Dothan David, Raisin Galiya, Malchi Nadav, Gordon Avi, Touitou Dan, Chertin Boris
The Department of Urology, Shaare Zedek Medical Center, Faculty of Medicine, Hebrew University, 91031, Jerusalem, Israel.
Int Urol Nephrol. 2022 Sep;54(9):2167-2174. doi: 10.1007/s11255-022-03280-8. Epub 2022 Jul 3.
Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic debilitating condition of unknown etiology. Intravesical lidocaine demonstrated pain relief in patients with IC/BPS. Intravesical oxybutynin has shown therapeutic efficacy in patients with urinary bladder disorders. However, loss of drug with urination requiring multiple administrations and immediate dilution of drug concentration by residual urine in the bladder mitigated intravesical use of both drugs in clinical practice. The aim of this study was to evaluate the efficacy and safety of fixed-dose combination of lidocaine and oxybutynin, forming in the urine a sustained delivery system named TRG-042.
In-vitro, we have quantitatively tested the concentration of lidocaine and oxybutynin released from TRG-042 in artificial urine. Following the successful in-vitro study weekly formulation of TRG-042 was instilled intravesically to six pigs. All pigs were followed with cystoscopy to assess the gradual degradation of the delivery system and to evaluate bladder response over 7 days. Daily blood samples were tested for drug quantization.
In-vitro studies have demonstrated oxybutynin and lidocaine sustained release over 1-week period coupled with full degradation of the matrix. None of the animals demonstrated any side effects following instillation. Cystoscopy examination observed gradual disintegration of TRG-042 over 1-week with no adverse reaction to the mucosa. Plasma concentrations of oxybutynin and lidocaine were uniformly stable over the 1-week period [1.46 ± 0.176 ng/ml and 4.29 ± 2.48 ng/ml respectively(mean ± SEM)] with almost undetectable concentration of N-desethyloxybutynin (NDO)[0.032 ± 0.068 ng/ml].
The in-vitro and animal data demonstrated that TRG-042 can safely be used for intravesical sustained release of lidocaine and oxybutynin in the treatment of BPS/IC.
间质性膀胱炎/膀胱疼痛综合征（IC/BPS）是一种病因不明的慢性致残性疾病。膀胱内注射利多卡因可缓解IC/BPS患者的疼痛。膀胱内注射奥昔布宁已显示出对膀胱疾病患者的治疗效果。然而，排尿时药物流失需要多次给药，且膀胱内残留尿液会立即稀释药物浓度，这在临床实践中限制了这两种药物的膀胱内使用。本研究的目的是评估利多卡因和奥昔布宁固定剂量组合的疗效和安全性，该组合在尿液中形成一种名为TRG-042的持续给药系统。
在体外，我们定量测试了TRG-042在人工尿液中释放的利多卡因和奥昔布宁的浓度。在体外研究成功后，每周将TRG-042制剂膀胱内注入6头猪体内。所有猪均接受膀胱镜检查，以评估给药系统的逐渐降解情况，并在7天内评估膀胱反应。每天采集血样进行药物定量检测。
体外研究表明，奥昔布宁和利多卡因在1周内持续释放，同时基质完全降解。给药后，没有动物出现任何副作用。膀胱镜检查观察到TRG-042在1周内逐渐分解，对黏膜无不良反应。在1周内，奥昔布宁和利多卡因的血浆浓度均匀稳定[分别为1.46±0.176 ng/ml和4.29±2.48 ng/ml（平均值±标准误）]，N-去乙基奥昔布宁（NDO）的浓度几乎检测不到[0.032±0.068 ng/ml]。
体外和动物实验数据表明，TRG-042可安全用于膀胱内持续释放利多卡因和奥昔布宁，以治疗BPS/IC。
