1281867 九、發明說明： 【發明所屬之技術領域】 本發明係有關於一種具有高生體使用率之經殺真 菌劑和聚合物塗覆的核心微粒狀物，尤其是指一種於口 服後能具有較佳的溶解效率及更快的溶解速度，加上微 粒狀物體積小，而可讓人體吸收範圍更廣，以能具有更 佳之吸收效果的「具有高生體使用率之經殺真菌劑和聚 合物塗覆的核心微粒狀物」創新設計者。 【先前技術】 按’伊托康唑或（+)-順-4-[4-[4-[-4[[2-(2,4〜二 氯本基）-2-（1廷-1，2, 4-三σ坐-1 -基甲基）-1，3-二曙茂燒 -4-基]甲氧基]苯基]-1-六氫吡肼基]苯基]-2, 4—二氫 -2-1(1一曱基丙基）-3H-1, 2, 4-三唑-3-酮是一種寬譜之 殺真菌化合物，用於口服、非經腸施藥及局部使用並揭 示於美國專利第4267179號。 然，上述美國專利第4267179號化合物於使用上， 伊托康嗅其本身物理性質是屬於難溶於水的物質，故〇 服後造成無法有效吸收；且一般經改善後之伊托康唑口 服製劑’容易受食物及個人胃酸PH值影響，造成個體 差異相當大，伊托康唑約在PH2· 〇以下溶解情形較佳， 故因其在人體内之溶解度較差、使用功效較不顯著，使 得即有我國88年12月11日公告第376322號「具有經 殺真菌劑和聚合物塗覆之核心之球狀物」的研發推出， 該具有經殺真菌劑和聚合物塗覆之核心之珠狀物主要 1281867 係包含： a) —中心、圓或球狀核心： b) -塗覆膜、其包含選自τ列親水性聚合物：經丙基甲 基纖維素、甲基丙烯_、㈣基纖維素及聚福_ (polyvidone)，和一選自伊托康唑（itrac〇naz〇le) 及沙普康唑（saperconazole)之殺真菌劑； C)-選自聚乙二醇之封閉塗覆聚合物層，特徵為該核心 直徑為600至700微米（25-30網目）；如此一來，以 達到於人體π服治療黴__，能具較佳之溶解 度、促進人體吸收效率者。 ，…▼ 一〜穴月批肌兴囷柙眾合物塗覆之核心之 珠狀物」雖可達到供㈣者口㈣療_錢之預期功 效’但於其實際實施使用上卻發現，由於雜心若太小 〔如30-35網目〕，其在塗覆過程中f會聚結成塊，使 得該核心直徑最小僅能定於25，網目之間，造成其於 口服進入人體後之溶解效率仍有所限制，而無法達到更 佳之溶解度、無齡❹錢得Μ之治療效果者。 【發明内容】 本發明具有高生體使用率之經殺真菌劑和聚合物 塗覆的核心微粒狀物，係利用特殊之塗覆層及包覆層， 將藥物喷於微粒核心上’口服後於胃中形成分散狀態9的 數千顆微粒，祕數量相當多，造叙收廣 效果佳，其主要包含：a·殺真_、高分子聚合物、 性物質、滑石粉、黏合劑、乙醇及二氯？賴 1281867 覆層；b·滑石粉、羥丙基甲基纖維素及可塑劑所組成之 抗凝結層；c·直徑為300至500微米〔30〜50網目〕之 微粒狀核心；使得其於製作使用上不僅能因添加有滑石 粉，令細小的微粒狀核心不會聚結成塊，且亦因該微粒 狀核心直徑變小及於塗覆膜中加入高分子聚合物與酸 性物質，使得該微粒於胃中溶解度極佳，溶解度快，其 於經口服進入人體内時，能大幅提高其溶解度且其特殊 包覆層可避免膠囊未破前微粒狀物相互黏結、增進人體 吸收功效，而更增其之實用價值性者。 【實施方式】 本發明主要係包含有： a· —塗覆層：具有伊托康唾（itraconazole)、泊洛 沙姆（poloxamer 407)高分子聚合物、酸性物質、 滑石粉、黏合劑、乙醇、二氯甲烷； b· —抗凝結層：具有滑石粉、羥丙基甲基纖維素、 可塑劑； c· 一微粒狀核心：其直徑約為300至500微米〔30~50 網目〕。 其中該抗凝結層被應用於藥物塗覆核心以防土微 粒狀物黏住而造成不想要之伴隨物效應而降低溶解速 率及生物可用性。本發明選用以滑石粉為主約占抗凝結 層之50-70%，以滑石粉之物理特質〔潤滑抗黏〕來作為 封閉塗覆層。 依據本發明適用於微粒狀物之核心材料為歧管，只 1281867 要此材料為藥物可接受且有適當的大小〔 30-50網目〕 及硬度。這些材料的例子有聚合物例如塑膠樹脂；無機 物質例如矽膠、玻璃、羥基磷灰石鹽〔氯化鈉或氯化鉀， 碳酸鈣或碳酸鎂〕及類似物；有機物質例如活性碳，酸 〔檸模酸，反丁烯二酸，酒石酸，維生素c及其他類似 的酸〕，醣類及其衍生物。特別適合的材料為醣類如蔗 糖，寡糖，多醣類及它們的衍生物，例如葡萄糖、鼠李 糖、半乳糖、乳糖、蔗糖、甘露糖醇、葡萄糖醇、糊精、 麥芽糊精、纖維素、羰甲基鈉纖維素、澱粉〔玉米、蕃 茄、小麥、木薯澱粉〕及其他類似的糖類。 其中，適用於依據本發明之微粒狀物核心之材料以 30-50網目糖球〔nf xvii，P1989〕為代表，該糖球包 含67.5-91.5%〔重量比〕之蔗糖，其餘為藥物惰性或 中性之澱粉或也可能為糊精。 較佳的微粒狀物大致包含： a. —塗覆層：具有（1)百分之20至40之伊托康唑 (itraconazole); (2)百分之17至30之泊洛沙姆 (poloxamer 407)高分子聚合物；（3)百分之2至10 之酸性物質〔如：棒樣酸、蘋果酸、醋酸·· ··等中性 酸〕，以檸檬酸為佳；（4)百分之15至30之滑石粉； (5) 百分之2至6之黏合劑〔如羥丙基曱基纖維素〕； (6) 乙醇（Alcohol) ; (7)二氯曱烷 (Dicholoromenthane) ° b· —抗凝結層··具有（1)百分之50至70之滑石粉；（2) 百分之25至35之羥丙基甲基纖維素；（3)百分之1 1281867 至10之可塑劑〔如：丙二醇〕。1281867 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a fungicide-containing and polymer-coated core microparticle having a high bioavailability, in particular, one which can be compared after oral administration. Good solubility and faster dissolution rate, combined with small volume of fine particles, which allows for a wider range of body absorption, and a higher bioavailability fungicide and polymer for better absorption. Innovative designer of coated core particles. [Prior Art] According to 'Itoconazole or (+)-cis-4-[4-[4-[-4[[2-(2,4~dichlorobenzyl)-2-) , 2, 4-tris(s)-l-ylmethyl)-1,3-dioxalyl-4-yl]methoxy]phenyl]-1-hexahydropyridinyl]phenyl]-2 , 4-dihydro-2-1(1-mercaptopropyl)-3H-1, 2,4-triazol-3-one is a broad spectrum fungicidal compound for oral, parenteral administration And partial use and disclosed in U.S. Patent No. 4,267,179. However, in the use of the above-mentioned U.S. Patent No. 4267179, it is a substance which is insoluble in water, and therefore cannot be effectively absorbed after being taken up; and the orally corrected itotazole is orally administered. The preparation 'is easily affected by the pH value of food and individual gastric acid, resulting in considerable individual differences. Itoconazole is better dissolved under PH2·〇, so it is less soluble in the human body and less effective in use. That is, the development and release of the "Candus with core of fungicide and polymer coating" announced on December 11, 1998 in China, the core of the core coated with fungicide and polymer. The main body of the 1281867 series comprises: a) a center, a circle or a spherical core: b) a coated film comprising a hydrophilic polymer selected from the group consisting of 1,4-methylcellulose, methacrylic _, (d) Cellulose and polyvidone, and a fungicide selected from itaconium naz〇le and saperconazole; C)-selected from polyethylene glycol Coating a polymer layer characterized by the core diameter 600-700 microns (25-30 mesh); Thus, in order to achieve the medication for the human π __ mold, the can having better solubility, absorption efficiency of the promoter body. ,... ▼ a ~ acupoints of the moon muscles of the core of the core coating of the core of the coating" Although it can reach the (four) of the mouth (four) treatment _ money expected effect 'but in its actual implementation but found that due to If the nucleus is too small (such as 30-35 mesh), it will aggregate into a block during the coating process, so that the core diameter can only be set at a minimum of 25, between the meshes, causing its dissolution efficiency after oral administration into the human body. There are restrictions, and it is impossible to achieve a better solubility, no treatment for the age of money. SUMMARY OF THE INVENTION The present invention has a high bioavailability fungicide and polymer coated core microparticles, which are sprayed onto the microparticle core by a special coating layer and a coating layer. Thousands of particles in the dispersed state 9 are formed in the stomach. The number of secrets is quite large, and the effect of the invention is good. It mainly includes: a·killing _, polymer, sex substances, talcum powder, binder, ethanol and Dichloro? Lai 1281867 coating; b. anti-condensation layer composed of talc powder, hydroxypropyl methylcellulose and plasticizer; c. particle core with diameter of 300 to 500 microns [30~50 mesh]; The use of not only the addition of talc, so that the fine particulate core does not coalesce into a block, but also because the particle core diameter becomes smaller and the polymer film and the acidic substance are added to the coating film, so that the particle is The solubility in the stomach is excellent and the solubility is fast. When it is orally introduced into the human body, it can greatly improve its solubility and its special coating layer can prevent the particles from sticking to each other before the capsule is broken, and enhance the absorption effect of the human body. Practical value. [Embodiment] The present invention mainly comprises: a·-coating layer: having itraconazole, poloxamer 407 polymer, acidic substance, talcum powder, binder, ethanol , methylene chloride; b · - anti-coagulation layer: with talc, hydroxypropyl methylcellulose, plasticizer; c · a particulate core: its diameter is about 300 to 500 microns [30 ~ 50 mesh]. Wherein the anti-coagulation layer is applied to the drug-coated core to prevent soil microparticles from sticking and causing unwanted concomitant effects to reduce dissolution rate and bioavailability. In the present invention, talc is mainly used to account for about 50-70% of the anti-coagulation layer, and the physical characteristic of the talc powder (lubrication and anti-adhesion) is used as the sealing coating layer. The core material suitable for the particulate material according to the present invention is a manifold, only 1281867. The material is pharmaceutically acceptable and has an appropriate size [30-50 mesh] and hardness. Examples of such materials are polymers such as plastic resins; inorganic substances such as silicone, glass, hydroxyapatite salts (sodium chloride or potassium chloride, calcium carbonate or magnesium carbonate) and the like; organic substances such as activated carbon, acid [ Carminic acid, fumaric acid, tartaric acid, vitamin C and other similar acids], sugars and their derivatives. Particularly suitable materials are sugars such as sucrose, oligosaccharides, polysaccharides and their derivatives, such as glucose, rhamnose, galactose, lactose, sucrose, mannitol, glucose alcohol, dextrin, maltodextrin , cellulose, sodium carboxymethyl cellulose, starch [corn, tomato, wheat, tapioca starch] and other similar sugars. Wherein, the material suitable for the core of the microparticles according to the present invention is represented by 30-50 mesh sugar spheres [nf xvii, P1989], which contains 67.5-91.5% [by weight] of sucrose, and the rest is pharmaceutically inert or Neutral starch or may also be dextrin. Preferred microparticles generally comprise: a. - coating layer: having (1) 20 to 40 percent itraconazole; (2) 17 to 30 percent poloxamer ( Poloxamer 407) high molecular weight polymer; (3) 2 to 10% acidic substances (such as: bar acid, malic acid, acetic acid, etc.), preferably citric acid; (4) 15 to 30 percent talc; (5) 2 to 6 percent binder (eg hydroxypropyl fluorenyl cellulose); (6) ethanol (Alcohol); (7) dichloro oxane (Dicholoromenthane ° b· — anti-coagulation layer ·· (1) 50 to 70% talc powder; (2) 25 to 35 percent hydroxypropyl methylcellulose; (3) 1 128 1867 To 10 plasticizers (such as: propylene glycol).
Ce —微粒狀核心：其直徑約為300至500微米〔30〜50 網目〕。 此外，該微粒狀物可進一步包含不同的添加物如增 厚劑，潤滑劑，界面活性劑，防腐劑，錯合及鉗合劑， 電解質及其他活性成份，如減火劑、殺菌劑、消毒劑或 維生素。 該微粒狀物可以方便地設計成不同的藥物劑型。適 當的劑型包含有效的微粒狀物殺真菌劑含量如上文中 所描述。較佳而言，此微粒狀物充填於硬的動物膠囊以 使得例如每個劑型可得到50至100毫克的活性成份含 里。例如尺寸為Ν〇·0的動物膠囊適用於設計微粒狀物 由重量百分之19至25的伊托康唑或沙普康唑，等於約 100毫克的活性成份。 ^依$康本發明之微粒狀物可以方便地以下列的方式 =備*藥物塗覆溶液藉著溶解適當含量的殺真菌劑及高 分子聚合物及酸性物質於適當的溶劑系統中，一個適當 =溶劑系統由二氯甲烧及醇類之混合物組成，以乙醇較 ’丨乙醇:與例如丁酮而改變特性。麵合物應當含有 量計5_二氯甲烷以作為藥物之溶劑，由於 基纖維素無法完全溶於二氯甲烧，因此至少 比Γ如:^需加人，以—個相當低的二氯甲烧/醇類 自80/20〔重蜃α Ί/>lcr去β / _頸扣們祀固 「番旦Ί比〕至55/45〔重篁比〕，特別是約60/40 里匕〕。固體含量，例如殺真菌劑及高分子聚合物， 1281867 在藥物塗覆溶液中範圍自4至7%〔重量比〕，以約6% 較隹。 30-50網目核心之藥物塗覆處理可以方便地在配備 了/個旋轉式喷霧造粒機中操作。 喷射速率應當小心地調整，喷射速率太慢會造成部 分藥物塗覆溶液乾掉而導致產物的損失，喷射速率太快 會造成過溼而結成塊狀物，塊狀物是最嚴重的問題，最 初可使用較低的喷射速率，待塗覆過程進行至微粒狀物 長的較大後再加快喷射速率。 藥物塗覆溶液應用之原子化空氣壓力也會影響塗 覆處理，低的原子化空氣壓力導致較大的顆粒形成及增 如凝結成塊的傾向，高的原子化空氣壓力可以想像的到 =有藥物溶液乾掉的危險，然而這個影響發現並不是問 翅，因此，原子化空氣壓力幾乎都設在最大值。 ，流體空氣體積可藉由操作儀器之排氣汽門而控 2，並且以能得到最佳的微粒狀物循環的方式而設計， 空氣體積太低將會造成珠狀物的流量不足；太高的空氣 趙，將會因為儀器產生的逆向氣流而防礙微粒狀物的 2%，在此過程中最佳條件可藉打開排氣汽門約最大值 + 50% ’再隨塗覆過程的進行而逐漸增加開口至約最大 值的60%而得到。 塗覆處理使用導入空氣溫度範圍自40°c至約50 ’而旋轉盤轉速約6〇,rpm條件下被良好地操作。 ^的溫度可能加速反應過程，但是缺點是溶劑蒸發太 致於塗覆液體無法均勻分佈在微粒狀物的表面，導 10 1281867 ㈣极覆層*形成含有太多的孔，當大體積的塗覆微粒 典時，藥物的溶解性可能會明顯地降低至無法接 =、’明顯地，最佳的反應過程溫度將進—步與使 備’核心及殺真菌劑的本質，分批體積，溶劑及 噴射速率有關。 最佳塗覆結果的參數設定在下文的實施例子中會 ==果在。這些條件下進行塗覆處理發現產生非 ^絲合物被應用於具有—錢轉式噴霧造粒 體化床製粒器的藥物塗覆核心，抗凝結溶液可藉 =解適當含罝的抗凝結聚合物於適當的溶劑系統^ ^備，此種系統例如二氯甲燒及醇類之混合物，以乙 醇較佳，該乙醇可與例如丁鲷而改變特性，使用之二氯 甲垸/醇類比例似用於薄物塗覆處理之比例，因此範圍 可自約80-20〔重量比〕至55/45〔重量比〕，特別是 0/40〔重篁比〕’在抗凝結噴射溶液中抗凝結聚合物含 量’範圍至4至m重量比〕，以約6%較佳，此抗凝結 噴射溶液在抗凝結處理中有利於攪拌，操作最後一個步 聚的參數設定必須和用於藥物塗覆過程中 條件在下文的例子中將詳細描述。 的 應用抗凝結聚合物層後可能需要進一步的乾燥步 驟，在喷射已經完成後，操作參數設定之儀器約5至 15分鐘能夠容易地除去過多的殘餘溶劑。 樂物塗覆過私及抗凝結過程兩者皆在惰性氣體如 氮氣下操作較佳，塗覆裝置應放在地上較佳，同時應提 1281867 供包—足夠的濃縮系統之適當溶劑回收系統。 藥物塗覆及封閉塗覆微粒狀物可使用標準自動膠 充填器充填於硬膠膠囊〔Νο·0〕中，適當的覆蓋及去離 子設備可有效地防止靜電電荷產生。 膠囊充填速度可能影響重量分佈而需要被控制。當 操作儀器至最大速度之75%至85%而在許多例子以全速 操作下，可得到良好的結果。 使用前述之處理參數，可以得到一個方便的，具再 現性的生產方法以便製備含有一個30-50網目核心，一 0 個殺真菌劑之塗覆層，一個高分子聚合物及一個薄的封 塗覆聚合物層之微粒狀物。藥性動力學研究顯示如此得 到微粒狀物具有良好的溶解性及生物可用性的特點。 範例： a) 伊托康嗤塗覆層溶液 取一適當容器加入二氯甲烷〔 337.5kg〕及乙醇 〔180kg〕，以攪拌器持續攪拌，並加入泊洛沙姆 (poloxamer 407)〔 22· 5kg〕及檸檬酸〔3kg〕擾拌溶 _ 解後，再加入伊托康唑〔30kg〕及羥丙基甲基纖維素 〔3kg〕，確認溶解後再加〔20· lkg〕滑石粉，最後過 師1 OOinesh師網備用。 b) 抗凝結塗覆層溶液 取一適當容器加入二氯甲烷〔15kg〕及乙醇 〔15kg〕以攪拌器持續攪拌，加入〔2· lkg〕羥丙基 甲基纖維素及〔 300g〕丙二醇攪拌溶解後再加入 12 1281867 〔4.5kg〕滑石粉，最後過篩lOOmesh篩網備用。 c) 載藥工程 一個配備為直徑lm之迴轉盤之旋轉式喷霧造粒 設備將30-50網目〔300-500微米〕之糖蕊〔70· 5kg〕 置入流動狀態之旋轉式喷霧造粒設備中運轉，以進口 風溫設定40°C-50°C進口風量為，每分鐘30-35立方 求’排氣風量為每分鐘38立方米迴轉盤轉速每分鐘 60-80轉，喷槍之壓力3. 5-4. 5公斤/平方公分喷量 由每分鐘450g慢慢增加至每分鐘800g，當載藥完成 後，以50°C-55°C的乾燥空氣乾燥20分鐘。 d) 外層塗膜層 乾燥完成後，以進口風溫度設定50-55°C，進口 風量及出口風量風量維持不變，迴轉盤轉速為每分鐘 80-90轉，喷槍壓力約4.5公斤/平方公分喷量為每 分鐘600-700g，持續操作至完成。 e) 最終乾燥 停止喷霧並將迴轉盤降至每分鐘10轉，進口風 溫度提高至55°C-60°C持續乾燥30分鐘，最後停止 加熱溫度，待產品冷卻至室溫時約25°C，取適當容 器盛裝下料。 f) 過篩 以多次元篩分機上層為16mesh篩網，下層為 30mesh篩網擺動過篩分為16mesh以上〔不良品〕， 16-30mesh〔良品〕，30mesh以下〔不良品〕，篩後以 13 1281867 密閉容器盛裝。 g)膠囊充填 將過篩完成之微粒狀物以全自動膠囊充填機充 填於No. 0號膠囊中，每膠囊含有約520毫克之微粒 狀物，相當等於100毫克之伊托康嗤。 由以上特殊配方組成之含伊托康唑膠囊溶解度 佳，大大提高生體可用率。 14 1281867 臨床實驗： 1·伊托康唾在人體代謝週期為96小時，本發明組合物 與習用組合物均含伊托康唑（itraconazole)lOO毫 克。 2·針對24位健康志願者，利用根據本發明製備的組合 物（Icomein M·)與市面上習用組合物（Sp〇ranox)進 行口服膠囊的實驗，並各在口服後第1、2、2· 5、3、 3· 5、4、4· 5、5、6、8、1〇、12、24、48、60、72、 8胃4、96小時進行抽血並比對血液中含伊托康唑之含 量。由附件二的數據中可顯示本發明組合物在24位 心願者的血中漢度曲線下面積值(AUC〇 t)的變異係數 為57.9 ,而附件一的數據顯示習用組合物在％位志 願者的血中濃度曲線下面積值(Αυ〇Μ)的變異係數為 Λ 〇 附件3呈現的對照組Β與對照組八在24位志願者 的度曲線下的面積比率平均值數據為ι ι〇,及 二為!·20’可明顯看出本發明組合 物的生體使用率優於習用組合物。 綜t所述，本發明實施例確能達到所之使用功 效，又其所揭露之具體構造，不僅 / .介去祕八叫认由4 1 1置未曾見於同類產品 中，亦未曾公開於巾請前，誠α 與要求，纽法提㈣明專狀h #刊法之規疋 並賜准專利，則實感德便。惠予審查， 15Ce - particulate core: it is about 300 to 500 microns in diameter [30 to 50 mesh]. In addition, the particulate matter may further comprise different additives such as thickeners, lubricants, surfactants, preservatives, mismatches and chelating agents, electrolytes and other active ingredients such as fire suppressants, bactericides, disinfectants Or vitamins. The particulates can be conveniently designed into different pharmaceutical dosage forms. Suitable dosage forms comprise an effective particulate fungicide content as described above. Preferably, the microparticles are filled in a hard animal capsule such that, for example, 50 to 100 mg of the active ingredient is obtained per dosage form. For example, an animal capsule having a size of Ν〇·0 is suitable for designing particulate matter from 19 to 25 percent by weight of itotazole or spaconazole, equal to about 100 mg of active ingredient. According to the invention, the microparticles can be conveniently prepared in the following manner by preparing a drug coating solution by dissolving an appropriate amount of a fungicide and a polymer and an acidic substance in a suitable solvent system. = The solvent system consists of a mixture of methylene chloride and an alcohol, which is characterized by the change in ethanol compared to '丨 ethanol: with, for example, methyl ethyl ketone. The topping should contain 5 - methylene chloride as a solvent for the drug. Since the base cellulose is not completely soluble in the methylene chloride, at least, for example, it is necessary to add a person to a relatively low dichloride. A calcined/alcohol from 80/20 [heavy 蜃α Ί/>lcr to β / _ neck buckles 祀 「 "番旦Ί ratio" to 55/45 [heavy ratio], especially about 60/40固体]. Solid content, such as fungicides and high molecular polymers, 1281867 in the drug coating solution ranging from 4 to 7% [by weight], about 6% 隹. 30-50 mesh core drug coating The treatment can be conveniently operated in a rotary spray granulator equipped with a spray rate. The spray rate should be carefully adjusted. If the spray rate is too slow, some of the drug coating solution will be dried and the product will be lost. The spray rate will be too fast. Over-wet and lumpy, the block is the most serious problem, initially using a lower spray rate, and the coating process is carried out until the particle length is longer and then the spray rate is increased. The atomized air pressure also affects the coating process, low atomic air pressure The force leads to the formation of larger particles and the tendency to condense into agglomerates. The high atomic air pressure can be imagined to the danger of the drug solution being dried out. However, this effect is not a question of fins. Therefore, the atomized air pressure is almost They are all set to the maximum value. The volume of fluid air can be controlled by operating the exhaust valve of the instrument, and it is designed in such a way as to get the best particle circulation. If the volume of air is too low, it will cause beads. Insufficient flow; too high air Zhao will block 2% of the particulate matter due to the reverse flow generated by the instrument. In this process, the optimal condition can be opened by opening the exhaust valve to a maximum of + 50% ' The opening is gradually increased to about 60% of the maximum value as the coating process proceeds. The coating process uses an inlet air temperature ranging from 40 ° C to about 50 Å and the rotating disk speed is about 6 Torr, which is well rpm. Operation. The temperature may accelerate the reaction process, but the disadvantage is that the solvent evaporates too much and the coating liquid cannot be evenly distributed on the surface of the particulate matter. The guide 10 1281867 (four) pole coating * forms too many holes, when large When the coated particles are coated, the solubility of the drug may be significantly reduced to no reach, 'obviously, the optimal reaction process temperature will advance and the essence of the core and fungicides will be batched. The volume, solvent and spray rate are related. The parameter setting of the optimum coating result will be == in the following examples. The coating treatment under these conditions found that the non-filament compound was applied to have a money-transfer type. The drug-coated core of the spray granulating bed granulator, the anti-condensation solution can be prepared by dissolving the appropriate antimony-containing anti-coagulation polymer in a suitable solvent system, such as dichloromethane and alcohols. The mixture is preferably ethanol, and the ethanol can be changed with, for example, butyl hydrazine, and the ratio of the chloroformamide/alcohol used is similar to that of the thin coating treatment, so the range can be from about 80 to 20 [weight ratio 〕 to 55/45 [weight ratio], especially 0/40 [heavy weight ratio] 'in the anti-condensation jet solution anti-coagulation polymer content 'range to 4 to m weight ratio], preferably about 6%, this Anti-condensation spray solution is good for stirring in anti-condensation treatment The parameter settings for the last step of the operation must be described in detail in the examples below for the drug application process. A further drying step may be required after application of the anti-condensation polymer layer. After the injection has been completed, the instrument with operating parameters can easily remove excess residual solvent for about 5 to 15 minutes. Both the over-coated and anti-condensation processes are preferably operated under an inert gas such as nitrogen, and the coating device should be placed on the ground, and a suitable solvent recovery system for a sufficient concentration system should be provided for the 1281867 package. The drug-coated and blocked coated microparticles can be filled in a hard gelatin capsule [Νο.0] using a standard automatic glue filler, and an appropriate covering and deionizing device can effectively prevent electrostatic charge generation. The capsule filling speed may affect the weight distribution and needs to be controlled. Good results are obtained when operating the instrument to 75% to 85% of maximum speed and in many cases at full speed. Using the aforementioned processing parameters, a convenient, reproducible production process can be obtained to prepare a coating comprising a 30-50 mesh core, a zero fungicide, a high molecular polymer and a thin seal. A particulate material covering the polymer layer. Pharmacokinetic studies have shown that the particulates are characterized by good solubility and bioavailability. Example: a) Itoconazole coating solution was added to a suitable container by adding dichloromethane [337.5 kg] and ethanol [180 kg], stirring was continued with a stirrer, and poloxamer 407 (22. 5 kg) was added. And citric acid [3kg] disturbed _ solution, then add itoxazole (30kg) and hydroxypropyl methylcellulose [3kg], confirm the dissolution and then add [20·lkg] talcum powder, finally Division 1 OOinesh division network standby. b) Anti-coagulation coating solution Take a suitable container, add dichloromethane [15kg] and ethanol [15kg] with stirring in a stirrer, add [2·lkg] hydroxypropyl methylcellulose and [300g] propylene glycol to dissolve. Then add 12 1281867 [4.5kg] talcum powder, and finally sieve the 100mesh sieve for use. c) Drug-loading engineering A rotary spray granulation device equipped with a rotary disk of diameter lm is used to rotate 30-50 mesh (300-500 micrometers) of sugar core (70·5kg) into a flowing state. In the granular equipment, the inlet air temperature is set to 40°C-50°C, and the inlet air volume is 30-35 cubic meters per minute. The exhaust air volume is 38 cubic meters per minute. The rotary disk speed is 60-80 revolutions per minute. The pressure of 3. 5-4. 5 kg / cm ^ 2 spray volume from 400g per minute slowly increased to 800g per minute, when the drug is completed, dried at 50 ° C -55 ° C dry air for 20 minutes. d) After the outer coating layer is dried, the inlet air temperature is set to 50-55 °C, the inlet air volume and the outlet air volume remain unchanged. The rotating disc speed is 80-90 rpm and the gun pressure is about 4.5 kg/square. The centimeters are sprayed at 600-700g per minute and are continuously operated to completion. e) Final drying stop spray and reduce the rotary disc to 10 revolutions per minute, the inlet air temperature is increased to 55 ° C -60 ° C for 30 minutes, and finally the heating temperature is stopped, about 25 ° when the product is cooled to room temperature C, take the appropriate container to fill the material. f) sieved to the 16mesh sieve on the upper layer of the multi-element screening machine, and the 30mesh sieve on the lower layer is sifted into 16mesh or more [defective], 16-30mesh [good], 30mesh or less (defective), and 13 after sieve 1281867 Contained in a closed container. g) Capsule filling The sieved fine particles are filled in a No. 0 capsule with a fully automatic capsule filling machine, each capsule containing about 520 mg of microparticles, which is equivalent to 100 mg of itoconazole. The isoconazole-containing capsules consisting of the above special formulas have good solubility and greatly improve the bioavailability. 14 1281867 Clinical Trials: 1. The Itocon saliva has a metabolic cycle of 96 hours in the human body, and both the composition of the present invention and the conventional composition contain 100 mg of itaconazole (itraconazole). 2. For 24 healthy volunteers, the oral capsule test was carried out using the composition prepared according to the present invention (Icomein M·) and the commercially available composition (Sp〇ranox), and each of the first, second, and second after oral administration. · 5, 3, 3 · 5, 4, 4 · 5, 5, 6, 8, 1 , 12, 24, 48, 60, 72, 8 stomach 4, 96 hours to draw blood and compare the blood with Iraq The content of toconazole. From the data in Annex II, it can be shown that the coefficient of variation of the area under the Hanvon curve (AUC〇t) of the composition of the present invention is 57.9, and the data of Annex I shows that the composition of the composition is volunteered in %. The coefficient of variation of the area under the blood concentration curve (Αυ〇Μ) is Λ 〇 The average area ratio of the control group 呈现 and the control group 8 under the curve of 24 volunteers is ι ι〇 It is apparent that the bioavailability of the composition of the present invention is superior to the conventional composition. In view of the above, the embodiment of the present invention can achieve the use efficiency, and the specific structure disclosed therein is not only /. The secret is not recognized in the same product, nor has it been disclosed in the towel. Please feel free to ask before, sincerity and requirements, Newfat (four) Ming specialization h # publication law and grant patents, it is really good. Benefit review, 15