精等之澱粉衍生物；結晶纖維素、結晶纖維素與輕質矽酸酐之噴霧乾燥品等纖維素衍生物；***膠；葡聚糖；或三聚葡糖等有機系賦形劑；或，輕質矽酸酐、合成矽酸鋁、矽酸鈣或偏矽酸鋁酸鎂等矽酸鹽衍生物；磷酸氫鈣等磷酸鹽；碳酸鈣等碳酸鹽；或，硫酸鈣等硫酸鹽等之無機系賦形劑，較佳為乳糖(造粒粉末)、結晶纖維素與輕質矽酸酐之噴霧乾燥品、D-甘露糖醇、偏矽酸鋁酸鎂、輕質矽酸酐，更佳為結晶纖維素與輕質矽酸酐之噴霧乾燥品。又，中間層可使用潤滑劑。作為潤滑劑，可列舉例如硬脂酸鎂、硬脂酸鈣、富馬酸硬脂酸鈉等硬脂酸衍生物；滑石等礦物資源；蔗糖脂肪酸酯等脂肪酸衍生物，較佳為硬脂酸鎂。The inactive additive to be used in the intermediate layer is not particularly limited as long as it does not react with the active ingredient, and examples thereof include an additive used as a usual excipient. As such an additive, for example, a sugar derivative such as lactose, lactose (granulated powder), white sugar, glucose, mannitol or sorbitol; a starch derivative such as corn starch, potato starch, α-starch or dextrin may be mentioned. a cellulose derivative such as a crystalline cellulose, a crystalline cellulose, and a spray dried product of light phthalic anhydride; an arabic gum; a dextran; or an organic excipient such as a diglycan; or a light phthalic anhydride, synthetic a phthalate derivative such as aluminum citrate, calcium citrate or magnesium metasilicate aluminate; a phosphate such as calcium hydrogen phosphate; a carbonate such as calcium carbonate; or an inorganic excipient such as a sulfate such as calcium sulfate. Preferred is lactose (granulated powder), spray dried product of crystalline cellulose and light phthalic anhydride, D-mannitol, magnesium metasilicate aluminate, light phthalic anhydride, more preferably crystalline cellulose and light bismuth A spray dried product of an acid anhydride. Also, a lubricant can be used for the intermediate layer. Examples of the lubricant include stearic acid derivatives such as magnesium stearate, calcium stearate, and sodium fumarate; mineral resources such as talc; and fatty acid derivatives such as sucrose fatty acid esters, preferably stearic acid. Magnesium acid.

本發明之固形製劑，又視必要，可含有適宜之藥理學上容許之賦形劑、潤滑劑、結合劑、崩壞劑、乳化劑、安定劑、矯味矯臭劑、稀釋劑等添加劑。The solid preparation of the present invention may, if necessary, contain suitable pharmacologically acceptable additives such as excipients, lubricants, binders, disintegrating agents, emulsifiers, stabilizers, flavoring agents, diluents and the like.

作為使用之「賦形劑」，可列舉例如乳糖、白糖、葡萄糖、甘露糖醇或山梨糖醇等之糖衍生物；玉米澱粉、馬鈴薯澱粉、α-澱粉或糊精等之澱粉衍生物；結晶纖維素等之纖維素衍生物；***膠；葡聚糖；或三聚葡糖等之有機 系賦形劑；或輕質矽酸酐、合成矽酸鋁、矽酸鈣或偏矽酸鋁酸鎂等之矽酸鹽衍生物；磷酸氫鈣等之磷酸鹽；碳酸鈣等之碳酸鹽；或硫酸鈣等之硫酸鹽等之無機系賦形劑。Examples of the "excipient" used include a sugar derivative such as lactose, white sugar, glucose, mannitol or sorbitol; a starch derivative such as corn starch, potato starch, α-starch or dextrin; and crystallization. Cellulose derivatives such as cellulose; gum arabic; dextran; or organic matter such as tripolyglucose An excipient; or a phthalate derivative such as light phthalic anhydride, synthetic aluminum citrate, calcium citrate or magnesium metasilicate aluminate; a phosphate such as calcium hydrogen phosphate; a carbonate such as calcium carbonate; An inorganic excipient such as a sulfate such as calcium sulfate.

作為使用之「潤滑劑」，可列舉例如為硬脂酸；硬脂酸鈣或硬脂酸鎂等之硬脂酸金屬鹽；滑石；膠狀矽石；蜂蠟或鯨蠟等之蠟類；硼酸；己二酸；硫酸鈉等之硫酸鹽；乙二醇；富馬酸；苯甲酸鈉；D,L-白胺酸；十二基硫酸鈉或十二基硫酸鎂等之十二基硫酸鹽；矽酸酐或矽酸水和物等之矽酸類；或，上述澱粉衍生物。Examples of the "lubricant" to be used include stearic acid; stearic acid metal salts such as calcium stearate or magnesium stearate; talc; colloidal vermiculite; waxes such as beeswax or cetyl wax; Adipic acid; sulfate such as sodium sulfate; ethylene glycol; fumaric acid; sodium benzoate; D, L-leucine; dodecyl sulfate such as sodium dodecyl sulfate or dodecyl magnesium sulfate; a tannic acid such as phthalic anhydride or citric acid water; or the above starch derivative.

作為使用之「結合劑」，可列舉例如為羥丙基纖維素、羥丙基甲基纖維素、聚乙烯吡咯啶酮、聚乙二醇(macrogol)，或與前述賦形劑相同之化合物。Examples of the "binding agent" to be used include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, or the same compounds as the aforementioned excipients.

作為使用之「崩壞劑」，可列舉例如低取代度羥丙基纖維素、羧甲基纖維素、羧甲基纖維素鈣或內部交聯羧甲基纖維素鈉等之纖維素衍生物；交聯聚乙烯吡咯啶酮；或、羧甲基澱粉或羧甲基澱粉鈉等之經化學修飾的澱粉‧纖維素類。Examples of the "cracking agent" to be used include cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, or internal cross-linked carboxymethylcellulose sodium; Cross-linked polyvinylpyrrolidone; or chemically modified starch ‧ cellulose such as carboxymethyl starch or sodium carboxymethyl starch.

作為使用的「乳化劑」，可列舉例如膨土或VEEGUM®等之膠性黏土；氫氧化鎂或氫氧化鋁等之金屬氫氧化物；十二基硫酸鈉或硬脂酸鈣等之陰離子界面活性劑；氯化芐烷銨等之陽離子界面活性劑；或，聚氧乙烯烷基醚、聚氧乙烯山梨聚糖脂肪酸酯或蔗糖脂肪酸酯等之非離子界面活性劑。Examples of the "emulsifier" to be used include a clay clay such as bentonite or VEEGUM®; a metal hydroxide such as magnesium hydroxide or aluminum hydroxide; and an anionic interface such as sodium dodecyl sulfate or calcium stearate. An active agent; a cationic surfactant such as benzalkonium chloride; or a nonionic surfactant such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester or sucrose fatty acid ester.

作為使用的「安定劑」可列舉例如對羥苯甲酸甲酯或 對羥苯甲酸丙酯等之對羥苯甲酸酯類；氯丁醇、苄醇或苯乙醇等之醇類；氯化芐烷銨；苯酚或甲酚等之酚類；硫柳汞；去氫乙酸；或山梨酸等。As the "stabilizer" to be used, for example, methylparaben or Parabens such as propyl paraben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalkonium chloride; phenols such as phenol or cresol; thimerosal; dehydroacetic acid; Or sorbic acid, etc.

作為使用的「矯味矯臭劑」，可列舉例如糖精鈉或阿斯巴甜等之甘味料；檸檬酸、蘋果酸或酒石酸等之酸味料；或薄荷腦、檸檬、或橘子等之香料等。Examples of the "flavoring and odorizing agent" to be used include a sweetener such as saccharin sodium or aspartame; a sour material such as citric acid, malic acid or tartaric acid; or a flavoring agent such as menthol, lemon or orange.

作為使用的「稀釋劑」，可列舉例如乳糖、甘露糖醇、葡萄糖、蔗糖、硫酸鈣、磷酸鈣、羥丙基纖維素、微結晶性纖維素、水、乙醇、聚乙二醇、丙二醇、甘油、澱粉、聚乙烯吡咯啶酮、偏矽酸鋁酸鎂或此等之混合物。Examples of the "diluent" to be used include lactose, mannitol, glucose, sucrose, calcium sulfate, calcium phosphate, hydroxypropylcellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, and propylene glycol. Glycerin, starch, polyvinylpyrrolidone, magnesium metasilicate aluminate or a mixture of these.

本發明中製劑之製造方法可使用Powder Technology and Pharmaceutical Processes(D. Chulia等人，Elsevier Science Pub. Co (December l, 1993))等刊物中記載之一般方法製造，並未特別設限。The method for producing the preparation of the present invention can be produced by a general method described in the publication of Powder Technology and Pharmaceutical Processes (D. Chulia et al., Elsevier Science Pub. Co (December 1, 1993), and the like, and is not particularly limited.

本發明之多層錠，例如可以本身公知之方法，將含有效成分之各層直接壓縮成形，或有效成分各自於各層依通常之濕式顆粒化或乾式顆粒化(壓縮)方法製造，接著，藉由將各層壓縮成形而製造。The multilayer ingot of the present invention can be directly compression-molded, for example, by a method known per se, or each of the active ingredients can be produced in each layer by a usual wet granulation or dry granulation (compression) method, followed by Each layer was produced by compression molding.

本發明之三層錠，例如可以本身公知之方法，各自將第1層、第2層(中間層)、第3層藉由使用通常之直接打錠用顆粒或濕式顆粒化或乾式顆粒化(壓縮)方法製造，接著，壓縮第1層、第2層、第3層，使用通常之三層錠成形裝置使各層結合而製造。又，本發明之三層錠可設置至少1層的膜包衣。The three-layer ingot of the present invention can be used, for example, by a method known per se, by using the usual direct ingot granules or wet granulation or dry granulation by using the first layer, the second layer (intermediate layer) and the third layer. The (compression) method is produced, and then the first layer, the second layer, and the third layer are compressed, and each layer is produced by bonding using a usual three-layer ingot forming apparatus. Further, the three-layer ingot of the present invention may be provided with at least one film coating.

本發明之有核錠，例如可以本身公知之方法作成內核部之內核錠，接著，使用有核打錠機將該內核錠以外層部被覆而製造。又，上述內核錠(內核)可於以外層被覆之前，施予薄膜包衣。又，上述內核錠可為1製劑中有1個內核錠，亦可有複數個。又，本發明之有核錠可設置至少1層之膜包衣。The core ingot of the present invention can be produced, for example, by forming a core ingot of a core portion by a method known per se, and then coating the core layer with a core ingot machine. Further, the core ingot (core) may be coated with a film before being coated on the outer layer. Further, the above-mentioned core ingot may have one core ingot in one preparation, or may have plural ones. Further, the core ingot of the present invention may be provided with at least one film coating.

包衣，例如使用膜包衣裝置進行，作為膜包衣基劑，可列舉例如糖衣基劑、水溶性膜包衣基劑、腸溶性膜包衣基劑、緩放性膜包衣基劑等。The coating is carried out, for example, by using a film coating device, and examples of the film coating base include a sugar coating base, a water-soluble film coating base, an enteric film coating base, a slow release film coating base, and the like. .

作為糖衣基劑，使用白糖，又，亦可組合選自滑石、沈降碳酸鈣、磷酸鈣、硫酸鈣、明膠、***膠、聚乙烯吡咯啶酮、三聚葡糖等1種或2種以上使用。The sugar-based base may be one or more selected from the group consisting of talc, precipitated calcium carbonate, calcium phosphate, calcium sulfate, gelatin, gum arabic, polyvinylpyrrolidone, and trimeric glucose. .

作為水溶性膜包衣基劑，可列舉例如羥丙基纖維素、羥丙基甲基纖維素、羥乙基纖維素、甲基羥乙基纖維素、羧甲基纖維素鈉等之纖維素衍生物；聚乙烯醇、聚乙烯醇-聚乙二醇接枝共聚物、聚乙烯醇-丙烯酸-甲基丙烯酸甲酯共聚物、聚乙烯縮醛二乙胺乙酸酯、胺基烷基甲基丙烯酸酯共聚物、聚乙烯吡咯啶酮、聚乙二醇等之合成高分子；三聚葡糖等之多糖類等。Examples of the water-soluble film coating base include celluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, methylhydroxyethylcellulose, and sodium carboxymethylcellulose. Derivatives; polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, polyvinyl acetal diethylamine acetate, aminoalkyl group A synthetic polymer such as a acrylate copolymer, a polyvinylpyrrolidone or a polyethylene glycol; a polysaccharide such as a trimeric glucose or the like.

作為腸溶性膜包衣基劑，可列舉例如羥丙基甲基纖維素酞酸酯、羥丙基甲基纖維素乙酸丁二酸酯、羧甲基乙基纖維素、乙酸酞酸纖維素等之纖維素衍生物；甲基丙烯酸共聚物L、甲基丙烯酸共聚物LD、甲基丙烯酸共聚物S等之丙烯酸衍生物；蟲膠等之天然物等。Examples of the enteric film coating base include hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, and the like. A cellulose derivative; an acrylic acid derivative such as a methacrylic acid copolymer L, a methacrylic acid copolymer LD or a methacrylic acid copolymer S; a natural product such as shellac or the like.

作為緩放性膜包衣基劑，可列舉例如乙基纖維素等之纖維素衍生物；胺基烷基甲基丙烯酸酯共聚物RS、丙烯酸乙酯‧甲基丙烯酸甲酯‧共聚物乳濁液等之丙烯酸衍生物等。The slow release film coating base may, for example, be a cellulose derivative such as ethyl cellulose; an amine alkyl methacrylate copolymer RS, an ethyl acrylate ‧ methyl methacrylate ‧ copolymer opaque Acrylic acid derivatives such as liquids.

上述包衣基劑可將其2種以上以適當比例混合使用。又，更必要時，可含有適宜之藥理學上容許之可塑劑、賦形劑、潤滑劑、隱蔽劑、著色劑、防腐劑等之添加劑。The above-mentioned coating base may be used in combination of two or more kinds in an appropriate ratio. Further, if necessary, it may contain additives such as a suitable pharmacologically acceptable plasticizer, excipient, lubricant, concealing agent, coloring agent, preservative, and the like.

本發明之固形製劑之有效成分之奧美沙坦酯與阿折地平之投與量與投與比率，可依個別藥劑之活性、患者之症狀、年齡、體重等種種條件變化。其投與量依症狀、年齡等而不同，經口投與時，視症狀成人每日的奧美沙坦酯5mg-80mg(較佳為10mg-40mg)、阿折地平8mg-32mg(較佳為8mg-16mg)可以一日1至6次(較佳為一日1次)投與。The administration amount and the administration ratio of the olmesartan medoxomil and the adipine in the active ingredient of the solid preparation of the present invention may vary depending on the activity of the individual agent, the symptoms of the patient, the age, the body weight, and the like. The dosage varies depending on the symptoms, age, etc., and when administered orally, the daily dosage of olmesartan medoxomil 5 mg-80 mg (preferably 10 mg-40 mg) and adipine flat 8 mg-32 mg (preferably 8mg-16mg) can be administered from 1 to 6 times a day (preferably once a day).

又，本發明固形製劑之有效成分之奧美沙坦酯與阿折地平之投與量之比率亦為大幅變動，例如奧美沙坦酯與阿折地平之投與量比率，重量比可為1:50至50:1之範圍內，較佳為1:5至5:1。最佳形態為含有奧美沙坦酯/阿折地平為20mg/16mg或10mg/8mg之錠劑。Moreover, the ratio of the dosage of the olmesartan medoxomil and the adipine in the active ingredient of the solid preparation of the present invention is also greatly changed, for example, the ratio of the administration ratio of olmesartan medoxomil to adipine, and the weight ratio can be 1: In the range of 50 to 50:1, preferably 1:5 to 5:1. The most preferred form is a lozenge containing olmesartan medoxomil/ adipine is 20 mg/16 mg or 10 mg/8 mg.

本發明之固形製劑，例如有效於預防或治療高血壓症或來自高血壓症之疾病(更具體而言，為高血壓症、心臟疾病[狹心症、心肌梗塞、心率不整、心衰竭或心肥大]、腎臟疾病[糖尿病性腎症、絲球體腎炎或腎硬化症]或腦血管性疾病[腦梗塞或腦出血])等。The solid preparation of the present invention is, for example, effective for preventing or treating hypertension or a disease derived from hypertension (more specifically, hypertension, heart disease [narrow heart disease, myocardial infarction, arrhythmia, heart failure or heart) Hypertrophy], kidney disease [diabetic nephropathy, spheroid nephritis or nephrosclerosis] or cerebrovascular disease [cerebral infarction or cerebral hemorrhage]).

實施例Example

以下，以實施例等更詳細說明本發明，但本發明不受此限定。Hereinafter, the present invention will be described in more detail by way of examples, but the invention is not limited thereto.

(實施例1)(Example 1)

使用以下表1所示成分之彼等量，製作混合顆粒1。奧美沙坦酯、低取代度羥丙基纖維素、羥丙基纖維素、乳糖以高速攪拌造粒機(VG-10，Powrex，約2kg規模)混合5分鐘後，注加純水攪拌3分鐘，造粒。所得造粒物使用篩粉機(screening mill)(Fiore，德壽工作所，裝置10mm角之孔徑篩)製成顆粒，於入風溫度90℃之流動層乾燥機(Glatt WST-5，Powrex)中乾燥後，於篩粉機(COMIL 197S，Powrex，裝置1.143mm之網眼)中整粒，獲得顆粒1。以表1所示比例量秤顆粒1、結晶纖維素及硬脂酸鎂，使用V型混合機混合獲得混合顆粒1。The mixed particles 1 were produced using the same amounts of the components shown in Table 1 below. Olmesartan medoxomil, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, and lactose were mixed by a high-speed stirring granulator (VG-10, Powrex, about 2 kg scale) for 5 minutes, and then mixed with pure water for 3 minutes. , granulation. The obtained granules use a screening mill (Fiore, Deshou Work Station, device) 10mm angle aperture sieve) is made into granules, dried in a fluidized layer dryer (Glatt WST-5, Powrex) with a temperature of 90 °C, and then sieved in a sieving machine (COMIL 197S, Powrex, device) In the 1.143 mm mesh), the whole granule was obtained, and the granule 1 was obtained. The pellet 1, the crystalline cellulose, and the magnesium stearate were weighed in the proportions shown in Table 1, and mixed to obtain the mixed pellet 1 using a V-type mixer.

其次，依以下表2所示成分使用彼等量，製作混合顆粒2。各量秤1：1(重量比)之阿折地平與D-甘露糖醇，以高速攪拌造粒機(亨舍爾攪拌機(Henschel Mixer)FM-20，三井三池製作所)混合5分鐘後，使混合物於錘片式粉碎機(Hammer mill)(Sample mill KII WG-l，不二Paudal)中粉碎。又，偏矽酸鋁酸鎂、輕質矽酸酐以高速攪拌造粒機(亨舍爾攪拌機FM20，三井三池製作所)混合後，於此混合物中注加聚山梨酸酯80，獲得聚山梨酸酯80吸附粉末。所得阿折地平粉碎品、聚山梨酸酯80吸附粉末、D-甘露糖醇、羧甲基纖維素鈣、低取代度羥丙基纖維素、碳酸氫鈉、輕質矽酸酐於高速攪拌造粒機(VG-10，Powrex，約2kg規 模)中混合，加入羥丙基纖維素之水溶液(固形分濃度6.5%)於高速攪拌造粒機(VG-10，Powrex)中進行7.5分鐘造粒。所得練合物以篩粉機(旋風粉碎機(Tornado Mill)，F. J. Stokes Corp.，裝置10mm角之孔徑篩)製成顆粒，於入風溫度90℃之流動層乾燥機(Glatt WST-5，Powrex)中乾燥後，於篩粉機(旋風粉碎機，F. J. Stokes Corp.，裝置1.143mm之網孔)中將顆粒整粒，獲得顆粒2。顆粒2、偏矽酸鋁酸鎂、輕質矽酸酐、滑石、硬脂酸鎂以表2所示比例量秤，使用V型混合機(德壽工作所)混合而獲得混合顆粒2。Next, the mixed particles 2 were produced by using the same amounts as those shown in the following Table 2. A scale of 1:1 (by weight) of adipine and D-mannitol was mixed by a high-speed stirring granulator (Henschel Mixer FM-20, Mitsui Miike Co., Ltd.) for 5 minutes. The mixture was pulverized in a Hammer mill (Sample mill KII WG-l, Fuji Paudal). Further, magnesium metasilicate aluminate and light phthalic anhydride were mixed by a high-speed stirring granulator (Henschel mixer FM20, Mitsui Miike Seisakusho Co., Ltd.), and then polysorbate 80 was added to the mixture to obtain a polysorbate. 80 adsorption powder. The obtained adipine pulverized product, polysorbate 80 adsorption powder, D-mannitol, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, sodium hydrogencarbonate and light phthalic anhydride are stirred at high speed for granulation. The machine (VG-10, Powrex, about 2 kg scale) was mixed, and an aqueous solution of hydroxypropylcellulose (solid content concentration: 6.5%) was granulated in a high-speed stirring granulator (VG-10, Powrex) for 7.5 minutes. The resulting lysate is a sifter (Tornado Mill, FJ Stokes Corp., device) 10 mm angle aperture sieve) granules, dried in a fluidized bed dryer (Glatt WST-5, Powrex) at a temperature of 90 ° C, and then sieved on a sifter (Cyclone Crusher, FJ Stokes Corp., apparatus) The granules were granulated in a 1.143 mm mesh to obtain granules 2. Granules 2, magnesium metasilicate aluminate, light phthalic anhydride, talc, and magnesium stearate were weighed in the proportions shown in Table 2, and mixed using a V-type mixer (Deshou Works) to obtain mixed particles 2.

其次以表3所示配方，量秤乳糖(造粒粉末)、硬脂酸鎂，於V型混合機(德壽工作所)中混合10分鐘而獲得混合顆粒3。Next, in the formulation shown in Table 3, the lactose (granulated powder) and magnesium stearate were weighed and mixed in a V-type mixer (Deshou Work Station) for 10 minutes to obtain mixed particles 3.

接著，以260mg混合顆粒2於第1層中、100mg混合顆粒3於第2層中、120mg混合顆粒1於第3層中而成的方式充填調整，於旋轉打錠機中使用長徑15mm、短徑7.3mm之異型杵，以2.5噸之壓縮壓成形打錠，獲得錠劑1。Next, 260 mg of the mixed granule 2 was placed in the first layer, 100 mg of the mixed granule 3 was placed in the second layer, and 120 mg of the mixed granule 1 was placed in the third layer, and the long diameter was 15 mm in the rotary tableting machine. A shaped crucible having a short diameter of 7.3 mm was formed into a tablet by a compression molding of 2.5 tons to obtain a tablet 1.

評價所得錠劑1於60℃之安定性試驗開始時、1週後、2週後之溶出性(30分鐘後之奧美沙坦酯溶出率)，結果示於表4。The dissolution property of the obtained tablet 1 at the start of the stability test at 60 ° C, after 1 week, and after 2 weeks (the dissolution rate of olmesartan meitrol after 30 minutes) was evaluated. Table 4 shows the results.

(比較例1)(Comparative Example 1)

將實施例1所示製法獲得之260mg混合顆粒2於第1層、120mg混合顆粒1於第2層的方式充填調整，於旋轉打錠機中以長徑15mm、短徑7.3mm之異型杵，以2.5噸之壓縮壓成形 打錠，獲得錠劑2。評價所得錠劑2於60℃之安定性試驗開始時、1週後、2週後之溶出性(30分鐘後之奧美沙坦酯溶出率)，結果示於表4。The 260 mg of the mixed granule 2 obtained in the method shown in Example 1 was filled and adjusted in the first layer and 120 mg of the mixed granule 1 in the second layer, and the diced strand having a long diameter of 15 mm and a short diameter of 7.3 mm was placed in a rotary tableting machine. Formed with a compression pressure of 2.5 tons Ingots were obtained and tablets 2 were obtained. The dissolution property of the obtained tablet 2 at the start of the stability test at 60 ° C, after 1 week, and after 2 weeks (the elution rate of olmesartan meridin after 30 minutes) was evaluated. Table 4 shows the results.

(實施例2)(Example 2)

如表3所示處方，量秤結晶纖維素‧輕質矽酸酐噴霧乾燥品、硬脂酸鎂，於V型混合機(德壽工作所)中混合10分鐘而獲得混合顆粒4。As shown in Table 3, the amount of crystalline cellulose ‧ light phthalic anhydride spray dried product, magnesium stearate was mixed in a V-type mixer (Deshou Work Center) for 10 minutes to obtain mixed granules 4.

將實施例1所示260mg混合顆粒2於第1層，100mg混合顆粒4於第2層，120mg混合顆粒1於第3層的方式充填調整，於旋轉打錠機中使用長徑15mm、短徑7.3mm之異型杵，以2.5噸之壓縮壓成形打錠，獲得錠劑3。260 mg of the mixed granule 2 shown in Example 1 was placed on the first layer, 100 mg of the mixed granule 4 was placed on the second layer, and 120 mg of the mixed granule 1 was filled and adjusted in the third layer, and a long diameter of 15 mm and a short diameter were used in the rotary tableting machine. A 7.3 mm shaped crucible was formed into a tablet by a compression molding of 2.5 tons to obtain a tablet 3.

評價所得錠劑3於60℃之安定性試驗開始時、1週後、2週後之溶出性(30分鐘後之奧美沙坦酯溶出率)，結果示於表4。The dissolution of the obtained tablet 3 at the start of the stability test at 60 ° C, after 1 week, and after 2 weeks (the dissolution rate of olmesartan medomilit after 30 minutes) was evaluated. Table 4 shows the results.

(實施例3)(Example 3)

依表3所示處方，量秤乳糖(造粒粉末)、低取代度羥丙基纖維素、羥丙基纖維素、結晶纖維素、硬脂酸鎂，於V型混合機(德壽工作所)中混合10分鐘而獲得混合顆粒5。According to the prescription shown in Table 3, the amount of lactose (granulated powder), low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, crystalline cellulose, magnesium stearate, in the V-type mixer (Deshou work office) The mixture was mixed for 10 minutes to obtain mixed particles 5.

將實施例1所示260mg混合顆粒2於第1層、100mg混合顆粒5於第2層、120mg混合顆粒1於第3層的方式充填調整，於旋轉打錠機中使用長徑15mm、短徑7.3mm之異型杵，以2.5噸之壓縮壓成形打錠，獲得錠劑4。The 260 mg of the mixed granule 2 shown in Example 1 was filled and adjusted in the first layer, 100 mg of the mixed granule 5 in the second layer, and 120 mg of the mixed granule 1 in the third layer, and the long diameter of 15 mm and the short diameter were used in the rotary tableting machine. A 7.3 mm shaped crucible was formed into a tablet by a compression molding of 2.5 tons to obtain a tablet 4.

評價所得錠劑4於60℃之安定性試驗開始時、1週後、2週後之溶出性(30分鐘後之奧美沙坦酯溶出率)，結果示於 表4。The dissolution property of the obtained tablet 4 at the start of the stability test at 60 ° C, after 1 week, and after 2 weeks (the dissolution rate of olmesartan meitrol after 30 minutes) was evaluated. Table 4.

(試驗例)(test example)

依據日本藥局方第14改正之項中記載的溶出試驗法第2法(槳攪法)，每分鐘75次回轉，使用日局第2液(JP-2)900mL作為試驗液，進行試驗。採取試驗開始30分鐘後之試驗液，使用0.45μm孔徑之膜過濾器過濾，濾液使用高速液體色層分析定量，而算出奧美沙坦酯之溶出率(Varian：溶出試驗器；Agilent technoloies：高速液體色層分析)。According to the second method (paddle stirring method) of the dissolution test method described in the section 14 of the Japanese Pharmacopoeia, the test was carried out by using 75 days of the second liquid (JP-2) as the test liquid. The test solution after 30 minutes from the start of the test was filtered using a membrane filter having a pore size of 0.45 μm, and the filtrate was quantified by high-speed liquid chromatography analysis to calculate the dissolution rate of olmesartan medoxomil (Varian: dissolution tester; Agilent technoloies: high-speed liquid) Chromatography).

試驗進行3錠，以其平均值表示。The test was carried out in 3 spindles and expressed as the average value.

由表4可知，本發明之固形製劑改善奧美沙坦酯之溶出性。As is apparent from Table 4, the solid preparation of the present invention improves the dissolution of olmesartan medoxomil.

産業上之可利用性Industrial availability

依據本發明可改善含有奧美沙坦酯及阿折地平之固形 製劑之溶出性。According to the invention, the solid form containing olmesartan medoxomil and adipine can be improved The dissolution of the formulation.

Claims (5)

一種固形製劑之溶出性改善方法，其含有奧美沙坦酯(olmesartan medoxomil)及阿折地平(azelnidipine)；其中，奧美沙坦酯及阿折地平以互不接觸的方式分離調配；固形製劑為錠劑之形態；該錠劑為多層錠；且該多層錠為三層錠，第1層含有奧美沙坦酯，夾著含有賦形劑之中間層的另一層含有阿折地平。 A method for improving dissolution of a solid preparation, comprising olmesartan medoxomil and azelnidipine; wherein olmesartan and adipine are separated and disposed in a non-contact manner; the solid preparation is an ingot The tablet is in the form of a multi-layer ingot; and the multi-layer ingot is a three-layer ingot, the first layer contains olmesartan medoxomil, and the other layer containing the intermediate layer containing the excipient contains adesodipine. 如申請專利範圍第1項之方法，其多層錠為由內核、中間層與外層構成的有核錠，其中內核含有奧美沙坦酯，外層含有阿折地平。 The method of claim 1, wherein the multi-layer ingot is a core ingot composed of an inner core, an intermediate layer and an outer layer, wherein the inner core contains olmesartan medoxomil and the outer layer contains adipine. 如申請專利範圍第1項之方法，其多層錠為內核、中間層、與外層構成的有核錠，其中內核含有阿折地平，外層含有奧美沙坦酯。 For example, in the method of claim 1, the multi-layer ingot is a core, an intermediate layer, and a core ingot composed of an outer layer, wherein the inner core contains adepinepine and the outer layer contains olmesartan medoxomil. 如申請專利範圍第1至3項中任一項之方法，其中賦形劑為選自乳糖、結晶纖維素、輕質矽酸酐組成之群之1或2種以上。 The method according to any one of claims 1 to 3, wherein the excipient is one or more selected from the group consisting of lactose, crystalline cellulose, and light phthalic anhydride. 如申請專利範圍第1至3項中任一項之方法，其係用於改善奧美沙坦酯之溶出性。The method of any one of claims 1 to 3 for improving the dissolution of olmesartan medoxomil.
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