【文章內(nèi)容簡介】 ut may even be solid pellets for tissue control of a process to minimize contamination for a small quantity of such a product can be achieved with relative the quantity of product increases，the problems of controlling the process to prevent contamination ，the preparation of sterile products has bee a highly specialized area in pharmaceutical standards established，the attitude of personnel，and the process control must be of a第13 單元 無菌產(chǎn)品 無菌產(chǎn)品 無菌產(chǎn)品是不含微生物活體的治療劑劑型，其主要包括非腸道用的、眼用的和沖洗用的制劑。這之中，非腸道用產(chǎn)品在藥物劑型當(dāng)中是（較為）特別的因?yàn)樗鼈兪峭ㄟ^皮膚和黏膜被注射到人體內(nèi)部的。這樣，由于它們進(jìn)入了高效率的人體第一道免疫防線——皮膚和黏膜，（所以）它們必須沒有微生物感染和有毒成分，同時(shí)又（必須）具有特別高的純度。這些產(chǎn)品的制備過程中涉及到的所有組分和（工藝）流程都必須經(jīng)過選擇和設(shè)計(jì)以盡可能地消除各種類型的污染，無論是來自物理的、化學(xué)的，還是微生物的。眼用制劑盡管沒有被引入到內(nèi)部體腔，但它仍與對污染（物）敏感的組織有接觸，因此，對眼用制劑也要求（與非腸道用制劑）類似的標(biāo)準(zhǔn)。沖洗液現(xiàn)在也要求滿足和非腸道用溶液一樣的標(biāo)準(zhǔn)，因?yàn)樵跊_洗過程中，大量的沖洗液都可以通過敞開的血管傷口或者擦傷的黏膜組織直接進(jìn)入到血液。因此，本章中描述的有關(guān)非腸道用溶液大批量生產(chǎn)的特點(diǎn)和標(biāo)準(zhǔn)，對于沖洗液同樣適用。無菌產(chǎn)品通常是溶液或者懸浮液，但甚至也可以是用于組織對端植入的固體藥丸。對于少量的這種產(chǎn)品，使其污染降到最低的工藝控制可以相對容易地實(shí)現(xiàn)。（但）隨著產(chǎn)品量的增加，控制工藝流程從而防止污染的困難也會增加。因而，無菌產(chǎn)品的制備已經(jīng)成為藥品加工里一個(gè)高度專業(yè)化的領(lǐng)域。制定的標(biāo)準(zhǔn)、人員的態(tài)度和工藝流程的控制都必須有著優(yōu)秀的水平。superior By far the most frequently employed vehicle for sterileproducts is water，since it is the vehicle for all natural body superior quality required for such use isdescribed in the monograph on Water for Injection in the may be even more stringent for someproducts， of the most inclusive tests for the quality of water isthe total solids content，a gravimetric evaluation of thedissociated and undissociated organic and inorganicsubstances present in the ，a lesstimeconsuming test，the electrolytic measurement ofconductivity of the water，is the one most frequently measurements can be obtained by immersingelectrodes in the water and measuring the specificconductance, a measurement that depends on the ioniccontent of the conductance may be expressed bythe meter scale as conductivity in micromhos，resistance inmegohms , or ionic content as parts per million(ppm)ofsodium validity of this measurement as anindication of the purity of the water is inferential in thatmethods of producing highpurity water，such as distillationand reverse osmosis，can be expected to removeundissociated substances along with those that are substances such as pyrogens，however，could be present in the absence of ions and not bedisclosed by the ，for contaminants other thanions，additional tests should be tests for quality of Water for Injection withpermitted limits are described in the USP paring the total solids permitted for Water forInjection with that for Sterile Water for Injection，one willnote that considerably higher values are permitted for SterileWater for is necessary because the latterproduct has been sterilized，usually by a thermal method，ina container that has dissolved to some extent in the ，the solids content will be greater than for thenonsterilized the other hand，the 10 ppm totalsolids officially permitted for Water for Injection may bemuch too high when used as the vehicle for many practice, Water for Injection normally should not have aconductivity of more than 1 micromho(1 megohm，approximately ppm NaCl).溶媒 到目前為止，最常被用于無菌產(chǎn)品的溶媒就是水，因?yàn)樗ㄒ玻┦撬凶匀惑w液的溶媒。該用途所要求的優(yōu)良特性在《美國藥典》的《注射用水》專題論文中有所描述。但對于某些產(chǎn)品來說，要求可能會更為苛刻。水質(zhì)檢驗(yàn)的一種最普遍的測試就是固體總含量，一種對水中解離的和不解離的有機(jī)物和無機(jī)物在重量上的評估。然而，一種用時(shí)較少的測試——水導(dǎo)電性的電解測量——則是最常用的（測試方法），它通過把電極浸入水中測出具體的電導(dǎo)率，就可以實(shí)現(xiàn)即刻測量，是一種基于水中離子含量的測量方法。電導(dǎo)率可以通過表頭刻度盤以電導(dǎo)／微姆歐、電阻／兆歐姆或者離子含量／ppm NaCl的形式顯示出來。作為水純度的指示，這種測量方法的正確性只是推理性的，因?yàn)橐恍┥a(chǎn)高純度水的方法，比如蒸餾和反滲透，可以將不解離的物質(zhì)同那些解離的物質(zhì)一起除去。但是不解離的物質(zhì)例如熱原，可以不以離子的形式存在，因而不能被這種方法檢測出來。因此，對于除離子之外的（其他）污染物，還需要進(jìn)行另外的檢測。具有特殊用途的注射用水的水質(zhì)附加測試在美國藥典中有專篇描述。當(dāng)把注射用水和無菌注射用水所允許的固體總含量做比較時(shí)，你會發(fā)現(xiàn)無菌注射用水允許有相當(dāng)高的值。這是必要的，因?yàn)楹笳呤墙?jīng)過滅菌的，通常是通過一種熱途徑，在一個(gè)在一定程度上溶解于水的容器中。因而，其固體含量會比沒有滅菌的產(chǎn)品要高得多。另一方面，官方對于注射用水所允許的10 ppm的固體總含量，對于許多產(chǎn)品來說，作為溶媒其值可能都太高了。事 實(shí)上，注射用水其電導(dǎo)一般不應(yīng) 該超過1微姆歐（1兆歐，大約 ppm NaCl）。Added Substances added to a product to enhance its stability are 添加到產(chǎn)品當(dāng)中用以提高產(chǎn)品穩(wěn)essential for almost every substances include 定性的物質(zhì)，對于幾乎每種產(chǎn)品solubilizers，antioxidants，chelating agents，buffers，來說都是必不可少的。這樣的物tonicity contributors，antibacterial agents，antifungal 質(zhì)包括增溶劑、抗氧劑、螯合劑、agents，hydrolysis inhibitors，antifoaming agents，and 緩沖劑、tonicity contributor、抗numerous other substances for specialized the 菌劑、殺菌劑、水解抑制劑、消same time，these agents must be prevented from adversely 沫劑和許多其他的有專門用途的affecting the general，added substances must be 物質(zhì)。同時(shí)，這些組分必須不能nontoxic in the quantity administered to the 對產(chǎn)品有不利影響。一般來說，should not interfere with the therapeutic efficacy nor with 添加劑必須在病人的給藥量范圍the assay of the active therapeutic must 內(nèi)是無毒的。它們不應(yīng)該干擾（產(chǎn)also be present and active when needed throughout the 品的）治療效果，也不能干擾有useful life of the ，these agents must be 效活性化合物的測定。在產(chǎn)品的selected with great care，and they must be evaluated as to 整個(gè)有效期內(nèi)，需要它們時(shí)，它their effect upon the entire extensive 們必須存在并且有效。因此，對review of excipients used in parenteral products and the 這些物質(zhì)必須非常小心地進(jìn)行挑means for adjusting pH of these products has recently been 選，而且對它們對整個(gè)配方的影published and should be referred to for more detailed 響也必須進(jìn)行評估。，最近已經(jīng)出版，更多的詳細(xì)信息 可參閱之。Formulation配方The formulation of a parenteral product involves the 非腸道用產(chǎn)品的配方涉及一個(gè)或bination of one or more ingredients with a medicinal 者更多組成部分間的結(jié)合，這些agent to enhance the convenience，acceptability，or 組成部分（各自）都含有一種用effectiveness of the is it preferable to 以提高產(chǎn)品方便性、可接受性或dispense a drug singly as a sterile dry powder unless the 者療效的有效成分。（人們）很少formulation of a stable liquid preparation is not 、On the other hand，a therapeutic agent is a chemical 干燥的粉末（的形式）配售，除pound subject to the physical and chemical reactions 非（把它做成）穩(wěn)定的液體制劑characteristic of the class of pounds to which it 。Therefore，a careful evaluation must be made of every 另一方面，治療劑（藥物的有效bination of two or mor