Azaya Proprietary PSN Technology
Azaya Therapeutic’s Protein Stabilized Nanoparticle (PSN™) technology utilizes a new, next generation nanotechnology to produce liposome-encapsulated drug products. The company’s interest in liposome-encapsulated agents is based on the potential for improved delivery of poorly soluble drugs, reduction in chemical and enzymatic degradation, and an improvement in the toxicity profile of an agent. This technology is a key advancement in the field of liposomal delivery, utilizing a proprietary single step manufacturing process that produces uniform particles less than 100 nanometers while stabilizing drug encapsulations.
Azaya’s first product line focuses on the greater unmet medical needs in the area of chemotherapeutics. Enhanced delivery of cytotoxic agents using PSN technology provides a safer, less expensive and more convenient use to preferentially target tumors through and enhanced permeation retention (EPR) effect. In addition, Azaya’s PSN technology offers an active targeting mechanism that utilizes protein identification of up-regulated tumor biomarkers.
Scientific Background:
Liposomes are vesicular sacs resembling tiny cells—their thin but durable lipid bilayer membranes separate an internal aqueous volume from the external medium. Water-soluble drugs can be encapsulated in the internal compartments, while water-insoluble drugs can be encapsulated in the hydrophobic region of the membrane. Depending on the production process used, each vesicle may contain a single membrane (unilamellar) or several layers of membrane (multilamellar). Typical liposome sizes range from 0.05 to several μm in diameter.
Since their discovery more than three decades ago, liposomes have been applied to the delivery of a wide range of drugs by virtually every route of administration. The prospect of targeting liposome encapsulated drugs to sites of disease (such as tumors) generated considerable attention in medical research the late 60’s and early 70’s. Although early liposomal formulations were shown to reduce toxicity in animal models, they were no more active than the standalone active ingredient, partly as a result of the stability of the liposome, typically emptying 50% of its contents as a consequence of rapid binding of plasma proteins. Furthermore, liposomes that survived destabilization in blood were rapidly sequestered by fixed macrophages residing in the liver and spleen (the mononuclear phagocyte system [MPS]), destroying the liposomes.
a. Advances:
During the late 70’s and early 80’s liposomes were reengineered to circulate longer in the blood and remain intact while doing so. This was done first by grafting the liposome with glycolipids, followed by a second generation and more robust grafting of the liposome with methoxypolyethylene glycol (mPEG), otherwise referred to as stealth™ liposomes. The PEG grafted liposomes increased the in vivo stability, reduced MPS uptake providing longer plasma residence times. In short, the liposome was engineered for use in the pharmaceutical industry, but still remand difficult to produce on large scale for production.
b. Traditional Manufacturing Process:
The traditional method used for the production of liposome products (e.g. Doxil) includes a multi step process; pre-formation of the liposome (pre-emulsion), pre-sizing via filter extrusion (0.05–0.45 μm), dialyzing the pre-liposome suspension with a 5% to 15% aqueous sucrose solution of the active ingredient (e.g. doxorubicin) and the liposome suspension, followed by an aseptic filtration and a final dispense into commercial vials. Alternatively, the cytotoxic agent can be loaded using a pH gradient to drive the drug molecules across the lipsome phospholipids membrane to its aqueous core, followed by sizing. These lengthy processes require several complex steps that need meticulous attention, resulting in a costly process for manufacturing.
In addition to the high cost associated with traditional liposomal production, the final product has a limited shelf life. Typically, the final liposome encapsulated drug product is packaged and delivered as a saline suspension that is stored at reduced temperatures. As a result these products have a finite shelf life less than 12 months.
c. Azaya Therapeutics New Technology:
As a result, Azaya Therapeutics developed its Protein Stabilized Nanoparticle (PSN™) technology that utilizes a one step manufacturing process. The liposome product is prepared in a single step that encapsulates the active drug Docetaxel (ATI-1123) in the lipid layer of the liposome while forming active nanoparticles in situ (60–80 nm). The active liposomal product is dispensed into vials and lyophilized to yield a dried powder that has an extended shelf life compared to conventional liposomes. Drug stability and release rates are predicted to be <5% in saline after 48 hours, while the reconstituted material that has been stored at 4ºC for several years shows complete retention of the encapsulated drug with <5% of the active ingredient released from the liposome.
While Azaya has successfully demonstrated the encapsulation of Docetaxel (ATI-1123), this process is geared toward the formulation of hydrophobic molecules that would otherwise have limited success as developmental drugs using traditional formulation methodologies. There are a variety of marketed cytotoxic agents that utilize traditional formulations that use toxic surfactants as carriers i.e. Cremophore EL and Tween 80. To mitigate the surfactant toxicity of these carriers, patients receiving chemotherapy with traditional formulations are pre-treated with corticosteroids, and the chemotherapy is administered slowly over several hours. Azaya’s PSL-based formulations does not require such surfactants, and should be administered over 30 min to 1 hr without steroid pre-treatment. All ingredients used in the PSN formulation have been approved by the FDA for use in other therapies (phospholipids, proteins and cholesterol). This will enable Azaya Therapeutics to decrease the development risk of potential products candidates, making them safer, less expensive and more convenient to use.
Although many of the known cyctotoxic agents are poorly soluble, Azaya’s PSN technology offers a potential solution that not only addresses formulation issues of poorly soluble compounds; it can also enhance the activity (efficacy) of known drug products through a passive targeting mechanism. As it would imply, passive targeting is a result of small particles being preferentially taken up into the cancer tumor, resulting in higher concentration of active drug at the diseased site. This is achieved by the enhanced permeation and retention effect (EPR); liposomes (small particles <200 nm in size) move into the tumor from the bloodstream through holes or gaps in the vessels supplying the tumor (vasculature leakage), accumulating a larger quantity of cytotoxic agent or nanoparticle within the diseased tissue.
Azaya’s single step manufacturing process incorporates key characteristics that enhance existing liposomal technology for drug delivery. To date, there have been only moderate advances and Azaya’s PSN technology is a large step towards a more efficient and economical drug delivery system. Additionally, standardized manufacturing produces uniform particles that are necessary for passive targeting of cancer tumors via the EPR effect. With this superior technology, Azaya Therapeutics has conducted pre-clinical studies that have demonstrated improved therapeutic potential; enhanced pharmacokinetics, enhanced inhibition of tumor xenograft models, and evidence of increased tumor uptake of active compound.
Azaya intends to use its PSN technology to improve the performance and reduce the non-specific cytotoxicity of leading marketed chemotherapeutics such as Taxotere (docetaxel) and CAMPTOSAR®, as well as, several experimental drugs that have been withdrawn from development due to their non-specific cytotoxicity and formulation difficulties.
