Transdermal Delivery of Buprenorphine Prodrugs

描述(申请人提供)：目前丁丙诺啡(BUP)用于阿片类药物滥用的治疗和疼痛控制。它也可能被不当使用和滥用为阿片类药物。在美国，丁丙诺啡以舌下和注射的形式销售。虽然该药物提供了有效的治疗，但这些形式的药物释放并不可取，因为它们的血药浓度峰值与副作用有关，而且作用持续时间较短。经皮给药减少了峰值相关的副作用，是慢性治疗的理想选择，因为一片贴片可以提供长达一周的恒定速率的药物。最初积极的初步数据鼓励AllTranz寻求资金，以开发新的丁丙诺啡前药，并通过经皮贴片或凝胶给药系统优化它们的使用。前体药物是经过化学修饰的母体药物，比母体更具皮肤渗透性，一旦穿过角质层，就会迅速分离回母体药物和前药部分。我们还将为这种阿片类药物输送系统创建威慑滥用的配方。与其他给药系统相比，经皮给药系统、贴剂和凝胶提供了许多改进。贴片和凝胶不需要吞咽，消除了口服副作用和苦涩的阿片类药物味道问题；也不需要用针刺破皮肤，消除疼痛和患者去看医生。通过皮肤渗透，药物可以直接进入体循环，避免首过效应，减少肝损害药物滥用者和危重患者的胃副作用和肝脏损害效应。欧洲可用的透皮BUP系统可以受益于更高的皮肤渗透率、粘附性的改善、滥用威慑机制、更小的贴片尺寸、使用后贴片中残留的药物更少，以及透皮凝胶的最终剂量灵活性。配方中需要的药物更少，这意味着当贴片被移除时，潜在滥用的药物更少，因为目前欧洲上市的贴片在治疗结束时仍含有50%的药物负荷。为了使滥用变得更加困难，我们将创建一种使用阿片类拮抗剂、非渗透性前药和/或包被颗粒的滥用威慑配方。改变后的拮抗剂将留在贴片或凝胶中，不会以治疗的速度进入人体，但如果试图通过注射或口腔途径滥用BUP，则会阻止BUP的兴奋效应。具体地说，我们的目标是合成BUP的前药，并用纳曲酮创建一种滥用威慑成分。然后，我们的目标是评估它们的体外人体皮肤渗透性，以获得最佳的通量。将对最佳药物进行组合和重新评估，以确保该配方在防止改变的纳曲酮输送的同时，在透皮吸收过程中增加前药物对BUP的渗透。在进一步的研究中，我们将开发原型产品并申请IND，并开始一期临床试验。我们将创造一种适销对路的透皮药物，它将在海洛因滥用和慢性疼痛的治疗中发挥重要作用。 与公共卫生相关：AllTranz正在寻求资金，以创建一种透皮前药物凝胶和改进的丁丙诺啡贴片，用于治疗阿片依赖和慢性疼痛。这些透皮系统将是滥用威慑，并比目前市场上销售的受控物质丁丙诺啡产品更有效。这种凝胶将是一种非侵入性的非口腔给药形式，具有终极的剂量灵活性，不需要贴片切割。这些贴片的设计将使其在使用后具有更少的残留药物含量，使它们从监管角度更具吸引力，如果可以使用更少的更具渗透性的药物，它们可能具有更好的粘附性，当在晚期疼痛中需要更高的释放率时，患者将受益于可能增加的药物加载，因为更快的前体药物渗透允许使用更小的贴片尺寸。

DESCRIPTION (provided by applicant): Currently buprenorphine (BUP) is used in the treatment of opioid abuse and for pain management. It can also be used improperly and abused as an opioid. In the United States, buprenorphine is marketed in sublingual and injectable forms. While the drug provides effective treatment, these forms of drug delivery are not desirable because of their peak plasma level related side effects and short duration of action. Transdermal delivery of drugs decreases peak-related side effects, and is ideal for chronic therapies as one patch can deliver a constant rate of drug for up to one week. Initial positive preliminary data has encouraged AllTranz to seek funding to develop new buprenorphine prodrugs and optimize their use through a transdermal patch or gel drug delivery system. Prodrugs are chemically modified parent drugs that are more skin permeable than the parent, and once they cross the stratum corneum quickly separate back into the parent drug and prodrug moiety. We will also create formulations for abuse deterrence for this opioid delivery system. Transdermal delivery systems, patches and gels, offer a number of improvements over other delivery systems. Patches and gels do not require swallowing, eliminating oral side effects and bitter opioid taste concerns; nor do they require skin puncture by needles, eliminating pain and patient visits to a physician. Permeation through the skin allows the drug to directly enter the systemic circulation and avoid the first pass effect, decreasing gastric side effects and liver damage effects in hepatocompromised drug abusers and critically ill patients. The transdermal BUP system that is available in Europe could benefit from a higher skin permeation rate, improvement in adhesion, an abuse deterrent mechanism, a smaller patch size, less residual drug remaining in the patch after use, and the ultimate dosing flexibility of a transdermal gel. Less drug needed in the formulation means less drug for potential abuse when the patch is removed, as currently the European marketed patches still contain fifty percent of their drug load at the end of treatment. To make abuse more difficult still, we will create an abuse deterrent formulation with opioid antagonist non-permeating prodrug and/or coated particles. The altered antagonist will remain in the patch or gel and not enter the body at a therapeutic rate, but will block the euphoria effect of BUP if abuse is attempted via the injectable or buccal routes. Specifically we aim to synthesize prodrugs of BUP and create an abuse deterrent component with naltrexone. We then aim to assess their in vitro human skin permeation for optimum flux. The optimal drugs will be combined and reassessed to see that the formulation provides increased permeation of BUP from prodrug during transdermal transport while the delivery of altered naltrexone is prevented. In further studies we will develop the prototype product and apply for an IND and begin Phase I clinical trials. We will create a marketable transdermal drug that will significantly ai in the treatment of heroin abuse and chronic pain. Public Health Relevance: AllTranz is seeking funding to create a transdermal prodrug gel and improved patch of buprenorphine for treatment of opioid dependence and chronic pain. These transdermal systems would be abuse deterrent and more effective than currently marketed products of the controlled substance buprenorphine. The gel would be a non-invasive non-oral dosage form with ultimate dosing flexibility without the need for patch cutting. The patches will be designed to have less residual drug content after use making them more appealing from a regulatory perspective, they could have better adhesion properties if less of a more permeable drug could be used, and when higher delivery rates are desirable in terminal pain the patient would benefit from the increased drug loading possible with the faster prodrug permeation allowing a smaller patch size to be used.