Long acting injected liposomal buprenorphine for chronic pain/addiction in people

产品说明：在本提案中，Comfort Care for Animals LLC（CCA）（麦迪逊，威斯康星州）将创建缓释（本阶段至少10-12天，最终目标为28天）可注射丁丙诺啡脂质体制剂，用于治疗人和动物的中度至重度术后疼痛或慢性疼痛，并用于治疗人的阿片类药物成瘾。这种创新的新型给药系统旨在解决广泛存在的问题，即为中度至重度疼痛提供长期，不可转移的阿片类药物疼痛缓解，同时消除镇痛中的低谷。我们选择丁丙诺啡用于此应用，因为它被广泛用作阿片类药物成瘾的维持治疗，以及手术和慢性疼痛的治疗，但我们的新型给药系统应该与各种其他药物一起使用。这种给药系统可以提供可靠的、持续时间长的镇痛或戒断症状抑制，由受过训练的医疗专业人员每月注射一次，从可能转移的药物中清除大量口服阿片类药物。两周到一个月的持续时间很好地对应于许多慢性疼痛患者的典型临床时间表。最后，脂质体的使用克服了与微球或植入物相关的炎症和过敏反应问题。在第一阶段，研究人员将：（1）确定我们专有的Quantload方法的最佳丁丙诺啡包封程序至少为75%，（2）确定体外释放特性和产品稳定性，通过1个月内泄漏小于20%确定，（3）在大鼠体内进行初步药代动力学研究。我们的初步数据表明，Quantload技术产生大于90%的装载效率，在体外4天内泄漏小于10%，在大鼠中血清浓度大于1 ng/mL长达12天。为了证明Quantload给药系统在该I期项目中的可行性，我们将在体外标准透析袋释放试验中获得至少4周的可重复释放期，在此期间每日样品中药物的累积释放量小于药物的20%，并且其可以在体内维持与镇痛水平相关的血清浓度长达一个月。在这样做的过程中，我们将证明商业上可行的脂质体丁丙诺啡产品的可行性，该产品可用于慢性疼痛或成瘾治疗。医生和兽医都将获得一种新的治疗工具，与目前的方法相比，这种工具需要更少的剂量，并能更好地缓解疼痛或控制对药物的渴望。这将提供积极的好处，降低与减少人员治疗时间相关的成本，为患者提供更好的疼痛治疗，消除与口服给药方案相关的低谷，并消除阿片类药物转移或患者环境中的意外暴露。

DESCRIPTION: In this proposal, Comfort Care for Animals LLC (CCA) (Madison, WI) will create slow-release (minimum 10-12 days in this Phase, with an ultimate goal of 28 days) injectable liposomal buprenorphine formulation to treat moderate to severe post-surgical or chronic pain in people and animals and to use as a treatment for opioid addiction in people. This innovative new drug-delivery system aims to address the widespread problem of providing long-term, non-divertible opioid pain relief for moderate to severe pain while also eliminating troughs in analgesia. We selected buprenorphine for this application because it is widely used as a maintenance therapy for opioid addiction, and as a treatment for surgical and chronic pain, but our novel delivery system should work with a large variety of additional drugs. This delivery system could provide reliable, long-duration analgesia or withdrawal symptom suppression from a single, monthly injection administered by trained medical professionals, removing a large amount of oral opiates from the pool of potentially-diverted drugs. The two week to month-long duration corresponds well to the typical, clinical schedule of many chronic-pain patients. And, finally, the use of liposomes overcomes the issues of inflammation and allergic reaction that have been associated with microspheres or implants. In Phase I, the investigators will: (1) determine the optimal buprenorphine encapsulation procedure for our proprietary Quantload methodology of at least 75%, (2) determine in vitro release characteristics and product stability as determined by leakage of less than 20% over a period of 1 month, and (3) conduct preliminary pharmacokinetics in vivo in rats. Our preliminary data indicate that Quantload technology produces greater than 90% loading efficiency, with less than 10% leakage in vitro over 4 days, and up to 12 days of serum concentrations greater than 1 ng/mL in rats. In order to demonstrate feasibility of the Quantload delivery system in this Phase I project, we will obtain a repeatable release period of at least 4 weeks in a standard dialysis bag release assay in vitro and a cumulative release of drug in daily samples over that period of less than 20% of the drug and that it can maintain serum concentrations in vivo for a period of up to one month that correlates with analgesic levels. In so doing, we will demonstrate the feasibility of a commercially-viable liposomal buprenorphine product that may be marketed either for chronic pain or addiction treatment. Both physicians and veterinarians will gain a new treatment tool that requires fewer doses and provides better pain relief or control of drug cravings when compared to current methods. This will offer positive benefits of reduced costs associated with reduced personnel time for treatments, better pain treatment for patients that eliminates troughs associated with oral dosing regimens, and elimination of opioid diversion or accidental exposure in the patient's environment.