The worldwide market for drug delivery systems is growing at an ever increasing rate and is being fueled by several significant needs: the commercial necessity of extending product life and product portfolios, the clinical need to enhance drug safety and patient compliance, and the technological challenge of delivering new therapeutics. Exploitation of new advances in drug delivery technology will give pharmaceutical companies a significant competitive advantage in an increasingly demanding marketplace.
Pharmos' nanotechnologies enable the delivery of a variety of compounds from simple substances to lipophilic compounds (suitable for oral, dermal and parenteral administration) and biological molecules. Our goal is to apply our nanodelivery technologies to new chemical entities or established therapeutic agents.
Emulsome™ Nanotechnology
The Emulsome nanocarrier technology is a lipid-based drug delivery system designed to act as a vehicle for drugs with poor water solubility. Emulsome particles consist of a microscopic lipid assembly with an internal fat core which dissolve the water-insoluble drugs in the absence of any surfactant or solvent.
Figure: Emulsome particleThe solvent-free and surfactant-free Emulsome technology has demonstrated high drug-encapsulation capacity for water-insoluble antifungal and anticancer drugs showing enhanced drug delivery and improved pre-clinical efficacy for parenteral routes. An example of the successful application of the technology is the development of an injectable ready-to-use Emulsome-based formulation for the antifungal agent amphotericin B.
Advantages:
- Superior bioavailability
- Reduced toxicity
- Improved pharmacological activity
NanoEmulsion Technology
A second lipid-based drug delivery system developed by Pharmos is the NanoEmulsion (NE) technology. The NE technology consists of spheric oily droplets (in the range of 100-200nm) uniformly dispersed in an aqueous medium. The emulsion droplet size reduction is essential to generate drug formulations with high stability.
The NE technology has been successfully applied in the formulation of ophthalmic preparations showing improved drug delivery and reduced ocular irritation in humans in Phase I/II clinical studies.
Figure: NanoEmulsion particlePreclinical data using the Carrageenan induced paw edema animal model showed enhanced anti-inflammatory activity with NSAID encapsulated in NE creams compared to conventional commercial formulations. A pharmacokinetic study using NE creams containing radiolabelled diclofenac and ketoprofen was performed to assess drug penetration through skin and to determine local tissue (muscle and joint) and plasma levels of drugs following topical administration. Compared to oral administration, NE-diclofenac and NE-ketoprofen topical creams showed 4-6 fold less drug in plasma, 60-80 fold more drug in muscle tissue, and about 9 fold more drug in joints.
An NE topical cream product containing diclofenac has been tested in a 48-hour human skin irritancy study involving 25 healthy volunteers. No irritation or allergic responses were observed after topical application. The NE diclofenac cream was further evaluated in a Phase I study in 16 healthy male and female volunteers during 2006. The study evaluated the safety, tolerability and pharmacokinetic profile of NE diclofenac topical cream following 14 days of three daily administrations. The NE diclofenac product was found to be safe and well tolerated with no severe or serious adverse events; subject compliance with the 14-day treatment period was excellent. The pharmacokinetic analysis demonstrated low systemic exposure of diclofenac with no drug accumulation following repeated daily administrations. A Phase 2a study of the NE diclofenac cream in osteoarthritis patients is currently underway. The study is expected to enroll 126 patients with osteoarthritic knee pain, with results expected in mid-2008.
The improved skin penetrative properties of the NE delivery technology, its low irritancy, and excellent human acceptance make this novel topical vehicle very promising to achieve increased transcutaneous drug penetration of lipophilic drugs. The site specificity of the NE technology results in a superior safety profile compared to oral administration while maintaining efficacy, thus improving patient compliance to the treatment.
The NE diclofenac cream is the first topical NSAID product being developed by Pharmos. An additional potential application for the topical NE technology is dermal delivery of local anesthetics and other compounds from different analgesic classes.
Advantages:
- Low systemic absorption
- Site-specificity and increased drug levels at injured tissues
- Reduced toxicity
- Improved pharmacological activity
Nanotechnologies for Vaccine Delivery
Formulation of several antigens like HIV rgp160 and Staphylococcus enterotoxin B (SEB) using these core technologies resulted in increased antibody titers and enhanced parenteral and intranasal immunogenicity of the incorporated immunogens, demonstrating the potential of nanotechnologies as vaccine carriers.
Emulsome particles having mucoadhesive properties (coated with a bioadhesive polymer) were designed to attach to the GI mucosal surfaces prolonging the residence time of the encapsulated antigens and improving their immunogenic activity. Mucosal immunity (production of IgA antibodies in mucosal fluids, including intestinal fluid) has been obtained with mucoadhesive Emulsome vaccine formulations. Emulsomes can also be formulated to act as depot for slow release of antigens avoiding the need for repeated vaccinations. The proposed therapeutic areas of Emulsome and NE-antigen formulations are induction of mucosal immunity, oral vaccination, HIV vaccine therapy, and vaccination against biological threat agents. The enhanced immunogenicity obtained with Pharmos' lipid-based vaccine carriers are encouraging for the development of safe, cost-effective and immunogenic human and veterinary vaccines to protect against viral infections and respiratory exposure to biologic toxins.
Nanotechnologies for Oral Delivery
Lipophilic substances possessing low water solubility often have poor oral bioavailability. These properties represent a rate-limiting step in their absorption from solid oral dosage forms with a subsequent reduction in their oral bioavailability. Nanoemulsions can also be spray-dried to obtain stable free-flowing dry powders quickly dispersible in water, which self emulsify in the gastrointestinal fluid, enhancing the oral absorption of the encapsulated substance.
Pharmos has obtained two new drug delivery US patents for the solubilization, enhanced absorption and increased oral bioavailability of water-insoluble drugs and biologicals using powdered drug-lipid coprecipitates and solid lipid complexes technologies.
For additional information please contact: Business.development@pharmos.com
