TW426527B

TW426527B - Cinolone composition

Info

Publication number: TW426527B
Application number: TW85103524A
Authority: TW
Inventors: De-Man Shiu
Original assignee: Sintong Chemical Ind Co Ltd
Priority date: 1996-03-25
Filing date: 1996-03-25
Publication date: 2001-03-21

Abstract

A solid pharmaceutic composition contains cinolone, 1 to 25% calcium monohydrogen phosphate, 1 to 25% lactose, 0.1 to 10% primogel, 0.1 to 5% starch, 0.01 to 1% magnesium stearin; 0.05 to 0.2% Tween 80 is added if necessary.

Description

4 2652 A7 B7 五、發明説明（) 1 產業上之刹用頜域本發明係揭示一種新颖含信諾隆（Cinolone)主成份之固型製劑，該固型製劑配合信諾隆（Cinolone)之化性與if 性，以達到理想之溶離效采。先閱讀背面之注毒 f知故藝：德國專利（DE-0S)第3,142,854號係申請有關硒朋新（Ciprofloxacin〉藥物之衍生物，該擁有η比喊结構之{:妾 10合物已經被發現具備抑制致病性細菌生長之活性，成爲{ 學治療劑中足以產生類似抗生素般，包栝抑制革蘭氏陽性與陰性致病性細菌生長之廣效性抑菌作用藥物。然而有居| 此類此匕咬結構之化合物已經出現許多種製備方法，可經“ :與之中間體反應，亦可經由已知衍生物加以氧& 15反應。4 2652 A7 B7 V. Description of the invention (1) Industrial brake jaw field The present invention discloses a novel solid preparation containing the main components of Cinolone. The solid preparation cooperates with Cinolone. Chemical properties and if properties, in order to achieve the ideal dissolution effect. First read the poison injection on the reverse side: German Patent (DE-0S) No. 3,142,854 is an application for a derivative of Ciprofloxacin drug. The {: 合物 10 compound with η ratio structure has been It was found to have the activity of inhibiting the growth of pathogenic bacteria, and it became a broad-spectrum antibacterial drug in the therapeutic agent sufficient to produce similar antibiotics, including the inhibition of the growth of Gram-positive and negative pathogenic bacteria. However, there are | Many compounds have been prepared for this kind of compound with a bite structure, which can be reacted with ": and its intermediates, and can also be reacted with oxygen & 15 through known derivatives.

I t 經濟部中央榡準局員工消費合作社印製雖然德國拜耳廡所獲得之專利131778公告號係将30 %至95%之喪邊疫咐衍生物與4.5%至25%之織維素4 粘著劑，〇%至30%之澱粉爲崩解佐劑，〇,5%至10%之 20羥丙基f基纖維素（HPMC)15cp及/或交聯聚乙烯基I從略^ 酮（PVP)爲崩解佐劑，和0%至3%潤滑刻。 24 本發明欲解決的課題 2 本紙張尺度適用中國國家標準（CNS ) A4规格（2丨0X297公廣） 426527 A7 B7 五、發明説明（） 1 有鍬於，铽專利資料僅係以一般帙製劓概念将f知之織維素爲粘著劑、澱粉爲崩解佐劑、或添加某些潤滑劑，對於辦衍生物之化性與物性並未曾探纣，甚至於藥品固堃劑型之溶離速率與血中濃度受到藥品之影響因數， 5 亦未加以研究。一般藥品產生療效之指標可歸納爲二；其一爲藥品於血中之濃度及所達到i中之最高濃度（Cmax)，其二爲給藥後達到最高▲中濃度之時間（Tmax)。固型劑型藥品之溶離 10效果以及血中濃度受到（1)藥品的物化性質（2)劑型（3) 試验儀器與試驗春數等因數所影響，已經屬於眾所皆知之事實。當然於生物醋内存在著許多足以環環相矜之狀態下 ’更可發現藥物本身的溶解度（Solubility)、藥物顆粒大小（Particle size)、藥物的结晶形態（Crystalline state 15 ) ’以及諸如同質多晶化（polymorphism)、水化作用狀態（It is printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Although the patent No. 131778 obtained by Bayer, Germany, is to bind 30% to 95% of the beast epidemic derivative and 4.5% to 25% of oryzanol. 4 0% to 30% of starch is a disintegrating adjuvant, 0.5% to 10% of 20 hydroxypropyl f-based cellulose (HPMC) 15cp and / or cross-linked polyvinyl I ketone ( PVP) is a disintegrating adjuvant, and 0% to 3% lubricated. 24 The problem to be solved by the present invention 2 The paper size is applicable to the Chinese National Standard (CNS) A4 specification (2 丨 0X297) 426527 A7 B7 V. Description of the invention () The concept of weaving oryzanol as an adhesive, starch as a disintegrating adjuvant, or adding certain lubricants has not been explored for the chemical properties and physical properties of derivatives, and even the dissolution rate of pharmaceutical solid dosage forms. Factors affecting blood concentrations due to drugs have not been studied. The indicators of general drug efficacy can be summarized as two: one is the concentration of the drug in the blood and the highest concentration (Cmax) in i reached, and the other is the time to reach the highest ▲ medium concentration (Tmax) after administration. The effects of dissolution of solid-form drugs and blood concentration are affected by (1) the physicochemical properties of the drug, (2) the dosage form, and (3) factors such as test instruments and test spring numbers, which are well-known facts. Of course, there are many states in the bio vinegar that are enough to be linked. 'Solubility of the drug itself (Solubility), Particle size of the drug (Particle size), Crystalline state of the drug (Crystalline state 15)' Crystallization (polymorphism), hydration state (

State of hydration)、溶質溶媒化合程度（s〇lvati〇n)、錯合物化作用（Complexat ion)等等均足以造成影響藥物溶離之快慢程度以及吸收量。經濟部中央標準局負工消費合作社印製 ' · - I I I n ^ n ^ (請先閲讀背面之注意事項再填寫本頁) 20 習知對於某些溶解度較差的藥品’可運用將藥品形成鹽類之方式；或經由研磨方式以減小藥物顆粒大小；或改變藥物分子之水合量；以增加其溶解度。例如安匹西林三水合物（Ampicillin trihydrate)轉變成爲安匹西林無水 24合物（Ampici 11 in Anhydrous)，可增加其溶解度。 3 本纸張尺度適用中國國家標準（CNS ) A4規格（210X297公釐> 426527 A7 B7 五、發明説明（ ! 發明説明 10 本發明々信諾隆（Cinolone)組合物々之首要目的係配合信諾隆（Cinolone)之化性與物性，製備一種新箱之固型製劑。本發明"信諾隆（Cinolone)組合物"之另一目的係製備一種達到理想溶離效篆之固型製劑。爲達前迷之目的本發明採用之手段信諾隆(Cinolone)係如下式之化合物，1-環兩基_6_ 氟-1,4-二氩-4-氧-7 -(1-礞赛基)-3-邊琳基舞酸）〇 (请先閱讀背面之注意事項再填寫本頁) 訂 15State of hydration), solute solvent combination (solovaton), complexation (Complexat ion), and so on are all sufficient to affect the speed of drug dissolution and absorption. Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Cooperatives '--III n ^ n ^ (Please read the precautions on the back before filling out this page) 20 Known for some poorly soluble drugs' the drug can be used to form salts Or by grinding to reduce the particle size of the drug; or to change the amount of hydration of the drug molecule; to increase its solubility. For example, the conversion of ampicillin trihydrate to ampici 11 in Anhydrous can increase its solubility. 3 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm > 426527 A7 B7) 5. Description of the invention (! Description of the invention 10 The primary purpose of the Cinolone composition of the present invention is a matching letter The chemical and physical properties of Cinolone, to prepare a solid formulation of a new box. Another purpose of the present invention "Cinolone composition" is to prepare a solid formulation that achieves the desired dissolution effect. To achieve the goal of the present invention, the means used in the present invention, Cinolone, is a compound of the formula: 1-cyclodiyl_6_fluoro-1,4-diargon-4-oxo-7- (1- 礞Saiji) -3-Bianlinji Mai acid) 〇 (Please read the notes on the back before filling in this page) Order 15

經濟部中央標嗥局貝工消費合作社印奴經測量信諾隆（Cinolone)之化性與物性，發現信羅隆鹽酸M(Cinolone.HCl)本身的溶解度極佳，原料本身粒子欠小以及其紿晶形態對於溶離率（Diss〇luti〇n rate/ 之影響度較徵小。然而.通常之固塑製劑隨其q)配方之差異、（2)製作過程之不同、（3)包裝义儲存環境，仍然足以左右固型製劑之溶離率（D丨ss〇iut i〇ri rate)與血中濃度 24 ° 20 本紙張尺度適用中國國家標準（CNS ) A4規格（210x 297公楚） 426527 A7 ___ B7___ 五、發明説明（） 1 本發明一種新穎含信諾隆（Cinolone)主成份之固型製劑，係選用乳糖（lactose)、源粉、嫂J旨酸錢、樸里牟傑 (primogel)、_酸氫巧（Dibasic calcium phosphate)、聚山梨醇酯（Tween)80爲材質。將該等材質依照比例均勻 5 風合，溶於適量溶媒經造粒乾燥後、過篩，壓鉸成直徑爲 llmm的叙劑。上述材質之添加量分別爲，1 %至25%之辨酸氨鈣，1¾至25%之乳糖，0.1%至10%之樸里牟傑 (卩厂丨111〇疼61)*0.1%至5%之激粉、0.01%至1%之硬脂酸镇0其中之後里牟傑（primogel)係一種救粉巍乙酸钻 10 (Sodium starch glycolate)。而較適宜用量分別爲 1 % 至12%之磷酸氫鈣，1%至17%之乳糖，0.1 %至8%之撲里牟傑（？1^111〇尽^1)，1%至3%之搬粉、0.1%至0.5 %之硬脂酸镁。所謂溶於適量溶媒，係選用水或乙酵、丙三醇之類有機溶媒，必要時可添加0.05%至0.2%聚山梨 15 酵垢（Tween) 80。經濟部中央標隼局員工消費合作社印製 I n n ~" 訂 (請先閲讀背面之注意事項再填寫本頁) 本發明先以一般製備固型製劑之概念選用符合藥典规定之信諾隆（Cinolone)成份，添加殿粉、樸里牟傑（ primogel〉、嶙酸氫約（Dibasic ca]cium phosphate)、硬 20脂酸镁爲材質。將該等材質依照比例均勻混合，溶於適量溶媒經造粒乾燥後、過篩，壓成鉸劑。分別以0.1N濃度孃酸溶液與酸鹼度（pH)值爲4.5的醋酸緩衝液（acetate buffer〉，檢品經UV分光儀分別每隔10分鐘物樣一次進行 24檢測溶離百分率之體外溶離試驗（In Vitro Dissolution ______ 本紙張尺度適用中國國家標準（CNS) A4規格（21 〇Χ 297公釐） 42β527 Α7 Β7The Inu slave of the Central Bureau of Standards, the Ministry of Economic Affairs, measured the chemical and physical properties of Cinolone, and found that the solubility of Cinolone.HCl is very good, the particles of the raw material itself are too small, and the The effect of morphology of crystals on the dissociation rate (Dissolotin rate /) is less significant. However, the usual solid plastic preparations vary with their q) formulations, (2) the manufacturing process is different, (3) packaging and storage The environment is still enough to control the dissociation rate (D 丨 s〇iut i〇ri rate) and blood concentration of the solid preparation 24 ° 20 This paper size applies the Chinese National Standard (CNS) A4 specification (210x 297 Gongchu) 426527 A7 ___ B7___ 5. Description of the invention (1) A novel solid preparation containing the main ingredients of Cinolone of the present invention, which is selected from the group consisting of lactose, source powder, sour money, primogel, _Dibasic calcium phosphate and Tween 80 are the materials. These materials are uniformly winded according to the ratio, dissolved in an appropriate amount of solvent, granulated and dried, and then sieved, and then pressed into a narcotic agent with a diameter of llmm. The added amounts of the above materials are: 1% to 25% ammonium dicalcium citrate, 1¾ to 25% lactose, 0.1% to 10% of Pu Li Mou Jie (Yanchang 丨 111 Pain 61) * 0.1% to 5 % Stearic acid powder, 0.01% to 1% stearic acid, 0 of which, Primogel is a sodium starch glycolate. The more suitable dosages are 1% to 12% of dibasic calcium phosphate, 1% to 17% of lactose, 0.1% to 8% of Puli Mojie (? 1 ^ 111〇 do ^ 1), 1% to 3% Powder, 0.1% to 0.5% magnesium stearate. The so-called dissolve in proper amount of solvent is water or organic solvents such as acetic acid and glycerol. If necessary, 0.05% to 0.2% Polysorbate 15 Tween 80 can be added. Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs of the Inn ~ " Cinolone), adding Dianfen, primogel, Dicaic caium phosphate, and magnesium stearate as materials. These materials are evenly mixed according to the proportion and dissolved in an appropriate amount of solvent. After granulation and drying, sieving and pressing into hinge agent. 0.1N concentration of citric acid solution and acetate buffer (pH) value of 4.5 acetate buffer (acetate buffer>, respectively, the test product by UV spectrometer every 10 minutes respectively In vitro dissolution test (In Vitro Dissolution ______) with 24 detection of dissolution percentage at one time. This paper size applies Chinese National Standard (CNS) A4 specification (21 〇 × 297 mm) 42β527 Α7 Β7

經濟部中央榡率局員工消費合作杜印製由於上迷基本材質所組成之製劑其溶離百分率比拜耳嚴級朋π》、新（Ciprofloxacin)250 mg暖衣叙更便，經添加 5 乳糖16.3%之實施例1，如圖1所示其溶離百分率仍比拜耳廠硒朋吠新煖衣鉸慢。經分別添加乳糖及磷酸氫鈣之實施例2、3,如圖2、3所示不論逋酸溶洗或醋酸緩衝液内其溶離百分率均比拜耳廠硒朋欢新膜衣锭快。 10 難然於 1990 年Drug Develp. and Ind. Phar*m.第 16 卷第6期第951-9621以及第16卷第10期第1717-17231 等文獻均報導，添加表面活性劑如聚山梨醇酯（Tween) 80 可促使含溶解度較小藥品之處方製劑增加溶離速率。由於實施例1之溶離百分率比拜耳廠硒朋呔新膜衣锭慢，經添 15加〇·〇5%聚山梨酵酿（Tween) 80之實施例4,但是如圖 4所示其溶離百分率不僅比實施例1慢，也仍然比拜耳廠硒朋新膜衣锭慢。即使聚山梨酵酯80添加量增至0.2% 之實施例5,其溶離百分率並不如文獻所報導之聚山梨鞟酯80可促使溶離速率增加。當然如實施例4、5所示所組成含有信諾隆(Cinolone〉主成份之固型製劑，均無法依賴聚山梨酵酯80添加量爲〇,〇5%或0.2%而達到增加溶離百分率之作用。此現象與下列情況之相異结果僅可作爲比較，當實施例2分別添加聚山梨鞟酯80達到0.05%成爲 24實施例6或添加〇·2%成爲實施例7，如圖5所示兩者之溶 6 本紙張尺度適用中國國家標準（CNS ) Α4規格（210X297公釐） ---------- ^-----------訂 (請先Μ讀背面之注意事項再填寫本頁) 經濟部中央標率局員工，消費合作社印製 4 265 27 A7 B7 五、發明説明（） 1 離耳分牟相近，扭均比實施例2之溶離1?分牟快，也比羿耳廠硒朋13之新膜·衣鉸快。當實施例3分別添加聚山梨酵酯 80達到0.05%成爲實施例8或添加0.2%成爲實施例9 ，如圖6所示兩者之溶離百分率相近，但比拜耳廠硒朋 5 新暖衣锭快，均比實施例3之溶離百分率便。將實施例9 之乳糖去除成爲實施例10，於II酸溶液如圖7所示或醋酸緩衝液内如圖8所示，其溶離百分率比實施例9之溶離贯分率或拜耳廉硒朋吹新疲衣叙快。 10 一般成人使用信諾隆（Cinolone)之劍量爲250 mg，爲探纣生物體内血中濃度，經3隻兔子動物實验分別選用實族例10，或拜耳戚爾朋欢新（Ciproxin) 250 rog膜l衣旋各以1/4劑量投藥，給藥後30分鐘依照間隔30分鐘爲採血時間。採得的兔血如圖9所示，結采發現實施例10之固 15型製劑，比拜耳廠袖朋新有更快速的達到最高也中濃度之時間（Tmax)。且生理可利用率亦比拜耳廠硒朋ίΐ大新較佳综上所迷本發明一種新穎含信諾隆（Cinolone)主成你 20之固型製劑，選用至25%之磷酸氫鈣，至25%之乳糖，0.1%至10%之樸里牟傑&「丨111〇防1)’0.1%至5 %之澱粉、0.01%至]%之硬脂酸鎂必要時可添加衆山梨醇酯（Tween〉80爲材質。将該等材質依照比例均勻 24洛合，溶於適量溶媒經造粒乾燥後、過篩’壓成叙劑。擁 7 (請先閱讀背面之注意事項再填寫本頁)The consumer cooperation of the Central Bureau of Economic Affairs of the Ministry of Economic Affairs of the People ’s Republic of China is due to the fact that the dissolution percentage of the formulation consisting of the basic materials of the above is more convenient than that of Bayer ’s strict friends, Ciprofloxacin 250 mg warm clothes. After adding 5 lactose 16.3% In Example 1, the dissolution percentage as shown in FIG. 1 is still slower than that of the selenium pampar new warm clothes hinge of Bayer Plant. After adding lactose and dibasic calcium phosphate respectively in Examples 2 and 3, as shown in Figures 2 and 3, the dissolution percentages in rhenium acid wash or acetic acid buffer solution are faster than those in the Bayer plant selenium penghuan new film-coated tablets. 10 Rarely, in 1990, Drug Develp. And Ind. Phar * m. Vol. 16 No. 6 Nos. 951-9621 and Vol. 16 No. 10 Nos. 1717-17231 reported that the addition of surfactants such as polysorbate Ester (Tween) 80 can increase the dissolution rate of prescriptions containing less soluble drugs. Since the dissolution percentage of Example 1 is slower than that of the new film-coated tablet of selenium peptone from Bayer factory, 15% 0.05% Tween 80 was added to Example 4, but the dissolution percentage is shown in FIG. 4 Not only slower than Example 1, but also slower than the selenium new film-coated tablet from Bayer. Even in Example 5 where the amount of polysorbate 80 was increased to 0.2%, the dissolution percentage was not as high as that reported in the literature. Polysorbate 80 could increase the dissolution rate. Of course, the solid preparations containing the main ingredients of Cinolone as shown in Examples 4 and 5 cannot rely on the addition of polysorbate 80 at 0.05% or 0.2% to achieve an increase in dissolution percentage. The difference between this phenomenon and the following situation can only be used as a comparison. When Example 2 was added with polysorbate 80 to reach 0.05%, it became Example 24 or 0.2% became Example 7, as shown in Figure 5. Show the dissolving of both 6 This paper size is applicable to China National Standard (CNS) Α4 specification (210X297 mm) ---------- ^ ----------- Order (please first M Read the notes on the back and fill in this page again.) Employees of the Central Standards Bureau of the Ministry of Economic Affairs, printed by the Consumer Cooperative. 4 265 27 A7 B7 V. Description of the invention () Dividing is faster, and faster than the new film and clothes hinge of the selenium 13 of the Er'er Plant. When Example 3 was added with polysorbate 80 to reach 0.05%, it became Example 8 or 0.2% became Example 9, as shown in Figure 6. The dissolution percentages of the two are similar, but faster than the new warming tablets of selenium 5 from the Bayer plant, and both are faster than the dissolution percentage of Example 3. Example 9 Lactose removal became Example 10, as shown in Figure 7 in the II acid solution or as shown in Figure 8 in the acetic acid buffer solution. Its dissolution percentage was faster than that of Example 9 or Bayer's selenium. 10 The average adult use of Cinolone sword is 250 mg, in order to explore the blood concentration in the organism, the real group example 10, or Bayer Chiproxin (Ciproxin) were used in 3 rabbit animal experiments. 250 rog membranes and liniment were administered in 1/4 doses, and the blood collection time was 30 minutes according to the interval of 30 minutes after the administration. The rabbit blood was collected as shown in FIG. 9, and the solid type 15 preparation of Example 10 was found. It has a faster time to reach the highest and middle concentration (Tmax) than the Bayer plant sleeve penxin. And the physiological availability is better than the Bayer plant selenium pendant Daxin. In summary, a novel letter-containing nonolon of the present invention ( Cinolone) is mainly used as a solid preparation for you. Choose from 25% calcium hydrogen phosphate, 25% lactose, and 0.1% to 10% Park Lee Mok Kit & "111〇防 1) '0.1% to 5 % Of starch, 0.01% to]% of magnesium stearate, if necessary, sorbitan ester (Tween> 80 as the material. These materials Luo a uniform ratio as 24, was dissolved in an appropriate amount of solvent granulated after drying and sieved 'pressed into Syrian agent. 7 pro (Read Notes on the back and then fill the page)

•IT 本紙張尺度適用中國國家標準（CNS ) A4規格（2l〇X297公釐） 4 265 27 經濟部中央標準局員工消費合作社印製 A7 _B7_ mnw。圖示説明 5 圖1.實施例1锭之溶離速率（pH =0.1) 1.....實施例1锭 2.....拜耳廠圖2.實施例2、3锭之溶離連率（pH =0.1) 1.....實施例2铉 2.....實施例3叙 3.....拜耳底 10圖3.實施例2、3鉸之溶離連率（pH =4.5) 1.....實施例2锭 2.....實施例3 # 3.....拜耳廠圖4.實施例1、4、5锭之溶離速率（pH =0.1) 1.....實施例1錠 2.....實施例4叙 15 3.....實施例5锭 4.....拜耳廠圖5.實施例2、6、7锭之溶離速率（pH =0.1) 1.....實施例2锭 2.....實施例6锭 3.....實施例7锭 4.....拜耳廠圖6.實施例3、8、9鉸之溶離速率（pH =0.1) 20 1.....實施例3錠 2.....賞施例8錠 3.....實施例9锭圖7.實施例10錠之溶離速率（pH =0.1) 1.....實施例10錠 2.....拜耳廠 24 8 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐） 4 2 652 7 A7 B7 五、發明説明（） 1 圖8.實施例10錠之溶離速率（pH =4.5) 1.....實施例10锭 2.....拜耳廠圖9.實施例10錠之血中濃度 1.....實施例10錠 2.....拜耳廠 5 實施例1 信諾隆（Cinolone) 291.1 mg 乳糖（lactose) 60.3 mg 10 澱粉 11.1 mg 樸里牟傑（primogel) 5.5 mg 硬脂酸链 2.0 mg 實施例2 15 ---------- 界-----„--訂 (請先閲讀背面之注意事項再填寫本頁) 經濟部中央標準局員工消費合作社印衆信諾隆（Cinolone) 291.1 mg 乳糖（lactose) 41.8 mg 磷酸氫鈣 18.5 mg 澱粉 Π.1 mg 20 襆里牟傑（primogel) 5*5 mg 硬脂酸镁 2.0 mg 實施例3 24 9 本紙張尺度適用中國國家標準（CNS ) A4规格（210X 297公釐） 426527 A7 B7 經濟部中央標準局員工消費合作社印製五 1 、發明説明（）信諸隆（Cinolone) 291.1 mg 乳糖（lactose) 23.3 mg 鱗酸氫好 37.0 mg 澱粉 11.1 mg 5 樸里牟傑（primogel) 5.5 mg 硬脂酸镁 2.0 mg 實施例4 10 信諾隆（Cinolone) 291.1 mg 乳糖（lactose) 60.1 mg 澱粉 11.1 mg 樸里牟傑（primogel) 5.5 mg 硬脂酸镁 2.0 mg 15 聚山梨醇醋（Tween) 80 0.2 mg 實施例5 信諾隆（Cinolone) 291.1 mg 20 乳糖（lactose) 59.6 mg 澱粉 11.1 mg 樸里牟傑（primogel) 5.5 mg 硬脂酸镁 2.0 mg 24 聚山梨醇酿（Tween) 80 0.7 mg 10 I-----^----- 水--------訂 {請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（2IOX297公釐） 426527 A7 产、發#儀6) 經濟部中央標準局員工消費合作社印製信諸隆（Cinolone) 291.1 mg 乳糖（lactose) 4L6 mg 磷酸氫鈣 18.5 mg 澱粉 11.1 mg 襆里牟傑（primogel) 5.5 mg 瑷脂酸镁 2.0 mg 聚山梨酵酿（Tween) 80 0.2 mg 施例7 信諾隆（Cinolone) 291.1 mg 乳糖（lactose) 41.1 mg 磷酸氫鈣 18.5 mg 澱粉 11.1 mg 樸里牟傑（primogel) 5.5 mg 硬脂酸镁 2.0 mg 聚山裂酵酿（Tween) 80 0.7 mg 施例8 信諾隆（Cinolone) 291.1 mg 乳糖（lactose) 23.1 Big 11 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（2[〇X297公釐） 4 265 2 7 A7 B7 經濟部中央標隼局員工消費合作社印製五、 1 發明説明（）磷酸氩鈣 37.0 mg 澱粉 11.1 mg 樸里牟傑（primogel) 5.5 mg 硬脂酸镁 2.0 mg 5 聚山梨轉能（Tween) 80 0.7 mg 實施例9 信諸隆（Cinolone) 291.1 mg 10 乳糖（lactose) 22.6 mg 鱗酸氫好 37.0 mg 澱粉 11.1 mg 樸里牟傑（primogel) 5.5 mg 硬脂酸镁 2.0 mg 15 聚山梨酵酿（Tween) 80 0.7 mg 實施例10 信諾隆（Cinolone) 291.1 mg 20 磷酸氫鈣 37.0 mg 澱粉 11.1 mg 樸里牟傑（primogel) 28.0 mg 硬脂酸镁 2.0 ig 24 聚山梨醇醋（Tween) 80 0.8 mg 12 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準（CNS ) A4規格（2!0'乂 297公釐） 42^527 A7 B7 五、發明説明（） 1 資施例11 信諾隆（Cinolone) 291.1 mg 乳糖（lactose) 56.6 mg 磷酸氩鈣 3.7 mg 澱粉 11.1 mg 樸里牟傑（primogel) 5.5 m 硬脂酸镁 2.0 mg 施例12 信錯隆（Cinolone) 291.1 mg 磷酸氫鈣 60.3 mg 澱粉 11.1 mg 樸里牟傑（primogel) 5.5 mg 硬脂酸镁 2.0 mg 施例13 {請先聞讀背面之注意事項再填寫本頁) 訂經濟部中央榡準局員工消費合作社印製禮外溶離试驗（In Vitro Dissolution Test) 分別各以900 mL，含0.1N濃度逋酸，與酸鹼值(PH) 20值爲4.5的醋酸緩衝液（acetate buffer)，保棒於37 土 0.5 °C環境下以50 rpm之轉速進行測試。檢品的扯樣點分别爲10分鐘’ 20分鐘，30分鐘，40分鐘四次抽樣。檢品經WV 分先鏡（UV spectrophotometer〉於 λ =316.5nm 24下進行溶離百分率之檢測。 13 本紙張尺度逋用中國國ί標準（CNS ) A4規格（210X297公釐） —""" 426527 A7 B7 五、發明説明（ Μχ 10 實施例14兔子Λ内的血中濃度採血方法：飼養於信東底内動物室中之家兔，於實验當日至勤物室選用2·5〜3 Kg、稱重並纪錄。以5 mi針筒柚取兔血作爲”空白樣品（blank)”。選用實施例1〇或拜耳廠硒朋新膜衣锭Ciproxin; 1-環丙基-6-氟-1·4-二氣-4-氧-7 _ (1-膝曝基)-3-峻琳基採酸）分別投藥。投藥後加分鐘依照間隔30分鐘爲採i時間。採得的兔血立即置人含無菌If素钠（Sodium Heparin)之離心管，以4,800 rpm速度進行離心10分鐘。柚取離心後之上層血清，並立即置入 -221冰箱冷凍。 f請先聞讀背面之注意事項再填寫本頁)• IT This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210 × 297 mm) 4 265 27 Printed by A7 _B7_ mnw, a staff consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Graphic description 5 Figure 1. Dissolution rate of the ingot of Example 1 (pH = 0.1) 1 ..... Example 1 of the ingot 2 ..... Bayer plant Figure 2. Dissolution rate of the ingot of Examples 2 and 3 (PH = 0.1) 1 .. Example 2 铉 2 ..... Example 3 and 3. Bayer bottom 10 Figure 3. Dissociation and dissociation rate of the hinges of Examples 2 and 3 (pH = 4.5) 1 ..... Example 2 ingot 2 ..... Example 3 # 3 ..... Bayer Plant Figure 4. Dissolution rate (pH = 0.1) of ingots in Examples 1, 4, and 5 1 ..... Example 1 ingot 2 ..... Example 4 described 15 3 ..... Example 5 ingot 4 ..... Bayer plant Figure 5. Example 2, 6 and 7 ingots Dissolution rate (pH = 0.1) 1 ..... Example 2 ingot 2 ..... Example 6 ingot 3 ..... Example 7 ingot 4 ..... Bayer plant Figure 6. Example Dissolution rate of 3, 8 and 9 hinges (pH = 0.1) 20 1 ..... Example 3 ingot 2 ..... Reward Example 8 ingot 3 ..... Example 9 ingot Figure 7. Implementation Example 10 Dissolution rate (pH = 0.1) 1 ..... Example 10 ingot 2 ..... Bayer factory 24 8 (Please read the precautions on the back before filling this page) This paper size applies to China Standard (CNS) A4 specification (210X297 mm) 4 2 652 7 A7 B7 V. Description of the invention () 1 Figure 8. Dissolution rate (pH = 4.5) of Example 10 ingot 1. Implementation ... Example 10 tablets 2. Bayer plant Figure 9. Blood concentration of Example 10 tablets 1. Example 10 tablets 2. Bayer factory 5 Example 1 Cinolone 291.1 mg lactose 60.3 mg 10 starch 11.1 mg primogel 5.5 mg stearic acid chain 2.0 mg Example 2 15 ---------- Bound ------------ Order (please read the precautions on the back before filling this page) Employees' Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China Cinolone 291.1 mg lactose 41.8 mg calcium hydrogen phosphate 18.5 mg starch Π.1 mg 20 襆Primogel 5 * 5 mg Magnesium Stearate 2.0 mg Example 3 24 9 This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 426527 A7 B7 Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed May 1. Description of the invention (Cinolone) 291.1 mg lactose 23.3 mg Hydrogen scalylate 37.0 mg Starch 11.1 mg 5 Primogel 5.5 mg Magnesium stearate 2.0 mg Example 4 10 Cinolone 291.1 mg lactose 60.1 mg starch 11.1 mg primogel 5.5 mg magnesium stearate 2.0 mg 15 Tween 80 0.2 mg Example 5 Cinolone 291.1 mg 20 lactose 59.6 mg starch 11.1 mg primogel 5.5 mg stearin Magnesium acid 2.0 mg 24 Polysorbate (Tween) 80 0.7 mg 10 I ----- ^ ----- Water -------- Order {Please read the precautions on the back before filling this page ) This paper size is in accordance with Chinese National Standard (CNS) A4 (2IOX297 mm) 426527 A7. Production and development # 6) Printed by Cinolone 291.1 mg lactose 4L6 mg Calcium hydrogen phosphate 18.5 mg Starch 11.1 mg Primogel 5.5 mg Magnesium stearate 2.0 mg Tween 80 0.2 mg Example 7 Cinolone 291.1 mg lactose 41.1 mg Calcium hydrogen phosphate 18.5 mg Starch 11.1 mg Primogel 5.5 mg Magnesium stearate 2.0 mg Tween 80 0.7 mg Example 8 Cinolone 291.1 mg lactose 23.1 Big 11 (Please read the notes on the back before filling this page) Zhang scale is applicable to Chinese National Standard (CNS) A4 specification (2 [〇297297 mm) 4 265 2 7 A7 B7 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention mg Primogel 5.5 mg Magnesium stearate 2.0 mg 5 Tween 80 0.7 mg Example 9 Cinolone 291.1 mg 10 lactose 22.6 mg mg Starch 11.1 mg Primogel 5.5 mg Magnesium Stearate 2.0 mg 15 Tween 80 0.7 mg Example 10 Cinolone 291.1 mg 20 Calcium Hydrogen Phosphate 37.0 mg Starch 11.1 mg Primogel 28.0 mg Magnesium Stearate 2.0 ig 24 Tween 80 0.8 mg 12 (Please read the precautions on the back before filling out this page) The paper size applies to Chinese National Standards (CNS) A4 specification (2! 0 '乂 297 mm) 42 ^ 527 A7 B7 V. Description of the invention (1) Example 11 Cinolone 291.1 mg lactose 56.6 mg calcium argon phosphate 3.7 mg starch 11.1 mg Park Lee Mou Kit primogel) 5.5 m magnesium stearate 2.0 mg Example 12 Cinolone 291.1 mg calcium hydrogen phosphate 60.3 mg starch 11.1 mg primogel 5.5 mg magnesium stearate 2.0 mg Example 13 {please first Please read the notes on the back of the page and fill in this page.) Order the In Vitro Dissolution Test printed by the Consumer Cooperative of the Central Economic and Technical Bureau of the Ministry of Economic Affairs, each with 900 mL, containing 0.1N osmic acid, and acid and alkali. Value (PH) 20 value of 4.5 acetate buffer (acetate buffer), ensure that the rod is tested at 37 rpm and 0.5 ° C at 50 rpm. The sampling points of the samples are 10 minutes, 20 minutes, 30 minutes, and 40 minutes. The inspection product is tested by WV spectrophotometer (UV spectrophotometer) at λ = 316.5nm 24. The percentage of dissolution is detected. 13 This paper uses the Chinese National Standard (CNS) A4 specification (210X297 mm) — " " & quot 426527 A7 B7 V. Description of the invention (Μχ 10 Example 14 Blood concentration in rabbit Λ) Blood collection method: The rabbits were housed in the animal room of Xindongdi, and they were selected on the day of the experiment to the material room 2.5 ~ 3 Kg, weighed and recorded. Rabbit blood was taken as a "blank" with a 5 mi syringe pomelo. Example 10 or Bayer's Selenxin film-coated tablet Ciproxin; 1-cyclopropyl-6- Fluorine-1 · 4-digas-4-oxy-7 _ (1-knee exposed group) -3-junlinyl acid picking) were administered separately. Minutes were added after the injection and the time interval was 30 minutes. The rabbit blood was immediately placed in a centrifuge tube containing Sodium Heparin and centrifuged at 4,800 rpm for 10 minutes. The upper serum was taken from the grapefruit and immediately placed in the -221 refrigerator to freeze. F Please read the back (Notes for filling in this page)

*1T 經濟部中央標箪局員工消費合作社印製樣品處理 15 分別取〇·2 rol 3隻兔子之血清置入〇.5 ml之歡量離心管，加入0.2 ml甲酵後，充份搖盪3〇秒鐘，以沉澱蛋白質。混合液以13500 rpm速度離心5分鐘後以0.2 "in 過濾腹過濾。量取40 ul濾液注入高速液態層析儀中分析0 20 高速液態層析條件 1* 1T Printed samples processed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs15 Take 0.22 rol of 3 rabbits' serum and place them in 0.5 ml centrifuge tubes, add 0.2 ml of formic acid, and shake thoroughly 3 0 seconds to precipitate protein. The mixture was centrifuged at 13,500 rpm for 5 minutes, and then filtered through a 0.2 " in filter. Measure 40 ul of the filtrate and inject it into the high-speed liquid chromatography for analysis. 0 20 High-speed liquid chromatography conditions 1

高速液態層析儀-島津(SHIMADZU) LC-10A Serise 管柱-C18 15054.6 βϊβ ID 檢出器(D^ector)-島津（SHIMADZU) RF-10A螢光檢出器 24 (Fluorescence Detector) 14 本紙張尺度適用中國國家標华（CNS ) A4規格（2丨0X297公瘦） 426527 A7 B7 五、發明説明（） 1 松 tit 方式（Detection) - 278 nm 數發光（Excite 七 ion) 456 nm檢出High Speed Liquid Chromatograph-Shimadzu LC-10A Serise Column-C18 15054.6 βϊβ ID Detector (D ^ ector)-Shimadzu RF-10A Fluorescence Detector 24 Paper Standards are applicable to China National Standards (CNS) A4 specifications (2 丨 0X297 male thin) 426527 A7 B7 V. Description of the invention () 1 Loose Tit method (Detection)-278 nm Number emission (Excite 7ion) 456 nm

移動相（Mobile Phase)- (25% MeOH + 75% 25mM KH2P 以磷酸（H3P0斗）調整酸鹼度（pH)值 5 流速-1.0 ml/miηMobile Phase-(25% MeOH + 75% 25mM KH2P Adjust the pH value with phosphoric acid (H3P0 bucket) 5 Flow rate-1.0 ml / miη

管柱溫度-40 °C 10 訂. 15 經濟部中央標準局員工消費合作社印製 20 4 2 5 11 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）Column temperature -40 ° C 10 order. 15 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 20 4 2 5 11 This paper size applies to China National Standard (CNS) A4 (210X297 mm)

Claims

Α8 Βδ C8 D8 426527 π, the scope of patent application 1. A synthetic composition of CinolonG, which contains an effective amount of Cinlon ((: 4〇〇〇〇), 1% to 25% calcium dibasic acid, 1% to 25% lactose, 0.1% to 10% primogel, 0.1% to 5% salvage powder, 0.01% to 1 % Of magnesium stearate 2. For example, please refer to the solid pharmaceutical group of item 1 of the patent scope, 1% to 12% of calcium phosphate * 1% to 17% of the yield 丨 ^ n, lactose, 0.1% to 8% of Pu Li Mou Jie (卩 1 ^ 11 | 〇861), 1% cage < > 3% powder, 0.1% to 0.5% magnesium stearate. 3. Such as The solid pharmaceutical combination Yang of the first patent application of the patent application, 0.05% to 0.2% polysorbate (Tween) δ〇 (Please read the precautions on the back before filling this page) Τ 'Central Ministry of Economic Affairs Printed by ISC, Shelley Consumer Cooperative, I.F. I.F., Ichiwaki 6 1 1 cm 7 9 2