201235348 六、發明說明： 【發明所屬之技術領域】 本發明涉及一種包含決奈達隆或其藥學上可接受的 鹽、兩親性脂質表面活性劑和磷脂的醫藥組成物。 【先前技術】 決奈達隆（Dronedarone)化學名為2-正丁基_3[4_(3_ 二-正丁基-胺基丙氧基）苯曱醯基]-5一甲基磺胺苯並呋喃 分子式 C31H44N2O5S，分子量 556. 765。 鹽酸決奈達隆是由赛諾菲-先德納寶公司 (Sanof i-Synthe 1 abo)最新開發的治療心律不整藥物。本品 為不含蛾的苯並料類衍生物，結構和特徵與胺蛾嗣類 似，但決奈達隆不含填，親脂性較低，因此既保持了胺班 酮的療效’又沒有胺賴的心、臟之外的不良反應，且半衰 期為1至2天，更便於調整藥物劑量。 鹽酸決奈達隆在含水介質中溶解度报低，特別的是它 溫'成pH依賴性，在如值3至5的範圍内 、容解产：的度’約是1_2mg/lDl ’在PH約6至7的範圍内， 因為他在邱值為7時溶解度只有 胃腸決奈達隆的轉性低這1點，導致其通過 ^腸道 =的生物率低，因為從胃簡道的過程是一 漸Γ低高的過程，這意味著鹽_奈達隆的溶解度逐 漸降低’喊導致魏決錢隆切 法從固體製射溶出或溶心很低。為提高鹽隆 95202 3 201235348 的生物度，必須找職提高鹽料奈達隆溶出 US20040044070公開了鹽酸決奈遠限从 又途瓜 咬丨金的注射劑。枰路 明在緩衝系統（pH值範圍為3至5)中力σ 匕發 生物，從而提高了有效成分的溶解度。f %糊精佴 決奈達隆的溶解度方法，製造過程複# 4調间鹽酸 較差。 ，而且穩定性可能 專利ZL98808158.X公開了 一種含笨並呋。_ 固體醫藥組成物，該發明發現非離子型表面舌陡于生物的 疋泊洛沙姆類非離子型表面活性劑，可以社^ 、 ...^ ^ 从使溶解於PH4.5 左右的浴液中的活性成分，在經高pH溶 在PH6-7溶液中，基本不會受pH升^心评傻此保持 个霄又卯开同的影響而析出沉澱， 從而提尚鹽酸決奈達隆在空腹下的生物利用度。該專利說 明書中所述的篩選過程可以看出，雖然—系列的非離子型 表面活性劑的❹，均能提高_決奈達隆在溶液中的保 持能力，但是，僅僅泊洛沙姆術在用量不大的情況下， 可顯示出㈣顯的效果。而其他種_表面活性劑均需要 較大的用量。 另外’據不全統計，大約有4〇%的新藥均存在溶解 度低的問題，這_口服給藥，”存在生物利用度低、 個體差異大等問題。為了解決這—問題，近年來，採用脂 質基質’特別是具有自乳化能力的兩親性脂質表面活性劑， 來改善難溶性絲的絲利缝，已絲藥鮮領域的熱 點。然而’在實際應用中，這類兩親性脂質表面活性劑的 用量往往較大’在-定程度上限製了其應用。 4 95202 201235348 發現明在以往經驗基礎上藉由大量實驗研究，驚+的 發現在兩親性脂質表面活性劑 =驚奇的 月曰;能大幅度提高魏決奈_溶解度了 中加入磷 【發明内容】 上可接受_ % 在於它含有決奈達隆或其藥學 兩親性月旨質表面活性劑，一種種樂予上可接受的 種藥用添加劑結合。它崎或;種，旨’並與-種或多 應用於抗心律不齊。有^律不齊活性作用’臨床上 硫酸:=藥學上可接受的鹽’包括但不限於鹽酸鹽、 :夂鹽'构梅酸鹽、馬來酸鹽、酒石酸鹽 酸鹽和富馬酸鹽，較佳為鹽酸鹽。 本發明的醫藥組成物中使用的兩親性脂質表面活性 齊U、·不限於’月桂酸聚乙二醇甘油酯、硬脂酸聚乙 =甘油Ss、油酸聚乙二醇甘油g旨、辛酸癸酸聚乙二醇甘 油酉曰辛k癸酸m聚甘油脂肪酸自旨、維生素e玻 J白酸目旨等。 磷脂，作為本發明的核心部分，包括，但不限於，大 豆磷脂、蛋黃磷脂、多烯磷脂醯膽鹼、氫化大豆磷脂等。 本發明的醫藥組成物為任何適合口服的固體醫藥組 成物，基本上被認為是由粉末狀的或者顆粒狀的固體成份 形成的醫藥組成物，該組成物可以常遇下製成顆粒劑、片 劑、膠囊劑。 95202 5 201235348 因此本發明的另一主題是關於片劑、膠囊劑、顆粒劑 或粉末形式的上述醫藥組成物。 本發明的醫藥組成物含有活性成份，兩親性脂質表面 活性劑，磷脂和賦形劑。 通常，本發明所述的醫藥組成物中的決奈達隆或其藥 學上可以接受的鹽，如鹽酸鹽，每個基本施用單位，如每 片或者每只膠囊，或每包顆粒劑，含有的量可以從5〇mg 至 500mg ’ 較佳為 2〇〇mg 至 400mg。 通常’本發明所述的醫藥組成物中的兩性脂質表面活 性劑’比例以劑型中活性成份的重量計算是丨.25至5〇%。 以片劑’膠囊劑，顆粒劑等口服給藥劑型的形式，兩親性 脂質表面活性劑的比例以劑型中活性成份的重量計算是 1· 5至20% ’較佳為2至10%。 通常，所述的醫藥組成物中，磷脂的比例以劑型中活 性成份的重量計算是0.5至15%。以片劑，膠囊劑，顆粒 劑等口服給藥劑型的形式，磷脂的比例以劑型中活性成分 的重量計算是1至10%，較佳為2至7. 5% 除了所述的兩親性表面活性劑和磷脂外，本發明的醫 藥組成物還可以含有口服形式的藥物研究，開發，生產中 通常使用的其他藥物賦形劑，如微晶纖維素，微粉矽膠， 交聯緩甲基纖維素鈉，曱基纖維素，羥乙基纖維素，曱基 經丙基纖維素，聚乙二醇（例如聚乙二醇6000)，乙烯吡咯 燒酮聚合物或共聚物（例如聚乙烯基吡咯烷酮）和硬脂酸鎂 等。 6 95202 201235348 本發明的醫藥組成物可以通過適當的步驟方法製備： a)將活f生成为、兩親性脂質表面活性劑和磷脂溶解於 有機溶劑或其水溶液中，所述有機溶劑選自乙醇、、 二氯曱院、丙酮； 、b)加入賦形劑，吸收溶劑，並㈣製粒，所述的賦形 劑選自氧化石夕、氧化铭或用於製備藥物片劑或膠囊的纖維 素衍生物中的一種或多種； 、 根據需要，還可以進-步使用崩解劑、潤滑劑等，可 以進一步壓製成片劑、包衣或者填充膠囊。 藉由大量的研究和試驗’本發明的研究者驚奇的發現， 在兩親性脂質表面活性劑的存在下，在鹽酸決奈達隆處方 中加入適量的填脂，能在原有基礎上，大幅提高藥物的溶 解度，提高固體製劑的溶出度，從而提高藥物的生物利用 度。本發明的有益效果為在醫藥組成物中加入磷脂，在降 低兩親性脂質表面活性劑的用量的同時，解決了鹽酸決太 達隆的溶解度問題。 、不 【實施方式】 ml更好的說明本發明，下面通過具體的實施方式身 下面时_、實關健為了朗本發明 七如々 、硯為對本發明的限製，其可能 存在夕種Μ離本發明的精神和範圍的變體。 實施例1 兩親性脂質表面活性剩的筛選 在ΡΗ6.7鱗酸鹽緩衝液中的保持試驗 95202 7 201235348 用pH4. 5的磷酸氫鹽（NaH2P〇4)緩衝液，在攝氏37度： 小時内製備以決奈達隆計2mg/inl的鹽酸決奈達隆溶液。然 後把溶液在中性磷酸鹽介質（如2肝〇4祕沾屮〇4)中稀釋到 1/10，最終溶液的pH是6.7。在攝氏37度下2小時後， 把溶液濾過5. Oura玻璃纖維濾膜，並用紫外分光光度計測 定溶液中的活性成分。 結果見下表： 不含鱗脂 成分 月桂酸聚乙二醇甘 油酯 所用表面活性劑占 決奈達隆的百分比 (X%) 25 達隆百分比〇〇 含5%磷脂 53 92 25 44 80 硬脂酸聚乙二醇甘 油酯 油酸聚乙二醇甘油 酯 25 49 83201235348 VI. Description of the Invention: [Technical Field] The present invention relates to a pharmaceutical composition comprising dronedarone or a pharmaceutically acceptable salt thereof, an amphiphilic lipid surfactant and a phospholipid. [Prior Art] Dronedarone chemical name is 2-n-butyl-3-[4_(3_di-n-butyl-aminopropoxy)phenylindolyl]-5-methylsulfonamide benzo Furan molecular formula C31H44N2O5S, molecular weight 556. 765. Dronedarone hydrochloride is a newly developed treatment for arrhythmia drugs by Sanofi-Synthe 1 abo. This product is a non-moth-containing benzoate derivative. Its structure and characteristics are similar to those of the amine moth, but dronedarone is not filled and has low lipophilicity, thus maintaining the efficacy of the amine ketone. The adverse reactions outside the heart and the dirty, and the half-life is 1 to 2 days, it is easier to adjust the drug dose. The solubility of dronedarone hydrochloride in an aqueous medium is low, in particular, it is pH-dependent, in the range of values 3 to 5, and the yield is about '1_2 mg/l Dl' at pH. In the range of 6 to 7, because his solubility at the Qi value of 7 is only 1 point lower than that of gastrointestinal dronedarone, resulting in a low biologic rate through the intestinal tract = because the process from the gastric bypass is A process of gradual low and low, which means that the solubility of the salt _ nedarone is gradually reduced, and the shouting leads to the dissolution of the solid solution or the low dissolution. In order to improve the biological capacity of Yanlong 95202 3 201235348, it is necessary to find a job to improve the dissolution of the salt material Nidalon. US20040044070 discloses that the hydrochloric acid drone is far from the injection of the glutinous gold. In the buffer system (pH range 3 to 5), the force σ 匕 is activated, which improves the solubility of the active ingredient. f % dextrin 溶解 The solubility method of dronedarone, the manufacturing process complex # 4 adjust the hydrochloric acid is poor. And stability may be disclosed in the patent ZL98808158.X. _ Solid pharmaceutical composition, the invention finds that the non-ionic surface tongue is steeper than the biological poloxamer-type nonionic surfactant, and can be dissolved in a bath of about pH 4.5 The active ingredient in the liquid is dissolved in the PH6-7 solution at a high pH, and is basically not affected by the pH rise. The precipitate is precipitated by the same effect, thereby precipitating the dronedarone hydrochloride. Bioavailability under fasting. The screening process described in this patent specification shows that although the series of nonionic surfactants can improve the retention of dronedarone in solution, only poloxamer is used. When the amount is not large, the effect of (4) can be displayed. Other types of surfactants require larger amounts. In addition, according to incomplete statistics, about 4% of new drugs have low solubility problems. This is a problem of low bioavailability and large individual differences. In order to solve this problem, in recent years, lipids have been used. The matrix 'especially the amphiphilic lipid surfactant with self-emulsification ability to improve the silky seam of the poorly soluble silk, has been a hot spot in the field of silk medicine. However, in practical applications, such amphiphilic lipid surface activity The amount of the agent tends to be large' to a limited extent to its application. 4 95202 201235348 Found that based on past experience based on a large number of experimental studies, the discovery of the amphipathic lipid surfactant = surprising month Can greatly improve the concentration of dysprosium _ solubility in the addition of phosphorus [invention] 7% acceptable in it contains dronedarone or its pharmacological amphiphilic surfactant, a kind of music is acceptable It is a combination of medicinal additives. It is a species of samarium; it is intended to be used in combination with or in addition to antiarrhythmia. There is a syndrome effect on 'clinical sulfuric acid: = pharmaceutically acceptable salt' including but It is not limited to the hydrochloride, the phosphonium salt, the maleate, the tartaric acid hydrochloride, and the fumarate, preferably the hydrochloride. The amphiphilic lipid used in the pharmaceutical composition of the present invention Surface activity, U, · not limited to 'lauric acid polyethylene glycol glyceride, stearic acid polyethylidene = glycerin Ss, oleic acid polyethylene glycol glycerol g, octanoic acid phthalic acid polyethylene glycol glycerin 酉曰 癸 k癸Acid m polyglycerin fatty acid, vitamin E glass J white acid, etc. Phospholipids, as a core part of the present invention, including, but not limited to, soybean phospholipids, egg yolk phospholipids, polyene phospholipids, choline, hydrogenated soybean phospholipids, etc. The pharmaceutical composition of the present invention is any solid pharmaceutical composition suitable for oral administration, and is basically considered to be a pharmaceutical composition formed of a powdery or granular solid component, which composition can be often made into granules, Tablets, Capsules. 95202 5 201235348 A further subject of the invention is therefore a pharmaceutical composition as described above in the form of a tablet, capsule, granule or powder. The pharmaceutical composition of the invention contains an active ingredient, an amphiphilic lipid surface active , phospholipids and excipients. In general, dronedarone or a pharmaceutically acceptable salt thereof, such as a hydrochloride salt, in the pharmaceutical composition of the present invention, each of the basic administration units, such as each tablet or capsule Or the amount of the granules per package may be from 5 〇 mg to 500 mg', preferably from 2 〇〇 mg to 400 mg. Generally, the ratio of the amphoteric lipid surfactant in the pharmaceutical composition of the present invention is in the dosage form. The weight of the active ingredient is calculated from 2525 to 5% by weight. In the form of an oral administration form such as a tablet capsule or granule, the ratio of the amphiphilic lipid surfactant is 1 in terms of the weight of the active ingredient in the dosage form. 5 to 20% 'preferably 2 to 10%. Generally, in the pharmaceutical composition, the proportion of phospholipid is 0.5 to 15% by weight of the active ingredient in the dosage form. 5%。 In addition to the amphiphilicity, the ratio of the active ingredient of the dosage form is from 1 to 10%, preferably from 2 to 7.5%, in the form of a tablet, a capsule, a granule, or the like. In addition to surfactants and phospholipids, the pharmaceutical composition of the present invention may also contain other pharmaceutical excipients commonly used in the research, development, and production of pharmaceuticals in oral form, such as microcrystalline cellulose, micronized silicone, crosslinked slow methyl fiber. Sodium, mercapto cellulose, hydroxyethyl cellulose, mercapto propyl cellulose, polyethylene glycol (eg polyethylene glycol 6000), vinyl pyrrolidone polymer or copolymer (eg polyvinylpyrrolidone) ) and magnesium stearate. 6 95202 201235348 The pharmaceutical composition of the present invention can be prepared by a suitable method: a) producing living f, an amphiphilic lipid surfactant and a phospholipid dissolved in an organic solvent or an aqueous solution thereof, the organic solvent being selected from the group consisting of ethanol , dichlorohydrazine, acetone; b) adding excipients, absorbing solvents, and (iv) granulating, said excipients being selected from the group consisting of oxidized stone, oxidized or used to prepare pharmaceutical tablets or capsules One or more of the derivatives of the hormone; and, if necessary, a disintegrating agent, a lubricant or the like may be further used, and may be further compressed into tablets, coatings or filled capsules. Through a large number of studies and experiments, the researchers of the present invention have surprisingly found that in the presence of an amphiphilic lipid surfactant, an appropriate amount of fat is added to the formulation of dronedarone hydrochloride, which can be substantially Improve the solubility of the drug, improve the dissolution of the solid preparation, thereby improving the bioavailability of the drug. The beneficial effects of the present invention are that the addition of phospholipids to the pharmaceutical composition solves the problem of solubility of gentamicin hydrochloride while reducing the amount of the amphiphilic lipid surfactant. The present invention is better illustrated by the following description of the present invention. The following is a description of the present invention by the specific embodiment of the present invention, which is a limitation of the present invention. Variations of the spirit and scope of the invention. Example 1 Screening of amphiphilic lipid surface activity remaining in ΡΗ6.7 sulphate buffer retention test 95202 7 201235348 with pH 4.6 hydrogen phosphate (NaH2P〇4) buffer at 37 degrees Celsius: A solution of 2 mg/inl of dronedarone hydrochloride in dronedarone was prepared in an hour. The solution is then diluted to 1/10 in a neutral phosphate medium (e.g., 2 hepatic sputum 4) and the pH of the final solution is 6.7. After 2 hours at 37 ° C, the solution was filtered through a 5. Oura glass fiber filter and the active ingredient in the solution was measured with an ultraviolet spectrophotometer. The results are shown in the table below: The surfactant used in the fragrance-free component of lauric acid polyethylene glycol glyceride accounted for the percentage of dronedarone (X%) 25 percentage of darlon 〇〇 5% phospholipid 53 92 25 44 80 stearic acid Acid polyethylene glycol glyceride oleic acid polyethylene glycol glyceride 25 49 83
提高決奈達隆在較高pH溶液中的百分比，同時加入賴 後，溶液中驗決奈達隆的百分比得到更為顯著的提高。 實施例2 : 鹽酸決奈達隆片 處方： £ 95202 201235348 成份 mg °/〇 鹽酸決奈達隆（以決奈達隆計400mg) 426 73. 45 月桂酸聚乙二醇甘油酉旨（Gelucire 44/14) 20 3. 45 大豆填脂 0 0 微晶纖維素 69 11. 90 微粉矽膠 10 1. 72 交聯羧曱基纖維素鈉 50 8. 62 硬脂酸鎂 5 0.86 580 100 步驟： 按處方比例，稱取鹽酸決奈達隆（江蘇恒瑞醫藥股份 有限公司合成）、月桂酸聚乙二醇甘油s旨和破脂。加入以決 奈達隆計活性成分50%量的乙醇，50°C水浴加熱至溶解。 按處方比例，加入微晶纖維素、微粉矽膠、交聯羧曱基纖 維素鈉，吸收溶劑並攪拌製粒，50°C乾燥後，將顆粒過20 目篩整粒，按處方比例加入硬脂酸鎂，混合後壓片。 特別說明：也可以採取本處方步驟，最後顆粒裝膠囊 或直接包裝，製成膠囊劑或顆粒劑。以下實施例也可以採 用類似辦法製成膠囊劑或顆粒劑，不再重複。 實施例3 : 鹽酸決奈達隆片 處方： 9 95202 201235348 成份 mg % 鹽酸決奈達隆（以決奈達隆計400mg) 426 73. 45 月桂酸聚乙二醇甘油酯（Gelucire 44/14) 20 3. 45 大豆填脂 5 0. 86 微晶纖維素 64 11. 04 微粉矽膠 10 1. 72 交聯羧曱基纖維素鈉 50 8. 62 硬脂酸鎂 5 0.86 580 100 步驟： 同實施例2。 實施例4 : 鹽酸決奈達隆片 處方： 成份 mg % 鹽酸決奈達隆（以決奈達隆計400mg) 426 73.45 月桂酸聚乙二醇甘油酯（Gelucire 44/14) 20 3. 45 蛋黃填脂 10 1. 72 微晶纖維素 59 10. 18 微粉矽膠 10 1. 72 交聯羧曱基纖維素鈉 50 8. 62 硬脂酸鎂 5 0.86 580 100 步驟： 同實施例2。 實施例5 : 鹽酸決奈達隆片 處方： 10 95202 201235348 成份 mg % 鹽酸決奈達隆（以決奈達隆計400mg) 426 73.45 月桂酸聚乙二醇甘油酯（Gelucire 44/14) 20 3. 45 氩化大豆構脂 20 3.45 微晶纖維素 49 8.45 微粉矽膠 10 1. 72 交聯羧曱基纖維素鈉 50 8. 62 硬脂酸鎂 5 0. 86 580 100 步驟： 同實施例2。 實施例6 : 鹽酸決奈達隆片 處方： 成份 mg % 鹽酸決奈達隆（以決奈達隆計400mg) 426 73.45 硬脂酸聚乙二醇甘油酯 20 3. 45 大豆磷脂 30 5. 17 微晶纖維素 39 6. 73 微粉矽膠 10 1. 72 交聯羧曱基纖維素鈉 50 8. 62 硬脂酸鎂 5 0. 86 580 100 步驟： 同實施例2。 實施例7 : 鹽酸決奈達隆片 處方： 11 95202 201235348 成份 mg % 鹽酸決奈達隆（以決奈達隆計400mg) 426 73.45 月桂酸聚乙二醇甘油酯（Gelucire 44/14) 20 3. 45 大豆構脂 40 6. 90 微晶纖維素 29 5. 00 微粉矽膠 10 1. 72 交聯羧甲基纖維素鈉 50 8. 62 硬脂酸鎂 5 0. 86 580 100 步驟： 同實施例2。 實施例8 : 鹽酸決奈達隆片 處方： 成份 mg % 鹽酸決奈達隆（以決奈達隆計400mg) 426 71. 00 月桂酸聚乙二醇甘油酯（Gelucire 44/14) 80 6. 67 大豆構脂 0 0 微晶纖維素 69 11.5 微粉矽膠 15 1.67 交聯羧曱基纖維素鈉 55 8.33 硬脂酸鎂 5 0.83 650 100 步驟： 同實施例2。 實施例9 : 鹽酸決奈達隆片 處方： 12 95202 201235348 成份 mg % 鹽酸決奈達隆（以決奈達隆計400mg) 426 54. 62 月桂酸聚乙二醇甘油酉旨（Gelucire 44/14) 200 25. 64 大豆構脂 2 0. 26 微晶纖維素 77 9.87 微粉矽膠 20 2.56 交聯羧曱基纖維素鈉 50 6.41 硬脂酸鎂 5 0.64 780 100.00 步驟： 同實施例2。 實施例10 : 鹽酸決奈達隆片 處方： 成份 mg % 鹽酸決奈達隆（以決奈達隆計400mg) 426 68.71 月桂酸聚乙二醇甘油酯（Gelucire 44/14) 5 0.81 蛋黃構脂 60 9.68 微晶纖維素 59 9.52 微粉矽膠 15 2.42 交聯羧曱基纖維素鈉 50 8.06 硬脂酸鎂 5 0.81 620 100.00 步驟： 同實施例2。 實施例11 : 鹽酸決奈達隆片 處方： 13 95202 201235348 成份 mg °/〇 鹽酸決奈達隆（以決奈達隆計400mg) 426 71. 00 月桂酸聚乙二醇甘油酯（Gelucire 44/14) 40 6.67 多烯磷脂醯膽鹼 20 3.33 微晶纖維素 49 8. 17 微粉矽膠 10 1. 67 交聯羧曱基纖維素鈉 50 8.33 硬脂酸鎂 5 0.83 600 100 步驟： 同實施例2。 實施例12 : 鹽酸決奈達隆片 處方： 成份 mg °/〇 鹽酸決奈達隆（以決奈達隆計400mg) 426 71. 00 維生素E琥拍酸酉旨 40 6. 67 氳化大豆填脂 30 5. 00 微晶纖維素 39 6. 50 微粉矽膠 10 1. 67 交聯羧曱基纖維素鈉 50 8. 33 硬脂酸鎂 5 0. 83 600 100 步驟： 同實施例2。 實施例13 : 鹽酸決奈達隆片 處方： 14 95202 201235348 成份 mg °/〇 鹽酸決奈達隆（以決奈達隆計400mg) 426 71. 00 辛酸癸酸聚乙二醇甘油酯（LABRASOL) 40 6. 67 大豆墙脂 40 6. 67 微晶纖維素 29 4. 83 微粉矽膠 10 1. 67 交聯羧曱基纖維素鈉 50 8. 33 硬脂酸鎂 5 0. 83 600 100 步驟： 同實施例2。 比較例 鹽酸決奈達隆片 按專利ZL98808158. X實施例1處方步驟，製備鹽酸 決奈達隆片。 實驗例1 :在pH6. 7填酸鹽緩衝液中的保持試驗 1) 鹽酸決奈達隆片（相當於鹽酸決奈達隆426mg)，於 200ml量瓶中，加入pH4. 5的填酸鹽緩衝液使溶解並定容 至刻度，在37°C下保持2小時。 2) 將此溶液用中性磷酸鹽介質（Na2HP〇4+NaH2P〇4)稀釋 到1/10，最終溶液的pH是6. 7。在37°C下保持2小時後， 把溶液濾過5. Oum玻璃纖維濾膜，並用紫外分光光度計， 在291 nm波長處測定溶液中的活性成分。 15 95202 201235348 實施例 在溶液中的鹽酸決奈達隆的％ 實施例2 26 實施例3 72 實施例4 85 實施例5 89 實施例6 90 實施例7 93 實施例8 39 實施例9 68 實施例10 65 實施例11 92 實施例12 95 實施例13 97 比較例 76 結論：與實施例2和實施例8相比（不含磷脂），含磷 脂的處方中（實施例3至7，9至13)鹽酸決奈達隆的溶解 度顯著提高。與比較例相比，含兩親性脂質表面活性劑和 磷脂的處方，能更顯著的提高鹽酸決奈達隆在高pH溶液中 的保持能力。 實驗例2 :溶出度測定 參照中國藥典2005年版附錄XC，採用槳法，溫度為 37°C±0. 5°C，pH6. 7的磷酸鹽緩衝液900ml為介質，於45 分鐘取樣，並用紫外分光光度法測定A值，計算累積溶出 百分率。 16 95202 201235348 實施例 決奈達隆45分鐘的溶出度（％) 實施例2 20 實施例3 40 實施例4 53 實施例5 60 實施例6 65 實施例7 62 實施例8 23 實施例9 39 實施例10 35 實施例11 55 實施例12 64 實施例13 66 比較例 35 結論：與實施例2和實施例8相比（不含磷脂），含磷 脂的處方中（實施例3至7,9至13)鹽酸決奈達隆在較高pH 介質中的溶出度顯著提高，且一般都高於比較例溶出度。 實驗例3:生物利用度測定 血漿的採集：39隻比格犬每個實驗例3隻，灌胃給予 實驗例 2，3，4，5，6，7，8，9，10，11，12，13，比較 例的製劑，給藥劑量：按30mg/kg鹽酸決奈達隆後，於給 藥前（Oh)和給藥後 1. 0，2. 0，3. 0，4. 0，5. 0，6. 0，7. 0， 8. 0，9. 0，10. 0，11. 0，12. 0，13. 0，14. 0，16. 0，18. 0， 20. 0，22. 0，24. Oh於前肢靜脈取血2. 0ml，置肝素化試管 中，3000rpm離心lOmin，分離血漿，-20°C保存待測。 血漿樣品的測定：犬血漿樣品經液-液萃取後，採用 LC/MS法測定。 17 95202 201235348 實施例 Auc〇— (ng-h/ml) Cmax (ng/ml) Tnmx(h) 實施例2 12265±980 1360±697 12. 68+2. 35 實施例3 48202±5437 3751±359 8.90±1.86 實施例4 59043±11010 4527+1379 7· 35±2· 12 實施例5 67713+1548 5220+1228 7.80±2.62 實施例6 73495±13590 5350±1110 6. 82±1.82 實施例7 78561±16823 5218+1892 9. 23±3. 50 實施例8 14326±1235 1736±568 11. 26±2. 13 實施例9 16345±7982 1896±986 10. 14±2. 01 實施例10 72653±11845 4156+1042 8. 57±2. 16 實施例11 62871±10379 4897+1134 9. 15±1.35 實施例12 68549±11742 5167±1241 6.34±1.47 實施例13 76582±12782 6342+1317 7. 45±2.03 比較例 35214±13542 2257±1059 10. 56±1. 87 結論：與實施例2和實施例8相比（不含磷脂），含磷 脂的處方中（實施例3至7, 9至13)鹽酸決奈達隆的生物 利用度顯著提高。與比較例相比，含兩親性脂質表面活性 劑和磷脂的處方，能更顯著的提高鹽酸決奈達隆的生物利 用度。 【圖式簡單說明】 無 【主要元件符號說明】 無 % 18 95202Increasing the percentage of dronedarone in the higher pH solution, while adding the Lai, the percentage of nedarone in the solution was more significantly improved. Example 2: Formulation of dronedarone hydrochloride tablets: £ 95202 201235348 Ingredient mg ° / 决 dronedarone hydrochloride (400 mg by dronedarone) 426 73. 45 lauric acid glycerol glycerin (Gelucire 44) /14) 20 3. 45 Soy fat filling 0 0 microcrystalline cellulose 69 11. 90 micronized rubber 10 1. 72 croscarmellose sodium 50 8. 62 magnesium stearate 5 0.86 580 100 Procedure: by prescription Proportion, weighed dronedarone hydrochloride (synthesis of Jiangsu Hengrui Pharmaceutical Co., Ltd.), lauric acid polyethylene glycol glycerol s and lipids. Ethanol in an amount of 50% by weight of the active ingredient was added to the solution, and heated to dissolve in a 50 ° C water bath. According to the prescription ratio, microcrystalline cellulose, micronized rubber, croscarmellose sodium, absorbing solvent and stirring and granulating. After drying at 50 °C, the granules are sieved through 20 mesh, and the hard fat is added according to the prescription ratio. Magnesium acid, after mixing, tableting. Special Note: This prescription step can also be taken, and finally the capsules are packaged or packaged directly to make capsules or granules. The following examples can also be made into capsules or granules in a similar manner and are not repeated. Example 3: Formulation of dronedarone hydrochloride tablets: 9 95202 201235348 Ingredient mg % dronedarone hydrochloride (400 mg by dronedarone) 426 73. 45 lauric acid polyethylene glycol glyceride (Gelucire 44/14) 20 3. 45 Soy fat filling 5 0. 86 Microcrystalline cellulose 64 11. 04 Micronized rubber 10 1. 72 croscarmellose sodium 50 8. 62 Magnesium stearate 5 0.86 580 100 Procedure: same as the examples 2. Example 4: Formulation of dronedarone hydrochloride tablets: Ingredient mg % dronedarone hydrochloride (400 mg by dronedarone) 426 73.45 lauric acid polyethylene glycol glyceride (Gelucire 44/14) 20 3. 45 egg yolk Filling 10 1. 72 microcrystalline cellulose 59 10. 18 micronized rubber 10 1. 72 croscarmellose sodium 50 8. 62 magnesium stearate 5 0.86 580 100 Procedure: Same as Example 2. Example 5: Formulation of dronedarone hydrochloride tablets: 10 95202 201235348 Ingredient mg % dronedarone hydrochloride (400 mg in dronedarone) 426 73.45 lauric acid polyethylene glycol glyceride (Gelucire 44/14) 20 3 45 argonized soybean resin 20 3.45 microcrystalline cellulose 49 8.45 micronized rubber 10 1. 72 croscarmellose sodium 50 8. 62 magnesium stearate 5 0. 86 580 100 Step: Same as Example 2. Example 6: Formulation of dronedarone hydrochloride tablets: Ingredient mg % dronedarone hydrochloride (400 mg by dronedarone) 426 73.45 Polyethylene glycol glyceryl stearate 20 3. 45 Soybean phospholipid 30 5. 17 Microcrystalline cellulose 39 6. 73 Micronized rubber 10 1. 72 croscarmellose sodium 50 8. 62 Magnesium stearate 5 0. 86 580 100 Procedure: Same as Example 2. Example 7: Formulation of dronedarone hydrochloride tablets: 11 95202 201235348 Ingredient mg % dronedarone hydrochloride (400 mg by dronedarone) 426 73.45 lauric acid polyethylene glycol glyceride (Gelucire 44/14) 20 3 45 Soybean body fat 40 6. 90 microcrystalline cellulose 29 5. 00 micronized rubber 10 1. 72 croscarmellose sodium 50 8. 62 magnesium stearate 5 0. 86 580 100 Step: same as the examples 2. Example 8: Formulation of dronedarone hydrochloride tablets: Ingredient mg % dronedarone hydrochloride (400 mg by dronedarone) 426 71. 00 lauric acid polyethylene glycol glyceride (Gelucire 44/14) 80 6. 67 Soybean body fat 0 0 microcrystalline cellulose 69 11.5 micronized rubber 15 1.67 croscarmellose sodium 55 8.33 magnesium stearate 5 0.83 650 100 Step: Same as Example 2. Example 9: Formulation of dronedarone hydrochloride tablets: 12 95202 201235348 Ingredient mg % dronedarone hydrochloride (400 mg by dronedarone) 426 54. 62 lauric acid polyethylene glycol glycerin (Gelucire 44/14 200 25. 64 Soybean structure 2 0.26 microcrystalline cellulose 77 9.87 micronized rubber 20 2.56 croscarmellose sodium 50 6.41 magnesium stearate 5 0.64 780 100.00 Step: Same as Example 2. Example 10: Formulation of dronedarone hydrochloride tablets: Ingredient mg % dronedarone hydrochloride (400 mg by dronedarone) 426 68.71 lauric acid polyethylene glycol glyceride (Gelucire 44/14) 5 0.81 egg yolk 60 9.68 microcrystalline cellulose 59 9.52 micronized rubber 15 2.42 croscarmellose sodium 50 8.06 magnesium stearate 5 0.81 620 100.00 Step: Same as Example 2. Example 11: Formulation of dronedarone hydrochloride tablets: 13 95202 201235348 Ingredient mg ° / 决 dronedarone hydrochloride (400 mg by dronedarone) 426 71. 00 lauric acid polyethylene glycol glyceride (Gelucire 44/ 14) 40 6.67 Polyene phospholipid choline 20 3.33 Microcrystalline cellulose 49 8. 17 Micronized rubber 10 1. 67 croscarmellose sodium 50 8.33 Magnesium stearate 5 0.83 600 100 Step: Same as Example 2 . Example 12: Formulation of dronedarone hydrochloride tablets: Ingredient mg ° / 决 dronedarone hydrochloride (400 mg by dronedarone) 426 71. 00 Vitamin E sulphonate 40 40 6. 67 氲化大豆Lipid 30 5. 00 Microcrystalline cellulose 39 6. 50 Micronized mash 10 1. 67 croscarmellose sodium 50 8. 33 Magnesium stearate 5 0. 83 600 100 Procedure: Same as Example 2. Example 13: Formulation of dronedarone hydrochloride tablets: 14 95202 201235348 Ingredient mg ° / 决 dronedarone hydrochloride (400 mg by dronedarone) 426 71. 00 octoate phthalate (LABRASOL) 40 6. 67 Soybean wall grease 40 6. 67 Microcrystalline cellulose 29 4. 83 Micronized rubber 10 1. 67 croscarmellose sodium 50 8. 33 Magnesium stearate 5 0. 83 600 100 Steps: same Example 2. Comparative Example Dronedarone hydrochloride tablets According to the prescription step of Patent Example ZL98808158. X, a dronedarone hydrochloride tablet was prepared. The sulphate of pH 4. 5 was added to a 200 ml volumetric flask, and the pH of the sulphate was added to the sulphate. The buffer was dissolved and brought to volume and held at 37 ° C for 2 hours. 2。 The solution was diluted with a neutral phosphate medium (Na2HP 〇 4 + NaH2P 〇 4) to 1/10, the pH of the final solution was 6.7. After 2 hours at 37 ° C, the solution was filtered through a 5. Oum glass fiber filter and the active ingredient in the solution was measured at 291 nm using an ultraviolet spectrophotometer. 15 95202 201235348 Examples % of dronedarone hydrochloride in solution Example 2 26 Example 3 72 Example 4 85 Example 5 89 Example 6 90 Example 7 93 Example 8 39 Example 9 68 Example 10 65 Example 11 92 Example 12 95 Example 13 97 Comparative Example 76 Conclusion: Compared with Example 2 and Example 8 (without phospholipids), in the formulation containing phospholipids (Examples 3 to 7, 9 to 13) The solubility of dronedarone hydrochloride is significantly improved. Compared with the comparative examples, the formulation containing the amphiphilic lipid surfactant and phospholipid can more significantly improve the retention of dronedarone hydrochloride in a high pH solution. Experimental Example 2: The dissolution was measured by reference to the Chinese Pharmacopoeia 2005 edition appendix XC, using a paddle method, a temperature of 37 ° C ± 0. 5 ° C, pH 6.7 phosphate buffer 900 ml as a medium, sampling in 45 minutes, and using ultraviolet The A value was measured spectrophotometrically and the cumulative dissolution percentage was calculated. 16 95202 201235348 Example Dissolution of dronedarone for 45 minutes (%) Example 2 20 Example 3 40 Example 4 53 Example 5 60 Example 6 65 Example 7 62 Example 8 23 Example 9 39 Implementation Example 10 35 Example 11 55 Example 12 64 Example 13 66 Comparative Example 35 Conclusion: Compared with Example 2 and Example 8 (without phospholipids), a formulation containing phospholipids (Examples 3 to 7, 9 to 13) The dissolution of dronedarone hydrochloride in higher pH media is significantly higher, and is generally higher than the dissolution rate of the comparative examples. Experimental Example 3: Bioavailability determination Plasma collection: 39 Beagle dogs, each of the experimental examples, were administered intragastrically with experimental examples 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 , 0,3. 0,4. 0, 0,0. 0,0. 0,0. 5. 0,6. 0,7. 0, 8. 0,9. 0,10. 0,11. 0,12. 0,13. 0,14. 0,16. 0,18. 0, 20. 0,22. 0,24. Oh in the forelimb vein blood 2. 0ml, placed in heparinized tubes, centrifuged at 3000rpm lOmin, plasma was separated, stored at -20 ° C to be tested. Determination of plasma samples: After the liquid-liquid extraction of the canine plasma samples, the LC/MS method was used. 17 95202 201235348 Example Auc〇—(ng-h/ml) Cmax (ng/ml) Tnmx(h) Example 2 12265±980 1360±697 12. 68+2. 35 Example 3 48202±5437 3751±359 8.90±1.86 Example 4 59043±11010 4527+1379 7·35±2·12 Example 5 67713+1548 5220+1228 7.80±2.62 Example 6 73495±13590 5350±1110 6. 82±1.82 Example 7 78561± 16823 5218+1892 9. 23±3. 50 Example 8 14326±1235 1736±568 11. 26±2. 13 Example 9 16345±7982 1896±986 10. 14±2. 01 Example 10 72653±11845 4156 +1042 8. 57±2. 16 Example 11 62871±10379 4897+1134 9. 15±1.35 Example 12 68549±11742 5167±1241 6.34±1.47 Example 13 76582±12782 6342+1317 7. 45±2.03 Comparison Example 35214 ± 13542 2257 ± 1059 10. 56 ± 1. 87 Conclusion: Compared with Example 2 and Example 8 (without phospholipids), the formulation containing phospholipids (Examples 3 to 7, 9 to 13) The bioavailability of Nidalon is significantly improved. Compared with the comparative example, the formulation containing the amphiphilic lipid surfactant and phospholipid can significantly improve the bioavailability of dronedarone hydrochloride. [Simple diagram description] None [Main component symbol description] None % 18 95202