Cochleate Lipid-Crystal Nano-Particle Targeted Drug Delivery
The advancement of medicine has brought us the security and convenience of popping a pill or receiving an injection for many of our ailments and medical conditions. Modern medicine has made great progress and tremendously improved our life-span, health-security and quality of life. However, solutions such as pills and injections typically rely on a diffusion-like process that essentially “soaks” our bodies in medicine with the hope it gets to every anatomical corner where it may be needed. For numerous medications, in particular for those with mild side effects, this approach works to reasonable satisfaction.
Unfortunately, many medications come with associated complications. Not all drugs are soluble enough to easily penetrate all desired tissues and many medications have serious side-effects. Medications with high toxicity can cause numerous painful and often damaging side effects in patients such as, nephrotoxicity (kidney toxicity), hepatotoxicity (liver toxicity), headaches, vomiting, and severe chest pains, amongst others. However, doctors continue to use these drugs because they are effective in treating diseases. Many highly effective medications with significant side effects include anti-bacterial, anti-fungal, anti-viral or anti-inflammatory drugs.
Our lipid-crystal nano-particle cochleate formulation technology offers a drug delivery solution with three differentiating and disruptive features:
- Oral availability;
- Multi-organ protection and enhanced safety; and
- Targeted delivery to the site of the infection and inflammation with the ability to effectively penetrate tissues.
Multi-organ Protection: The key innovation of our cochleate technology is our ability to package medication inside lipid-crystal particles. Because of their crystal nature, these particles are truly solid and hold on tightly to their medication pay-load. This is where the cochleate technology differs markedly from other lipid delivery technology, such as liposomal delivery. Liposomes are liquid delivery systems which typically leak some of their drug content into our circulatory systems, thus still exposing our vulnerable organs and tissues to toxic effects of often potent medications. Keeping organ-toxic medications inside the lipid-crystal particles strongly differentiates our cochleate technology from other drug delivery approaches.
Targeted Delivery: The size of our lipid-crystal cochleate particles is typically in the range of 50-500 nm. This is very small and by comparison close to the size of a large virus or a small bacteria. Our body produces several cell-types that are designed to remove viruses and bacteria from our system. These cell types, such as macrophages, are part of our immune system and “swallow” the bacteria and viruses they encounter in order to protect us from infections. Because of the size our lipid-crystal cochleate particles and the phospholipid surface structure (the cell membranes of bacteria are also made up from phospholipids), macrophages tend to absorb these cochleate particles very well. These macrophages may contain already the microbes we would like to eradicate or may be on their way to a site of infection or inflammation in our body, taking their pay-load along.
Florescent labeled cochleates in the fungus
Cochleate interacting with a macrophage in cell culture
Cochleate Formulations: “Encochleation” was invented by Dr. Raphael J. Mannino, our Chief Technology Officer when he was Professor of Medicine at Rutgers University, and was further perfected by Dr. Mannino along with some of our key-scientists. Cochleates have a multilayer crystalline, spiral structure with no internal aqueous space. The structure is formed when a series of solid lipid sheets roll up and capture drug molecules in between the sheet, a process referred to as “encochleation.” Encochleation involves combining calcium and soy-derived phospholipids (PS), two naturally occurring materials classified as GRAS (generally recognized as safe) by the FDA, through a tightly controlled crystallization process to envelop the Active Pharmacological Ingredient (API). The result is a lipid-crystal encochleated drug formulation made up of nano-sized particles.
Once the cochleate, with the drug inside, is administered, it is engulfed by target cells in the body, such as macrophages , and taken directly to the site of infection or inflammation. Once the encochleated drug is captured by the macrophage or other cells, the lower calcium levels inside the macrophage compared to the high level of calcium outside the macrophage triggers the cochleate to open, thus releasing the drug inside the cell. Because the drug is locked up in the solid cochleate particle or in the target cells, the rest of the body is protected from the toxicity of the desired medication.
Oral Drug Delivery: Numerous pharmaceutical compounds have been encochleated by us and tested in animals. Our most advanced encochleated medication has also been tested in a phase I study in humans. In most of these studies, including the human study, the encochleated medications were orally administered. We believe that the unique cochleate crystal-structure protects the drug from degradation when it passes through the gastrointestinal (GI) tract and that its lipid surface features facilitate the particle to be absorbed into the blood stream.
Many drugs that are currently on the market are only effective in treating diseases when given intravenously (IV). For example, many anti-infective drugs must be administered via IV in order to be effective. IV administration presents several challenges to care, such as risk of infection, patient discomfort from injections, and higher cost of care than oral administration (IV delivery must be performed by a doctor or nurse, often within a very expensive hospital setting). Although several technologies have been used to attempt to convert IV drugs to orally delivered medications, success has been limited due to the difficulty in achieving adequate bioavailability (i.e., the amount of drug that is absorbed into the body) with oral formulation. The potential application of the cochleate technology for the delivery of injectable medications offers significant clinical and commercial value if successfully demonstrated in human clinical trials.
We believe that the anti-fungal medication Amphotericin B is a good example to demonstrate the unique features of the cochleate technology (see above). Current commercially available formulations of amphotericin B cannot be absorbed through the GI tract and therefore must be given intravenously. By encochleating amphotericin B, in the above mouse candidiasis (a pathogenic yeast infection) model study which was conducted at the PHRI in Newark NJ, we demonstrated comparable survival with the oral administration at a quarter of the IV dose. The very mild side effect/toxicity profile observed with the encochleated treatment group is consistent with lower dose and drug shielding properties of the cochleate technology. With this technology, we are able to offer a categorically different formulation that delivers amphotericin B, orally, to the target cell, with reduced toxicity.
We have significant experience with a range of pharmaceutical compounds in various animal models. This chart below demonstrates the versatility of the technology and its broad application potential.
Matinas BioPharma is open to exploring partnerships with biotech and pharmaceutical companies to develop new drugs using cochleates. For partnership inquiries, please contact us.