对β-内酰胺类抗生素高分子聚合物质控现状的分析及相关问题思

对β－内酰胺类抗生素高分子聚合物质控现状的分析及相关问题思考【摘要】本文综述了β－内酰胺类抗生素高分子聚合物测定的国内外研究进展，介绍了聚合物测定的原理和具体方法，分析了目前在聚合物测定中存在的问题，并针对问题提出了处理建议。

【关键词】高分子聚合物、质控现状、测定方法1、概述抗生素是临床用量最大和较易发生不良反应的药物。

其中最常见的一类不良反应就是过敏反应。

多年来的研究已证明，在β－内酰胺类抗生素所致的速发型过敏反应中，药物分子本身只是半抗原，药物中存在的高分子聚合物才是引发速发型过敏反应的真正过敏原，因此严格控制抗生素中高分子聚合物的含量有着重要的意义。

本文综述了高分子聚合物测定方法在国内外的研究进展，对实际测定过程中遇到的问题作简单的分析和探讨。

2、高分子聚合物的分类抗生素中的高分子杂质系指药品中分子量大于药物本身的杂质总称，其分子量一般在1000～5000Da，个别可达10000Da左右。

β－内酰胺类抗生素中的高分子杂质按其来源通常被分为两类：外源性杂质和内源性杂质。

外源性杂质包括蛋白、多肽、多糖等类杂质或抗生素和蛋白、多肽、多糖等的结合物，来源于发酵工艺，如青霉素中的青霉噻唑蛋白、青霉噻唑多肽等。

内源性杂质是指抗菌药物的自身聚合产物，聚合物既可来自生产过程，又可在储存中形成，甚至在用药时也可产生。

对于现在的生产工艺，外源性的高分子杂质已经较少产生，对内源性聚合物的控制是当前抗生素高分子杂质质量控制的重点。

金少鸿等人的研究[1]表明，高分子聚合物不仅能引发IgE介导的过敏反应，而且青霉素类的抗生素还能经胃肠道吸收而引发过敏反应。

故对β－内酰胺类抗生素中的高分子聚合物进行严格的控制，可以保证临床用药的安全有效。

3、高分子聚合物的质控现状分析3.1 对中国药典近年来收载品种的分析为了对β-内酰胺类抗生素药物中的高分子聚合物进行有效控制，中国药典对收载的部分品种进行了聚合物质控，具体如下：表1、中国药典2005年版收载的测定高分子聚合物的相关品种从表1可知，2005年版药典增订品种中除了头孢类外，以青霉素类的药物为主，这改变了2000年版药典中青霉素类药物无高分子聚合物检查的情况。

从分子结构上来说，青霉素类的药物其实更容易发生聚合情况，因此，在2005年版药典中增加了对青霉素类药物的高分子聚合物质量控制。

3.2对国外药典收载品种的分析美国药典23版曾收载了头孢他啶中高聚物的含量测定，检测方法为HPLC外标法，但由于高分子杂质具有高度不均一性和不确定性，无法制备出具有固定含量的对照品等原因，目前USP 24版已不再收载。

英国药典中至今未有收载相关品种。

比较国内外药典，可以发现目前国外对于高分子聚合物的控制仍然没有明确的药典方法，这主要是由于高分子聚合物的对照品难以制备，中国药典收载的自身对照外标法定量测定β-内酰胺类抗生素中高聚物的检测方法，通过两种流动相的转换，以药品自身对照品取代高分子杂质对照品对β-内酰胺类抗生素中的高聚物进行检测，在一定程度上解决了国外无法解决的问题，在某种意义上填补了一项空白，为高分子聚合物的检测指出了一个新的方向。

4、高分子聚合物的测定原理、测定方法及问题讨论关于高分子聚合物的测定方法，国内外已有许多报道，主要的方法是色谱法。

其分离模式有三类：（1）反相模式；（2）离子交换模式；（3）凝胶色谱模式。

由于结构不同的高分子杂质通常具有相似的生物学特性，故在药品质量控制中只需控制高分子杂质的总量，就能达到控制致敏物质的目的。

因此，根据分子量差异进行分离的凝胶色谱模式是简便易行的分离模式。

胡昌勤等人开发了一个以葡聚糖凝胶Sephadex G-10为基础的凝胶色谱分析方法[2]，可方便地用于对各种β－内酰胺类抗生素中高分子杂质的分离和分析。

4.1 凝胶色谱分析方法的原理在Sephadex G-10凝胶色谱系统中，由于Sephadex G-10的排阻分子量仅为700d，因此，除部分寡聚物外，β－内酰胺类抗生素中的高分子杂质在色谱过程中均不保留；即所有的高分子杂质表现为单一的色谱峰，其Kav＝0。

在特定条件下，β－内酰胺类抗生素由于分子间的氢键、静电相互作用、疏水相互作用等次级相互作用，可以形成缔合物，导致其表观分子量增大；此时在Sephadex G-10凝胶色谱系统中和高分子杂质具有相似的色谱行为，即在Kav＝0处表现为单一的色谱峰。

利用此原理，在Sephadex G-10凝胶色谱系统中，以药物自身为对照品，测定其在特定条件下缔合时的峰响应指标；再改变色谱条件，测定样品中的高分子杂质和药物分离后在Kav＝0处的峰响应指标；按外标法计算，即得药品中的高分子杂质相当于药品本身的相对含量。

4.2 测定方法通常的凝胶色谱分离系统采用两种流动相，流动相A为pH=7.0的磷酸盐缓冲液，流动相B为纯化水或0.1％十二烷基硫酸钠；凝胶介质：Sephadex G-10；检测波长254nm；对照溶液采用自身对照品配制。

（1）系统适用性试验用蓝色葡聚糖2000的溶液（1mg/ml）作为参比溶液，测定在流动相A、流动相B中的Kav=0的保留时间，并计算出理论板数及拖尾因子。

系统适用性试验中规定，在两种流动相系统中蓝色葡聚糖2000峰的保留时间比值应在0.93～1.07之间，对照溶液主峰和供试品溶液中聚合物峰与相应色谱系统中蓝色葡聚糖2000峰的保留时间的比值均应在0.93～1.07之间。

（2）方法学验证线性关系考察：制备系列的对照溶液，浓度范围为规定浓度的20％～200％，共制备7份样品，以测得的峰面积与溶液浓度进行线性回归，分析是否呈线性。

最低检测限与测定量（浓度）：把已知低浓度的试样测得的信号与空白样品测得的信号比较，计算出能被可靠测出的最低浓度或量，一般以信噪比3：1相应浓度确定最低检测限，以检测限×103的量或浓度作为测定量（浓度）。

F值测定的重现性考察：F值为对照溶液的浓度（mg）与测得的峰面积的比值，要求日内、日间的相对标准偏差在5％以内。

供试品溶液的浓度与聚合物测定结果的相关性考察：制备系列的供试品溶液，浓度范围为规定浓度的50％～200％，共三份样品，以测得的高聚物峰面积对溶液浓度进行线性回归，相关系数r应大于0.99。

聚合物测定结果的重现性：同批样品，重复测定6次，考察日内与日间的重现性。

4.3 实验中常见问题分析及解决方法（1）对照溶液主峰的拖尾：在以纯水为流动相的色谱过程中，除缔合分子由于次级相互作用可导致缔合外，一些β-内酰胺类抗生素和葡聚糖凝胶间也存在一定的相互作用，因而导致缔合峰严重拖尾，因此若在流动相中加入适当的抑制剂，可改善缔合峰的拖尾。

根据胡昌勤等人的研究[2]，在流动相中加入0.5％的葡萄糖溶液或0.01mol/L的甘氨酸溶液替代纯水作为流动相可以明显改善缔合峰的拖尾现象。

（2）对照溶液主峰保留时间与蓝色葡聚糖2000峰保留时间不一致：在实际操作中，出现某些品种对照溶液主峰保留时间与蓝色葡聚糖2000峰保留时间的比值超过1.07，如头孢拉定，原因可能是Sephedex G-10对头孢拉定有一定吸附作用。

在使用含0.2mol/L氢氧化钠和0.5mol/L氯化钠的溶液冲洗凝胶柱过夜后，用水冲洗至中性，可改善上述保留时间不一致的状况。

（3）阿莫西林品种的对照溶液不能满足系统适用性要求：系统适用性试验项下要求对照溶液连续进样5次，其峰面积相对标准偏差不大于5.0％。

阿莫西林对照溶液在进样过程中峰面积越来越小，峰高逐渐降低，峰宽逐渐增宽，RSD一般都会超过5.0％，日间重复的RSD也不能符合要求。

把流动相B由水改为0.01％SDS溶液与0.5％葡萄糖溶液，也表现出相同的色谱行为。

推测该现象的原因与阿莫西林分子结构有关。

可以考虑采用母核结构与阿莫西林相似的青霉素对照品来取代阿莫西林对照品，并加校正因子计算结果。

（4）青霉素V钾的高分子聚合物测定方法的不完善在中国药典2005年版收载的青霉素V钾质量标准中，以254nm为青霉素V钾的检测波长，而青霉素V钾的最大吸收波长其实在236nm，在实际测量中，基于目前国内的高分子杂质测定仪，检测波长是不可调的，固定为254nm，所以我们都统一采用254m作为青霉素V钾高分子聚合物的检测波长。

由于部分青霉素V钾原料和片剂样品中高分子聚合物的含量本来就低，检测波长又不是最大吸收波长，常常导致无法检出的情况。

如果将来生产的高分子杂质测定仪能调节检测波长，应该能改善这种情况。

5、小结β-内酰胺类抗生素中的高分子聚合物是产生过敏反应的主要原因，控制β－内酰胺类抗生素中的高分子聚合物含量，可以保证临床用药的安全有效。

国外药典目前尚无有效控制高分子杂质的检测手段。

中国药典收载的自身对照外标法定量测定β-内酰胺类抗生素中高聚物的检测方法，通过两种流动相的转换，以药品自身对照品取代高分子杂质对照品对β-内酰胺类抗生素中的高聚物进行检测，在一定程度上解决了国外无法解决的问题，在国际上属于领先。

但由于该方法研究时间不长，与传统的HPLC等成熟的色谱测定方法仍有差距，如各品种高分子聚合物的限度确定也比较笼统，缺乏临床有效数据的支持，在实际药品检测中也会遇到各种的具体问题，因此，为了更加有效地控制聚合物的含量，保证药品的质量，我们还有许多工作要做。

参考文献1、金少鸿，胡昌勤．β-内酰胺抗生素过敏反应研究进展．中国新药杂志，1994；3：382、胡昌勤，金少鸿．自身对照外标法定量测定β-内酰胺抗生素中的高分子杂质．中国抗生素杂志，1997；22（1）：23-27（英文版）Two regulations promulgated for implementation is in the party in power for a long time and the rule of law conditions, the implementation of comprehensive strictly strategic plan, implementation in accordance with the rules and discipline to manage the party, strengthen inner-party supervision of major initiatives. The two regulations supporting each other, the < code > adhere to a positive advocate, focusing on morality is of Party members and Party leading cadres can see, enough to get a high standard; < rule > around the party discipline, disciplinary ruler requirements, listed as "negative list, focusing on vertical gauge, draw the party organizations and Party members do not touch the" bottom line ". Here, the main from four square face two party rules of interpretation: the first part introduces two party Revised regulations the necessity and the revision process; the second part is the interpretation of the two fundamental principles of the revision of laws and regulations in the party; the third part introduces two party regulations modified the main changes and needs to grasp several key problems; the fourth part on how to grasp the implementation of the two regulations of the party. < code > and < Regulations > revised the necessity and revisedhistory of the CPC Central Committee the amendment to the Chinese Communist Party members and leading cadres honest politics several guidelines > and < Chinese Communist Party discipline and Punishment Regulations > column 1 by 2015 to strengthen party laws and regulations focus. 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Content is too complicated, "eight prohibition, 52 are not allowed to" hard to remember, and also difficult to put into practice; the second is concisely positive advocated by the lack of prohibited provisions excessive, no autonomy requirements; the third is banned terms and discipline law, both with the party discipline, disciplinary regulations repeat and Criminal law and other laws and regulations repeat; the fourth is to "clean" the theme is not prominent, not for the existing problems, and is narrow, only needle of county-level leading cadres above. < rule > is in 1997 < Chinese Communist Party disciplinary cases (Trial) > based on revision, in December 2003 the promulgation and implementation, to strengthen the construction of the party play very important role. Along with the development of the situation, which many provisions have been unable to fully meet the comprehensive strictly administering the practice needs. One is Ji law, more than half of the provisions and criminal law and other countries laws and regulations Repetition; two is the political discipline regulations is not prominent, not specific, for violation of the party constitution, damage theauthority of Party Constitution of misconduct lack necessary and serious responsibility to pursue; third is the main discipline for the leading cadres, does not cover all Party members. Based on the above situation, need to < the criterion of a clean and honest administration > and < rule > the two is likely to be more relevant regulations first amendment. By revising, really put the authority of Party discipline, the seriousness in the party tree and call up the majority of Party members and cadres of the party constitution of party compasses party consciousness. (II) two party regulations revision process the Central Committee of the Communist Party of China attaches great importance to two regulations revision . Xi Jinping, general books recorded in the Fifth Plenary Session of the eighth session of the Central Commission for Discipline Inspection, on the revised regulations < > made clear instructions. According to the central deployment, the Central Commission for Discipline Inspection from 2014 under six months begin study two regulations revision. The Standing Committee of the Central Commission for Discipline Inspection 4 review revised. Comrade Wang Qishan 14 times held a special meeting to study two regulations revision, amendment clarifies the direction, major issues of principle, path and target,respectively held a forum will listen to part of the province (area) secretary of the Party committee, Secretary of the Discipline Inspection Commission, part of the central ministries and state organs DepartmentThe first party committee is mainly responsible for people, views of experts and scholars and grassroots party organizations and Party members. Approved by the Central Committee of the Communist Party of China, on 7 September 2015, the general office of the Central Committee of the Party issued a notice to solicit the provinces (autonomous regions, municipalities) Party, the central ministries and commissions, state ministries and commissions of the Party (party), the General Political Department of the military, every 3 people organization of Party of two regulations revision opinion. Central Commission for Discipline Inspection of extensive solicitation of opinions, careful study, attracting, formed a revised sent reviewers. In October 8 and October 12, Central Committee Political Bureau Standing Committee and the Political Bureau of the Central Committee After consideration of the two regulations revised draft. On October 18, the Central Committee of the Communist Party of China formally issued two regulations. Can say, two laws amendment concentrated thewisdom of the whole party, embodies the party. Second, < code > and < Regulations > revision of the basic principles of two party regulations revision work and implement the party's eighteen, ten eight plenary, the spirit of the Fourth Plenary Session of the Eleventh Central Committee and General Secretary Xi Jinping important instructions on the revised < low political criterion > and < Regulations >, highlighting the ruling party characteristics, serious discipline, the discipline quite in front of the law, based on the current, a long-term, advance as a whole, with Bu Xiuding independent < rule > and < rule >. Main principle is: first, adhere to the party constitution to follow. The constitution about discipline and self-discipline required specific, awaken the party constitution of party compasses party consciousness, maintaining the authority of the constitution. General Secretary Xi Jinping pointed out that "no rules, no side round. Party constitution is the fundamental law, the party must follow the general rules. In early 2015 held the eighth session of the Central Commission for Discipline Inspection Fifth Plenary Session of the 16th Central Committee, Xi Jinping again pointed out that constitution is the party must follow the general rules, but also the general rules." the revision of the< code > and < rule > is Method in adhere to the regulations established for the purpose of combining rule of virtue is to adhere to the party constitution as a fundamental to follow, the constitution authority set up, wake up the party constitution and party rules the sense of discipline, the party constitution about discipline and self-discipline specific requirements. 4 second is to adhere to in accordance with the regulations governing the party and the party. The Party of rule of virtue "de", mainly refers to the party's ideals and beliefs, excellent traditional style. 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After the revision of the < code >, a total of eight, 281 words, including lead, specification and Party member cadre clean fingered self-discipline norms, etc. Part 3 members low-cost clean and self-discipline, the main contents can be summarized as "four must" "eight code". Lead part, reiterated on ideal and faith, fundamental purpose, the fine traditions and work style, noble sentiments, such as "four must" the principle of requirements, strong tone of self-discipline, The higher request for 6 andsupervised tenet, the foothold in permanent Bao the party's advanced nature and purity, to reflect the revised standards requirements. Members of self-discipline norms around the party members how to correctly treat and deal with the "public and private", "cheap and rot" thrifty and extravagance "bitter music", put forward the "four norms". 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(2) the revised regulations, the main changes in the revised Regulations > to fully adapt to thestrictly requirements, reflects the according to the regulations governing the law of recognition of deepening, the realization of the discipline construction and Jin Ju. < rule > is party a ruler, members of the basic line and follow. And the majority of Party members and cadres of Party organizations at all levels should adhere to the bottom line of thinking, fear discipline, hold the bottom line, as a preventive measure, to keep the party's advanced nature and purity. 1, respect for the constitution, refinement and discipline. Revised < rule > from comprehensive comb physical constitution began, the party constitution and other regulations of the Party of Party organizations and Party discipline requirements refinement, clearly defined in violation of the party constitution will be in accordance with regulations to give the corresponding disciplinary action. The original 10 categories of misconduct, integration specification for political discipline, discipline, honesty and discipline masses Ji Law and discipline and discipline and other six categories, the content of < rule > real return to Party discipline, for the majority of Party members and listed a "negative list. 7 2, highlighting the political discipline and political rules. > < Regulations according to the stage of the discipline of outstandingperformance, emphasizing political discipline and political rules, organization and discipline, in opposition to the party's leadership and the party's basic theory, basic line, basic program and basic experience, the basic requirement of behavior made prescribed punishment, increase the cliques, against the organization such as violation of the provisions, to ensure that the central government decrees and the Party of centralized and unified. 3, adhere to strict discipline in the law and discipline In front, Ji separated. Revised < Regulations > adhere to the problem oriented, do Ji separated. Any national law existing content, will not repeat the provisions, the total removal of 79 and criminal law, repeat the content of the public security management punishment law, and other laws and regulations. In the general reiterated that party organizations and Party members must conscientiously accept the party's discipline, die van comply with national laws and regulations; at the same time, to investigate violations of Party members and even criminal behavior of Party discipline and responsibility, > < Regulations distinguish five different conditions, with special provisions were made provisions, so as to realize the connection of Party discipline and state law. 4, reflect Wind building and anti-corruptionstruggle of the latest achievements. < rule > the party's eighteen years implement the spirit of the central provisions of the eight, against the requirements of the "four winds" and transformation for disciplinary provisions, reflecting the style construction is always on the road, not a gust of wind. In the fight against corruption out of new problems, increase the trading rights, the use of authority relatives profit and other disciplinary terms. Prominent discipline of the masses, the new against the interests of the masses and ignore the demands of the masses and other disciplinary terms and make provisions of the disposition and the destruction of the party's close ties with the masses.Discipline to protect the party's purpose. 8 of these regulations, a total of three series, Chapter 15, 178, more than 24000 words, after the revision of the regulations a total of 3 series, Chapter 11, 133, 17000 words, divided into "general" and "special provisions" and "Supplementary Provisions" Part 3. Among them, add, delete, modify the provisions of the proportion of up to nearly 90%. 1, the general general is divided into five chapters. The first chapter to the regulations of the guiding ideology, principles and scope of application of the provisions, highlight the strengthening ofthe party constitution consciousness, maintenance the authority of Party Constitution, increase the party organizations and Party members must abide by the party constitution, Yan Centralized centralized, would examine at all levels of the amended provisions implementing and maintaining Party discipline, and consciously accept the party discipline, exemplary compliance with national laws and regulations. The second chapter of discipline concept, disciplinary action types and effects of the regulations, will be a serious warning from the original a year for a year and a half; increase the Party Congress representative, by leaving the party above (including leave probation) punishment, the party organization should be terminated its representative qualification provisions. The third chapter of the disciplinary rules of use prescribed in the discipline rectifying process, non convergence, not close hand classified as severely or heavier punishment. "Discipline straighten "At least eighteen years of five years, these five years is to pay close attention to the provisions of the central eight implementation and anti -" four winds ". The fourth chapter on suspicion of illegal party disciplinary distinguish five different conditions, with special provisions were madeprovisions, to achieve effective convergence of Party and country 9 method. < rule > the provisions of Article 27, Party organizations in the disciplinary review found that party members have committed embezzlement, bribery, dereliction of duty dereliction of duty and other criminal law act is suspected of committing a crime shall give cancel party posts, probation or expelled from the party. The second is < Regulations > Article 28 the provisions of Party organizations in the disciplinary review But found that party members are stipulated in the criminal law, although not involved in a crime shall be investigated for Party discipline and responsibility should be depending on the specific circumstances shall be given a warning until expelled punishment. This situation and a difference is that the former regulation behavior has been suspected of a crime, the feeling is quite strict, and the latter for the behavior not involving crime, only the objective performance of the provisions of the criminal code of behavior, but the plot is a crime to slightly. < Regulations > the 29 provisions, Party organizations in the discipline review found that party members and other illegal behavior, affect the party's image, the damage to the party, the state and the people's interests, we should depend on the situationSeriousness given disciplinary action. The loss of Party members, seriously damaging the party's image of behavior, should be given expelled from the party. At this article is party member is in violation of the criminal law outside the other illegal acts, such as violates the public security administration punishment law, customs law, financial laws and regulations behavior. The fourth is < cases > Article 32 stipulates, minor party members and the circumstances of the crime, the people's Procuratorate shall make a decision not to initiate a prosecution, or the people's court shall make a conviction and exempted from criminal punishment shall be given within the party is removed from his post, probation or expelled from the party. Party members and crime, sheets were fined in accordance with For acts; the principal Ordinance amended the provisions of the preceding paragraph. This is the new content, in order to achieve Ji method effective convergence. Five is < > the thirty third article 10 of the provisions, the Party member due to an intentional crime is sentenced to criminal law (including probation) sheets or additional deprivation of political rights; due to negligence crime and was sentenced to three years or more (excluding three years) a penalty, shall give expelled punishment. Due to negligence crime is convictedand sentenced to three years (including three years) in prison or be sentenced to public surveillance, detention, shall in general be expelled from the party. For the individual may not be expelled from the party, should control Approval. This is followed and retained the original > < Regulations the provisions of punishment party authorization rules and report to a level party organizations. For is "party members with criminal acts, and by the criminal punishment, generally should be expelled from the party". The fifth chapter of probationary Party member of the discipline and discipline after missing members of the treatment and punishment decisions, such as the implementation of the provisions, clear the related party discipline and punishment decision made after, for duties, wages and other relevant alteration formalities for the longest time. 2, sub sub section will the original regulations of10 categories of acts of violation of discipline integration revised into 6 categories, respectively, in violation of the punishments for acts of political discipline "in violation of discipline behavior of punishment" in violation of integrity of disciplinary action points "of violation punishments for acts of mass discipline" "the violation of work discipline, punishment" in violation of discipline of life behaviorpunishment "6 chapters. 3, annex" Supplementary Provisions "clear authority making supplementary provisions of, cases of interpretative organ, as well as regulations implementation time and retroactivity etc.. 11 (3) learning understanding > < regulations needs to grasp several key problems The first problem -- about the violation of political discipline behavior > < new ordinance chapter 6 the political discipline column for the six disciplines, that is the main opposition to Party leadership and the opposition of the basic theory, basic line, basic program and basic experience, basic requirements of misconduct made provisions of the disposition, especially the eighteen since the CPC Central Committee put forward the Yan Mingzheng treatment of discipline and political rules requirements and practical achievements transformation for Discipline article, increase the false debate central policies, cliques, against the organization review, make no discipline of the principle of harmony terms. These are the party's eighteen years in comprehensive strictly Process combined with the practice of rich content. (1) false debate the central policies and undermine the Party of centralized and unified the problem is made in accordance with the provisions of the party constitution. Constitution in general programme requirements。