200536570 (1) 玖、發明說明 【發明所屬之技術領域】 本發明係關於難溶解性主藥，例如紅黴素 (erythromycin )衍生物之口服持續釋放配方，其可在胃 腸液中被消化。本發明特別係關於可以每日一錠方式投服 的開羅理黴素（clarithromycin )藥學組成物。 【先前技術】 紅黴素和它的衍生物均屬抗菌劑，彼等有廣泛的抗菌 力，和青黴素（penicillin )的抗菌活性有部份相同，特 別是對於革蘭氏陽性球菌，如腸球菌、溶血性鏈球菌A 群、肺炎球菌及葡萄球菌，爲有效的。通常服用的劑量是 每天服用2-4次，連續服用10〜14天。對於非住院患者而 言，每天服用2〜4次可能造成不方便，或會忘記服用；因 此，最好是降低每日服用的次數。特別是對非住院患者， 固態之持續釋放配方可降低服用的次數。持續釋放配方是 爲了使藥物在血中濃度相對於時間的變化維持在穩定的狀 態，如此可使每天服用2〜4次之患者避免在服用下一錠時 有藥物過量的情形產生。 使用藻酸鹽膠來製備控制釋放型藥錠是已知的。一種 水溶性的藻酸鹽，例如藻酸鈉，可與鈣鹽反應，如此可使 藻酸鹽被轉變成不溶於水的藻酸鈉-鈣膠。可藉由改變藻 酸鹽分子量、藻酸鹽含量、多價陽離子及交聯劑的類型、 和（或）陽離子在藻酸鹽中之含量度，來改變藻酸鹽膠之 -5 - 200536570 (2) 控制釋放性質。美國專利第4,8 4 2,8 66號中即有揭示利用 藻酸鈉和藻酸鈉-鈣來製備固態控制釋放劑型。 上述所提及的專利技術並不能應用在含有水溶性很低 之主藥的配方中，例如，用開羅理黴素和藻酸鹽作成的配 方，其溶離太慢且其在活體動物試驗中之生體可利用性並 無再現性。對於水溶性很低的藥，可利用藻酸鹽爲基質並 添加入有機酸，作成固態的控制釋放劑型。美國專利第 5,7 05，190號（其相當於中華民國專利第429，154號）揭 示一種控制釋放劑型，含有水溶性藻酸鹽類、藻酸鹽複合 物及有機羧酸（其可促進活性成分之溶離）。活性成分之 一例子爲開羅理黴素，其很容易溶解於胃液中，以及於小 腸的上端部位（pH 5 ·0)易溶解，在該部位開羅理黴素最 可能被吸收；但開羅理黴素在小腸下端部位（pH 6到8 ) 不易溶解，故爲了增加在此部位之溶解度，在配方中使用 檸檬酸。美國專利第5,70 5, 1 90號所申請之口服藥學組成 物中，藻酸鈉對藻酸鈉-鈣的重量比約爲1 6 : 1到1 : I，而 有機酸（例如檸檬酸）對主藥的莫耳比爲1 : 1。 在美國專利第5,7 05,1 9 0號中，其固態控制釋放之藥 學組成物包含藻酸鈉、藻酸鈉-鈣和有機羧酸（例如檸檬 酸）。然而，此配方無法解決或降低關於腸胃道不適方面 之副作用，包括噁心、嘔吐及味覺失常等症狀。爲了克服 上述這些問題，因此發展出含有難溶性主藥（例如紅黴 素）之改良控制釋放劑型，如敘述在美國專利第 6,010,718號者。這些配方包含了藥學上可接受的高分子 -6 - 200536570 (3) 聚合物，如羥丙基甲基纖維素，來改善快速釋放劑型之味 覺，及降低腸胃道之副作用。美國專利第6 5 5 5 1，6 6 ] B 1號 和美國專利第6,010,718號內容相似，但前者包含了較多 對於病人之腸胃道之副作用硏究結果，且證明服用開羅理 黴素之持續釋放配方之病人顯著較不會因爲腸胃副作用而 停藥，且這些病人身上所發生之腸胃副作用顯著較不嚴 重 ° 如同美國專利第5,7〇5，190號中所揭示的，Klaricid® XL 銳(Abbott Laboratories Ltd·，Q u e e n b o r ο υ g h 5 Kent, ME11 5EL，英國，開羅理黴素持續釋放錠）含有500毫 克的開羅理黴素和其他非活性組份如：檸檬酸、藻酸鈉、 藻酸鈉-鈣、乳糖、聚乙烯吡咯酮（povidone )、滑石 粉、硬脂酸、硬脂酸鎂、羥丙基甲基纖維素、丙二醇、二 氧化鈦（E1711)、山梨酸、 啉（quinoline)黃色色素 (E 1 04 )等。而此配方所含之藻酸鈉（水溶性的藻酸 鹽）、藻酸鈉-鈣（水不溶性的藻酸鹽）、及檸檬酸（有 機羧酸）係用來幫助開羅理黴素溶離。藻酸鈉與藻酸鈉· 鈣的含量相差懸殊，所以要混合均勻是困難的。在美國專 利第5,705，190號中雖提及藻酸鈉對藻酸鈉-鈣的比是 16:1到1:1，但其在Klaricid® XL錠中之實際重量比爲 8 : 1。若將藻酸鈉和藻酸鈉-鈣二者的含量調整至接近’例 如其比例爲2M或1 : 1 ’則對生體相等性硏究上之需求而 言，開羅理黴素之溶離速率仍然慢很多。 200536570 (4) 【發明內容】 本發明要點 此發明的目的是提供一個供口服的含有難溶解性主藥 (例如紅黴素衍生物）之控制釋放型藥學配方，在此配方 中只需要用藻酸鈉，便足以代替先前技藝中所使用之藻酸 鈉和藻酸鈉-鈣的組合物。藻酸鈉可用以形成黏性的膠狀 溶液’且雖然可溶於水中，但不溶於pH小於3的酸性溶 液中。所以藻酸鈉可保護紅黴素衍生物在胃液中不會快速 溶解’因而改進紅黴素衍生物之安定性。只用藻酸鈉不僅 可以控制紅黴素衍生物之釋放，也可避免在製造過程中各 組份很難混合均勻的問題。 另一方面，本發明提供一種供口服的含有難溶解性主 藥（例如紅黴素衍生物）之控制釋放型藥學組成物，且有 膜衣包覆。本發明之藥學組成物在與快速釋放型藥學組成 物比較下，有較改良之口感，且腸胃道不適方面之副作用 被降至最低。 本發明之詳述 本發明提供一種每日服藥一次的療法，係藉著使需要 此治療之病人口服含有難溶解性主藥（例如紅黴素衍生 物）之固態控制釋放型藥學組成物，其較好的劑型是錠 劑。 紅黴素是一種大環內酯抗生素，它溶解於酒精及一般 的有機溶劑，但只微溶於水中；在低於pH 4之溶液中極 -8- 200536570 (5) 端的不穩定。紅黴素衍生物可包括以下諸類型：（1 )在 脫氧糖胺（desosamine)之雙甲基胺基上的酸加成鹽，例如 葡萄庚糖酸鹽 （glucoheptonate )， 乳糖酸鹽 (lactobionate )和硬脂酸鹽（stearate ) ; (2)在脫氧糖 胺（desosamine)之 OH基上之酯，例如乙基碳酸酯 (ethylcarbonate )、乙基琥珀酸酯（e t h y 1 s u c c i n a t e )及 丙酸酯（propionate);及（3)開羅理黴素等。 本發明的藥學組成物可包含已知之其他的藥品以和紅 黴素衍生物合倂使用，只要此種合倂治療爲需要的或有利 的；而這些與治療胃炎、潰瘍或胃食道逆流疾病 (GERD )有關之其他藥物，可爲抗潰瘍或抗胃炎的藥 物’例如選自：抑制胃分泌的化合物，如賜法每卓D坐 (sulfamethoxazole)、咪唑尼達（metronidazole)、希 每得定（cimetidine)、因達盤邁（indapamide)、阿延 諾（atenolol)、二氮平（diazepam)、奧美拉口坐 (omeprazole)、雷尼得定（ranitidine)、斯克拉非 (sucralfate )等；或制酸劑如氫氧化鎂、氫氧化鋁、碳 酸鈉、喜每賜康（simethicone)等。 上述這些藥物在藥學組成物中之含量範圍可爲整體組 成物或整個藥錠的20%到90%。對開羅理黴素而言，此含 量範圍較佳可爲整體組成物或整個藥錠重量的40%到 8 0%。 本發明雖然較佳係使用藻酸鈉，但其他陽離子，例如 鉀離子、銨離子及其他的鹼性金屬離子，亦可取代鈉離子 200536570 (6) 來形成水溶性的藻酸鹽類。水溶性藻酸鹽之含量範圍可爲 整體組成物或整個藥錠重量的10%到40%。 在本發明的控制釋放配方中所需的有機羧酸爲一有足 夠效力來創造低ρ Η値微環境的酸，也就是於水解劑型之 附近形成pH小於7的微環境。此主藥對酸的重量比例範 圍可從1 : 1到6 : 1，而以4: 1的比例最佳。該酸以含有3 到2 0個碳原子的脂肪族有機羧酸爲佳，例如琥珀酸、酒 石酸、蘋果酸、戊二酸、順丁烯二酸、麩胺酸、檸檬酸、 杏仁酸等，而以檸檬酸最佳。 控制釋放配方中的藻酸鈉，在腸胃道的胃液中會反應 成爲藻酸，而藻酸可微溶於水中，且會在控制釋放劑型的 表層形成一層薄膜，用以控制藥物的釋放，此係因爲該膜 會控制藥物的擴散。結果是，水不溶的藻酸鹽，例如藻酸 鈉-鈣，已不再需要被使用以控制開羅理黴素的釋放。 在本發明控制釋放配方中作爲非主成分的其他成分包 括：藥學上可接受之賦形劑、稀釋劑、保存劑、潤滑劑、 滑動劑、及經許可之色素。本發明之劑型也可在外層被塗 覆與藥物釋放的控制或修正無關之物質。 【實施方式】 實施例1 1 ·控制釋放型藥錠的製粒 所有的錠劑配方係以如下述之一般製造方法而製備。 開羅理黴素、藻酸鈉、乳糖和硬酯酸全部通過4 0號篩 -10- 200536570 (7) 網，來移去任何大的結塊，而這些已過篩的物質在混合機 (S u p e r m i X e r )中混合 2 0分鐘，再緩緩加入聚乙烯吡咯 酮和檸檬酸溶液形成適合的顆粒。這些濕的顆粒通過16 號篩網，且用 6 0 。C的熱風乾燥直到這些顆粒以卡氏 (K a r 1 F i s h e r )水份測定儀測定水分含量爲5〜7 %。這些 乾燥的顆粒通過2 0號篩網後，和潤滑劑在V型混合機上 混合2分鐘。 2.打錠 將旋轉打錠機裝設橢圓形的模具，分別將如以下表一 所示的錠劑調配物I、11與111壓成適合的厚度和脆度。 錠劑調配物的組成如以下表1所示： 200536570 (8)200536570 (1) 发明. Description of the invention [Technical field to which the invention belongs] The present invention relates to an oral sustained release formulation of a poorly soluble main drug, such as an erythromycin derivative, which can be digested in the gastrointestinal fluid. The present invention particularly relates to a clarithromycin pharmaceutical composition which can be administered as a tablet daily. [Previous technology] Erythromycin and its derivatives are antibacterial agents, they have a wide range of antibacterial power, and have the same antibacterial activity as penicillin, especially for Gram-positive cocci, such as enterococci , Hemolytic streptococcus A group, pneumococcus and staphylococcus are effective. The usual dose is 2-4 times a day for 10 to 14 consecutive days. For non-inpatients, taking 2 to 4 times a day may cause inconvenience or forget to take it; therefore, it is best to reduce the frequency of daily use. Especially for non-hospital patients, a solid sustained release formulation can reduce the frequency of administration. Sustained-release formulations are designed to keep the concentration of the drug in the blood relative to time in a stable state, so that patients taking 2-4 times a day can avoid the situation of overdose when taking the next tablet. It is known to use alginate gums to prepare controlled release tablets. A water-soluble alginate, such as sodium alginate, reacts with the calcium salt, which allows the alginate to be converted into a water-insoluble sodium alginate-calcium gum. The alginate gum can be changed by changing the molecular weight of alginate, the content of alginate, the type of polyvalent cations and cross-linking agents, and / or the content of cations in alginate-5-200536570 ( 2) Controlled release properties. U.S. Patent No. 4,8 4 2,8 66 discloses the use of sodium alginate and sodium alginate-calcium to prepare solid controlled release dosage forms. The above-mentioned patented technology cannot be applied to the formulations containing the main drug with very low water solubility. For example, the formulation made of carisin and alginate is too slow to dissolve and it has been used in live animal experiments. Bioavailability is not reproducible. For medicines with very low water solubility, alginate can be used as a matrix and organic acids can be added to make solid controlled release dosage forms. U.S. Patent No. 5,7 05,190 (which is equivalent to Republic of China Patent No. 429,154) discloses a controlled release dosage form containing water-soluble alginates, alginate complexes and organic carboxylic acids (which promote Dissociation of the active ingredient). An example of an active ingredient is karomycin, which is easily soluble in gastric juice, and easily soluble in the upper part of the small intestine (pH 5 · 0), where karomycin is most likely to be absorbed; It is not easy to dissolve in the lower part of the small intestine (pH 6 to 8), so in order to increase the solubility in this part, citric acid is used in the formula. In the oral pharmaceutical composition filed in U.S. Patent No. 5,70 5, 1 90, the weight ratio of sodium alginate to sodium alginate-calcium is about 16: 1 to 1: 1, and organic acids such as citric acid ) The molar ratio to the main drug is 1: 1. In U.S. Patent No. 5,7 05,190, a solid-state controlled release pharmaceutical composition includes sodium alginate, sodium alginate-calcium, and an organic carboxylic acid (e.g., citric acid). However, this formula does not address or reduce the side effects associated with gastrointestinal upset, including nausea, vomiting, and taste disorders. In order to overcome these problems, an improved controlled release formulation containing a poorly soluble main drug such as erythromycin has been developed, as described in U.S. Patent No. 6,010,718. These formulations contain pharmaceutically acceptable polymers -6-200536570 (3) polymers such as hydroxypropyl methylcellulose to improve the taste of fast release dosage forms and reduce gastrointestinal side effects. U.S. Patent No. 6 5 5 5 1,6 6] B 1 and U.S. Patent No. 6,010,718 are similar in content, but the former contains more results on the gastrointestinal side effects of the patient, and proves the continuity of taking karomycin Patients who release the formulation are significantly less likely to discontinue medication due to gastrointestinal side effects, and those patients have significantly less severe gastrointestinal side effects. As disclosed in U.S. Patent No. 5,705,190, Klaricid® XL (Abbott Laboratories Ltd., Queenbor ο υ gh 5 Kent, ME11 5EL, UK, Cairo Risomycin Continuous Release Tablets) contains 500 mg of Cairo Risomycin and other inactive ingredients such as: citric acid, sodium alginate, Sodium alginate-calcium, lactose, povidone, talc, stearic acid, magnesium stearate, hydroxypropyl methylcellulose, propylene glycol, titanium dioxide (E1711), sorbic acid, quinoline Yellow pigment (E 1 04) and so on. And this formula contains sodium alginate (water-soluble alginate), sodium alginate-calcium (water-insoluble alginate), and citric acid (organic carboxylic acid) are used to help dissolve cairolimin. The contents of sodium alginate and sodium alginate and calcium are very different, so it is difficult to mix them evenly. Although U.S. Patent No. 5,705,190 mentions that the ratio of sodium alginate to sodium alginate-calcium is 16: 1 to 1: 1, the actual weight ratio in Klaricid® XL tablets is 8: 1. If the content of both sodium alginate and sodium alginate-calcium is adjusted to be close to 'for example, the ratio is 2M or 1: 1', then the dissolution rate of karomycin is required for the study of the biological equality. Still a lot slower. 200536570 (4) [Summary of the invention] The main point of the present invention is to provide a controlled-release pharmaceutical formulation containing a poorly soluble main drug (such as a erythromycin derivative) for oral administration. In this formulation, only algae is required. Sodium is sufficient to replace the composition of sodium alginate and sodium alginate used in the prior art. Sodium alginate can be used to form a viscous gelatinous solution 'and although it is soluble in water, it is insoluble in acidic solutions having a pH of less than 3. So sodium alginate can protect the erythromycin derivative from rapid dissolution in gastric juice ', thus improving the stability of the erythromycin derivative. Using only sodium alginate can not only control the release of the erythromycin derivative, but also avoid the problem that the components are difficult to mix uniformly during the manufacturing process. In another aspect, the present invention provides a controlled-release pharmaceutical composition containing a poorly soluble main drug (e.g., an erythromycin derivative) for oral administration, and is coated with a film coating. Compared with the rapid-release pharmaceutical composition, the pharmaceutical composition of the present invention has a better taste, and the side effects of gastrointestinal discomfort are minimized. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a once-a-day medication regimen by orally administering a solid-state controlled release pharmaceutical composition containing a poorly soluble main drug (such as a erythromycin derivative) to a patient in need of such treatment. The preferred dosage form is a lozenge. Erythromycin is a macrolide antibiotic. It is soluble in alcohol and common organic solvents, but only slightly soluble in water. It is extremely unstable at the -8-200536570 (5) end in solutions below pH 4. Erythromycin derivatives can include the following types: (1) acid addition salts on the bismethylamino group of desosamine, such as glucoheptonate, lactobionate And stearate (stearate); (2) esters on the OH group of desosamine, such as ethylcarbonate, ethylsuccinate, and propionate ( propionate); and (3) cairo risomycin and the like. The pharmaceutical composition of the present invention may contain other medicines known for use in combination with erythromycin derivatives as long as such combination therapy is necessary or advantageous; and these are related to the treatment of gastritis, ulcers, or gastroesophageal reflux disease ( GERD) other drugs may be anti-ulcer or anti-gastritis drugs, for example, selected from: compounds that inhibit gastric secretion, such as sulfamethoxazole, metronidazole, and cimetidine ( cimetidine), indapamide, atenolol, diazepam, omeprazole, ranitidine, sucralfate, etc .; Or antacids such as magnesium hydroxide, aluminum hydroxide, sodium carbonate, simethicone and so on. The content of these drugs in the pharmaceutical composition may range from 20% to 90% of the entire composition or the entire tablet. For Cairomycin, this content range may preferably be 40% to 80% by weight of the entire composition or the entire tablet. Although the present invention preferably uses sodium alginate, other cations, such as potassium ions, ammonium ions, and other alkaline metal ions, can also replace sodium ions 200536570 (6) to form water-soluble alginates. The content of water-soluble alginate can range from 10% to 40% of the weight of the entire composition or the entire tablet. The organic carboxylic acid required in the controlled-release formulation of the present invention is an acid sufficient to create a low ρΗ 値 microenvironment, that is, a microenvironment having a pH of less than 7 is formed near the hydrolyzed dosage form. The weight ratio of this main medicine to acid can range from 1: 1 to 6: 1, and the best ratio is 4: 1. The acid is preferably an aliphatic organic carboxylic acid having 3 to 20 carbon atoms, such as succinic acid, tartaric acid, malic acid, glutaric acid, maleic acid, glutamic acid, citric acid, mandelic acid, etc. And citric acid is the best. The sodium alginate in the controlled release formulation will react to alginic acid in the gastric juice of the gastrointestinal tract, and alginic acid is slightly soluble in water, and will form a film on the surface of the controlled release dosage form to control the release of the drug. This is because the membrane controls the diffusion of the drug. As a result, water-insoluble alginates, such as sodium-calcium alginate, are no longer required to be used to control the release of cairocin. Other ingredients that are non-primary ingredients in the controlled release formulation of the present invention include: pharmaceutically acceptable excipients, diluents, preservatives, lubricants, lubricants, and approved pigments. The dosage form of the present invention may also be coated on the outer layer with a substance not related to the control or modification of drug release. [Embodiment] Example 11 [1] Granulation of controlled-release medicinal tablets All the tablet formulations were prepared by a general manufacturing method as described below. Cairomycin, sodium alginate, lactose and stearic acid all pass through the No. 40 sieve-10- 200536570 (7) net to remove any large agglomerates, and these sieved substances are mixed in the mixer (S upermi X er) for 20 minutes, and then slowly add polyvinylpyrrolidone and citric acid solution to form suitable granules. These wet granules passed through a No. 16 screen and used 60. The hot air of C is dried until the particles have a moisture content of 5 to 7% as measured by a K a r 1 F i s h e r. These dried granules were passed through a No. 20 sieve and mixed with a lubricant on a V mixer for 2 minutes. 2. Ingot-making The rotary ingot-making machine is equipped with an oval mold, and the tablet formulations I, 11 and 111 shown in Table 1 below are pressed into a suitable thickness and crispness. The composition of the tablet formulation is shown in Table 1 below: 200536570 (8)
表I 配方 I II III 成分 毫克/錠劑 毫克/錠劑 毫克/錠劑 開羅理黴素 500 500 500 檸檬酸單水合物 110 120 125 藻酸鈉 250 250 245 乳糖單水合物 88 78 78 聚乙烯吡咯酮K 3 0 12 12 12 硬脂酸 5 5 5 滑石粉 5 5 5 硬脂酸鎂 10 10 10 3 .形成膜狀塗層 使用一水性懸浮液來塗覆錠劑，該水性懸浮液包含羥 丙基甲基維素、聚乙二醇、山梨醇、二氧化鈦和純水，結 果約增加錠劑總重量之2.5 %。 實施例 2 溶離度硏究 1.溶離度試驗，依據美國藥典第27版第463頁 (2004) 0 · 1 Μ醋酸鈉緩衝溶液：其製法爲：取醋酸鈉三水合 物1 3 · 6 1 g，置於1升容量瓶中，加水溶並稀釋至容量，混 -12- 200536570 Ο) 合均勻，以0.1M醋酸調整其PH値爲5.0。 溶媒：9 0 〇 m L之上述0 . 1 ]V[醋酸鈉緩衝溶液。 裝置 2 : 5 0 r p m 取樣時間點：第1、2、4、6、8、1 0、1 2、1 8與2 4 小時。 移動相：其製法爲：取甲醇與〇.〇67M磷酸二氫鉀液 之混合物（甲醇對0.06 7M 磷酸二氫鉀液之比例爲 6 5 0:3 5 0)，加磷酸調整其pH爲4.〇， 以孔徑0.5 μπι或 更細之濾器過濾並脫氣處理，必要時可再予以調整。 標準品溶液：其製法爲··取約2 7 m g之經準確秤重的 開羅理黴素，在50 mL定量瓶中以40 mL之如上述溶媒 溶解’若需要可進行搖動及超音波振盪，以確保溶解完 全。以溶媒稀釋至定量，混勻後以孔徑0 · 5 μιη或更細之 濾器過濾。取濾液作爲標準品溶液。此溶液每mL含有約 5 4 pg之開羅理黴素。 層析裝置：液相層析裝置，具波長 2 1 0 nm檢測 器，及 4.6 mm X 15 cm Inertsil 0DS-2 層析管：5 μιη，層 析管溫度保持約50 °C，移動相流速每分鐘約1 mL。將標 準品溶液與受試品溶液進行層析，記錄其反應：由開羅 理黴素波峰値所測得之管柱效率，其爲不小於75 0理論板 數，其波峰曳尾因數爲不小於0.9亦不大於2 ;而重複注 入之相對標準差爲不大於2.0%。 測定法··取標準品溶液與受試品溶液（該受試品溶 液爲將取得之樣品經定量之移動相稀釋所形成之溶液’起 -13- 200536570 (10) 始每m L含有約5 4 μ g之開羅理黴素）等量（約2 0〜5 0 pL )，分別注入層析裝置層析之，記錄其層析圖，測計 各主波峰。依照下式計算開羅理黴素在溶離試驗中所溶離 的量（單位爲μ g ): 900 (CD)(ru/rs) 其中 C :標準品溶液每mL含開羅理黴素之pg數 D :配製受試品溶液時之適當稀釋倍數 ru和 rs :分別爲檢品溶液及標準品溶液主成分之波 峰値 2 .溶離度結果和討論 分別以來自 Abbott Laboratories Ltd.(Queenborough， Kent，ME11 5EL，英國）Klaricid® XL 錠（開羅理黴素， 5 0 0 mg) ’和本發明的持續釋放型開羅理黴素錠劑各6 粒’在如上述之0 · 1 Μ醋酸鈉緩衝溶液中，進行如上述之 溶離度硏究’其溶離度試驗的條件如上所述。而兩者來自 不同來源錠劑之溶離度結果如下表U示之。 表」j〆！!. i開羅,理黴素錄劑之溶離度硏究 1 2 4 6 8 10 12 18 24 溶離結果數 1 (- 甲均値 :)， % Klaricid® XL 3.52 9.24 21.87 36.09 46.33 55.75 62.25 86.41 本發明 4.27 9 .ΊΊ 23.29 3 7.53 49.53 58.80 66.4 1 8 1.93 90.53 -14 - 200536570 (11) 本發明：本發明之持續釋放型開羅理黴素錠劑 二者的溶離曲線如圖1所示，此圖爲 Klaricid® XL (O RI)和本發明 （PBF)之開羅理黴素持續釋放型錠的溶 離曲線圖。Table I Formulation I II III Ingredient mg / Lozenge mg / Lozenge mg / Lozenge Cairomycin 500 500 500 Citric acid monohydrate 110 120 125 Sodium alginate 250 250 245 Lactose monohydrate 88 78 78 Polyvinylpyrrole Ketone K 3 0 12 12 12 Stearic acid 5 5 5 Talcum powder 5 5 5 Magnesium stearate 10 10 10 3. Forming a film-like coating An aqueous suspension is used to coat lozenges, the aqueous suspension containing hydroxypropyl Methylmethyvin, polyethylene glycol, sorbitol, titanium dioxide, and pure water, resulting in an increase of about 2.5% of the total weight of the lozenge. Example 2 Research on dissolution 1. Dissolution test according to USP 27th Edition, page 463 (2004) 0 · 1 M sodium acetate buffer solution: The preparation method is as follows: take sodium acetate trihydrate 1 3 · 6 1 g , Put in a 1 liter volumetric flask, add water to dissolve and dilute to volume, mix -12-200536570 0) mix well, adjust its pH to 5.0 with 0.1M acetic acid. Solvent: 900 m L of the above 0.1] V [sodium acetate buffer solution. Device 2: 50 r p m Sampling time points: 1, 2, 4, 6, 8, 10, 12, 18, and 24 hours. Mobile phase: The preparation method is as follows: take a mixture of methanol and 0.067M potassium dihydrogen phosphate solution (the ratio of methanol to 0.06 7M potassium dihydrogen phosphate solution is 6 5 0: 3 5 0), and adjust the pH to 4 by adding phosphoric acid. .〇, filter with a pore size of 0.5 μm or finer and degas, and adjust it if necessary. Standard solution: its preparation method is to take approximately 27 mg of accurately weighed cairolimin and dissolve it in a 50 mL dosing bottle with 40 mL of the solvent as described above. Shake and ultrasonic vibration if necessary, To ensure complete dissolution. Dilute with solvent to a certain amount. After mixing, filter through a filter with a pore size of 0.5 μm or finer. Take the filtrate as the standard solution. This solution contains approximately 54 pg of karomycin per mL. Chromatography device: liquid chromatography device with a wavelength of 210 nm and a 4.6 mm X 15 cm Inertsil 0DS-2 chromatography tube: 5 μm. The temperature of the chromatography tube is maintained at about 50 ° C. Approximately 1 mL. The standard solution and the test solution are chromatographed, and the reaction is recorded: the column efficiency measured by the Cairo Rimonycin wave crest is not less than 75 0 theoretical plates, and the peak tailing factor is not less 0.9 is also not greater than 2; and the relative standard deviation of repeated injections is not greater than 2.0%. Assay method ·· Take the standard solution and the test solution (the test solution is a solution formed by diluting the obtained sample by a quantitative mobile phase) from -13- 200536570 (10) starting with about 5 per ml 4 μg of Cairo-Romycin) were equally injected (about 20 ~ 50 pL), and injected into the chromatographic device for chromatography. The chromatogram was recorded and the main peaks were measured. Calculate the dissolution amount (unit: μg) of Kailoridemycin in the dissolution test according to the following formula: 900 (CD) (ru / rs) where C: pg number of Kairolidemycin per mL of the standard solution D: The appropriate dilution times ru and rs when preparing the test solution: the peaks of the main components of the test solution and the standard solution 値 2. The dissolution results and discussions are from Abbott Laboratories Ltd. (Queenborough, Kent, ME11 5EL, UK) Klaricid® XL tablets (Cairolimin, 500 mg) '6 tablets each of the sustained-release cairolimin tablets of the present invention' were performed in a 0.1 M sodium acetate buffer solution as described above As mentioned above, the conditions of the dissolution test are as described above. The dissolution results of the two tablets from different sources are shown in Table U below. "J〆!" !. i Cairo, research on the dissolution rate of risomycin recorder 1 2 4 6 8 10 12 18 24 Number of dissolution results 1 (-Methionol :),% Klaricid® XL 3.52 9.24 21.87 36.09 46.33 55.75 62.25 86.41 The present invention 4.27 9 .ΊΊ 23.29 3 7.53 49.53 58.80 66.4 1 8 1.93 90.53 -14-200536570 (11) The present invention: The dissolution curves of both the sustained-release type Cairorisin tablets of the present invention are shown in FIG. Dissolution profiles of Klaricid® XL (O RI) and Cairorisin sustained release tablets of the present invention (PBF).
表 III -一在六次測試中，每一個 Klaricid® XL 錠 劑 （ORI)之溶離結果，平均値以（ave)表示，相對標準差 以 （RSD) 表示 ORI-1 ORI-2 ORI-3 ORI-4 ORI-5 ORI-6 ORI (ave) ORI (SD) ORI (RSD) 0 0 0 0 0 0 0 0 0 0 1 3.41% 3.09% 3.56% 2.90% 3.79% 4.35% 3.52% 0.00518 14.73% 2 9.91% 8.51% 9.50% 8.06% 9.20% 10.22% 9.24% 0.008235 8.92% 4 23.35% 21.62% 20.61% 20.31% 21.87% 23.43% 21.87% 0.013195 6.03% 6 37.01% 35.82% 36.44% 34.11% 35.80% 37.34% 36.09% 0.011507 3.19% 8 47.44% 45.98% 45.35% 45.30% 46.39% 47.54% 46.33% 0.009818 2.12% 10 56.36% 54.77% 57.72% 54.81% 55.08% 55.77% 55.75% 0.011439 2.05% 12 62.62% 60.29% 64.72% 61.83% 61.70% 62.37% 62.25% 0.014533 2.33% 18 74.38% 75.13% 78.24% 76.52% 77.40% 77.13% 76.47% 0.014559 1.90% 24 86.03% 85.09% 86.63% 85.70% 87.20% 87.81% 86.41% 0.010007 1.16% -15- 200536570 (12) 表 IV -…在六次測試中，每一個本發明之開羅理黴素持 續釋放型錠劑（PBF)的溶離結果，平均値以（ave)表示， 相對標準差以 （RSD)表示 PBF-1 PBF-2 PBF-3 PBF-4 PBF-5 PBF-6 PBF (AVE) PBF (SD) PBF (RSD) 0 0 0 0 0 0 0 0 0 0 1 3.89% 3.85% 5.14% 4.52% 4.04% 4.17% 4.27% 0.004478 10.49% 2 9.48% 9.21% 10.71% 9.89% 9.64% 9.68% 9.77% 0.004692 4.80% 4 22.92% 23.08% 24.49% 23.15% 23.04% 23.07% 23.29% 0.005403 2.32% 6 37.06% 37.73% 38.73% 38.07% 37.04% 36.53% 37.53% 0.00734 1.96% 8 48.82% 50.04% 50.79% 50.31% 48.91% 48.31% 49.53% 0.008975 1.81% 10 57.70% 59.66% 60.41% 59.39% 58.07% 57.54% 58.80% 0.010809 1.84% 12 65.49% 66.82% 67.92% 67.25% 65.76% 65.20% 66.41% 0.009905 1.49% 18 81.50% 82.17% 83.82% 82.06% 81.29% 80.71% 81.93% 0.009772 1.19% 24 90.23% 90.25% 92.38% 90.29% 90.13% 89.91% 90.53% 0.00836 0.92% 二者的溶離曲線如圖1所示，此圖爲Klaricid® XL錠劑 (ORI)和本發明 （PBF)之開羅理黴素持續釋放型錠劑的 溶離曲線圖，由圖1可見二者在各時間點的溶離度非常的 接近，只除了在第十八小時之溶離度相差有5.46% (亦 即，8 1 . 9 3 % - 7 6.4 7 % = 5.4 6 % )外，其他各點均小於 5 %，因此二者在臨床試驗中，可能彼此爲生體相等性 的。 此外，KUricid® XL錠劑和本發明之開羅理黴素持續 -16- 200536570 (13) 型錠劑的每一錠的各個時間點溶離結果，如表ΙΠ和表 IV所示，在對於κ 1 a r i c i d ® X L錠劑之六次測試中，在每 個時間點的相對標準誤差（RSD)在1.16%與14.37%之 間，而對於本發明之開羅理黴素持續釋放型錠劑之六次測 試中，在每個時間點的相對標準誤差（RSD)在〇.92%與 1 0 · 4 9 %之間。因此，Κ1 a r i c i d ® X L錠劑和本發明之開羅理 黴素持續釋放型錠劑的平均相對標準誤差分別是4 · 7 1 % 和2 · 9 8 %。 此表示了本發明之多個開羅理黴素持續釋放 型錠劑彼此間之溶離型態較相似，而相比之下顯出，多個 Klaricid® XL錠劑彼此間之溶離型態較不相似。此項優點 係因爲本發明中使用藻酸鈉，反觀Klaricid® XL錠劑中 使用藻酸鈉和藻酸鈉-鈣之組合物，而在Klaricid® XL錠 劑之製造過程中該兩種不同的藻酸鹽會引起較難混合的問 題。 本發明的優點 A·本發明在與使用兩種不同藻酸鹽來製備持續釋放 型錠劑之美國專利第5,7 0 5，190號比較下，顯出爲較易於 操作且成本可較爲降低。 B ·在本發明之控制釋放配方的藻酸鈉，在腸胃道的 胃液中會反應成爲藻酸，而藻酸可微溶於水中，且會在控 制釋放劑型的表層形成一層薄膜，用以控制藥物的釋放， 此係因爲該膜會控制藥物的擴散。 C.由表II的數據可知，本發明之錠劑在和 -17- 200536570 (14) ΚΙ aric id® XL·錠劑比較下，其溶離度並沒有顯著的差異； 然而，由表111與IV可知，本發明者有明顯較小的平均 相對標準誤差（RSD)，因此可得知本發明之多個開羅理黴 素持續釋放型錠劑彼此間之溶離型態較相似，而相比之下 顯出，多個 Klaricid® XL錠劑彼此間之溶離型態較不相 似。 【圖式簡單說明】 圖1示出KUricid® XL (以ORI代表）和本發明（以 pBF代表）之開羅理黴素持續釋放型錠在PH5.〇緩衝溶液 中的溶離曲線圖。Table III-The dissolution results of each Klaricid® XL lozenge (ORI) in six tests, the average 値 is expressed as (ave), and the relative standard deviation is expressed as (RSD) ORI-1 ORI-2 ORI-3 ORI -4 ORI-5 ORI-6 ORI (ave) ORI (SD) ORI (RSD) 0 0 0 0 0 0 0 0 0 0 1 3.41% 3.09% 3.56% 2.90% 3.79% 4.35% 3.52% 0.00518 14.73% 2 9.91 % 8.51% 9.50% 8.06% 9.20% 10.22% 9.24% 0.008235 8.92% 4 23.35% 21.62% 20.61% 20.31% 21.87% 23.43% 21.87% 0.013195 6.03% 6 37.01% 35.82% 36.44% 34.11% 35.80% 37.34% 36.09% 0.011507 3.19% 8 47.44% 45.98% 45.35% 45.30% 46.39% 47.54% 46.33% 0.009818 2.12% 10 56.36% 54.77% 57.72% 54.81% 55.08% 55.77% 55.75% 0.011439 2.05% 12 62.62% 60.29% 64.72% 61.83% 61.70% 62.37% 62.37 % 62.25% 0.014533 2.33% 18 74.38% 75.13% 78.24% 76.52% 77.40% 77.13% 76.47% 0.014559 1.90% 24 86.03% 85.09% 86.63% 85.70% 87.20% 87.81% 86.41% 0.010007 1.16% -15- 200536570 (12) Table IV -... In six tests, the dissolution results of each of the karomycin sustained release tablets (PBF) of the present invention were expressed as (ave) on average, Express the standard deviation as (RSD) PBF-1 PBF-2 PBF-3 PBF-4 PBF-5 PBF-6 PBF (AVE) PBF (SD) PBF (RSD) 0 0 0 0 0 0 0 0 0 0 0 1. 3.89 % 3.85% 5.14% 4.52% 4.04% 4.17% 4.27% 0.004478 10.49% 2 9.48% 9.21% 10.71% 9.89% 9.64% 9.68% 9.77% 0.004692 4.80% 4 22.92% 23.08% 24.49% 23.15% 23.04% 23.07% 23.29% 0.005403 2.32% 6 37.06% 37.73% 38.73% 38.07% 37.04% 36.53% 37.53% 0.00734 1.96% 8 48.82% 50.04% 50.79% 50.31% 48.91% 48.31% 49.53% 0.008975 1.81% 10 57.70% 59.66% 60.41% 59.39% 58.07% 57.54. % 58.80% 0.010809 1.84% 12 65.49% 66.82% 67.92% 67.25% 65.76% 65.20% 66.41% 0.009905 1.49% 18 81.50% 82.17% 83.82% 82.06% 81.29% 80.71% 81.93% 0.009772 1.19% 24 90.23% 90.25% 92.38% 90.29 % 90.13% 89.91% 90.53% 0.00836 0.92% The dissolution curves of the two are shown in Figure 1. This figure shows the dissolution of Klaricid® XL lozenges (ORI) and the cairolimin continuous release type lozenges of the present invention (PBF). From the graph, it can be seen from Figure 1 that the dissolution of the two at each time point is very close, except that the difference in dissolution at the eighteenth hour is 5.46% (that is, 8 1. 9 3 %-7 6.4 7% = 5.4 6%), the other points are less than 5%, so the two may be biologically equal to each other in clinical trials. In addition, the KUricid® XL lozenge and the cairolimin of the present invention lasted from 16 to 200536570 (13) lozenges at each time point for each lozenge, as shown in Tables III and IV. In the six tests of aricid ® XL lozenges, the relative standard deviation (RSD) at each time point was between 1.16% and 14.37%, and for the six tests of the karomycin sustained release tablet of the present invention The relative standard error (RSD) at each time point was between 0.92% and 10 · 49%. Therefore, the average relative standard errors of K1 arcid ® X L lozenges and the sustained-release Kailoride dosing lozenges of the present invention are 4.71% and 2.98%, respectively. This indicates that the dissolution patterns of the multiple karomycin sustained-release tablets of the present invention are similar to each other, and in contrast, the dissolution patterns of the multiple Klaricid® XL tablets are less similar to each other . This advantage is due to the use of sodium alginate in the present invention, in contrast to the use of a combination of sodium alginate and sodium alginate in Klaricid® XL lozenges, which are different in the manufacturing process of Klaricid® XL lozenges Alginate can cause more difficult mixing problems. Advantages of the present invention A. The present invention appears to be easier to operate and more cost effective compared to US Patent No. 5,705,190 which uses two different alginates to prepare a sustained release lozenge. reduce. B. The sodium alginate formulated in the controlled release formulation of the present invention will react to form alginic acid in the gastric juice of the gastrointestinal tract, and alginic acid is slightly soluble in water, and will form a film on the surface layer of the controlled release dosage form for controlling The release of the drug is because the film controls the diffusion of the drug. C. From the data in Table II, it can be seen that the dissolution rate of the tablets of the present invention is not significantly different from that of -17-200536570 (14) KI aric id® XL · tablets; however, Tables 111 and IV It can be seen that the inventors have a significantly smaller mean relative standard error (RSD), so it can be known that the dissolution patterns of the multiple cairolimin sustained-release tablets of the present invention are similar to each other, compared to It appears that the dissolution profiles of multiple Klaricid® XL lozenges are less similar to each other. [Brief description of the figure] FIG. 1 shows the dissolution profile of KUricid® XL (represented by ORI) and the karomycin sustained-release tablet of the present invention (represented by pBF) in a pH 5.0 buffer solution.