BZB Group

Bupisome*

DEVELOPMENT AND CLINICAL EVALUATION OF BUPISOME: A NOVEL, ULTRA-LONG ACTING LOCAL ANESTHETIC FOR THE MANAGEMENT OF PAIN

Yechezkel Barenholz PhD, Laboratory of Membrane and Liposome Research, Hebrew University, Hadassah Medical School, Elyad Davidson MD, Department of Anesthesiology, Hadassah University Hospital, Jerusalem Israel and Gilbert J. Grant MD, Department of Anesthesiology, New York University School of Medicine, New York University, New York, NY

ABSTRACT

            Pain resulting from surgery, trauma, and various medical conditions causes considerable human suffering. Furthermore, pain has deleterious effects on many physiological functions, which may lead to medical complications, cause additional suffering, delay hospital discharge, and increase health care costs. For example, postoperative inhibition of deep breathing and coughing due to a painful incision may lead to pneumonia.

Currently, pain tends to be inadequately treated, and existing therapeutic options have many drawbacks. Systemically administered opiates, the most commonly prescribed treatment for moderate-to-severe pain, are associated with many side effects that negatively impact many physiologic functions, and may result in respiratory depression, sedation, impaired bowel motility, urinary retention, nausea and vomiting. Healthcare providers often fail to adequately treat pain due to fears of complications of the therapy itself. Opiates, for example, are frequently under-dosed for worry of producing respiratory depression and addiction. Patients often share these fears and therefore fail to request sufficient medication, perpetuating the inevitable cycle of pain, suffering, and secondary complications.

A more rational approach to treating pain would be to numb the painful site, for example, by directly injecting local anesthetics into a wound. However, because currently available local anesthetics are relatively small molecules, they are rapidly removed from the injection site and the pain relief they provide is thus short-lived, lasting for only a few hours. There is a clear need for a local anesthetic with a prolonged duration of action.

We have developed an ultra-long acting local anesthetic formulation, liposomal bupivacaine (BUPISOME). Liposomes are carrier vehicles composed of naturally occurring lipid and cholesterol, the building blocks of all cells. We pack the liposomes with bupivacaine, a local anesthetic that has been in clinical use for more than 30 years. The relatively large size of the liposomes assures that they remain at the site of administration for a prolonged time, where they act as a depot from which the encapsulated bupivacaine is slowly released. Thus, the nerves in the vicinity are continually bathed in a small amount of local anesthetic, which is sufficient to produce long lasting analgesia, up to 2 to 3 days. Furthermore, by varying the amount of bupivacaine encapsulated in the liposomes, we can control the duration of analgesia.

BUPISOME is a proprietary formulation (US patent # 6,162,462, issued December 19, 2000:  “Liposomal bupivacaine compositions prepared using an ammonium sulfate gradient.”), developed by a collaborative effort between Hebrew University-Hadassah Medical School and New York University Medical School. The formulation is based on techniques that enable efficient loading of drug into the liposomal vehicle, resulting in a favorable drug-to-lipid ratio, nearly 10-fold greater than any published liposomal bupivacaine formulation. Furthermore, this particular formulation yields a controllable rate of bupivacaine release.

In pre-clinical animal testing and in human trials, BUPISOME produced predictable, reliable, and long-lasting analgesia following a single administration. Animal studies demonstrated its safety and superior efficacy to standard bupivacaine. Based on this data, BPISOME was registered as an Investigational New Drug (IND) with the U.S. Food and Drug Administration (FDA). Human studies (phase I & II) performed in volunteers and patients at Hadassah Hospital and at NYU have confirmed its safety and efficacy.

Further development is required in order to bring BUPISOME to market. First, the formulation requires optimization to improve its shelf life stability during storage. Second, more extensive evaluation of its safety is required in animal models. Third, the safety and efficacy of BUPISOME must be confirmed in more extensive human trials (phase III studies). Clinical trials will require that BUPISOME be manufactured in a GMP (Good Manufacturing Practice)-certified facility.

SPECIFIC AIMS

In this proposal, we outline three Specific Aims required to further develop BUPISOME:

1)       Optimization of BUPISOME with a focus on stability of the formulation during storage

We developed the prototype BUPISOME formulation with an emphasis on analgesic efficacy. To date, we invested considerable effort in optimizing the lipid composition and the architecture of the liposomes. Product stability, which has not yet been a focus of our work, now requires attention. The stability of the prototype BUPISOME (2 - 6 months) has been sufficient to conduct our clinical trials, however, a greater shelf life is needed to increase the likelihood of successful marketability.

To achieve this goal, we plan to evaluate some minor modifications in the manufacturing process, and their effect on bupivacaine release rates. We will then perform stability studies to determine the optimal physical and chemical conditions for storage of the product, and the most effective type of packaging to use. Once the formulation of the product is finalized, GMP facilities will be used to produce product for clinical trials. Based on our experience to date with small-scale BUPISOME production, and based on the fact that other similar (non-anesthetic) liposomal formulations are already commercially available and in clinical use, we do not foresee scale-up of production as a likely problem.

1)      Assessment of local and systemic toxicity in animals

To date, we have performed preliminary studies of potential systemic and local toxicological effects of BUPISOME in small animals. These preliminary studies have been sufficient to obtain approval from the FDA and the Israel Ministry of Health to perform clinical trials. The FDA has now requested additional and more comprehensive animal data before they will permit us to proceed with other clinical trials that we have proposed. Specifically, they have indicated that local histopathological and systemic pharmacokinetic studies be performed in large animals, to rule out potential localized neurotoxic effects, and systemic effects due to unexpected liposomal drug release, respectively.

2)      Assessment of safety and efficacy in humans

Preliminary studies in volunteers and in patients have demonstrated the safety and efficacy of BUPISOME (see p reliminary results section below). However, more extensive and larger clinical trials are required to demonstrate its safety and efficacy for a wide variety of uses. The following tale summarizes our plans for clinical trials and the current status of our plans:

METHODS

1)  Liposomal Preparation and Stability Studies

The prototype BUPISOME formulation will be modified slightly by refining the drug loading conditions in order to change drug release characteristics. The release profiles will then be studied in vitro at 4^o, 22^o, and 37 ^oC to determine the optimal formulation for storage. Simultaneously, our simple

and reliable previously described mouse model will be used to assess analgesia in vivo, to be certain that the amount of bupivacaine released is sufficient to produce analgesia.

2)  Toxicological Evaluation in Animals

A large animal model, sheep, will be used to for evaluation of histopathological and pharmacokinetic study of BUPISOME. The large size of sheep permits multiple injections in the same animal so that each can serve as its own control, and easy instrumentation of their vasculature. Furthermore, the sheep intercostal nerves are easily injected. Local toxic effects will be assessed in the sheep after injection of various concentrations of BUPISOME (0.5%, 1%, 2%, 3%, 4%) or standard bupivacaine or control (saline, “empty” liposomes). Sheep will be killed at 2 days and 4 weeks after injection to determine the acute and chronic effects, respectively. Tissue specimens (nerve and muscle biopsies) will be fixed and prepared for histological examination by pathologists blinded to the nature of the injections. Eight – ten specimens will be obtained per group. For pharmacokinetic studies, standard or liposomal bupivacaine will be administered via the internal jugular vein and arterial and venous concentrations will be assayed over time using HPLC.

            3)  Clinical Trials

The paradigm for clinical trials has been established in our preliminary studies. Where possible, the same subjects will be used as their own controls (e.g., for pharmacokinetic studies in volunteers). Efficacy studies will typically use two groups of patients, those injected with standard bupivacaine or various concentrations of BUPISOME. This design will avoid the ethical dilemma of administering a placebo to patients in pain.

PRELIMINARY RESULTS

1)  In Vitro Studies

In vitro studies confirmed that bupivacaine is gradually released from the liposomal vehicle, and that the rate of release is temperature-related. Thus, when BUPISOME is refrigerated  ( 4^oC),  the bupivacaine release rate is sufficiently slow to allow for storage, but at body temperature (37^oC) the release rate is more rapid, resulting in adequate tissue concentration of drug to block nerve conduction and produce long-lasting analgesia.

2)  Pre-clinical Studies (mice & rats)

Studies in mice and rats have demonstrated that BUPISOME prolongs the duration of analgesia up to 20-fold compared to standard bupivacaine.

3)  Clinical Studies

Studies in humans paralleled our findings in animals.  In volunteers receiving intradermal injections, there was a dose-dependent prolongation of analgesia with BUPISOME (see figure). Two per cent BUPISOME produced a median analgesic duration of 48 hours, compared with 1 hour after injection of the conventional drug (bupivacaine hydrochloride, 0.5%). In another study, in obstetric patients injected paracervically following delivery, uterine involutional pain was significantly less during the 6 – 24 hour interval postpartum when BUPISOME was administered compared to conventional bupivacaine.

SUMMARY:

BUPISOME is a novel drug that fills a pressing need for a safe and reliable ultra-long acting local anesthetic that is designed to produce prolonged analgesia after a single injection. Its introduction into clinical practice is expected to revolutionize the way in which pain is managed, and to provide relief to many millions of patients suffering from painful conditions. This proposal outlines our plans to bring our invention, BUPISOME, to market to fill this profound need.

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Last modified: 03/16/04