Insulin human (rDNA origin, Novo Nordisk)

Marks the first-time insulin has ever been administered in a form other than injection Testing shows insulin administered in transdermal form can persist much longer in the blood than insulin administered by subcutaneous injection Patients with Type 1 diabetes could replace up to 20 insulin injections over a period of five days Work completed within framework of Proof-of-Concept project carried out jointly with Warsaw-based Bioton S.A. Wroclaw, Poland--(News - April 30, 2024) - Wrocław, Poland-based Biotts, a biopharmaceutical company and global pioneer in Transdermal Drug Delivery (through the skin in the form of patches without injections), has become the world's first company to successfully complete transdermal delivery of insulin. The Proof-of-Concept project, carried out jointly with Warsaw, Poland-based Bioton, has just concluded, with an active form of insulin successfully transferred using Biotts' patented transdermal technology. The project objectives have been met with results so promising that both companies are prepared to proceed to the next phase. "This is a major breakthrough. In addition to proving that insulin can successfully be delivered through the skin, this study also demonstrated that insulin administered in this way can persist in the body significantly longer compared with injected insulin," says Dr. Paweł Biernat, CTO and co-founder of Biotts. "Animal testing showed that when insulin was transferred through the skin it remained at a constant level in the body for at least five days, comparing very favorably with injected insulin, which remains active for less than one day. It is also worth noting that the insulin administered in transdermal form, had a much more stable concentration pro that delivered by injection, which is a prime benefit of transdermal drug delivery." Dr. Biernat cautions that while these results are very impressive, the company is still in the early stages of its research. "This is another innovative project for Bioton in an effort to help patients with diabetes. Using existing and new molecules with this new drug delivery mechanism will make our products more widely available, as well as reduce the burden for people with diabetes. We are proud to be on this journey with another Polish biotech company. Biotts and we remain committed to improving patient care," says Bioton CEO Jeremy Launders. He adds that drug delivery devices have a pivotal role in ensuring effective treatments and enhancing the quality of life of patients. Positive results from the Proof-of-Concept study have proven the effectiveness of Biotts' patented transdermal carrier system MTC-YTM once again. Biotts has demonstrated that large molecules, much larger than the 500 Da (human insulin is a 5808 Da - monomer - molecule) reported in earlier studies, can be efficiently transported through the skin. Insulin in the form of a transdermal patch can realistically improve patient care and convenience while significantly reducing medical waste. "An important takeaway from the study is that we showed bioavailability of transdermal insulin of 55%. This means that patients with type 1 diabetes will be able to replace up to 20 insulin injections over a period of five days with a single patch that only needs to be worn for a few hours. Thus, patients will receive better and more comfortable treatment, without an increase in the cost of therapy, and without generating excess medical waste. This confirms that this state-of-the-art product can be a viable alternative for patients who are seeking non-invasive alternatives to diabetes treatment. The number of these patients is increasing every year. This is especially meaningful considering the impact this can have on children with T1D, particularly in the developing world. Our goal is to provide patients with effective treatment in the most convenient way possible, and the Proof-of-Concept results demonstrate that we are getting closer than ever to fulfilling that promise," says Jan Henk Hendriks, CEO of Biotts. Biotts is the first company to successfully complete transdermal delivery of insulin. "Patients will receive better and more comfortable treatment, without an increase in the cost of therapy, and without generating excess medical waste," says Jan Henk Hendriks, CEO of Biotts. To view an enhanced version of this graphic, please visit: "This is a major breakthrough. In addition to proving that insulin can successfully be delivered through the skin, this study also demonstrated that insulin administered in this way can persist in the body significantly longer compared with injected insulin." - Dr. Pawel Bierant, Chief Technical Officer and Co-Founder of Biotts. To view an enhanced version of this graphic, please visit: The company is currently taking next steps to bring transdermal insulin to market and make it available to patients around the world as quickly as possible, conceivably as soon as 2027. For more information, visit: . About Biotts Headquartered in Wrocław, Poland, Biotts is driven by its mission to enhance the quality of life for patients through the relentless pursuit of technological innovation. Comprised of a dedicated team of scientists and pharmacists boasting decades of collective experience, Biotts specializes in the development of proprietary drug products and transdermal systems. The company is committed to crafting impactful solutions that empower patients and revolutionize healthcare outcomes. With a passion for pioneering advancements, Biotts is at the forefront of shaping a brighter, healthier future for individuals worldwide. About Bioton S.A. European Biotech Company producing human insulin: API and finished forms in cartridges and vials. For more than 20 years, we have been providing people with diabetes with efficacious and safe medicines. Bioton S.A. is an unquestionable leader on the Polish market, and in the world's top eight commercial manufacturers of recombinant human insulin. Bioton S.A. continuously invests in the development of Polish biotechnology. We were the first company in Poland, which in cooperation with a Polish scientific institute, managed to commercialize the results of the Biotech Transfer. We apply the most current therapeutic and technological solutions to alleviate diabetes treatment for patients. We strive to build comprehensive solutions for the prevention and treatment of diabetes. Bioton S.A. offers CMO/CDMO and QC services. Our activities are based on QbD in line with cGMP standards. Bioton S.A. supplies also a range of innovative gastroenterological FSMP (Foods for Special Medical Purposes). Media contact Resource Advantage Dan Green dgreen@resourceadvantage.com To view the source version of this press release, please visit

德谷门冬双胰岛素不仅经济实惠、用药简单，而且还具有依从性高、低血糖风险低、药物副作用少等优点。 随着糖尿病病程的延长，患者胰岛β细胞功能逐渐减退并持续胰岛素抵抗，胰岛素将成为部分2型糖尿病（T2DM）患者改善血糖控制、达到良好糖化血红蛋白（HbA1c）目标的主要治疗手段。胰岛素的研发目标是能够模拟正常生理性胰岛素的分泌，即不但能够提供良好的餐时胰岛素覆盖，而且同时达到良好的基础覆盖，如目前常见的双时相胰岛素，但由于其两种成分通常互相干扰而无法达到稳定长效的血糖控制[1]。而基础+餐时胰岛素的给药模式虽然能够模拟胰岛素生理分泌的过程，但由于给药过程繁琐、易用混等问题导致血糖无法达标[2] 。 随着胰岛素制剂更新迭代，临床上面临着更换胰岛素治疗的有效性及其带来的安全性问题，国外研究表明，与预混胰岛素、基础胰岛素等相比，德谷门冬双胰岛素（insulin degludec and insulin aspart, IDegAsp）对T2DM患者的血糖控制更佳[3-5]。 据调查，我国居民喜爱碳水程度居全球首位，对于日常碳水食用比例越高，其餐后血糖将会相应的增高！ IDegAsp是2019年进入我国的新型可溶性双胰岛素制剂，由70%长效德谷胰岛素和30%短效门冬胰岛素构成，其两种成分相互独立，保留了各自药动学和药效学特征[6]。因此可提供较佳的餐时和基础胰岛素覆盖。全球性Ⅲ期临床试验结果表明，每日2次给予IDegAsp与门冬胰岛素30（insulin aspart 30,  IAsp30）相比，患者餐后血糖（PPG）及空腹血糖（FPG）控制更佳、低血糖风险更低[7]。也就是说， IDegAsp能有效解决因食用碳水过多而导致餐后血糖升高的问题！ 现为大家分享1例确诊为T2DM患者经治疗后，转换为IDegAsp来长期控制空腹及餐后血糖的案例。 病例： 患者男，33岁。以“口干、多饮、多尿、消瘦3月余”为主诉入院。3月前，患者出现口干、多饮、多尿、体重减轻4 kg，但未就诊。此次就诊后测血糖：FPG 11.64 mmol/L，餐后2小时血糖 20.58 mmol/L，HbA1c 9.40%。 查体：身高：172 cm，体重82 kg，体重指数（BMI）27.7 k g/m2，腰围90 cm。 辅助检查：血糖相关：FPG 11.64 mmol/L，餐后2小时血糖 （2h-PPG）20.58 mmol/L， HbA1c 10.1%。尿糖4+，酮体+。患者馒头餐试验结果见表1。血脂分析：甘油三酯（TG）2.23 mmol/L，总胆固醇（TC）6.56 mmol/L，高密度脂蛋白胆固醇（HDL-C）1.12 mmol/L，低密度脂蛋白胆固醇（LDL-C）4.62 mmol/L。肝功能：谷丙转氨酶（ALT）64 U/L 。肾功能：血肌酐41.2 μmol/L，估算的肾小球滤过率（eGFR）120.9 ml/（min·1.73m2），24小时尿微量白蛋白20 mg，尿白蛋白/肌酐12.5 mg/g。。 表1：患者馒头餐试验结果 心脏超声：二尖瓣、三尖瓣轻度关闭不全，左室收缩功能测定在正常范围。 治疗：腹部+泌尿系+前列腺+阴茎超声：脂肪肝，余未见异常。颈动脉+双下肢动脉超声：双下肢动脉二维及彩色多普勒超声未见异常，双侧颈动脉二维及彩色多普勒超声未见明显异常。 糖尿病并发症筛查：内脏脂肪测定：内脏脂肪面积122 cm2，腹部皮下脂肪面积227 cm2。下肢多普勒检查提示：右侧下肢ABI指数是1.08，左侧下肢ABI指数是1.12，提示患者右侧下肢动脉供血正常，左侧下肢动脉供血正常。感觉震动阈值检查：提示患者未发生糖尿病周围神经病变。眼底病变筛查：右眼无糖尿病视网膜病变，未见明显异常；左眼无糖尿病视网膜病变，未见明显异常。 入院诊断 1.代谢综合征（2型糖尿病、混合性高脂血症、中心型肥胖）；2.包皮炎；3.肝功能损害；4.维生素D缺乏；5.脂肪肝；6.二尖瓣轻度关闭不全；7.三尖瓣轻度关闭不全。 入院治疗方案 指导饮食，加强运动；胰岛素泵强化降糖；己酮可可碱注射液改善循环；阿托伐他汀钙片20 mg调脂、稳定斑块；甘草酸类护肝；泌尿外科会诊给予外用药物治疗。 胰岛素泵强化降糖方案为：入院后予胰岛素泵18 U（三餐前6U-6U-6U）降糖和二甲双胍恩格列净片500 mg bid治疗，第9日调整胰岛素泵用量至20 U（三餐前6U-6U-6U）。入院后予胰岛素泵的治疗方案和结果如图1所示。 图1.入院后予胰岛素泵降糖治疗的治疗方案及血糖情况 胰岛素泵治疗将血糖降至可控范围后，调整治疗方案为每天早晚餐前皮下注射德谷门冬双胰岛素18 U-18 U+早晚餐前二甲双胍恩格列净片500 mg Bid。 讨论 此病例特点为： 1.青年男性，病程短； 2.口干、多饮、多尿、消瘦3月； 3.查体：BMI ：27.7 kg/m2，腹型肥胖； 4.入院后辅助检查； HbA1c 10.1%，血脂异常，脂肪肝。入院后给予胰岛素泵和二甲双胍将患者的空腹血糖及餐后血糖调至预期目标。 该患者的血糖控制目标为：空腹血糖4.4～7.0 mmol/L；非空腹血糖＜10 mmol/L；HbA1c ＜7%。该患者后期选用德谷门冬双胰岛素每天两次早晚餐皮下注射。最终降糖方案为早晚餐前德谷门冬双胰岛素18 U-18 U+早晚餐前二甲双胍恩格列净片500 mg Bid。 院外电话回访显示，患者无低血糖事件发生；自行监测FPG为5~6 mmol/L，2h-PPG 8～10 mmol/L；通过加强饮食控制及运动后，体重较前下降3 kg。 目前临床短期胰岛素强化治疗方案主要包括胰岛素泵皮下持续输注（CSII）、基础-餐时胰岛素1～3次/d注射、预混胰岛素2～3次/d注射等[8]。CSII因经济等原因在国内没有广泛应用。餐时-基础胰岛素（4次/d）或预混胰岛素类似物（3次/d）治疗患者需住院，接受多次胰岛素注射，血糖监测频繁，影响治疗依从性。预混人胰岛素2次/d注射难以满足临床需求，中、晚餐前以及夜间低血糖风险较高，降糖效果及治疗依从性低于预混胰岛素类似物[9]。 因此，寻找注射次数少、治疗方案简单、安全性高的胰岛素强化治疗方案是临床需求。 从患者角度来看，IDegAsp副作用小、经济实惠、用药简单。从医生角度来看，其依从性高、低血糖风险小、药物副作用小、心脑血管事件风险低。IDegAsp是按固定配比7：3的德谷胰岛素（IDeg）和门冬胰岛素（IAsp）构成，在溶液中可保持独立的化学稳定性，且皮下注射后可发挥各自的药代动力学作用。基础成分德谷胰岛素可在皮下注射后形成稳定的可溶性多六聚体储库，德谷胰岛素单体逐渐从该储库中分离，被持续和缓慢地吸收入循环系统，并通过脂肪酸侧链与白蛋白可逆结合，从而获得超长、平稳的降糖作用。餐时成分门冬胰岛素在注射后以单体的形式迅速入血起效，发挥餐时胰岛素作用[10]。预混胰岛素、基础胰岛素、基础-餐时胰岛素方案控制不佳的患者可转换为IDegAsp方案治疗，降糖效果和安全性良好，总体低血糖及确证性夜间低血糖发生率降低[11-13]。 总而言之，德谷门冬双胰岛素不仅经济实惠、用药简单，而且还具有依从性高、低血糖风险低、药物副作用少等优点。从我国国情角度来看，我国碳水化合物供能比高，T2DM餐后血糖升高明显，德谷门冬双胰岛素既能快速、高效的降低餐后血糖和空腹血糖，而且还能使血糖达到一个稳定状态，此外，还具有降低确证性低血糖、夜间低血糖的发生率等优势！ 参考文献 [1] LECHLEITNER M, CLODI M, ABRAHAMIAN H, et al. Insulin  therapy of type 2 diabetes mellitus （Update 2019） ［J］. Wien Klin  Wochenschr, 2019, 131（Suppl 1）: 39 - 46. [2] SHARMA AK, TANEJA G, KUMAR A, et al. Insulin analogs:  glimpse on contemporary facts and future prospective ［J］. Life  Sci, 2019, 219: 90 - 99. [3] FUJIMOTO K, IWAKURA T, ABURAYA M, et al. Twice-daily  insulin degludec/insulin aspart effectively improved morning and  evening glucose levels and quality of life in patients previously  treated with premixed insulin: an observational study［J］.  Diabetol Metab Syndr, 2018, 10（1）: 64. [4] JANG HN, YANG YS, OH TJ, et al. Low fasting glucose-to estimated average glucose ratio was associated with superior  response to insulin degludec/aspart compared with basal insulin in  patients with type 2 diabetes ［J］. J Diabetes Investig, 2022, 13  （1）: 85 - 93. [5] FULCHER GR, AKHTAR S, AL-JASER SJ, et al. Initiating or  switching to insulin degludec/insulin aspart in adults with type2  diabetes: a real-world, prospective, non-interventional study across  six countries ［J］. Adv Ther, 2022, 39（8）: 3735 - 3748. [6] GLASTRAS SJ, COHEN N, DOVER T, et al. The clinical role of  insulin degludec/insulin aspart in type 2 diabetes: an empirical  perspective from experience in Australia ［J］. J Clin Med, 2020, 9 （4）: 1091. [7] CHO KY, NAKAMURA A, OBA-YAMAMOTO C, et al. Switching to once-daily insulin degludec/insulin aspart from basal insulin  improves postprandial glycemia in patients with type 2 diabetes mellitus: randomized controlled trial［J］. Diabetes Metab J. 2020 Aug;44(4):532-541. [8] 2型糖尿病短期胰岛素强化治疗专家共识.编写委员会.2 型糖尿病短期胰岛素强化治疗专家共识（2021年版）.中华糖 尿病杂志，2022，14：21-31. [9] Wen WL，Tsai KB，Lin YH，et al.Successful management of type IV hypersensitivity reactions to human insulin analogue with injecting mixtures of biphasic insulin aspart and dexamethasone.J Formos Med Assoc，2019，118：843-848. [10]Haahr H，Fita EG，Heise T.A review of insulin Degludec/insulin Aspart：pharmacokinetic and pharmacodynamic properties and their implications in clinical use.Clin Pharmacokinet，2017，56：339-354. [11] Philis TA，Astamirova K，Gupta Y，et al.Similar glycaemic control with less nocturnal hypoglycaemia in a 38-week trial comparing the IDegAsp co-formulation with insulin glargine U100 and insulin aspart in basal insulin-treated subjects with type 2 diabetes mellitus.Diabetes Res Clin Pract，2019，147：157- 165. [12] Franek E，Haluzík M，Canecki VS，etal.Twice-daily insulin degludec/insulin aspart provides superior fasting plasma glucose control and a reduced rate of hypoglycaemia compared with biphasic insulin aspart 30 in insulin-naïve adults with type 2 diabetes. Diabet Med，2016，33：497-505. [13] Kumar A，Franek E，Wise J，et al.Efficacy and safety of once-daily insulin degludec/insulin aspart versus insulin glargine（U100）for 52 weeks in insulin-naïve patients with type 2 diabetes：a random ized controlled trial.PLoS One，2016，11：e0163350. 作者简介： 张君   教授 •南宁市第二人民医院内分泌科 •副主任医师，硕士研究生 •广西中医药大学本科毕业，广西医科大学内分泌硕士研究生，现任南宁市医学会内分泌学分会秘书，南宁市医学会预防医学会委员，善长于糖尿病及相关并发症，甲亢、代谢紊乱等内分泌相关疾病，2019年在广州南方进修学习，至今发表论文数篇，具有扎实的中、西医系统理论，熟悉内科常见病、急、重病的救治。