修正本 1297609 九、發明說明： 【發明所屬之技術領域】 本發明係關於一種口服控制釋放劑型之藥學組合物，包括一種立 即釋放之膜衣及持續釋放基體核心之配方組合物，一種活性成份立即 釋放膜衣包覆(inner film-coating)，與阻光外包衣(outer fnnvcoating)。 主要由假麻黃鹼(Pseudoephedrine)或其具有生體活性之相關鹽類與 抵斯樂鼻定(Desloratadine)所組成而用於治療上呼吸道疾病鼻炎、鼻 充血、過敏等感冒徵候與疾病的病人。 【先前技術】 本發明係關於一種口服控制釋放劑型之藥學組合物，包括由假麻 黃驗或其具有生體活性之相關鹽類及由另一具有非鎮靜性抗組織胺抵 斯樂鼻定(Desloratadine)所形成，用於治療上呼吸道疾病鼻炎、鼻充 血、過敏等感冒徵候與疾病的病人。 假麻黃鹼(Pseudoephedrine)以及具生體活性而為醫藥上可接受 之鹽類，如假麻黃鹼鹽酸鹽(Pseudoephedrine HCI)，假麻黃驗硫酸鹽 (Pseudoephedrine sulfate)等，均是一種腎上腺激素性或擬交感神經興 奮劑，經由内因性腎上腺素胺類釋出之間接作用，而刺激甲型（α type)、乙一型（召1type)和乙二型（/5 ztype)腎上腺素激性接受體 (adrenergic recept〇rs)而呈現相關的藥理作用，使鼻黏膜血管收縮而 緩解鼻腔或耳咽管充血現象，緩解呼吸道之阻塞，另外可經由弛缓支 氣管肌肉之作用，使支氣管擴張增加換氣量。一般經口服後起始作用 時間約為15〜30分鐘，作用時間(duration)約3小時，半衰期平均約 7小時，是以本藥適合做成持續釋放之控釋劑型以提高治療品質，並 使假麻黃驗可在人體達到12小時或12小時以上之持續釋放效果。 抵斯樂鼻定(Desloratadine)係揭示於美國專利第4,659,716號， 並經報導證實具有抗組織胺活性，能迅速解除過敏性鼻炎的相關症 狀，如鼻塞、流鼻水、搔癢以及眼睛搔癢和灼熱感，對因慢性麻疹以 修正本 1297609 及過敏性皮膚病所引起的症狀亦能有迅速緩解的作用。抵斯樂鼻定 (Desloratadine)之推薦π服劑量為每日5mg到l〇〇mg，而最被喜好之 每曰口服劑量為10mg到20mg。 抵斯樂鼻定(Desloratadine)係已知另一三環狀長效型抗組織胺成 份樂鼻定(Loratadine)之主要活性代謝產物，此樂鼻定被歸類為第二代 之H1接受體選擇性拮抗劑(hh select antagonists)。一般之&接受體 拮抗劑往往存在著某些副作用，例如具有抗膽鹼激素效應 (anticholinergiceffects)所引起的疲勞、思睡、頭痛等現象，更有甚者 如亞特雷(astemizole)及特芬丁 (terfenadine)已知具有影響心臟電傳 導、心律不整等不良副作用；並且伴隨有延長心電圖之QT波之不良 效應等。且一般已知堇托雷(Ketoconazole)、伊托雷(丨tracongzole)及 紅黴素(Erythromycin)會干擾細胞色素(Cytochrome) P450作用，因此 抑制了某些非鎮靜性抗組織胺如特芬丁 (terfenadine)、亞特雷 (astemizole)及羅芬丁(loratadine)等之代謝作用，此類會干擾細胞色素 (Cytochrome) P450作用者因此被歸類為對羅芬丁(|〇ratadine)等藥物 有不良副作用者。 而抵斯樂鼻定(Desloratadine)係樂鼻定(Loratadine)之主要活 性代謝產物’減少三環狀長效型抗組織胺樂鼻定(Loratadine)成份之副 作用。抵斯樂鼻定被歸類為第二代之Η!接受體選擇性拮抗劑(h! se|ect antagonists)。此類抗組織胺藥物僅微具或者不具有引起疲勞、思睡、 頭痛等現象之抗膽鹼激素效應(anticholinergiceffects)，更不至於像亞 特雷(astemizole)及特芬丁(terfenadine)—般，具有影響心臟電傳導、 心律不整等不良副作用。 【發明内容】 本發明揭示一種立即釋放之膜衣及持續釋放基體核心之配方組合 物’包含一種假麻黃素鹽為活性成份之持續釋放基體核心(core matnx) ’ 一種抵斯樂鼻定為另一活性成份立即釋放膜衣包覆(inner 6 1297609 修正本 film-coating)，以及阻光外包衣(outer film_coating)。 本發明之控制釋放劑型藥學組合物以控釋之假麻黃鹼為核心錠， 外層包覆立即釋放之抵斯樂鼻定(Des|〇ratad|ne)為一新發明^藥物組 ^f別於以假麻黃鹼合併樂鼻定(loratadine)之藥物組合，其’口服= 藥以每天一次為原則，既可提高病人服藥之順從性，更可提高广串又 生活品質。 间;丙〜、之 本發明揭示一種製備控制釋放劑型藥學組合物方法，以羥丙基甲 基纖維素(HPMC)和二十二烷酸甘油脂(g|yCery| behenate)兩種賦形 劑’當延長釋放劑型的聚合基體核心(Matrix)中控釋劑，慢慢地將所邦 要釋放之藥物釋放出來。 心 【實施方式】 本發明揭示一種獨特之口服複方劑型，其劑型是把含非鎮定性之 抗組織胺抵斯樂鼻定(Desloratadine)包覆在，一種具有延長釋放效果 之基體核心(Matrix)上，其基體核心可令假麻黃素鹽之持續釋放效果 (Control_release)達到12小時或12小時以上，在臨床治療上可以改呈 感冒所引起之上呼吸道疾病感染所引發之鼻充血及過敏性鼻炎相關症 候與病狀之病人。 抵斯樂鼻定(Desloratadine)是一種非常新的H1接受體選擇性拮抗 劑(Η! select antagonists)抗組織胺，能夠有效治療季節性過敏性鼻炎 症狀一如鼻洋及癢症。 因此將抵斯樂鼻定（Desloratadine)和假麻黃素鹽酸鹽 (Pseudo印hedrine HCI)，假麻黃鹼硫酸鹽(PSeud〇ephedrine H2S04) 合併使用是本臨床治療上之新發明。 本發明揭示一種立即釋放之膜衣及持續釋放基體核心之配方組合 物，其係包含一種假麻黃素鹽為活性成份之持續釋放基體核心(core matrix)，另外以立即釋放膜衣包覆(innerfilm_coating)第二種活性成份 抵斯樂鼻定(Desloratadine)，以及阻光外包衣(outer film-coating)。 修正本 1297609 本發明之控制釋放劑型藥學組合物以控釋之假麻黃鹼為核心錠， 外層包覆立即釋放之抵斯樂鼻定(Des|〇ratad•丨ne)為一種新發明之藥物 、、且a此藥物組合有別於以假麻黃驗合併樂鼻定(|〇ratadine)之藥物組 否。本發明之藥物組合其口服投藥以每天一次為原則，既可提高病人 服藥之順從性，更可提高病患之生活品質。 本發明揭示一種製備控制釋放劑型藥學組合物方法，以羥丙基曱 基纖維素(HPMC)和二十二烷酸甘油脂(glycery| behenate)兩種賦形 劑’當延長釋放劑型的聚合基體核心(Matrix)中控釋劑，慢慢地將所想 要釋放之藥物釋放出來。因此將假麻黃素鹽平均分散在具有上述控釋 效果的基體核心中(Matrix)，藉由上述之延長控釋之聚合基體(Mat|1x)MODIFICATION 1297609 IX. DESCRIPTION OF THE INVENTION: FIELD OF THE INVENTION The present invention relates to a pharmaceutical composition of an oral controlled release dosage form comprising an immediate release film coat and a sustained release matrix core formulation composition, an active ingredient immediately Release film-coating, and outer fnnvcoating. A patient mainly composed of Pseudoephedrine or its bioactive related salt and Desloratadine for the treatment of cold respiratory symptoms, rhinitis, allergies and other cold symptoms and diseases. . [Prior Art] The present invention relates to a pharmaceutical composition of an oral controlled release dosage form comprising a salt associated with pseudoephedrine or its biological activity and a non-sedating antihistamine (Desloratadine) is formed for the treatment of cold respiratory symptoms, diseases such as rhinitis, nasal congestion, allergies and other diseases. Pseudoephedrine and pharmaceutically acceptable salts such as Pseudoephedrine HCI and Pseudoephedrine sulfate are a kind of Adrenal or sympathomimetic stimulants that stimulate the intermolecular release of endogenous adrenergic amines, while stimulating alpha (alpha type), type B (call 1 type) and type 2 (/5 ztype) adrenaline Sexual receptor (adrenergic recept〇rs) and related pharmacological effects, the nasal mucosa vasoconstriction relieves nasal or eustachian tube congestion, relieves obstruction of the respiratory tract, and can increase the amount of ventilation through bronchiectasis by relaxing the bronchial muscles. . Generally, the initial action time after oral administration is about 15 to 30 minutes, the duration of treatment is about 3 hours, and the half-life is about 7 hours on average. It is a controlled release dosage form suitable for sustained release of the drug to improve the treatment quality and make the fake The ephedra test can achieve a sustained release effect in the human body for 12 hours or more. Desloratadine is disclosed in U.S. Patent No. 4,659,716, which has been reported to have antihistamine activity and rapidly relieve symptoms associated with allergic rhinitis such as nasal congestion, runny nose, itching, and itchy eyes and burning sensation. It can also relieve the symptoms caused by chronic measles by correcting this 1297609 and allergic skin diseases. Desloratadine's recommended dose for π is 5 mg to 1 mg per day, and the most recommended oral dose per dose is 10 mg to 20 mg. Desloratadine is the main active metabolite of Loratadine, another three-ring long-acting anti-histamine component. This is a second-generation H1 receptor. Selective antagonists (hh select antagonists). Generally & acceptor antagonists often have some side effects, such as fatigue caused by anticholinergic effects, sleepiness, headache, etc., and even more such as attemizole and special Terfenadine is known to have adverse side effects that affect cardiac electrical conduction, arrhythmia, and the like, and is accompanied by adverse effects of QT waves that prolong the electrocardiogram. It is generally known that Ketoconazole, 丨tracongzole and erythromycin (Erythromycin) interfere with the action of cytochrome (Cytochrome) P450, thus inhibiting certain non-sedating antihistamines such as tephenerine. Metabolic effects of (terfenadine), attemizole, and loratadine, which interfere with cytochrome (Cytochrome) P450, are therefore classified as drugs such as 〇ratadine Have adverse side effects. Desloratadine, the main active metabolite of Loratadine, reduces the side effects of the three-ring long-acting anti-histamine component. The sylvestre is classified as the second generation! Receiver selective antagonists (h! se|ect antagonists). These antihistamines are only slightly or have anticholinergic effects that cause fatigue, sleepiness, headache, etc., and are not as good as astemzole and terfenadine. It has adverse side effects that affect cardiac electrical conduction and arrhythmia. SUMMARY OF THE INVENTION The present invention discloses an immediate release film coating and a sustained release matrix core formulation composition 'containing a pseudoephedrine salt as an active ingredient of a sustained release matrix core (core matnx) Another active ingredient is immediately released into the film coat (inner 6 1297609 modified film-coating), and outer film_coating. The controlled release dosage form pharmaceutical composition of the present invention is controlled by the release of pseudoephedrine as a core ingot, and the outer layer is coated with immediate release of Des|〇ratad|ne as a new invention. In the combination of pseudoephedrine and loratadine, the 'oral=medicine is based on the principle of once a day, which can improve the compliance of patients taking medicine, and can improve the quality of life and quality. The invention discloses a method for preparing a controlled release dosage form pharmaceutical composition, which comprises two kinds of excipients: hydroxypropylmethylcellulose (HPMC) and behenic acid glycerolipid (g|yCery| behenate) 'When a controlled release agent is added to the polymeric matrix core of the extended release dosage form, the drug to be released is slowly released. [Embodiment] The present invention discloses a unique oral compound dosage form, which is coated with a non-stable anti-histamine anti-Desloratadine, a matrix core with extended release effect (Matrix) In addition, the core of the matrix can make the sustained release effect (Control_release) of pseudoephedrine salt reach 12 hours or more, and can be modified into a nasal congestion and allergic reaction caused by a cold respiratory infection caused by a cold in clinical treatment. Patients with rhinitis-related symptoms and conditions. Desloratadine is a very new H1 receptor selective antagonist (anti-histamine) that is effective in treating seasonal allergic rhinitis symptoms such as nasal and itching. Therefore, the combination of Desloratadine and pseudoephedrine hydrochloride (Pseudo-hedrine HCI) and pseudoephedrine sulfate (PSeud〇ephedrine H2S04) is a new invention in clinical treatment. The present invention discloses an immediate release film coating and a sustained release matrix core formulation composition comprising a pseudoephedrine salt as an active ingredient in a sustained release core matrix, additionally coated with an immediate release film coat ( Innerfilm_coating) The second active ingredient is Desloratadine, and outer film-coating. MODIFICATION 1297609 The pharmaceutical composition of the controlled release dosage form of the present invention is controlled by the release of pseudoephedrine as a core ingot, and the outer layer is coated with immediate release of Des|〇ratad•丨ne as a newly invented drug. And, the drug combination is different from the drug group that is combined with the sputum sputum (|〇ratadine). The pharmaceutical combination of the present invention is administered orally once a day, which not only improves the compliance of the patient, but also improves the quality of life of the patient. The invention discloses a method for preparing a controlled release dosage form pharmaceutical composition, which comprises a hydroxypropyl decyl cellulose (HPMC) and a glyceryl | behenate two excipients as a polymeric matrix of an extended release dosage form. A controlled release agent in the core that slowly releases the drug that it is intended to release. Therefore, the pseudoephedrine salt is dispersed evenly in the matrix core having the above controlled release effect (Matrix), and the controlled release polymerized matrix (Mat|1x) is extended by the above.
之釋放，可在活體外(Invitro)達到12小時或12小時以上之持續釋放。W 另外再將含有非鎮靜抗組織胺藥物，抵斯樂鼻定(Des丨〇ratacHne) 以即溶膜衣包覆(film-coating)技術之方式，定量包覆在前述之具有12 小時或12小時以上持續釋放(contr〇||ed_re|ease)的假麻黃素鹽酸鹽 (Pseudoephedrine HCI)，假麻黃驗硫酸鹽(pseud〇ephedrine hbSO4) 的聚合基體核心（core matrix)上，以達到立即釋放之效果 (lmmediate_release)〇 如何將假麻黃素鹽酸鹽(Pseudoephedrine HCI)，假麻黃驗硫酸鹽 (Pseudoephedrine ΗΘ〇4)及其他具生體活性之假麻黃素鹽類，設計 成具有12小時或24小時之控釋效果的基體核心(Matrjx)，及將水溶性 鲁 不佳之抵斯樂鼻定(Desloratadine)包覆在基體核心(Matrix)上。當經由 口服後，包覆在基體核心上之藥物抵斯樂鼻定(Des|〇ratad|ne)以非常 快之速度溶解，緊接著假麻黃素鹽經由基體核心，以一定之溶解速度 釋放出來’因控釋賦形劑之多寡及主成份之含量多少，而達到12小時 或24小時之持續釋放劑型，正是本發明技術重點。 · 在發展本發明之複方口服劑型組合物之過程，發現假麻黃素鹽酸 鹽(Pseudoephedrine HCI)，假麻黃驗硫酸鹽(pseu(j〇ephedrine H2SO4) 及其他具生體活性之假麻黃素鹽類，當採用羥丙基甲基纖維素(HPMC) 8 1297609 修正本 當控釋劑足以影做麻黃素_之釋鱗間長久性，·賴慎 選擇羧丙基甲基纖維素(HPMC)之義及黏度。市場上經丙基甲基 素(HPMC)之種類及黏度有許多種；4⑻〇 cps之幾丙基甲基纖維 (HPMC)2906、15000Cps之羥丙基甲基纖維素(HpMC)22〇8，等等了 單獨採用4000 Cps之經丙基甲基纖維素(HpMC)29〇6，或θ 15000cps經丙基甲基纖維素(HPMC)22〇8，當控釋劑，均無法令假= * ^ 0 ^ M (Pseudoephedrine HCI) , (Pseudo印hedrine HbSO4)達到12小時以上之控釋效果。歷經多次^ 驗，發現使用15000Cps羥丙基甲基纖維素(HPMC)22〇8和二十二二 酸甘油脂雜成分相互搭轉為控糊，在各侧_巾添加之經丙 基甲基纖維素與二十二院酸甘油脂相互間約維持11:1之比率，便可達 到12小時以上之控釋效果。 將主成份假麻黃素鹽和羥丙基甲基纖維素和二氧化矽及乳糖相混 和，採用濕式造粒法造粒，先將聚乙烯砒咯酮溶於純水及酒精中，進 打快速混和造粒，便可制很均自之轉齡。經絲後，再添 加，脂酸雜二十二駿甘油脂伽_，並且㈣最狀顆粒水 合篁在3%以下。接著進行核心之打錠工程，進行各項測試，不斷地更 改各成分之比例，以達到硬度及脆度都相當不錯，流動性也很好之錠 劑核心顆粒。 接著將抵斯樂鼻定(Desloratadine)成分包覆在核心上之工作，因 抵斯樂鼻定(Desloratadine)之水溶性不是很好，如果直接用水當溶 劑，無法均勻的分布在基體核心，且溶解效果也不盡理想。而後發現 以純^ :酒精(1.5 : 1)當溶劑溶解效果最好，又以聚乙烯砒咯酮··抵斯 樂鼻疋(1 · 1)之比例混和形成複合物(c〇mplex)，有提高抵斯樂鼻定之 溶解度及安定性之作用。所以將抵斯樂鼻定和聚乙烯砒咯酮溶於純水 =酒精，再直接經由自動膜衣機將其溶液包覆在前面所述之基體核心 k劑上’完成抵斯樂鼻定之複方包覆工作。 修正本 Ϊ297609 、最後再進行膜衣外包覆工程，因抵斯樂鼻定和假麻黃素鹽兩種主 成伤對光線和、屋度都相當敏感，為避免光線和溼度足以影響長期架儲 期，探纣經由外包衣之包覆工作，以阻絕抵斯樂鼻定直接接觸空氣和 阻光之效果。其包覆方法，乃將市售二代歐巴代(〇padfy ]1)原料調製 成15%〜17%之純水溶液，再藉由自動膜衣機將其包覆在錠劑核心 上，完成整個錠劑製造過程。本發明之複方口服劑型組合物，其錠劑 之外觀，包含有球形、圓凸、橢圓形、長圓柱形……等形狀。 本發明複方口服劑型組合物之製備過程如下： [1】·製造錠劑核心(core Tablets)方法 1.將假麻黃素鹽類、羥丙基甲基纖維素、二氧化矽和乳糖分別依照 處方稱重，放入快速混和機内混和6分鐘。 2·將已稱重之聚乙烯砒咯酮均勻地溶於純水和乙醇之混和溶液中。 3.再將步驟2之混和溶液，慢慢倒入步驟彳中之快速混和機中， 進行濕式造。 4_將完成之顆粒，倒入透氣式乾燥機盤内，在5〇〇c下乾燥至水份 含量在1 %〜3%之間。 ' 5.將已乾燥之顆粒，放入1 mm篩網之整粒機中整粒。 6·經整粒之顆粒放入雙錐型混和機中，再加入硬脂酸鎂和二烷酸甘 油脂，混和3分鐘。 7.採用快速20支迴轉式打錠機進行打鍵，並且進行製程管制(丨n process control)試驗。 此基體核心錠劑製程管制如下： 重量：400 ±3%毫克 厚度：6.0〜6.3rnm 硬度：10Kg ±2 Kg 脆度：<1% 修正本 1297609 [Π]·活性成分及外包衣包覆： Α·活性成分溶液之製備 1·活性包衣溶液製備 將等量抵斯樂鼻定和聚乙稀卻!^各酮溶於(ι·5 ·· 1)之純水及乙醇 中，用攪拌機攪拌至完全溶解為止。 2_外包衣溶液製備 將二代歐巴代(Opadry Π)溶於純水溶液中，其濃度維持在大 約為15%〜17%之間最好。 B·外包衣包覆方法The release can be sustained in vitro (Invitro) for up to 12 hours or more. W will additionally contain non-sedating antihistamines, and Des丨〇ratacHne will be coated in the above-mentioned 12 hours or 12 by means of instant film-coating techniques. Pseudoephedrine HCI, which is continuously released (contr〇||ed_re|ease) for more than an hour, on the polymer matrix of pseudoephedrine hbSO4 Immediate release effect (lmmediate_release) How to design Pseudoephedrine HCI, Pseudoephedrine ΗΘ〇4 and other pseudoephedrine salts with biological activity A matrix core (Matrjx) with a controlled release effect of 12 hours or 24 hours, and a water-soluble Lu Desloratadine coated on the matrix core. When administered orally, the drug coated on the core of the matrix is dissolved at a very fast rate, followed by the release of pseudoephedrine salt through the matrix core at a certain rate of dissolution. It is the technical focus of the present invention to provide a sustained release dosage form that achieves 12 hours or 24 hours due to the amount of controlled release excipients and the amount of the main ingredient. · In the process of developing the compound oral dosage form composition of the present invention, it was found that pseudoephedrine hydrochloride (Pseudoephedrine HCI), pseudoephedrine sulfate (pseu (j〇ephedrine H2SO4) and other pseudoactive hemp Flavin salts, when using hydroxypropyl methylcellulose (HPMC) 8 1297609 modified as a controlled release agent is sufficient to affect the long-term release of ephedrine _, 赖慎 choose carboxypropyl methylcellulose (HPMC) meaning and viscosity. There are many kinds of propyl methyl ketone (HPMC) on the market and viscosity; 4 (8) 〇 cps propyl methyl fiber (HPMC) 2906, 15000 Cps hydroxypropyl methyl fiber (HpMC) 22〇8, and so on, using 4000 Cps of propylmethylcellulose (HpMC) 29〇6, or θ 15000 cps by propylmethylcellulose (HPMC) 22〇8, when controlled release The agent could not make the false = * ^ 0 ^ M (Pseudoephedrine HCI), (Pseudo printed hedrine HbSO4) achieve controlled release effect for more than 12 hours. After repeated tests, it was found that 15000 Cps hydroxypropyl methylcellulose (HPMC) was found. ) 22〇8 and docate diglycerides are mixed into a paste, and propylmethylcellulose is added to each side of the towel. The 12-yard acid glyceride can maintain a ratio of about 11:1 to achieve a controlled release effect of more than 12 hours. The main component pseudoephedrine salt and hydroxypropyl methylcellulose and cerium oxide and lactose phase Mixing, granulation by wet granulation, first dissolving polyvinylpyrrolidone in pure water and alcohol, and then mixing and granulating quickly, it can be made into a very uniform age. After the warp, add it again. The fatty acid is 22 bromo glycerol gamma, and (4) the most granular hydrazine hydrate is below 3%. Then the core ingot project is carried out, various tests are carried out, and the proportion of each component is continuously changed to achieve hardness and brittleness. The core particles are quite good, and the fluidity is also very good. The next step is to coat the core with Desloratadine. The water solubility of Desloratadine is not very good. If water is used directly as a solvent, it cannot be evenly distributed in the core of the matrix, and the dissolution effect is not satisfactory. Then it is found that pure ^: alcohol (1.5:1) has the best solvent dissolution effect, and polyvinylpyrrolidone·· The proportion of the sinus (1 · 1) is mixed The compound (c〇mplex) has the effect of improving the solubility and stability of the spleen. Therefore, it is dissolved in pure water = alcohol and then directly passed through the automatic film coat machine. The solution is coated on the base core k agent described above to complete the compound coating work of the syllabus. Correction Ϊ 297609, and finally the outer coating of the film coating, due to the snail and the fake ephedra The two main wounds of the salt are quite sensitive to the light and the house. In order to avoid the light and humidity enough to affect the long-term storage period, the exploration is carried out by the coating of the outer coating to prevent the direct contact with the air and The effect of blocking light. The coating method is to prepare a commercially available second-generation Opadry (1padfy) 1) raw material into a pure aqueous solution of 15% to 17%, and then coated on the core of the tablet by an automatic film coater to complete The entire tablet manufacturing process. The compound oral dosage form composition of the present invention has a shape of a tablet comprising a spherical shape, a rounded convex shape, an elliptical shape, a long cylindrical shape, and the like. The preparation process of the compound oral dosage form composition of the present invention is as follows: [1]·Production of core tabletss 1. The pseudoephedrine salt, hydroxypropylmethylcellulose, cerium oxide and lactose are respectively The prescription was weighed and mixed in a fast blender for 6 minutes. 2. The weighed polyvinylpyrrolidone is uniformly dissolved in a mixed solution of pure water and ethanol. 3. Pour the mixed solution of step 2 into the rapid mixer in step , and dry it. 4_ Pour the finished granules into a ventilated dryer tray and dry at 5 °c until the moisture content is between 1% and 3%. ' 5. Place the dried granules in a 1 mm sieve granulator. 6. The granules of the granules were placed in a double-cone mixer, and then magnesium stearate and glyceryl dicarbonate were added and mixed for 3 minutes. 7. Use a fast 20-spindle ingot to perform keying and perform a process control test. The core core tablet process control is as follows: Weight: 400 ± 3% mg Thickness: 6.0 to 6.3 rnm Hardness: 10 Kg ± 2 Kg Brittleness: < 1% Revision 1297609 [Π]· Active ingredient and outer coat coating: Α·Preparation of active ingredient solution 1·Preparation of active coating solution: Equal amount of snails and polyethylene; but each ketone is dissolved in pure water and ethanol of (ι·5 ·· 1), using a blender Stir until completely dissolved. 2_Overcoat solution preparation The second generation Opadry (Opadry®) is dissolved in a pure aqueous solution, and the concentration is maintained to be preferably between about 15% and 17%. B·Overcoat coating method
1.將已製備之錠劑核心，放入自動膜衣機中，再將活性包衣溶液 喷覆在錠劑中，調整膜衣機之入風口溫度及膜衣鋼之適當轉 速，以達到最高包覆效力。 2·完成活性包衣溶液之包覆後，再繼續進行外包衣溶液之包覆喷 霧工作，直到喷完外包衣(二代歐巴代)溶液，再進行5至10 分鐘乾燥，降溫取出錠劑，整個製造流程便告完成。 本發明提供一種持續釋放基體核心之配方組合物，包含一種活性 持續釋放基體核心(core matrix) 包含成份 毫克/核心1. Put the prepared tablet core into an automatic film coater, spray the active coating solution on the tablet, adjust the temperature of the air inlet of the film coater and the appropriate speed of the coat steel to achieve the highest Coating effectiveness. 2. After completing the coating of the active coating solution, continue the coating spray of the outer coating solution until the outer coating (second generation Opadry) solution is sprayed, and then dried for 5 to 10 minutes, and the ingot is cooled. The entire manufacturing process is completed. The present invention provides a formulation composition for sustained release matrix core comprising an active sustained release core matrix comprising components mg/core
假麻黃素鹽 120〜360 羥丙基甲基纖維素 88〜264 二氧化矽 4〜12 乳糖 160〜480 一十二燒酸甘油脂 聚乙烯碗咯酮 硬脂酸鎂 基體核心重量範圍 8〜24 16 〜48 4〜12 400〜1200毫克 11 1297609 修正本 (2) 另一種活性成份立即釋放膜衣包覆(inner film-coating) 包含成份 毫克/核心 抵斯樂鼻定 2.5〜7.5 聚乙烯石比略酮 2.5〜7.5 膜衣重量範圍 5〜15毫克 (3) 阻光外包衣(outer film-coating) 包含成份 毫克/核心 二代歐巴代(Opadry n)White 31k58901 12〜36 總錠劑重量範圍(基體核心+包衣） 417〜1251毫克 | 將完成之錠劑用塑膠瓶及鋁箔膠片包裝好，放在25π±2^;6〇rh ±5%和 30°C±2°C ; 60RH±5%及 40°C±2°C ; 75RH±5%之三種不同溫 度及濕度壞境中，固定時間點取出做成份分析及體外溶離試驗，置貯 存有效期可達24個月以上之久。 /'、 模擬人體胃料三種不同pH值，進行本發觀劑之料溶離試 驗(In vitro)。 Α·在37°C±0.5t：之0.1N鹽酸(Ηα)溶液下，採用哪阳她在 50 rpm條件下，進行彳2小時溶離試驗。 鲁Pseudoephedrine salt 120~360 Hydroxypropyl methylcellulose 88~264 Ceria 4~12 Lactose 160~480 Twelve calcined glycolipids Polycyanophenone magnesium stearate core weight range 8~ 24 16 ～48 4~12 400~1200 mg 11 1297609 Amendment (2) Another active ingredient immediate release film coating (inner film-coating) Contains ingredients mg/core to snail nose 2.5~7.5 polyethylene stone Bis- ketone 2.5~7.5 film coat weight range 5~15 mg (3) Outer film-coating Ingredients mg/core second generation Opadry n White 31k58901 12~36 total tablet weight Scope (matrix core + coating) 417~1251 mg | The finished tablet is packaged in plastic bottle and aluminum foil film, placed at 25π±2^;6〇rh ±5% and 30°C±2°C; 60RH ±5% and 40 °C ± 2 °C; 75RH ± 5% of the three different temperature and humidity conditions, fixed time points for component analysis and in vitro dissolution test, storage period of up to 24 months. /', simulate the three different pH values of the human stomach material, and carry out the dissolution test of the present agent (In vitro). Α· At 37 ° C ± 0.5 t: 0.1 N hydrochloric acid (Ηα) solution, using yang, she was subjected to a 彳2 hour dissolution test at 50 rpm. Lu
B.在37C±0_5°C之pH 4_5之緩衝液(buffer)溶液下，採用USP paddte 在 50 rpm 條件下，_ 12 〇 C·在37C(0.5c之pH 6.8之緩衝液(buffer)溶液下，採用USP paddle 在 50 _ 條彳τ，_ 12 〇 一匕衣中之活f生成分抵斯樂鼻定(〇的丨的⑽㈣在模擬人體胃腸道 種不，pH值办離试驗，如表一所 固 便已 來，達到99%之溶屮农· 肝® 出率，而基體核心中所含假麻黃素鹽 12 修正本 1297609 (Pseudoephedrine HCI)，在12小時内有緩釋現象。如第一圖所示， 在〇_1 N鹽酸(HCI)、pH 4·5之緩衝液(bUffer)或是pH 6 8缓衝液 (buffer)等二種模擬人體腸胃道之pH值溶出率，並無太大差異性。因 此可以使用任一種pH值之緩衝溶液來檢測基體核心中假麻黃素鹽的 溶出率情況。 本發明口服劑型中，持續釋放基體核心中之活性成份—假麻黃素 鹽酸鹽(Pseudo印hedrine HCI)，使用另一種醫藥成份一硫酸假麻黃素 硫酸鹽(Pseudoephedrine hSO4)，仍然具有相同之持續釋放效果。 凡是熟悉該技藝的人士在閱讀下列經由不同圖式所展示之較佳實 施例詳細說明後，無疑地將非常清楚本發明所揭示之目的和優點。 實例1 本發明提供一種12小時較佳膜衣持續釋放之配方組合物，包含一 種活性持續釋放基體核心(core matrix) 包含成份 毫克/核心 假麻黃素鹽 120 羥丙基甲基纖維素 88 二氧化矽 4 乳糖 160 二十二烷酸甘油脂 8 聚乙稀>6比嘻酮 16 硬脂酸鎂 4 一種活性成份立即釋放膜衣包覆(jnner fj|m-C〇ating) 包含成份 毫克/核心 抵斯樂鼻定 2.5 聚乙婦规洛_ 2.5 膜衣重量範圍 5毫克 13 修正本 1297609 ⑶阻光外包衣(outer film-coating) 包含成份 毫克/核心 二代歐巴代(Opadry I〇White 31 k58901 12 總錠劑重量範圍(基體核心+包衣） 417毫克 實例2 本發明提供一種持續釋放之配方組合物，包含一種活性持續釋放 基體核心(core matrix) 包含成份 毫克/核心 假麻黃素鹽 360 羥丙基甲基纖維素 264 二氧化矽 12 乳糖 480 二十二烧酸甘油脂 24 聚乙烯砒咯酮 48 硬脂酸鎂 12 基體核心重量範圍 1,200毫克 (2)另一種活性成份立即釋放膜衣包覆(inner film-coating) 包含成份 毫克/核心 抵斯樂鼻定 7.5 聚乙稀础洛酮 7.5 膜衣重量範圍 15毫克 (3)阻光外包衣(outer film-coating) 包含成份 毫克/核心 二^ 歐巴代(Opadryn) White 31k58901 36 總錠劑重量範圍(基體核心+包衣） 1,251毫克 修正本 1297609 實例3 本發明提供一種12小時或24小時延長釋放之配方組合物，包含 一種活性持續釋放基體核心(core matrix) 包含成份 毫克/核心 假麻黃素鹽 240 羥丙基甲基纖維素 176 '一氧化^^ 16 乳糖 320 二十二烧酸甘油脂 16 聚乙烯>6比略酮 32 硬脂酸鎂 8 基體核心重量範圍 8〇〇毫克 (2)另一種活性成份立即釋放膜衣包覆(inner film-coating) 包含成份 毫克/核心 抵斯樂鼻定 5 聚乙稀>6比略酮 5 膜衣重量範圍 1〇毫克 (3)阻光外包衣(outerfilm-coating) 包含成份 毫克/核心 二代歐巴代(Opadry Π) White 31k58901 24 總錠劑重量範圍(基體核心+包衣） 834毫克B. Under a buffer solution of pH 4_5 at 37C ± 0_5 ° C, using USP paddte at 50 rpm, _ 12 〇 C · at 37 C (0.5 c pH 6.8 buffer solution) Using USP paddle in 50 _ 彳τ, _ 12 〇 匕 之 活 生成 生成 生成 生成 生成 生成 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 鼻 模拟 模拟 模拟Table 1 has been fixed, reaching 99% of the dissolution of the liver and liver, and the pseudoephedrine salt contained in the core of the 12 modified 1297609 (Pseudoephedrine HCI), sustained release within 12 hours. As shown in the first figure, the pH dissolution rate of two kinds of simulated human gastrointestinal tracts, such as 〇_1 N hydrochloric acid (HCI), pH 4·5 buffer (bUffer) or pH 6 buffer (buffer), There is not much difference. Therefore, any pH value buffer solution can be used to detect the dissolution rate of pseudoephedrine salt in the core of the matrix. In the oral dosage form of the present invention, the active ingredient in the core of the matrix is continuously released - pseudoephedrine Pseudo-hedrine HCI, using another pharmaceutical ingredient, pseudo-ephedrine sulfate (Pseudoephedrine hSO4), The objects and advantages of the present invention will be apparent from the following detailed description of the preferred embodiments illustrated herein. A 12 hour optimal film release sustained release formulation comprising an active sustained release core matrix comprising the component mg/core pseudoephedrine salt 120 hydroxypropyl methylcellulose 88 cerium oxide 4 lactose 160 didodecanoic acid glyceride 8 polyethylene>6 ketone ketone 16 magnesium stearate 4 An active ingredient immediate release film coating (jnner fj|mC〇ating) Contains ingredients mg/core to snail nose 2.5 2.5 聚 妇 _ _ 2.5 film weight range 5 mg 13 Revision 1297609 (3) Outer film-coating Contains ingredients mg / core second generation Opadry (Opadry I 〇 White 31 k58901 12 total ingots Agent Weight Range (Base Core + Coating) 417 mg Example 2 The present invention provides a sustained release formulation composition comprising an active sustained release matrix core (core matrix Contains Ingredient mg/core pseudoephedrine salt 360 Hydroxypropyl methylcellulose 264 Ceria 12 Lactose 480 Twenty-two glycerin glycerol 24 Polyvinyl fluorenone 48 Magnesium stearate 12 Matrix core weight range 1,200 Mg (2) Another active ingredient immediate release film coating (inner film-coating) Ingredient mg/core to snail nose 7.5 Polyethyl ketone 7.5 Film coat weight range 15 mg (3) Blocking outsourcing Outer film-coating Ingredients mg/core 2 Opadryn White 31k58901 36 Total tablet weight range (matrix core + coating) 1,251 mg Revision 1297609 Example 3 The present invention provides a 12 hour or 24 An hourly extended release formulation containing an active sustained release core matrix containing ingredients mg/core pseudoephedrine salt 240 hydroxypropyl methylcellulose 176 'oxidized ^^ 16 lactose 320 22 burned Acid Glycerin 16 Polyethylene > 6 ketone ketone 32 Magnesium stearate 8 Matrix core Weight range 8 〇〇 mg (2) Another active ingredient immediate release film coating (nerer film-coati Ng) Ingredients mg/core to snail nose 5 Polyethylene > 6 ketones 5 film coat weight range 1 〇 mg (3) Outer film-coating Contains mg/core II Opadry White White 31k58901 24 Total lozenge weight range (matrix core + coating) 834 mg
綜上所述，本發明具備原創性、新穎性及進步性。雖然本發明以 一些較佳實施例揭露如上，然其並非用以限定本發明，任何熟習此技 術者，在不脫離本發明之精神和範圍内，當可作為些許之更動與潤飾， 因此本發明之保遵範圍當視後附之申請專利範圍所界定為準。 15 修正本 1297609 表一 時間 -- —____ 溶出率(Dissolution%)* 0.1NHCI 抵斯樂鼻定 0.1NHCI 鹽酸假麻黃素 PH4.5buffer 鹽酸假麻黃素 pH6.8buffer 鹽酸假麻黃素 85% 24.3 26.0 24.6 99%~一 34.4 36.7 34J — —— 4 ---- 42.3 44.8 41.7 48.8 51.6 47.7 54.9 57.3 53.2 60.0 62.6 58.2 64.8 67.7 62.8 69.1 72.1 66.9 76.9 79.4 74.7 83.8 85.9 82.0 8 10 L3IJ * · “ 89.3 90.8 88.8 93.7 94.3 93.5 97.6 97.1 97.0 99.6 98.6 99.9 101.5 100.9 102.3 103.3 102.5 105.2 ••溶出率之Medium volume為500ml，採用6顆錠劑之平均值 【圖式簡單說明】 f 一 12小時較佳膜衣持續釋放之配方組合物體外溶離試驗 第一圖12小時較佳膜衣持續釋放之配方組合物之溶離試驗圖。 1 ...0.1 N 鹽酸(HCI) 2·_·ρΗ4_5 之緩衝液(buffer) 3···ρΗ6·8 之緩衝液(buffer) 【主要元件符號說明】 無In summary, the present invention is original, novel, and progressive. While the present invention has been described above in terms of a preferred embodiment thereof, it is not intended to limit the invention, and the present invention may be modified and modified as a matter of course, without departing from the spirit and scope of the invention. The scope of the warranty is subject to the definition of the patent application scope attached. 15 Amendment 1297609 Table 1 time ---____ Dissolution rate (Dissolution%) * 0.1NHCI Ariel Nasal 0.1NHCI hydrochloric acid pseudoephedrine PH4.5buffer hydrochloric acid pseudoephedrine pH6.8buffer hydrochloric acid pseudoephedrine 85% 24.3 26.0 24.6 99%~34.4 36.7 34J ——— 4 ---- 42.3 44.8 41.7 48.8 51.6 47.7 54.9 57.3 53.2 60.0 62.6 58.2 64.8 67.7 62.8 69.1 72.1 66.9 76.9 79.4 74.7 83.8 85.9 82.0 8 10 L3IJ * · “ 89.3 90.8 88.8 93.7 94.3 93.5 97.6 97.1 97.0 99.6 98.6 99.9 101.5 100.9 102.3 103.3 102.5 105.2 ••Dissolution rate of Medium volume is 500ml, using the average of 6 tablets [simplified description] f 12-hour preferred film release sustained release The formulation of the composition of the external dissolution test of the first chart of the first 12 hours of the preferred release of the film composition of the composition of the dissolution test chart. 1 ... 0.1 N hydrochloric acid (HCI) 2 · _ · ρ Η 4_5 buffer (buffer) 3 ··ρΗ6·8 buffer (buffer) [Main component symbol description]