Kappelgaard Anne-Marie, Bojesen Anders, Skydsgaard Karsten, Sjögren Ingrid, Laursen Torben
Scientific Marketing GHT, Novo Nordisk A/S, Bagsvaerd, Denmark.
Horm Res. 2004;62 Suppl 3:98-103. doi: 10.1159/000080507.
Growth hormone (GH) treatment is a successful medical therapy for children and adults with GH deficiency as well as for growth retardation due to chronic renal disease, Turner syndrome and in children born small for gestational age. For all of these conditions, treatment is long term and patients receive daily subcutaneous injections of GH for many years. Patient compliance is therefore of critical importance to ensure treatment benefit. One of the major factors influencing compliance is injection pain. Besides the injection device used, pain perception and local tissue reaction following injection are dependent on the preservative used in the formulation and the concentration of GH. Injection pain may also be related to the buffer substance and injection volume. A liquid formulation of GH, Norditropi SimpleXx, has been developed that dispenses with the need for reconstitution before administration. The formulation uses phenol (3 mg/ml) as a preservative (to protect product from microbial degradation or contamination) and histidine as a buffer. Alternative preservatives used in other GH formulations include m-cresol (9 mg/ml) and benzyl alcohol (3-9 mg/ml). Buffering agents include citrate and phosphate. Phenol has been successfully used as a preservative in drug formulations for more than 50 years and is considered a safe and effective agent which complies with strict international requirements for preservatives in drug formulations. In toxicological studies, no or only mild local reactions have been observed following subcutaneous administration of phenol (7.5 mg/ml), m-cresol (3-4 mg/ml) and benzyl alcohol (9 mg/ml). No general toxicity reactions were observed after subcutaneous administration of these agents. Clinical evaluation of the preservatives and buffers used in Norditropin SimpleXx showed that pain perception was similar between formulations containing phenol and benzyl alcohol, whereas m-cresol was associated with more painful injections than benzyl alcohol. Furthermore, patients reported more pain following injection of a citrate-buffered solution than after a histidine-buffered solution. More pain was also reported following large volume injections and following injections with solutions containing high protein concentrations. In summary, optimization of the preservative and buffer content of a liquid GH formulation may reduce injection pain and lead to improved patient compliance.
生长激素（GH）治疗对于患有生长激素缺乏症的儿童和成人，以及因慢性肾病、特纳综合征导致生长迟缓的患者和小于胎龄儿来说，是一种成功的医学疗法。对于所有这些病症，治疗都是长期的，患者需要多年每日皮下注射生长激素。因此，患者的依从性对于确保治疗效果至关重要。影响依从性的主要因素之一是注射疼痛。除了所使用的注射装置外，注射后的疼痛感知和局部组织反应取决于制剂中使用的防腐剂以及生长激素的浓度。注射疼痛也可能与缓冲物质和注射体积有关。已经开发出一种生长激素液体制剂诺德生长激素简易型（Norditropi SimpleXx），其在给药前无需复溶。该制剂使用苯酚（3毫克/毫升）作为防腐剂（以保护产品免受微生物降解或污染），并使用组氨酸作为缓冲剂。其他生长激素制剂中使用的替代防腐剂包括间甲酚（9毫克/毫升）和苯甲醇（3 - 9毫克/毫升）。缓冲剂包括柠檬酸盐和磷酸盐。苯酚已在药物制剂中成功用作防腐剂超过50年，被认为是一种安全有效的试剂，符合药物制剂中防腐剂的严格国际要求。在毒理学研究中，皮下注射苯酚（7.5毫克/毫升）、间甲酚（3 - 4毫克/毫升）和苯甲醇（9毫克/毫升）后，未观察到或仅观察到轻微的局部反应。皮下注射这些试剂后未观察到一般毒性反应。对诺德生长激素简易型中使用的防腐剂和缓冲剂的临床评估表明，含苯酚和苯甲醇的制剂之间的疼痛感知相似，而间甲酚注射比苯甲醇更疼痛。此外，患者报告注射柠檬酸盐缓冲溶液后的疼痛比组氨酸缓冲溶液后更严重。大量注射以及注射含高蛋白浓度溶液后也报告了更多疼痛。总之，优化生长激素液体制剂的防腐剂和缓冲剂含量可能会减轻注射疼痛并提高患者依从性。
