TW200948398A - Vancomycin hydrochloride tablet - Google Patents
Vancomycin hydrochloride tablet Download PDFInfo
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- TW200948398A TW200948398A TW098112481A TW98112481A TW200948398A TW 200948398 A TW200948398 A TW 200948398A TW 098112481 A TW098112481 A TW 098112481A TW 98112481 A TW98112481 A TW 98112481A TW 200948398 A TW200948398 A TW 200948398A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/14—Peptides containing saccharide radicals; Derivatives thereof, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
Description
200948398 六、發明說明： 【發明戶斤屬之技術領威3 發明領域 本發明係關於含有萬古黴素之經口劑。更詳細地說， 係有關服用後在腸内被溶解，對感染性腸炎的治療等等為 有效之含有鹽酸萬古黴素的片劑。 Φ200948398 VI. Description of the invention: [Technical Leading of Inventor of the Family] Field of the Invention The present invention relates to an oral agent containing vancomycin. More specifically, it is a tablet containing vancomycin hydrochloride which is dissolved in the intestine after administration, treatment for infectious enteritis, and the like. Φ
發明背景 鹽酸萬古徽素係來自於東方鏈徽菌（Streptomyces orientals)的糖肽類(giyC〇peptide)抗生素’由於對其他抗生 素很難奏效之MRSA(耐甲氧西林金黃色葡萄球菌， Methicillin-resistant Staphylococcus Aureus)是有效的，故在作為 抗MRS A劑上多所使用。 因鹽酸萬古黴素即使經口投藥也幾乎不會被消化器官 所吸收’故-般是做成注射劑使用。例如，pcT國際專利 A開A報(參照下述專利文獻i)所教示之鹽酸萬古黴素的冷 東乾燥製赌本是被理解為注射劑。 面，對於由MRSA所引起之感染性腸炎的治疼 和，骨髓移植時以、、# '' 寸乂4化官内殺菌為目的等之情形，經口 藥是有效的，鹽酸萬 ^ 萬古黴素的散劑在市場上被販售。但是， 時、、肩將忒散劑適當地溶解再服用，製劑的調製煩 卜服用’谷解了散劑的溶液時，有苦味、澀味， 用困難。因此，克服服用性和苦味等缺點之錠劑受到期 但是，鹽酸萬士 寻。 农礙素本身非常容易吸濕，製造錠劑本 200948398 身就有困難。專利文獻2中雖然記載了含有容易吸濕的藥物 和PEG8000之固體分散劑，但是關於具體的錠劑製造並無 記載。此外，專利文獻3中雖然記載了關於控制鹽酸萬古黴 素的溶出之粒劑(pellet)，但是所使用之聚合物並不是聚乙 二醇而是聚氧乙烯(polyethylene oxide)。而且該粒劑，是以 鹽酸萬古黴素的持續性為目的之物質，而非以改善服用性 和苦味為目的。 【先前技術文獻】 【專利文獻】 【專利文獻1】國際公開第01/47542號公報 【專利文獻2】特表2006-514052 【專利文獻3】特表2000-513028 C發明内容3 發明概要 發明欲解決之課題 本發明人等在製得可以簡便地服用之鹽酸萬古黴素的 心劑之目的下，對高分子基質(polymer matrix)錠劑做了種 種檢討。鹽酸萬古黴素經口劑的問題點之一為，鹽酸萬古 黴素的苦味強。例如，如果將錠劑表面皮膜化，雖然可以 克服苦味，但是塗佈藥膜用的製劑程序必需採用另外的作 法之外’這樣的作法會讓溶出變慢且難以使有效成份之鹽 酸萬古黴素在腸内1〇〇〇/0釋出。另外，塗佈藥膜時，由於使 用水等的溶劑，所以在高吸濕性且吸濕下，有對容易分解 之鹽酸萬古黴素造成不良影響之可能性。 200948398 此外’常被當做鹽酸筮▲ 文罵古黴素的原料藥使用之鹽酸魄 的吸濕性造成錠劑製造的固 ^ _難。已知錠劑製造用的賦形劑. 結合劑有多種，但是本幸♦ $千所需求的是既安定並賦予做為 錠劑的適度硬度，且在. 腔内不崩解，移行至腸内後又會 完全崩解之键劑設計。 用以欲解決課題之手段 檢討的結果得知 ’使用特定的聚乙二醇之基質錠劑不 僅提供適度硬度的錠劑，永 ❹ Ο 仰制服用時的苦味，而且可以賦 予有效成份合適的釋放特性。 亦即，本發明係關於以下之發明。 一種含有鹽酸萬古徽素之鍵劑，特徵在於其相對於 鹽酸萬古黴素100重量份’含有平均分子量2600〜3800的聚 乙二醇及/或平均分子量7300〜9300的聚乙二醇1〇〜80重 量份。 2. 上述1記載的錠劑，其中進一步含有流化劑 (fluidizing agent)。 3. 上述2記載的錠劑，其中流化劑為二氧化矽。 4. 上述3 §己載的錠劑，其中流化劑為水合二氧化矽 (hydrated silica)。 5. 上述1〜4之任一項記載的錠劑，其中相對於鹽酸萬 古黴素100重量份，流化劑為0.5〜20重量份。 6. 上述1〜5之任一項記載的錠劑，其中進一步含有賦 形劑。 7. 上述6記載的錠劑，其中賦形劑是從纖維素類、糖 類、糖醇類及無機物質選出之1或2種以上。 200948398 8·上述7記載的錠劑，其中賦形劑是從結晶纖維素、 赤蘚糖醇、D-山梨糖醇、木糖醇、D_甘露醇、麥芽糖醇、 蔗糖、葡萄糖、乳糖、還原麥芽糖水飴、無水磷酸氫鈣、 矽酸銘鎮（magnesium alUmin〇metasilicate)、合成水滑石 (synthetic hydrotaldte)、沉澱碳酸鈣、碳酸鎂、玉米澱粉&⑽ starch)及部份〇1化澱粉選出之1或2種以上。 9·上述8記載的錠劑，其中賦形劑為結晶纖維素。 10_上述1〜9之任一項記载的錠劑，其中相對於鹽酸萬 古黴素100重量份，賦形劑為2.5〜25重量份。 11. 上述1〜10的任一項記栽的錠劑，其中進一步含有 潤滑劑。 12. 上述11記載的錠劑，其中潤滑劑為硬脂酸鎂。 13·上述1〜12之任一項§己栽的鍵劑，其中相對於鹽酸 萬古黴素100重量份，潤滑劑為〇 〇1〜5重量份。 14·上述1〜13之任一項記栽的錠劑，其中相對於製劑 全量，含有鹽酸萬古黴素10〜99重量份，平均分子量26〇〇 〜3800的聚乙二醇及/或平均分子量73〇〇〜93〇〇的聚乙二 醇1〜50重量份’水合二氧化毅卜1〇重量份，結晶纖維 素1〜20重量份’及硬脂酸鎂0.01〜5重量份。 15. 上述1〜14之任一項記栽的錠劑，其中錠劑的硬度 為30N以上。 16. 上述1〜15之任-項記栽的錠劑，其在日本藥局方 溶出试驗法中，在第〗液之試驗開始的分鐘後，鹽酸萬古徽 素的溶出率為90%以上。 200948398 17. 上述16記載的錠劑’其在日本藥局方溶出試驗法 中，在第1液之試驗開始5分鐘後，鹽酸萬古黴素的溶出率 為20%以下’而且60分鐘後鹽酸萬古黴素的溶出率為9〇。/〇以 上。 18. —種錠劑的製造方法，特徵在於其係將含有處於吸 濕平衡狀態之鹽酸萬古黴素的粉末予以打錠。 19. 一種錠劑的製造方法，包含以下步驟： i) 將含有鹽酸萬古黴素的粉末予以打錠之步驟， ii) 將在前述i)步驟所獲得之錠劑予以粉碎的步驟， iii) 將在前述ii)步驟所獲得之固形物予以打錠的步驟， iv) 使以前述iii)步驟製得之錠劑在濕度〇.丨〜2%的室溫 下乾燥之步驟。 20. —種控制錠劑中鹽酸萬古黴素之溶出率的方法，其 係包含’使之含有平均分子量2600〜3800的聚乙二醇及/或 平均分子量7300〜9300的聚乙二醇之處理而構成的方法。 21. 上述20記載的方法，其在準據日本藥局方溶出試驗 法之溶出試驗中，將第1液之試驗開始60分鐘後的鹽酸萬古 黴素溶出率控制在90%以上。 22. 上述20記載的方法，其在準據日本藥局方溶出試驗 法之溶出試驗中’將第1液之試驗開始5分鐘後的鹽酸萬古 黴素溶出率控制在20%以下，且試驗開始60分鐘後的鹽酸 萬古黴素溶出率控制在9〇〇/0以上。 23· —種控制錠劑中藥物之溶出率的方法，其係包含使 之含有平均分子量2600〜3800的聚乙二醇及/或平均分子 200948398 量7300〜9300的聚乙二醇之處理而成的方法。 24.上述23記載的方法，其在準據日本藥局方溶出試驗 法之溶出試驗中，將第1液之試驗開始60分鐘後的藥物溶出 率控制在90%以上。 上述23記載的方法，其在準據日本藥局方溶出試驗法 之溶出試驗中，將第1液之試驗開始5分鐘後的藥物溶出率 控制在20%以下，且試驗開始60分鐘後的藥物溶出率控制 在90%以上。 發明效果 若依據本發明，可以提供服用時感覺不到苦味，且， 由胃移行至小腸時有效成份被釋出之，對於感染性腸炎的 治療等有用之鹽酸萬古黴素的經口用錠劑。 圖式簡單說明 第1圖依據A法之錠劑製造步驟。 第2圖使用各種結合劑（水溶性高分子）時之鹽酸萬古黴 素的溶出率。 第3圖變更結合劑（水溶性高分子）的混合量時之鹽酸萬 古黴素的溶出率。 第4圖依據B法之錠劑製造步驟。 I：實施方式3 用以實施發明之形態 本發明中使用之鹽酸萬古黴素可以依據例如美國專利 第3067099號記載的方法製造。此外，也可以使用市售的醫 藥品等級的原料藥。因為鹽酸萬古黴素的遊離鹼基難溶於 水，所以不適合直接當做製劑化的原料藥，許多情形是將 200948398 、驗基變換成水溶性鹽之後再使用。因此本發明中使用 風酸萬古黴素的藥學上可容許鹽類，水溶性鹽，可舉例 酸|硫酸鹽等之水溶性無機鹽及水溶性有機鹽。尤 其以鹽酸鹽為佳。 鹽酸萬古黴素的含量，相對於製劑全量為10〜99重量 伤，以20〜90重量份為佳，30〜80重量份較佳。如果較該 量夕，錠劑的服用量會有增多之可能性；如果較該量多， 則有無法充分地抑制鹽酸萬古黴素的吸濕性之虞。 本發明的鹽酸萬古黴素錠劑含有作為有效成份之鹽酸 萬古黴素及作為結合劑之聚乙二醇。在此所使用之聚乙二 醇，其平均分子量（依據第丨5改正日本藥局方，聚乙二醇 4000的項目中所記載之平均分子量試驗做測定）為，300〜 20000的範圍者；具體而言可以舉例如PEG300、PEG600、 PEG1000、PEG1540、PEG2000、PEG4000、PEG6000、 PEG20000、聚乙二醇3〇〇、聚乙二醇4〇〇、聚乙二醇600、 聚乙二醇1500、聚乙二醇1540、聚乙二醇4000、聚乙二醇 6000、聚乙二醇20000。以平均分子量2600〜3800的聚乙二 醇或平均分子量7300〜9300的聚乙二醇為適合被使用，具 體而言，有PEG4000、PEG6000、聚乙二醇4000、聚乙二醇 6000。 聚乙二醇的含量，相對於鹽酸萬古黴素100重量份為10 〜80重量份，以12.5〜75重量份為佳，15〜70重量份較佳。 另外，相對於製劑全量為1〜50重量份，以3〜45重量份為 佳，5〜40重量份較佳。如果較該量為少，會有不能得到保 9 200948398 證保持製品安定的形狀之旋劑硬度的疑慮，如果較該量為 多’則有錠劑崩解時間變慢的可能性，同時有鹽酸萬古黴 素溶出速度變慢的可能性。 本發明之含鹽酸萬古黴素錠劑，除上述聚乙二醇以 外，可含有流化劑、賦形劑、濶滑劑。 流化劑可以是使用於一般製劑學中之物質，具體而言 可例不如二氧化矽、氧化鈦等。二氧化矽，具體者可例示 如水合二氧化發、輕質無水矽酸（light anhydrous silicicBACKGROUND OF THE INVENTION Hydrochloric acid hydrochloride is a glycopeptide (giyC〇peptide) antibiotic from Streptomyces orientals. It is difficult to work with other antibiotics. MRSA (methicillin-resistant Staphylococcus aureus, Methicillin-resistant) Staphylococcus Aureus) is effective and is therefore used as an anti-MRS A agent. Because vancomycin hydrochloride is hardly absorbed by the digestive organs even if it is administered orally, it is generally used as an injection. For example, the cold-drying gambling of vancomycin hydrochloride, which is taught by the PCT International Patent A (refer to the following patent document i), is understood to be an injection. In the case of the treatment of infectious enteritis caused by MRSA, and the purpose of intrauterine sterilization in the case of bone marrow transplantation, the oral medicine is effective, and the genus The powder is sold on the market. However, when the preparation is prepared by dissolving the preparation, the preparation of the preparation is annoying. When the solution of the preparation is used, it has a bitter taste and astringent taste, and it is difficult to use. Therefore, the tablet which overcomes the shortcomings such as the ingestion and bitterness is subjected to the expiration date. However, the hydrochloric acid is found. Agrochemicals are very easy to absorb moisture, and it is difficult to make tablets. Patent Document 2 describes a solid dispersing agent containing a drug which is easily hygroscopic and PEG 8000, but it is not described in the production of a specific tablet. Further, in Patent Document 3, a pellet for controlling the elution of vancomycin hydrochloride is described, but the polymer used is not polyethylene glycol but polyethylene oxide. Further, the granule is a substance for the purpose of the persistence of vancomycin hydrochloride, and is not intended to improve the taking and bitterness. [PRIOR ART DOCUMENT] [Patent Document 1] International Publication No. 01/47542 [Patent Document 2] Japanese Patent Application Laid-Open No. Hei No. Hei. No. Hei. Solution to Problem The inventors of the present invention conducted various reviews on a polymer matrix tablet for the purpose of preparing a heart agent of vancomycin hydrochloride which can be easily administered. One of the problems with the vancomycin hydrochloride oral solution is that the bitter taste of vancomycin hydrochloride is strong. For example, if the surface of the tablet is coated, although the bitterness can be overcome, the formulation procedure for applying the film must be carried out by another method. 'This method makes the dissolution slow and it is difficult to make the active ingredient vancomycin hydrochloride. Released in the intestines at 1〇〇〇/0. Further, when the drug film is applied, since a solvent such as water is used, it is likely to have an adverse effect on vancomycin hydrochloride which is easily decomposed under high hygroscopicity and moisture absorption. 200948398 In addition, the hygroscopicity of guanidine hydrochloride, which is often used as a raw material for guanidine hydrochloride ▲ guanomycin, makes it difficult to manufacture tablets. Known excipients for the manufacture of tablets. There are a variety of binders, but fortunately, the demand for both is stable and imparted to the tablet as a moderate hardness, and does not disintegrate in the cavity, and migrates to the intestines. The key agent design will be completely disintegrated inside and outside. As a result of the review of the means to solve the problem, it was found that 'the use of a specific polyethylene glycol matrix tablet not only provides a tablet of moderate hardness, but also gives a bitter taste when used in uniform, and can give a proper release of the active ingredient. characteristic. That is, the present invention relates to the following invention. A key agent containing valeric acid hydrochloride, characterized in that it contains 100 parts by weight of vancomycin hydrochloride and contains polyethylene glycol having an average molecular weight of 2,600 to 3,800 and/or polyethylene glycol having an average molecular weight of 7,300 to 9,300. 80 parts by weight. 2. The tablet according to 1, wherein the tablet further contains a fluidizing agent. 3. The tablet according to the above 2, wherein the fluidizing agent is cerium oxide. 4. The above 3 § loaded tablets, wherein the fluidizing agent is hydrated silica. 5. The tablet according to any one of the above 1 to 4, wherein the fluidizing agent is 0.5 to 20 parts by weight based on 100 parts by weight of vancomycin hydrochloride. 6. The tablet according to any one of the above 1 to 5, which further comprises an excipient. 7. The tablet according to the above 6, wherein the excipient is one or more selected from the group consisting of celluloses, sugars, sugar alcohols, and inorganic substances. 200948398. The tablet of the above 7, wherein the excipient is from crystalline cellulose, erythritol, D-sorbitol, xylitol, D-mannitol, maltitol, sucrose, glucose, lactose, reduction Maltose leeches, anhydrous calcium hydrogen phosphate, magnesium al Umin 〇 metasilicate, synthetic hydrotaldte, precipitated calcium carbonate, magnesium carbonate, corn starch & (10) starch, and selected saponified starch 1 or more. 9. The tablet according to the above 8, wherein the excipient is crystalline cellulose. The tablet according to any one of the above 1 to 9, wherein the excipient is 2.5 to 25 parts by weight based on 100 parts by weight of vancomycin hydrochloride. 11. The tablet according to any one of the above 1 to 10, which further contains a lubricant. 12. The tablet according to the above 11, wherein the lubricant is magnesium stearate. 13. The key agent according to any one of the above 1 to 12, wherein the lubricant is 〜1 to 5 parts by weight based on 100 parts by weight of vancomycin hydrochloride. 14. The tablet according to any one of the above 1 to 13, wherein the tablet contains 10 to 99 parts by weight of vancomycin hydrochloride, and the average molecular weight is 26 〇〇 3800 PEG and/or average molecular weight, relative to the total amount of the preparation. 1 to 50 parts by weight of polyethylene glycol of 73 〇〇 to 93 ', 1 part by weight of hydrated dioxide, 1 to 20 parts by weight of crystalline cellulose, and 0.01 to 5 parts by weight of magnesium stearate. 15. The tablet according to any one of the above 1 to 14, wherein the tablet has a hardness of 30 N or more. 16. In the above-mentioned 1~15--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- . 200948398 17. The tablet according to the above-mentioned item 16, wherein in the Japanese Pharmacy Dissolution Test Method, after 5 minutes from the start of the test of the first liquid, the dissolution rate of vancomycin hydrochloride is 20% or less 'and after 60 minutes The dissolution rate of themycin was 9 〇. /〇上上. A method for producing a tablet, characterized in that a powder containing vancomycin hydrochloride in a moisture-absorbent equilibrium state is tableted. A method for producing a tablet comprising the steps of: i) a step of injecting a powder containing vancomycin hydrochloride, ii) a step of pulverizing the tablet obtained in the above step i), iii) The step of ingoting the solid matter obtained in the above step ii), iv) drying the tablet obtained by the above step iii) at room temperature of 〇 丨 2%. 20. A method for controlling the dissolution rate of vancomycin hydrochloride in a tablet, which comprises 'treating polyethylene glycol having an average molecular weight of 2,600 to 3,800 and/or polyethylene glycol having an average molecular weight of 7,300 to 9,300 And the method of composition. 21. The method according to the above 20, wherein in the dissolution test according to the Japanese Pharmacy Dissolution Test Method, the vancomycin hydrochloride dissolution rate after 60 minutes from the start of the first liquid test is controlled to 90% or more. 22. The method according to the above 20, wherein the dissolution rate of vancomycin hydrochloride after 5 minutes from the start of the first liquid test is controlled to be 20% or less in the dissolution test according to the Japanese Pharmacy Dissolution Test Method, and the test is started. The dissolution rate of vancomycin hydrochloride after 60 minutes was controlled at 9 〇〇/0 or more. 23. A method for controlling the dissolution rate of a drug in a tablet, which comprises treating a polyethylene glycol having an average molecular weight of 2,600 to 3,800 and/or a polyethylene glycol having an average molecular weight of 200948398 and 7300 to 9300. Methods. 24. The method according to the above 23, wherein the drug elution rate after 60 minutes from the start of the test of the first liquid is controlled to 90% or more in the dissolution test according to the Japanese Pharmacopoeia dissolution test. The method according to the above 23, wherein in the dissolution test according to the Japanese Pharmacy Dissolution Test Method, the drug elution rate after 5 minutes from the start of the test of the first liquid is controlled to 20% or less, and the drug after 60 minutes from the start of the test The dissolution rate is controlled above 90%. According to the present invention, it is possible to provide an oral lozenge of vancomycin hydrochloride which is useful for the treatment of infectious enteritis, such as when the stomach is transferred to the small intestine and the active ingredient is released during the administration. . BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a manufacturing step of a tablet according to the method A. Fig. 2 shows the dissolution rate of vancomycin hydrochloride when various binders (water-soluble polymers) are used. Fig. 3 shows the dissolution rate of vancomycin hydrochloride when the amount of the binder (water-soluble polymer) is mixed. Figure 4 is a manufacturing step of the tablet according to the B method. I: Embodiment 3 Mode for carrying out the invention The vancomycin hydrochloride used in the present invention can be produced according to, for example, the method described in U.S. Patent No. 30,670,99. In addition, commercially available pharmaceutical grade APIs can also be used. Since the free base of vancomycin hydrochloride is hardly soluble in water, it is not suitable as a raw material for formulation. In many cases, the test base is converted into a water-soluble salt and then used. Therefore, in the present invention, a pharmaceutically acceptable salt of vancomycin, a water-soluble salt, and a water-soluble inorganic salt such as an acid|sulfate or a water-soluble organic salt can be used. Especially the hydrochloride salt is preferred. The content of vancomycin hydrochloride is preferably from 10 to 99 parts by weight based on the total amount of the preparation, preferably from 20 to 90 parts by weight, more preferably from 30 to 80 parts by weight. If it is more than this amount, the dosage of the tablet may increase. If it is more than this amount, the hygroscopicity of vancomycin hydrochloride may not be sufficiently suppressed. The vancomycin hydrochloride tablet of the present invention contains vancomycin hydrochloride as an active ingredient and polyethylene glycol as a binding agent. The polyethylene glycol used herein has an average molecular weight (measured according to the average molecular weight test described in the item of the Japanese Pharmacopoeia, polyethylene glycol 4000 according to Section 5), and is in the range of 300 to 20000; Specific examples thereof include PEG300, PEG600, PEG1000, PEG1540, PEG2000, PEG4000, PEG6000, PEG20000, polyethylene glycol 3〇〇, polyethylene glycol 4〇〇, polyethylene glycol 600, polyethylene glycol 1500, Polyethylene glycol 1540, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 20000. Polyethylene glycol having an average molecular weight of 2,600 to 3,800 or polyethylene glycol having an average molecular weight of 7,300 to 9,300 is suitably used, and specifically, PEG 4000, PEG 6000, polyethylene glycol 4000, and polyethylene glycol 6000 are used. The content of the polyethylene glycol is preferably 10 to 80 parts by weight based on 100 parts by weight of vancomycin hydrochloride, preferably 12.5 to 75 parts by weight, more preferably 15 to 70 parts by weight. Further, it is preferably from 3 to 45 parts by weight, more preferably from 5 to 40 parts by weight, based on 1 to 50 parts by weight of the total amount of the preparation. If it is less than this amount, there will be doubts about the hardness of the spinner that can not obtain the shape of the product. If it is more than this amount, there is a possibility that the tablet disintegration time becomes slow, and at the same time, there is hydrochloric acid. The possibility that vancomycin dissolves slowly. The vancomycin-containing tablet of the present invention may contain a fluidizing agent, an excipient, and a slip agent in addition to the above polyethylene glycol. The fluidizing agent may be one used in general formulation, and specifically, it may be, for example, cerium oxide, titanium oxide or the like. As the cerium oxide, for example, hydrated oxidized hair, light anhydrous silicic acid (light anhydrous silicic)
acnd)、重質無水石夕酸等，以水合二氧化矽較適合使用。流 化劑的含量相對於鹽酸萬古黴素1〇〇重量份，為〇5〜2〇重 量份’以1〜17.5重量份為佳，3〜15重量份較佳。而，相 對於製劑全量為重量份，以Q 5〜8重量份為佳，】 7重量伤較佳。如果較該量為少，因為贼萬古黴素原剩 藥本身疋m所以會有流動性變得更差之虞；如果較 該量為多時’則有H酸萬錢素本身的含量相對降低之可 能性。Acnd), heavy anhydrous oxalic acid, etc., is suitable for hydrating cerium oxide. The content of the fluidizing agent is preferably from 1 to 17.5 parts by weight, more preferably from 3 to 15 parts by weight, per 1 part by weight of vancomycin hydrochloride. Further, it is preferably 5 5 to 8 parts by weight based on the total amount of the preparation, and 7 weight loss is preferred. If the amount is less, because the thief vancomycin original drug itself 疋m, there will be a worse flow of liquidity; if the amount is more than the case, then the content of H-acid ketone itself is relatively reduced The possibility.
賦形劑可以是-般製劑學中所使用者’具體而言可例 示如結晶纖維素、赤蘇糖醇、D-山梨糖醇、木糖醇、D_甘 露醇、麥芽糖醇、蔗糖、葡萄 葡甸糖、孔糖、還原麥芽糖水飴、 無水磷酸氫鈣、矽酸鋁鎂、人 、σ战水滑石、沉澱碳酸鈣、碳 酸鎂、玉米澱粉、部份01化激 冰《 . 物寺’以結晶纖維素為適合於 使用。賦形劑的含量相對於強酿 现酸萬古黴素100重量份，為2.5 〜25重量份，以5〜22.5重量份為 w馬佳，7.5〜20重量份較佳。 而，相對於製劑全量則是1〜 里垔伪孕 重蕙份，以2.5〜17.5重量份 10 200948398 為佳， ’5〜15重量份較佳。 潤π劑可例示如硬脂酸鎂、 合二氧化#、硬脂酸詞等，The excipient may be a user in the general formulation 'specifically, such as crystalline cellulose, erythritol, D-sorbitol, xylitol, D-mannitol, maltitol, sucrose, grapes Glucosamine, pore sugar, reduced maltose leeches, anhydrous calcium hydrogen phosphate, aluminum magnesium citrate, human, σ war hydrotalcite, precipitated calcium carbonate, magnesium carbonate, corn starch, part of the 01 ice cream ". Crystalline cellulose is suitable for use. The content of the excipient is from 2.5 to 25 parts by weight, preferably from 5 to 22.5 parts by weight, based on 100 parts by weight of the strong acid vancomycin, of 7.5 to 20 parts by weight. Further, it is preferably 1 to 7.5 垔 孕 孕 , , , , 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 2009 The hydrating agent can be exemplified by magnesium stearate, oxidized #, stearic acid, and the like.
重量份，為0.01〜5重 0‘1〜3重量份較佳。 遂鎂'蔗糖脂肪酸酯、滑石、水 ’以硬脂酸錯為適合於使用。潤 奇佳’ 0.1〜3重量份較佳。而，相 5重量份，以〇.〇5〜4重量份為佳， '、他的添加劑有橋味劑(例如：抗壞血酸）、香料(例如： 薄荷醇)等。 本土明較佳之態樣係如下所示。亦即，相對於製劑全 里夂萬古黴素為1〇〜99重量份，平均分子量26〇〇〜％⑼ 的聚乙二醇及/或平均分子量7300〜9300的聚乙二醇為1〜 50重量份，流化劑為〇1〜1〇重量份，賦形劑為重量 伤’潤滑劑為0.01〜5重量份。相對於製劑全量宜為，鹽酸 萬古黴素20〜90重量份，平均分子量2600〜3800的聚乙二 醇及/或平均分子量7300〜9300的聚乙二醇3〜45重量份， 流化劑0.5〜8重量份，賦形劑2.5〜17.5重量份，潤滑劑0.05 〜4重量份。較佳者為，相對於製劑全量，鹽酸萬古黴素為 30〜80重量份，平均分子量2600〜3800的聚乙二醇及/或平 均分子量7300〜9300的聚乙二醇5〜40重量份，流化劑1〜7 重量份，賦形劑5〜15重量份，潤滑劑0.1〜3重量份。 本發明之合適態樣係如下所示。亦即，相對於製劑全 量，鹽酸萬古黴素為10〜99重量份，聚乙二醇4000及/或聚 乙二醇6000為1〜50重量份，水合二氧化矽〇.1〜1〇重量 11 200948398 B曰纖維素1〜20重量份，硬脂酸鎮〇〇卜5重量份。 一對於製劑全量’鹽酸萬古黴素為加〜卯重量份，聚乙 ^醇侧及/或聚乙二醇_為3〜45重量份，水合二氧化 重置伤，結晶纖維素2.5〜17·5重量份，硬脂酸錢 〇·〇5〜4重量份者為佳。較佳的是，相對於製劑全量，鹽酸 萬古黴素為30〜崎量份，聚乙二醇棚及/或聚乙二醇 〇為5〜40重·£份’水合二氧切卜7重量份，結晶纖維 素5〜15重量份’硬脂酸鎂G.1〜3重量份。The parts by weight are preferably 0.01 to 5 parts by weight and 0 '1 to 3 parts by weight. Indole magnesium 'sucrose fatty acid ester, talc, water' is suitable for use with stearic acid. It is preferred that Runqijia '0.1 to 3 parts by weight. On the other hand, 5 parts by weight of the phase is preferably 5 to 4 parts by weight, ', and his additives include a humectant (for example, ascorbic acid), a fragrance (for example, menthol), and the like. The best way to see the local is as follows. That is, the polyethylene glycol having an average molecular weight of 26 〇〇 to % (9) and/or the polyethylene glycol having an average molecular weight of 7300 to 9300 is 1 to 50 with respect to the preparation of vancomycin 1 〇 to 99 parts by weight. The parts by weight of the fluidizing agent are 〜1 to 1 part by weight, and the excipients are weight-damaged, and the lubricant is 0.01 to 5 parts by weight. The total amount of the preparation is preferably 20 to 90 parts by weight of vancomycin hydrochloride, polyethylene glycol having an average molecular weight of 2,600 to 3,800, and/or 3 to 45 parts by weight of polyethylene glycol having an average molecular weight of 7,300 to 9,300, and a fluidizing agent of 0.5. To 8 parts by weight, the excipient is 2.5 to 17.5 parts by weight, and the lubricant is 0.05 to 4 parts by weight. Preferably, the vancomycin hydrochloride is 30 to 80 parts by weight, the polyethylene glycol having an average molecular weight of 2600 to 3800, and/or the polyethylene glycol having an average molecular weight of 7300 to 9300 is 5 to 40 parts by weight, based on the total amount of the preparation. The fluidizing agent is 1 to 7 parts by weight, the excipient is 5 to 15 parts by weight, and the lubricant is 0.1 to 3 parts by weight. A suitable aspect of the invention is as follows. That is, the vancomycin hydrochloride is 10 to 99 parts by weight, the polyethylene glycol 4000 and/or the polyethylene glycol 6000 is 1 to 50 parts by weight, and the hydrated cerium oxide. 1 to 1 〇 weight is relative to the total amount of the preparation. 11 200948398 B 曰 cellulose 1 to 20 parts by weight, stearic acid saponin 5 parts by weight. For the total amount of preparation 'vancomycin hydrochloride is added ~ 卯 parts by weight, polyethylene glycol side and / or polyethylene glycol _ is 3 ~ 45 parts by weight, hydrated dioxide reset injury, crystalline cellulose 2.5 ~ 17 · 5 parts by weight, preferably 5 to 4 parts by weight of stearic acid. Preferably, the vancomycin hydrochloride is 30 to the amount of the sacrificial portion relative to the total amount of the preparation, and the polyethylene glycol shed and/or the polyethylene glycol oxime is 5 to 40 parts per gram of 'hydrated dioxypyrazole 7 weight. Parts, crystalline cellulose 5 to 15 parts by weight of 'magnesium stearate G. 1 to 3 parts by weight.
人相對於鹽酸萬古黴素原料藥本身的強烈苦味和溫味， 二有萬古黴素之本發明錠劑會抑制溶出初期的溶出率，幾 乎感覺不到苦味。另-方面，爲了進行消化管内殺菌，近 乎全部的鹽酸萬古黴素必須在某種程度的時間，合宜的是 投藥60分鐘後，由錠劑中溶出。因此，溶出表現宜為，在 日本藥局方的溶出試驗中，試驗開始6〇分鐘後的溶出率為The strong bitterness and warm taste of human relative to the vancomycin hydrochloride drug substance itself, and the vanamycin of the present invention having vancomycin inhibits the dissolution rate at the initial stage of dissolution, and hardly tastes bitter. On the other hand, in order to perform gastrointestinal sterilization, nearly all of vancomycin hydrochloride must be dissolved in the tablet for a certain period of time, preferably after 60 minutes of administration. Therefore, the dissolution performance should be such that in the dissolution test of the Japanese Pharmacopoeia, the dissolution rate after the start of the test is 6 minutes.
9〇%以上’較佳的是在日本藥局方的溶出試驗中，試驗開 始5分鐘後鹽酸萬古黴素的溶出率在2〇%以下，6〇分鐘後的 溶出率在90%以上。另外’雖然也要視藥物的水溶解度而 定’但是透過含有平均分子量2600〜3800的聚乙二醇及/或 平均分子量7300〜9300的聚乙二醇之方式，鹽酸萬古黴素 以外的藥物也可以達到上述之溶出表現。再者，鹽酸萬古 黴素的原料藥本身，在試驗開始5分鐘内溶出率即達到 100%。 本發明之錠劑的硬度為可耐受一般的服用之硬度，此 外，如果是分包散裝時錠劑也不會破損的程度之錠劑硬度 12 200948398 亦可，具體而言在30N以上，以35N以上為佳，40N以上較 佳。 爲了妥善處理鹽酸萬古黴素的吸濕性，本發明人等採 用以下的製劑方法。本發明的鹽酸萬古黴素錠劑，可以適 當地利用以下的方法(A法或B法）製造。 1 · A法 放置鹽酸萬古黴素使其吸收一定量的水分後，會與大 氣中的水分達到平衡’亦即達到吸附平衡(這稱為完成吸濕 原體）。該完成吸濕原體，可以和非吸濕性之一般的製劑原 料同樣地進行處理，依據一般的製劑方法製造含有完成吸 濕原體之錠劑後’使其乾燥而得到本發明的鹽酸萬古黴素 錠劑（參照後述試驗例〗）。製造完成吸濕原體的條件是必須 將鹽酸萬古黴素的原藥在合適者為25°C、相對濕度60%的 環境下，放置24小時以上。此外，完成吸濕原體是用鹵素 水分測定儀測定水分值，考量該水分值以決定添加劑的混 合量。 2. B法 秤量吸濕性的鹽酸萬古黴素和各添加劑後，加以混合 並打錠，製造鹽酸萬古黴素的錠劑（以下稱該錠劑為「藥渣 鍵(slag tablet)」）。粉碎該藥 >查錠而得到之顆粒的吸濕性在 24小時的時間為3%以下非常小，可以定量其所含有之鹽酸 萬古黴素。在該時間點，測定粉碎藥渣錠而成之顆粒的水 分值，考量該水分值，秤量必要量的添加劑之後予以混合， 再度打錠而得之錠劑乾燥後，獲得本發明的鹽酸萬古黴素 13 200948398 錠劑（參照後述試驗例2)。再者，在本製造方法中並不須要 製造鹽酸萬古黴素的完成吸濕原體，是較實用之製造方法。 由於鹽酸萬古黴素吸濕性高，故在上述A法及B法中， 宜使打錠而得之錠劑乾燥，尤以在低濕度（濕度約0.1〜2%) 的室溫下使其乾燥者為佳。乾燥可將錠劑放置在低濕下的 室溫’亦可對著錠劑吹送低濕的室溫空氣。濕度以大約0.8% 特別合適。 【實施例】 以下將用實施例及比較例說明本發明，惟本發明不限 定於此。 (試驗例1)結合劑（水溶性高分子）的檢討 1.旋劑製造法(A法，參照第1圖） (1) 完成吸濕原體的製造 將預定量的鹽酸萬古黴素在25°C、相對濕度60%環境 下放置24小時以上，使其吸濕至達到吸濕平衡為止。然後， 用鹵素水分測定儀測定水分值，算出鹽酸萬古黴素中吸濕 的水分值。 (2) 錠劑的製造 秤量預定量之示於表丨的鹽酸萬古黴素及各添加劑，篩 過後加以混合，製成混合粉末。將潤滑劑之硬脂酸鎂投進 該混合粉末，加以混合，做成製錠粉末。將製錠粉末用以 下的條件進行伙，製造錠劑。將所製造之錠劑於通氣溫 度40C下乾燥9G分鐘後，在五氧化三麟末共存下保存於 乾燥器（相對濕度0%)中作為追加乾燥，減壓下，在室溫(乃 14 200948398 °C)放置約120分鐘。另外，鹽酸萬古黴素的預定量是考量 前述的吸濕水分以進行秤量。 打鍵條件 打錠機：ABS100S型靜態壓縮機（J T卜一シ社製）More preferably, it is in the dissolution test of the Japanese Pharmacopoeia. After 5 minutes from the start of the test, the dissolution rate of vancomycin hydrochloride is 2% or less, and the dissolution rate after 6 minutes is 90% or more. In addition, although it depends on the water solubility of the drug, it is also a drug other than vancomycin hydrochloride, which contains polyethylene glycol having an average molecular weight of 2,600 to 3,800 and/or polyethylene glycol having an average molecular weight of 7,300 to 9,300. The above dissolution performance can be achieved. Further, the drug substance of vancomycin hydrochloride itself has a dissolution rate of 100% within 5 minutes from the start of the test. The hardness of the tablet of the present invention is such that it can withstand the hardness of the general use. In addition, if the tablet is not damaged when the package is in bulk, the hardness of the tablet can be 12 200948398, specifically, 30 N or more. More than 35N is preferred, and 40N or more is preferred. In order to properly treat the hygroscopicity of vancomycin hydrochloride, the present inventors have employed the following formulation methods. The vancomycin hydrochloride tablet of the present invention can be suitably produced by the following method (A method or B method). 1 · Method A Place vancomycin hydrochloride to absorb a certain amount of water and then equilibrate with the moisture in the atmosphere', that is, to achieve adsorption equilibrium (this is called completion of the hygroscopic substance). The finished hygroscopic substance can be treated in the same manner as the non-hygroscopic general preparation raw material, and the tablet containing the finished hygroscopic substance is produced according to a general preparation method, and then dried to obtain the present invention. Peptide tablets (see test examples described later). The condition for producing the hygroscopic substance is that the original drug of vancomycin hydrochloride must be allowed to stand for 24 hours or more in an environment of 25 ° C and a relative humidity of 60%. Further, the completion of the hygroscopic substance is measured by a halogen moisture meter, and the moisture value is taken into consideration to determine the mixing amount of the additive. 2. Method B After the hygroscopic vancomycin hydrochloride and each additive are weighed, they are mixed and tableted to produce a vancomycin hydrochloride tablet (hereinafter referred to as the "slag tablet"). The granules obtained by pulverizing the granules have a hygroscopicity of 3% or less in a period of 24 hours, and the vancomycin hydrochloride contained therein can be quantified. At this point of time, the moisture value of the granules obtained by pulverizing the slag ingot is measured, the amount of the moisture is measured, the necessary amount of the additive is weighed, mixed, and the tablet is dried again to obtain the hydrochloric acid of the present invention. Vancomycin 13 200948398 Lozenge (refer to Test Example 2 described later). Further, in the present production method, it is not necessary to manufacture a hygroscopic substance of vancomycin hydrochloride, which is a practical manufacturing method. Since vancomycin hydrochloride has high hygroscopicity, in the above methods A and B, it is preferred to dry the tablet obtained by tableting, especially at a low humidity (humidity of about 0.1 to 2%) at room temperature. The dryer is better. Drying can place the tablet at room temperature under low humidity. It can also blow low humidity room temperature air to the tablet. Humidity is particularly suitable at about 0.8%. [Examples] Hereinafter, the present invention will be described by way of Examples and Comparative Examples, but the present invention is not limited thereto. (Test Example 1) Review of binding agent (water-soluble polymer) 1. Spinning agent production method (A method, see Fig. 1) (1) Completion of production of hygroscopic substance A predetermined amount of vancomycin hydrochloride was obtained at 25 Allow to stand for 24 hours or more at °C and 60% relative humidity to absorb moisture until the moisture absorption equilibrium is reached. Then, the moisture value was measured by a halogen moisture meter to calculate the moisture content of hygroscopicity in vancomycin hydrochloride. (2) Preparation of tableting agent A predetermined amount of vancomycin hydrochloride and each additive shown in the table are weighed and sieved, and mixed to prepare a mixed powder. Magnesium stearate of the lubricant is added to the mixed powder and mixed to prepare an ingot powder. The ingot powder was used in the following conditions to prepare a tablet. The prepared tablet was dried at aeration temperature of 40 C for 9 G minutes, and then stored in a desiccator (relative humidity 0%) in the coexistence of pentoxide pentoxide as additional dryness, under reduced pressure, at room temperature (Nai 14 200948398) °C) Place for about 120 minutes. Further, the predetermined amount of vancomycin hydrochloride is measured in consideration of the aforementioned moisture absorption. Keystroke condition Ingot machine: ABS100S type static compressor (J T Bu Yi Co., Ltd.)
打錠壓力：7kN 錠劑形狀：圓形錠，（M〇mm、2段R(R1 : 22，R2 : 2.5) 表1 實施例1 實施例2 比較例1 比較例2 比較例3 鹽酸萬古黴素 61.9 61.9 61.9 61.9 45.0 聚乙二醇4000 37.1 - - - - 聚乙二醇6000 _ 37.1 - - - HPC-SL - - 37.1 - HPMC - - - 37.1 D-甘露醇 - - - - 45.0 水合二氧化矽 - - - 9.0 硬脂酸鎂 1.0 1.0 1.0 1.0 1.0 合計 100.0 100.0 100.0 100.0 100.0 (數字為重量％) HPC-SL :經丙基纖維素(hydroxypropylcellulose) HPMC :經丙基甲基纖維素(hydroxypropyl methylcellulose) ❹ 2.錠劑硬度的測定 (測定方法） 用ERWEKA錠劑硬度測定裝置(ERWEKA社製）測定錠 劑硬度(錠劑2錠的平均）。 (測定結果） 測定實施例1、2 ’比較例1〜3的錠劑硬度，結果彙整 於表2。其結果，比較例3非常脆，僅用手輕押即破損。其 他錠劑如表2所示，每一種都是實用上無問題之硬度，超過 15 200948398 目標硬度40N。 表2 實施例1 實施例2 比較例1 ----一- 比較例2 比較例3 錠劑硬度（Ν) 87 55 187 68 非常脆 3.苦味官能試驗 給5名成年^子服用在上述所製造之_，評估將錠劑 含在口腔内30秒左右時的苦味。Tableting pressure: 7kN Tablet shape: round ingot, (M〇mm, 2 segments R (R1: 22, R2: 2.5) Table 1 Example 1 Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 Vancomycin Hydrochloride 61.9 61.9 61.9 61.9 45.0 Polyethylene glycol 4000 37.1 - - - - Polyethylene glycol 6000 _ 37.1 - - - HPC-SL - - 37.1 - HPMC - - - 37.1 D-mannitol - - - - 45.0 Hydrated dioxide矽- - - 9.0 Magnesium stearate 1.0 1.0 1.0 1.0 1.0 Total 100.0 100.0 100.0 100.0 100.0 (number is % by weight) HPC-SL: hydroxypropylcellulose HPMC: hydroxypropyl methylcellulose ❹ 2. Measurement of the hardness of the tablet (measurement method) The hardness of the tablet (the average of 2 tablets of the tablet) was measured using an ERWEKA tablet hardness measuring device (manufactured by ERWEKA). (Measurement results) Measurement Examples 1 and 2 'Comparative The hardness of the tablets of Examples 1 to 3 was summarized in Table 2. As a result, Comparative Example 3 was very brittle, and was broken only by hand with light. Other tablets were as shown in Table 2, each of which was practically problem-free. , exceeding 15 200948398 target hardness 40N. Table 2 Example 1 Example 2 Comparative Example 1 ----1 - Comparative Example 2 Comparative Example 3 Lozenge hardness (Ν) 87 55 187 68 Very brittle 3. Bitterness functional test was given to 5 adult children in the above-mentioned _, evaluation of the lozenge contained in the oral cavity The bitterness in about 30 seconds.
(試驗結果） 對實施例1、2，比較例1 2 ’進行苦味官能試驗之結 果，每一種錠劑幾乎都未感覺到苦味。 4.溶出試驗 (試驗方法） 根據日本藥局方第15改正中之溶出試驗法，進行試 驗。使用溶出試驗液第1液_.2)，㈣判法（paddle(Test results) As a result of the bitterness-feature test of Examples 1, 2 and Comparative Example 1 2', almost no bitterness was observed for each of the tablets. 4. Dissolution test (test method) The test was carried out according to the dissolution test method of the Japanese Pharmacopoeia's 15th correction. Use the dissolution test solution 1st solution _.2), (4) the judgment method (paddle
method)進行溶出試驗嶋紫轉數：、♦溶出之萬古徽 素量是以紫外可見分光光产 ^ 九度/則定法測定溶出試驗液之 28〇nm的吸光度的方式求得。 (試驗結果） 對實施例1、2 ’比較例19沾土 2的錠劑，進行溶出試驗的 結果示於第2圖。其結果，如果θ 如禾疋使用聚乙二醇4000、6000 作為水溶性高分子的旋劑（實施例Μ)，在試驗開始ό〇分鐘 後溶出率幾為100%。另_古& _’如果是使用羥丙基纖維 素、經丙基曱基纖維素作為水溶性高分子的錠劑（比較例 16 200948398 1、2)，試驗開始60分鐘後的溶出率，不足90%。 從以上的結果可知，結合劑（水溶性高分子）以本發明的 聚乙二醇為合適。 (試驗例2)結合劑（水溶性高分子）混合量的研究 1.錠劑製造方法 錠劑的製造方法和試驗例1相同。依據示於表3之處方 製造錠劑。用聚乙二醇6000作為結合劑，變更鹽酸萬古黴 素和聚乙二醇的混合比率。 籲 表3 實施例3 實施例4 實施例5 鹽酸萬古黴素 62.5 67.6 78.1 聚乙二醇6000 32.5 27.0 15.6 含水二氧化矽 4.0 4.3 5.0 硬脂酸鎂 1.0 1.1 1.25 合計 100.0 100.0 100.0 (數字為重量％) 2.錠劑硬度的測定 © 與試驗例1同樣地測定錠劑硬度，結果示於表4。其結 果，試驗例3〜5之任一者的錠劑都超過目標的錠劑硬度 40N。 表4 實施例3 實施例4 實施例5 片劑硬度(N) 74 67 51 3.苦味官能試驗 與試驗例1同樣地進行苦味官能試驗。其結果，實施例 17 200948398 3〜5之任一者的錠劑幾乎都未感覺到苦味。 4.溶出試驗 與試驗例1同樣地進行溶出試驗。結果示於第3圖。其 結果’相對於鹽酸萬古黴素之聚乙二醇6000的比例如果增 多’溶出速度雖有略微降低之趨勢，但試驗開始60分鐘後 的浴出率，實施例3〜5之任一者的錠劑都幾為1〇〇%。 (試驗例3)實際生產中錠劑的製造方法(B法參照第4圖） 1.藥渣鍵劑的製造方法Method) The dissolution test was performed on the number of turns of the purple: ♦ The amount of the smear of the smear was determined by the UV-visible spectrophotometry. The absorbance at 28 〇nm of the dissolution test solution was determined by a nine-degree method. (Test results) The results of the dissolution test of the tablets of Example 1, 2' Comparative Example 19 soiled 2 are shown in Fig. 2. As a result, if θ such as PEG and 6000 were used as a water-soluble polymer (Example Μ), the dissolution rate was several 100% after the start of the test. In addition, if it is a tablet using hydroxypropylcellulose and propylmercaptocellulose as a water-soluble polymer (Comparative Example 16 200948398 1, 2), the dissolution rate after 60 minutes from the start of the test, Less than 90%. From the above results, it is understood that the binder (water-soluble polymer) is suitably the polyethylene glycol of the present invention. (Test Example 2) Study on the amount of the binder (water-soluble polymer) 1. Formulation method of the tablet The method for producing the tablet was the same as in Test Example 1. Tablets were prepared according to the conditions shown in Table 3. The mixing ratio of vancomycin hydrochloride and polyethylene glycol was changed by using polyethylene glycol 6000 as a binder.例 3 Example 3 Example 4 Example 5 Vancomycin Hydrochloride 62.5 67.6 78.1 Polyethylene glycol 6000 32.5 27.0 15.6 Aqueous cerium oxide 4.0 4.3 5.0 Magnesium stearate 1.0 1.1 1.25 Total 100.0 100.0 100.0 (Number is % by weight 2. Measurement of the hardness of the tablet The hardness of the tablet was measured in the same manner as in Test Example 1. The results are shown in Table 4. As a result, the tablets of any of Test Examples 3 to 5 exceeded the target tablet hardness by 40N. Table 4 Example 3 Example 4 Example 5 Tablet hardness (N) 74 67 51 3. Bitterness functional test A bitterness functional test was carried out in the same manner as in Test Example 1. As a result, the tablet of any of Examples 17 200948398 3 to 5 hardly felt bitterness. 4. Dissolution test A dissolution test was carried out in the same manner as in Test Example 1. The results are shown in Figure 3. As a result, 'the ratio of the polyethylene glycol 6000 to vancomycin hydrochloride increased, 'the dissolution rate slightly decreased, but the bathing rate after 60 minutes from the start of the test, or any of Examples 3 to 5 The tablets are all 1% by weight. (Test Example 3) Manufacturing method of tablet in actual production (refer to Figure 4 for method B) 1. Method for producing dregs bond agent
錠劑的處方示於表5。秤量預定量之有效成份，即鹽酸 萬古黴素及各添加劑。將所秤量之鹽酸萬古黴素及各添加 劑篩過，加以混合，製成混合粉末。將預定量之潤滑劑， 即硬脂酸鎂添加到混合粉末，混合後，製成製錠粉末，用 打錠機以下述打銳條件進行壓縮成型（第—壓錠）。該鍵劑稱 為藥渣錠劑。 取泠錢劑的製造法The formulation of the tablet is shown in Table 5. Weigh a predetermined amount of the active ingredient, vancomycin hydrochloride and each additive. The weighed amount of vancomycin hydrochloride and each additive were sieved and mixed to prepare a mixed powder. A predetermined amount of a lubricant, that is, magnesium stearate, is added to the mixed powder, and after mixing, an ingot powder is prepared, and compression molding (first pressing) is performed by a tableting machine under the following sharpening conditions. This key is called a dregs lozenge. Manufacturing method of taking money
使用菲茲微粉碎機(Fitz Mill)或4碎型造粒機(p( MiU)將藥渣錠劑粉碎成5〇〇卿以上的顆粒占⑽以 15〇μΐΏ以下的顆粒占5G%以下的狀態，製成造粒顆粒Μ _素水分収儀敎造粒雌的水分值，加人預定量自 乙二醇6_、結晶纖維素’加以混合將潤滑劑，即石】 舰投人舰合齡t，料纽雖，以下述打則 將該顆粒射價顧縮㈣。㈣，結晶纖維素是把鹽 萬古黴素的吸财分也考量進去，添㈣使得鍵劑全體 成為_重#%。對著觀縮成型之鍵劑吹送低濕(濕度〇.; 18 200948398 的壓縮空氣，藉以進行乾燥，製造最終錠劑（實施例6)。 表5 實施例6 鹽酸萬古黴素 69.4(250mg力價） 聚乙二醇6000 16.7(60mg) 結晶纖維素 適量（標準值30mg) 水合二氧化矽 4.4(16mg) 硬脂酸鎂 1.1 (4mg) 合計 100.0 (數字為重量％) 產業之可利用性 本發明可以提供服用時無苦味，對感染性腸炎的治療 等為有用之鹽酸萬古黴素的經口投藥用錠劑。 I：圖式簡單說明3 第1圖依據A法之錠劑製造步驟。 第2圖使用各種結合劑（水溶性高分子）時之鹽酸萬古黴 素的溶出率。 第3圖變更結合劑（水溶性高分子）的混合量時之鹽酸萬 古黴素的溶出率。 第4圖依據B法之錠劑製造步驟。 【主要元件符號說明】 (無） 19Using a Fitz Mill or a 4-crush granulator (p (MiU)), the slag tablet is pulverized into 5 〇〇 or more particles (10), and the particles below 15 〇 μ 占 are 5 G% or less. State, made into granulated granules _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Age t, although the material is new, the particle price is reduced by the following (4). (4), crystalline cellulose is considered to be the salt vancomycin, and the addition of (4) makes the key agent become _ heavy #% The final tablet was prepared by blowing low-humidity (humidity ;.; 18 200948398 compressed air) to the shrink-molding key agent. The final tablet was prepared (Example 6). Table 5 Example 6 Vancomycin Hydrochloride 69.4 (250 mg force) Price) Polyethylene glycol 6000 16.7 (60mg) Crystalline cellulose (standard value 30mg) Hydrated cerium oxide 4.4 (16mg) Magnesium stearate 1.1 (4mg) Total 100.0 (number is % by weight) Industry availability The invention can provide vancomycin hydrochloride which is useful for treating infectious enteritis and the like without bitterness. Oral administration of pharmaceutical tablets. I: Simple description of the figure 3 Figure 1 is a procedure for the preparation of tablets according to method A. Figure 2 shows the dissolution rate of vancomycin hydrochloride when various binders (water-soluble polymers) are used. The dissolution rate of vancomycin hydrochloride when the amount of the binder (water-soluble polymer) is mixed is changed. Fig. 4 is a manufacturing procedure of the tablet according to the method B. [Explanation of main component symbols] (None) 19
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| JP2008107608A JP5114281B2 (en) | 2008-04-17 | 2008-04-17 | Tablets containing vancomycin hydrochloride |
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| CN106963939A (en) * | 2017-03-22 | 2017-07-21 | 永信药品工业（昆山）股份有限公司 | Vancomycin hydrochloride pharmaceutical composition and preparation method thereof |
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| JP2011153119A (en) * | 2010-01-27 | 2011-08-11 | Mylan Seiyaku Ltd | Tablet containing vancomycin or salt thereof |
| JP2010120967A (en) * | 2010-02-24 | 2010-06-03 | Shionogi & Co Ltd | Tablet containing vancomycin hydrochloride |
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| US4670258A (en) * | 1984-02-10 | 1987-06-02 | Vanderbilt University | Storable prepackaged aqueous solutions of vancomycin |
| EP0819254A1 (en) * | 1995-04-04 | 1998-01-21 | Abbott Laboratories | Reagents and methods for the detection and quantification of vancomycin in biological fluids |
| ES2248908T7 (en) * | 1997-06-06 | 2014-11-24 | Depomed, Inc. | Dosage forms of drugs orally and gastric retention for continued release of highly soluble drugs |
| JP2008050264A (en) * | 2004-12-21 | 2008-03-06 | Eisai Co Ltd | Dry granulated substance |
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