Transdermal Delivery of Buprenorphine Prodrugs

丁丙诺啡前药的透皮递送

• 批准号: 7611813
• 负责人: Audra L. Stinchcomb
• 金额: $ 11.5万
• 依托单位: ALLTRANZ, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7611813
• 关键词: Adhesions; Adverse effects; Back; Blood Circulation; Buprenorphine; Chronic; Chronically Ill; Critical Illness; Data; Deglutition; Diffusion; Dosage Forms; Dose; Dose-Rate; Drug Delivery Systems; Drug Formulations; Euphoria; Europe; European; Funding; Gel; Heroin Abuse; Human; In Vitro; Injectable; Injection of therapeutic agent; Liver; Marketing; Mastication; Naltrexone; Narcotic Antagonists; Nausea and Vomiting; Needles; Opiate Addiction; Opioid; Oral; Pain; Pain management; Parents; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Physicians; Plasma; Prodrugs; Property; Puncture procedure; Research; Residual state; Route; Skin; Stomach; Stratum corneum; Subutex; System; Taste Perception; Therapeutic; Transdermal substance administration; United States; Visit; buprenorphine abuse; chronic pain; design; drug abuser; effective therapy; flexibility; improved; opioid abuse; particle; prevent; prototype; public health relevance

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.

描述（由申请人提供）：目前丁丙诺啡（BUP）用于治疗阿片类药物滥用和疼痛管理。它也可以被不当使用和滥用作为阿片类药物。在美国，丁丙诺啡以舌下和注射形式销售。虽然药物提供了有效的治疗，但这些形式的药物递送是不期望的，因为它们的峰值血浆水平相关的副作用和短的作用持续时间。药物的经皮递送减少了与峰值相关的副作用，并且对于慢性治疗是理想的，因为一个贴剂可以递送恒定速率的药物长达一周。最初积极的初步数据鼓励AllTranz寻求资金开发新的丁丙诺啡前药，并通过透皮贴剂或凝胶药物递送系统优化其使用。前药是化学修饰的母体药物，其比母体药物更具有皮肤渗透性，并且一旦它们穿过角质层就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递送系统创建滥用威慑制剂。经皮给药系统、贴剂和凝胶剂与其他给药系统相比提供了许多改进。贴片和凝胶不需要吞咽，消除了口服副作用和苦味阿片类药物的味道问题;它们也不需要用针头刺穿皮肤，消除了疼痛和患者就医。通过皮肤渗透允许药物直接进入体循环，避免首过效应，减少肝功能损害的药物滥用者和重症患者的胃副作用和肝损伤效应。在欧洲上市的透皮BUP系统可以受益于更高的皮肤渗透率、粘附力的改善、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给药灵活性。制剂中所需的药物较少意味着当贴剂被移除时潜在滥用的药物较少，因为目前欧洲市售的贴剂在治疗结束时仍含有其载药量的50%。为了使滥用更加困难，我们将创建具有阿片样物质拮抗剂非渗透性前药和/或包衣颗粒的滥用威慑制剂。改变后的拮抗剂将保留在贴剂或凝胶中，不会以治疗速率进入体内，但如果试图通过注射或口腔途径滥用，则会阻断BUP的欣快效应。具体来说，我们的目标是合成BUP的前药，并与纳洛酮一起产生滥用威慑成分。然后，我们的目标是评估其在体外人体皮肤渗透的最佳流量。最佳药物将被组合并重新评估，以观察制剂在经皮转运期间提供来自前药的BUP的增加的渗透，同时防止改变的纳洛酮的递送。在进一步的研究中，我们将开发原型产品并申请IND，并开始I期临床试验。我们将创造一种可销售的透皮药物，在治疗海洛因滥用和慢性疼痛方面具有显著的疗效。 公共卫生相关性：AllTranz正在寻求资金来开发透皮前药凝胶和改进的丁丙诺啡贴剂，用于治疗阿片类药物依赖和慢性疼痛。这些透皮系统将是滥用威慑，比目前市售的受控物质丁丙诺啡产品更有效。该凝胶将是一种非侵入性非口服剂型，具有最终的剂量灵活性，而无需贴片切割。贴剂将被设计为在使用后具有较少的残留药物含量，使得它们从监管角度来看更有吸引力，如果可以使用较少的更可渗透的药物，则它们可以具有更好的粘附性质，并且当在终末疼痛中期望更高的递送速率时，患者将受益于可能的增加的药物负载，其中更快的前药渗透允许使用更小的贴剂尺寸。