Nanocochleate Advantages

Nanocochleate Technology is Unique
Within the universe of hundreds of drug delivery technology companies, there are just a few companies proposing to provide oral delivery of injectables. In each case, the carrier is a proprietary mixture of synthetic chemicals that is customized for the particular cargo molecule. These technologies appear to be limited to attempts to deliver peptides (e.g., insulin) and polysaccharides (e.g., heparin) that target extracellular targets. From our perspective, we think that trying to deliver therapeutics that have a relatively narrow concentration range for efficacy and safety is difficult. That is to say, whether delivering insulin or heparin, too much of the drug acutely causes serious side effects and too little of the drug is also unacceptable.
Beta-cyclodextrin derivatives have been developed for delivery of relatively water-insoluble molecules administered by intravenous administration.
To the best of our knowledge, no delivery technology shares the following features with nanocochleates: platform nanotechnology that does not require customization for each cargo molecule, food-safe ingredients, no covalent bond between carrier and cargo molecules, low cost, ease of manufacture and of sterilization, protection from hydrolysis/oxidation/enzymatic/ thermal degradation, stabilized at low pH, reduced plasma levels of free drug (high tissue to plasma concentration ratio), targets delivery of cargo molecules into the interior of cells.
This technology maintains several key advantages over competing technologies:
There is no drug discovery expense. BDSI can use its naturally-occurring drug delivery technology to deliver a wide variety of existing, proven therapeutics. The delivery vehicle does not require modification to the pharmaceutical being delivered.
It is the only one that uses a naturally-occurring substance, phosphatidylserine, to provide for oral delivery of injectables. Competing companies are trying to use synthetic chemicals. Competing drug delivery technologies use complex proprietary mixtures of synthetic chemicals to provide for oral delivery of drugs like heparin. Each therapeutic drug often requires a unique mixture of synthetic chemicals for oral delivery.
In contrast, BDSI can use its naturally-occurring drug delivery technology without modification to deliver a wide variety of therapeutics.
BDSI has demonstrated that it can target delivery of antimicrobials to the cells in the body that fight infection. This means that the technology improves the effectiveness of the therapy while at the same time it reduces unwanted side-effects: smart drugs™. Competing companies are using technology which helps target delivery of a few select injectables in the body, but they don’t provide for oral delivery of the injectables.
BDSI nanocochleates are easy to manufacture: We use an inexpensive, uncomplicated manufacturing method. The company’s drug delivery vehicle can be derived from soy beans. Example: There are lipid formulations of IV Amphotericin B available that reduce toxicity without improving the effectiveness, but their manufacturing costs have made them very expensive to manufacture
To the best of our knowledge, no delivery technology shares the following features with nanocochleates: platform nanotechnology that does not require customization for each cargo molecule, food-safe ingredients, no covalent bond between carrier and cargo molecules, low cost, ease of manufacture and of sterilization, protection from hydrolysis/oxidation/enzymatic/ thermal degradation, stabilized at low pH, reduced plasma levels of free drug (high tissue to plasma concentration ratio), targets delivery of cargo molecules into the interior of cells.
High stability: Nanocochleate delivery vehicles are stable phospholipids-divalent cation precipitates composed of simple, naturally occurring materials, for example, phosphatidylserine and calcium. They have a unique multilayered structure consisting of a large, continuous, solid, lipid bilayer sheet rolled up in a spiral, with no internal aqueous space. Nanocochleates can be stored in a cation-containing buffer, or lyophilized to a powder and stored at room temperature. Lyophilized nanocochleates can be placed in capsules and given orally, or reconstituted with liquid prior to in vitro use or in vivo administration. Lyophilization has no adverse effects on nanocochleate morphology or functions. Nanocochleate preparations have been shown to be stable for more than two years at 4°C in a cation-containing buffer, and at least one year as a lyophilized powder at room temperature. Encochleation imparts increased stability to drugs, proteins and DNA. Nanocochleates containing insulin have been shown to retain full biologic activity when stored as a lyophilized powder at room temperature for one year.
Encapsulation: the drug delivery encapsulates the cargo molecule. There is no chemical bond, and therefore no new chemical entity (NCE).
Targeted delivery: Nanocochleates can be envisioned as membrane fusion intermediates. When a nanocochleate comes into close approximation to a target membrane, a fusion event between the outer layer of the nanocochleate and the cell membrane occurs. This fusion results in the delivery of a small amount of the ennanocochleated material into the cytoplasm of the target cell. The nanocochleate may slowly fuse or break free of the cell and be available for another fusion event, either with this or another cell. Nanocochleates may also be taken up by endocytosis, and fuse from within endocytic vesicles especially in the case where PS is used as the phospholipids and the cells have PS receptors.
Resistance to environmental attack: The unique structure of the nanocochleate provides protection from degradation for associated “ennanocochleated” molecules. Traditionally, many drugs can be damaged from exposure to adverse environmental conditions such as sunlight, oxygen, water and temperature. Since the entire nanocochleate structure is a series of solid layers, components within the interior of the nanocochleate structure remain intact, even though the outer layers of the nanocochleate may be exposed to harsh environmental conditions or enzymes.
Oral availability: The drug delivery technology is being developed to enable oral availability of a broad spectrum of compounds, such as those with poor water solubility which have been difficult to administer.
Minimizing side effects: The technology may reduce toxicity, stomach irritation and other side effects of the drug. By reducing significantly the concentration of free drug in the plasma, systemic toxicities seem to be reduced.
Patient compliance: A potential benefit of the nanocochleate includes reducing unpleasant taste and unpleasant intestinal irritation.
Release characteristics: The nanocochleate technology offers the potential to be tailored to control the release of the drug depending on desired application.
Strong patent position: BDSI has a strong ownership position of nanocochleate delivery technologies. BDSI has exclusive, worldwide license to eight issued U.S. patents and three issued foreign counterparts thereof, and two U.S. patent applications, providing broad coverage to nanocochleate formulations and applications.

Bioral™ Anti-Inflammatory Drugs
Phagocytes, a specific class of white blood cells, are a major part of our first line of defense against invasion by foreign particles, including microbial infections such as viruses, bacteria and fungi. Phagocytes recognize foreign particles, bind to, and engulf, (that is, phagocytize), them. Once the particles have been phagocytized, the phagocyte can become activated. Within an activated phagocyte, a series of biochemical reactions is induced leading to the production of several compounds whose main goal is the destruction of the foreign particles. Activated phagocytes are a central component of the immune systems attempt to eradicate invading microorganisms. This process is known as the acute inflammatory response. However, the inflammatory response can be so powerful that healthy tissue is often injured during the process of destroying infections.
Cell-Targeted Anti-Inflammation
When acute inflammation persists chronic inflammation takes over. Chronic inflammation is the major cause of tissue destruction in many human autoimmune diseases, such as rheumatoid arthritis. Commonly used anti-inflammatory agents, such as aspirin, ibuprofen, and naproxen work by inhibiting important steps in the biochemical reactions the lead to aspects of phagocyte activation. However, many anti-inflammatory agents adversely affect portions of the gastrointestinal tract. A drug delivery vehicle which could preferentially deliver anti-inflammatory agents to phagocytes while protecting the gastrointestinal tract could be beneficial.
Results in an In Vivo Model
Nanocochleates have been successfully used to deliver antimicrobial drugs to infected phagocytes, in both in vitro and in vivo models, resulting in the eradication of the infection. Cochleates are solid particles which are stabilized at low pH. Since drugs formulated within cochleates are inside a multilayered solid particle, not only is the drug protected from the stomach, but the stomach is also protected from the drug. In addition, since cochleates are composed of naturally occurring compounds, they do not activate phagocytes.
BDSI scientists have prepared formulations of various NSAIDS in cochleates. These tiny particulate structures are just barely visible as small dots when observed by phase-contrast microscopy at 1000X magnification.
“Nano-encapsulated” formulations prepared with a fluorescent die are aggressively engulfed by a macrophage cell line in culture.
“Nano-Encapsulated” aspirin and acetaminophen are 5-10 fold more efficient at inhibiting nitric oxide synthase, one of the enzymes used by macrophage during the inflammatory response, than free drug.
This could be explained by the rapid and extensive engulfment of drug filled cochleates by these cells, concentrating the drug with the cell.
In Vivo Studies: The ability of cochleates to protect the gastrointestinal from aspirin toxicity and to enhance the anti-inflammatory e efficacy of aspirin was evaluated in vivo using a standard carrageenen rat model for acute inflammation. Results observed indicate the cell-targeted delivery offers significant improvement in efficacy vs. the control standard aspiring model.
BEMA Transmucosal Delivery Technology
BEMA delivery discs are water-soluble, bioerodable, cellulose-based pharmaceutical delivery devices for application to mucosal surfaces. BEMA devices deliver a rapid, reliable dose of their drug across mucous membranes (e.g. the mouth) for time-critical conditions like sedation and pain relief for cancer, or trauma cases where IV lines or injections are unavailable or not practical.
The devices are composed of an adhesive layer and a non-adhesive backing layer, with both layers capable of holding the desired drug. Upon application, the disc adheres to the mucosal surfaceand delivers the dose of medication. The BEMA system permits control of two critical factors for dose to dose reproducibility: 1) the contact area for mucosal drug delivery, and 2) the time the drug is in contact with that area.
In contrast to competing transmucosal delivery systems like lollipops and matrix-based delivery systems, BEMA products:
· Adhere to mucosa in seconds, dissolve in minutes
· Absorption is determined by the product, Do not require the patient to swish or move the product around in the mouth for absorption
· Have a narrow, reproducible delivery rate, not susceptible to varying or intermittent contact with mucous membranes as with other systems
· Dissolve completely, leaving no residual product or waste
· Are inexpensive
BDSI's Current BEMA Products In Development
BEMA Fentanyl (Breakthrough Pain in Patients on Opioids)
There is a clear need for additional narcotic agents in alternative dosage forms to provide rapid pain relief.
BEMA Fentanyl is expected to meet the need for new narcotics and will be ideal for:
· breakthrough pain in opioid-tolerant patients
· post-operative patients following step-down from IV narcotics; hospitalized patients or outpatients without IV access
· emergency rooms patients where available IV lines are limited or impractical
Other Buccal Products
Emezine™ (Anti-Emetic, Post-Operative Nausea, Oncology/Chronic Disease)
Postoperative nausea and vomiting (PONV) occurs in approximately 30% of patients undergoing operative procedures. Many factors influence the risk and severity of PONV. These include patient specific factors (age, gender), operative procedure (type and duration of procedure) anesthetic related factors (type and duration) and postoperative factors (presence of pain, oral intake). Although significant progress has been made in the prevention of symptoms, patients continue to have difficulty with PONV. Vomiting can result in dehydration, electrolyte imbalances, prolonged recovery room stay, hospital admissions and loss of work. Anti-emetic agents are most effective when given prior to the surgical procedure or at cessation of anesthesia and frequently must be continued for several hours after the operative procedure. Products commonly employed for prevention and treatment of PONV are limited to dopamine receptor antagonists (droperidol, prochlorperazine) and serotonin receptor antagonists (ondansetron, granisetron, dolasetron, palonosetron). Dopamine receptor antagonists were the first agents used for PONV and remain the most effective agents.
Anti-emetic products are provided as injectable, oral and rectal formulations. Injectable products require that the patient be in a medical facility and have an intravenous injection line in place. Oral products have limitations because delayed gastric emptying that is associated with nausea and vomiting impedes the absorption of the product and actual product ingestion can be nauseating. Rectal suppositories are inconvenient as well as slow and unpredictable in onset. There is a need for alternative delivery systems. BDSI's Emezine™:
· Will be the first buccal anti-emetic in US market place
· May offer predictability and speed of onset similar to IM injection
· Avoids discomfort of injections & inconvenience of suppositories