Portable Transdermal Acoustic Patch for Delivery of Large Molecules to Improve HIV Patient Medication Regime Compliance by Elimination of Side-Effects, Including Injection Site Reactions

 描述（由申请人提供）：本IIB期SBIR完成了开发，进行了深入的临床前测试，并完成了便携式经皮声学贴片（TAP）的验证和确认，用于输送大分子，以通过消除副作用（包括注射部位反应）来提高HIV患者用药方案的依从性。全世界有近3 700万人感染艾滋病毒，其中约240万人在北美、西欧和中欧。艾滋病毒的主要治疗方法是高效抗逆转录病毒疗法，它使用多种药物来阻止病毒复制。艾滋病毒药物治疗方案必须采取近乎完美的遵守，以最大限度地发挥效益，防止病毒耐药性的发展。如果HIV病毒对治疗产生耐药性，必须尝试补救药物，如融合抑制剂T-20。虽然T-20非常有效，但除注射疼痛外，一个主要的副作用是注射部位反应（ISR），98%的患者会出现这种情况，尽管存在依从性差的风险，但在一项临床研究中，患者的依从性（处方剂量的95%）降低至58%。需要一种无不良副作用的抗逆转录病毒药物输送方法，以及一种可在发展中国家使用的低成本、简单的输送方法。TAP使用~20 kHz超声波轻轻打开皮肤角质层中的微通道，使大分子（> 500 Da）药物（如T-20）能够到达血液系统。TAP被设计为在低声强水平（100 mW/cm 2）下工作，不会引起显著的皮肤变化。TAP是一种平台技术，可提供大分子药物，如广泛中和抗体、新型进入抑制剂和T-20，而无需ISR，从而提高患者依从性和积极的治疗临床结局。II期项目符合特定目的，证明在30天猪研究（N = 31）中，T-20可以以临床相当的剂量输送，而不会造成皮肤损伤。IIB期将确定经皮递送的T-20的剂量线性，并证明在体内猪模型中，T-20的临床剂量（≥ 2.0 µ g/mL）在三个不同解剖区域（皮肤厚度）的递送。IIB阶段具体目标：目标1 TAP设计和T-20活动验证（1 - 12个月）。验收标准：T-20在体外超声应用30分钟后保持HIV抗病毒活性（p <0.05）。60/60（如适用）有源贴片和10/10控制盒通过验证测试：a）性能，B）安全性（包括IEC），c）运输振动和d）可靠性和寿命。15/15例受试者通过可用性测试。目的2优化给药和治疗达到临床T-20血浆水平（8 - 14个月）。验收标准：TAP（Beta-II）治疗持续时间和T-20剂量确定为治疗一周后在猪模型中产生至少2.0 µ g/mL的T-20 Ctrough水平。目标3：针对FDA试验用器械豁免的猪皮研究（15 - 24个月）。验收标准。证明在3个不同解剖区域的猪体内皮肤中，采用最佳处理参数可实现足够的T-20生物利用度（Ctrough ≥ 2.0 µ g/mL）。

 DESCRIPTION (provided by applicant): This Phase IIB SBIR finalizes development, conducts in depth preclinical testing, and completes Verification and Validation of the Portable Transdermal Acoustic Patch (TAP) for Delivery of Large Molecules to Improve HIV Patient Medication Regime Compliance by Elimination of Side-Effects, Including Injection Site Reactions. Nearly 37 million people worldwide are living with HIV, with roughly 2.4 million in North America and Western and Central Europe. The main treatment approach for HIV is Highly Active Antiretroviral Therapy, which uses multiple medications to arrest viral replication. HIV medication regimens must be taken with near perfect compliance to maximize benefits and prevent the development of viral resistance. If the HIV virus becomes resistant to treatment, salvage drugs, such as the fusion inhibitor T-20, must be tried. While T- 20 is very effective, a major side-effect - additional to injection pain - is an injection site reaction (ISR), which is experienced by 98% of patients and reduced the rate of adherence (95% of prescribed doses) of patients in one clinical study to 58%, despite the risks of poor compliance. A method to deliver antiretrovirals without adverse side effects is needed, as well as a low-cost, simple delivery approach usable in developing nations. TAP uses ~20 kHz ultrasonic waves to gently open micro-channels in the skin's stratum corneum, enabling large molecule (> 500 Da) medications like T-20 to reach the blood system. TAP is designed to operate at low acoustic intensity levels (100mW/cm2) that do not cause significant skin changes. TAP is a platform technology that delivers large molecule drugs such as broadly neutralizing antibodies, novel entry inhibitors, and T-20 without the ISR - leading to greater patient compliance and positive therapeutic clinical outcomes. The Phase II project met the Specific Aims, demonstrating that T-20 could be delivered at clinically comparable doses, without causing skin damage, in a 30 day porcine study (N=31). The Phase IIB will determine the dose linearity of T-20 delivered transdermally, and demonstrate delivery of a clinical dose (≥ 2.0µg/mL) of T-20 at three differet anatomical regions (skin thicknesses) in an in vivo porcine model. Phase IIB Specific Aims: Aim 1 TAP design and T-20 activity verified (Months 1-12). Acceptance Criteria: T-20 maintains HIV antiviral activity in vitro after 30-min ultrasound application (p<0.05). 60/60 (where applicable) Active Patches and 10/10 Control Boxes pass Verification tests: a) Performance, b) Safety (including IEC), c) Shipping vibration, and d) Reliability and Lifetime. 15/15 Subjects pass Usability. Aim 2 Optimized dosing and treatment achieve clinical T-20 plasma levels (Months 8-14). Acceptance Criteria: TAP (Beta-II) treatment duration and T-20 dosage determined that produce T-20 Ctrough levels of at least 2.0 µg/mL in porcine model after one week of treatment. Aim 3 Porcine skin study towards FDA Investigational Device Exemption (Months 15-24). Acceptance Criteria. Demonstrate sufficient T-20 bioavailability (Ctrough ≥ 2.0 µg/mL) is achieved with optimal treatment parameters for porcine skin in vivo at 3 different anatomical regions.