Technology Watch: Nanotechnology Emerges in Drug Delivery

30 September 2002 00:00  [Source: ICB Americas]

The increasing development of large molecule, biological-based drugs such as peptides, proteins and other biopharmaceuticals has led to the need for new drug delivery systems. These macromolecules often exhibit low oral bioavailability due to poor permeability and instability in the GI tract and therefore cannot effectively reach the desired area. Researchers are investigating several new potential techniques for delivering the active ingredient to the patient in a more palatable way as well as increasing the potency and bioavailability of traditional small molecule drugs. Several companies are developing novel systems based on nanotechnology that provide targeted delivery of drug actives and have potential to provide a mechanism for treating previously incurable diseases.

Nanotechnology refers to the use of nanometer-sized particles to achieve a specific set of goals. This field has exploded over the last several years and has received significant attention from government, private research and venture capital groups. The US government as well as governments in Europe and Asia are heavily funding nanotechnology programs. In the US, the National Nanotechnology Initiative (NNI) received $422 million in 2001 and will receive a total of $519 million in 2002 and has a budget of $710 million for 2003.

Eugene Wong, assistant director of NSF (the NationalScience Foundation) for Engineering, explains that nanotechnology will lead to "new materials with improved strength and wear characteristics, better catalysts for the chemical industry, new drugs and food products, and new materials for electronics and information technology."

For drug delivery, there are four key benefits and advantages provided by the use of nanotechnology, according to Stephen Benoit, CEO of NanoMed Pharmaceuticals. Nanotechnology allows for targeted delivery of drugs and vaccines to specific cells and tissues. It also enables and enhances the ability to deliver poorly-water soluble compounds (i.e. Class II), and those compounds characterized by low solubility and low permeability (i.e. Class IV compounds). Use of nanotechnology further provides the ability to achieve longer sustained and controlled release profiles. Also, alternative routes of delivery, such as inhalation and needle-free injection devices, can be enhanced with nanotechnology.

"We believe that the use of nano-scale biocompatible materials will afford patients freedom from the pain and side effects of pills and injections; laser-like targeting of just the right tissues and cells to treat or prevent disease; and whole new classes of treatments that are not possible with today's delivery systems," notes Mr. Benoit.

Current drug delivery technologies fall into four categories-proven, emergent, development and seed. Proven technologies are already in use in patients, while emergent technologies have been validated but are not widely used. Development technologies are being evaluated in industry, and seed technologies are being investigated in the research community. Nanotech-nology seems to be in the developmental stage but quickly moving towards the emergent phase, says Mr. Benoit.

The potential for nanotechnology in the drug delivery market is a function of the needs of drug and vaccine formulators as well as the degree to which certain therapeutic areas have unmet medical needs. The global market for advanced drug delivery systems was more than $16 billion in 2000 and is estimated to grow to more than $27 billion in the next five years, which translates to an average annual growth rate of approximately 11 percent, according to Mr. Benoit. Sales of poorly soluble drugs (solubility less than 50 percent) and poor bioavailability accounted for roughly $57 billion, according to J. Gregory Ford, President of SkyePharma Canada Inc., which offers another strong market outlet for nanotechnology-based drugs.

Developments within this market are continuing at a rapid pace, especially in the area of alternatives to injected macromolecules, as drug formulators seek to cash in on the $8 billion worldwide market for genetically engineered protein and peptide drugs and other biological therapeutics. Moreover, the ability to target precise sites for drug delivery is causing sales of site-specific delivery systems to grow at an average annual growth rate of 26.5 percent.

Mark Modzelewski, founder and director of the Nanobusiness Alliance (NA), an organization created to advance the emerging business of nanotechnology, the biggest challenge for companies developing nanotechnology-based drug delivery systems will be educating the pharmaceutical companies about the advantages of the technology so that they will actually adopt the new systems. Gaining approval from the Food and Drug Administration will be another hurdle.

The application of nano-formulation technology can make oral or parenteral delivery of most, but not all, poorly water-soluble drugs possible or practical, says Richard Vickers, vice president of commercial licensing, Elan Drug Delivery Inc. "It is reported by many sources that as much as 40 percent or more of the drug candidates generated by medicinal chemists are poorly water soluble. Therefore, the commercial potential of nanoparticulate formulation technology is large."

NanoMed Pharmaceuticals Inc. is an early-stage advanced drug delivery company founded in 2000 by Russell Mumper and Michael Jay, who are on the faculty at the University of Kentucky College of Pharmacy as well as being the inventors of the company's Nanotemplate Engineering platform technology. The two men were joined in 2001 by Stephen Benoit as a co-founder and CEO. NanoMed is privately funded and is in the process of raising its first round of venture capital. The company expects to be cashflow positive in 2004.

Nanotemplate Engineering is a proprietary, reproducible and scalable manufacturing process that consistently yields well-defined, uniform solid nanoparticles less than 100 nanometers in diameter. These nanoparticles are made using all pharmaceutically acceptable materials and can be engineered to contain or carry small molecules, peptides, proteins, plasmid DNA, diagnostic agents, and radio- or biological-sensors.

NanoMed is focused on using its core platform technology to develop novel nanoparticle-based advanced drug delivery systems that target drugs and vaccines to specific cells and tissues for the treatment of infectious diseases, neurodegenerative diseases, and cancer. The company will enter into strategic alliances with pharmaceutical and biotechnology company partners to commercialize its enabling platform technology. As NanoMed grows, it will seek opportunities to use its proprietary advanced drug delivery systems to develop and independently market its own drugs. Nanotemplate Engineering is the subject of US and worldwide patent applications.

In the immediate term, NanoMed will conduct its research and development activities under contract with the founders' labs at the University of Kentucky's College of Pharmacy, the Center for Pharmaceutical Science & Technology (CPST) and the Advanced Science & Technology Commercial-ization Center (ASTeCC). The CPST is a fully integrated analytical and formulation development and FDA-registered pharmaceutical clinical manufacturing facility using current good manufacturing practices, and the ASTeCC is the University of Kentucky's incubator for multidisciplinary collaborations and start-up ventures.

A potential blockbuster application of NanoMed's core platform technology will be to deliver drugs to the brain. NanoMed has obtained in-situ blood-brain barrier (BBB) transport of two different types of nanoparticles (in four separate studies) with no adverse effects at the BBB and with uptake comparable to existing central nervous system (CNS) therapeutic agents. The ultimate aim of this work is to develop a drug-loaded nanoparticle that is able to achieve high brain penetration, display a favorable drug (e.g. neurotrophic factors) release profile in the CNS with no toxicity.

The founders' labs have received a $1.9 million Phased Innovation Award from the National Institutes of Health, National Institute of Biomedical Imaging and Bioengineering to continue this development effort. NanoMed is also actively pursuing corporate partners to accelerate and expand this opportunity. Overall, NanoMed is performing seven feasibility studies involving nanoparticle formulations for potential partners. These studies capitalize on two key areas of competitive strength-vaccine delivery and brain drug delivery. The successful completion of any one of these studies is expected to lead to the formalization of a corporate partnership in 2003 and result in the filing of an investigational new drug application in 2003.

Advectus Life Sciences Inc. received the requisite approvals on March 18, 2002, and began trading on the TSX Venture Exchange as a development stage company focused on the development and commercialization of a patented process for the treatment of brain tumors using nanotechnology for the delivery of approved anticancer drugs across the blood-brain barrier. This development stage is expected to take between 24 and 36 months according to the company president, James H. Disher.

"This technology has the potential for producing the first really effective treatment for brain cancer," says J. Michael Morgan, vice president, pharmaceutical development. Unfortunately, few anti-cancer agents can effectively cross the blood-brain barrier and thus are ineffective for this kind of cancer. Even surgery, followed by radiation therapy has been found to only slow the disease progress of glioblastomas to an average of one year of patient survival.

"We have shown that our technology can take an effective drug right to the brain tumor and effectively cure brain cancer in laboratory animals. Thus, we have the potential of slowing the progress of, or even curing, brain cancers in humans, with a few simple intravenous injections. We believe that even if the initial treatments only increase life span with no disruption to expected quality of life in as little as 10 percent of the treated patients, there would be compelling reasons for clinicians to use the technology."

Advectus' patented technology uses nanoparticles composed of a poly(butylcyanoacrylate), to which the drug adheres. To facilitate transport to the brain and prevent the body's immune system from destroying the particles, they are then coated with the surfactant Polysorbate-80. Following simple intravenous administration, Apo-lipoproteins begin adhering to the coated particles, which then appear to mimic low-density lipoproteins (LDL).

These "camouflaged" particles pass through the BBB and degrade, releasing the approved, anti-cancer drug, doxorubicin, to be absorbed by the tumor. The exact mechanism of this delivery is not yet known but most likely depends partly on the numerous LDL receptors in the cells making up the BBB as well as an even higher percentage of LDL receptors found in primary brain tumors, such as glioblastomas, explains Dr. Morgan.

Unlike many competitor products, Advectus' nanotechnology has the potential to treat several tumor types (primary and secondary) in most patients. It will also most likely allow the adhered drug to access all parts of the brain, and not only the margins of cavities remaining after tumor removal.

Advectus Life Sciences Inc. has entered into a collaboration agreement with the University of North Carolina at Chapel Hill (UNC-CH) to determine the efficacy of its patented nanoparticle based-delivery system on several different types of tumor lines that commonly metastasize to the brain. The cell lines include lung carcinoma, breast carcinoma, melanoma, renal cell carcinoma, and colon carcinomas.

Initially, the technology was tested in these cell lines in vitro (cell culture) and was very successful. As this article comes to press, the in vivo stage will be underway measuring the effectiveness of the treatment against several of these metastatic tumors that are growing in the brains of live rodents. The work is intended to lead into Phase I clinical trials in humans with the Cancer Center at UNC-CH.

Advectus has also entered into a contract with the University of Kentucky Research Foundation Center for Pharmaceutical Science and Technology (CPST) for the cGMP manufacture of its patented nanoparticle-based technology. The work currently underway at this FDA-approved facility consists of the technology transfer, scale-up, and GMP-manufacture of pre-clinical and clinical supplies of materials to suffice through Phase II clinical trials.

Joerg Kreuter, professor and director of the Department of Pharmaceutical Technology at the J. W. Goethe University, Frankfurt, Germany, is an originator of the technology and co-patent holder. Dr. Kreuter has several research programs underway which are testing the ability of the Polysorbate-80-coated nanoparticle to deliver several other cancer drugs to brain tumors.

Dr. Kreuter also holds a large government grant that will cover most of the costs projected for the GLP preclinical toxicology testing of Advectus' current formulation (P80DOX-NP), which will be required for regulatory submission. The protocol for the pivotal preclinical study (GLP, repeated-dose study in rodents, with pharmacokinetics and full histopathology) has been finalized with Aventis/ProTox, a major contract laboratory located near Frankfurt, and is ready for submission to the FDA for prior approval.

"Due to the several years of research that are behind our patent coverage, and given that the pre-clinical development is going so well and that there are so many other related areas we can get into, we have seen an ever increasing level of interest from our competitors in the pharmaceutical industry. I think it is safe to say that whether we continue to hold everything 'in house' or partner with other pharmaceutical companies, our work and successes will continue to be part of this new frontier for years to come," says Mr. Disher.

Another entry in nanotechnology is Targesome, which was founded in late 1998 and is a venture-backed private company that expects to attain profitability by 2008. Targesome's technology involves the attachment of antibodies or small molecules to a nanoparticle in order to develop a new class of therapeutic agent. "These new nanoparticle drugs are superior to existing drugs because they have increased efficacy, improved safety profiles, and slower clearance and vascular confinement for small molecule drugs," says Karen J. Brunke, vice president of business development.

"Because Targesome can attach or encapsulate almost any existing drug to or in the nanoparticle, the company is uniquely positioned to leverage the target discovery and therapeutic development of other companies," Ms. Brunke says. Targesome is currently focused on oncology opportunities and is exploring other large therapeutic markets.

Targesome has developed liposomes that are either coated with a polymer or contain a polymerizable lipid for increased stability. These liposomes can be targeted to receptors by attaching small molecules, peptides or antibodies to the surface of the nanoparticle. The selectively-targeted receptors are upregulated during the disease process. In addition to the drug on the surface of the nanoparticle, this same particle may carry a payload of drug.

Key advantages of the Targesome approach are the multivalent display of small molecules on the surface, the capacity for a high payload, the confinement of the nanoparticles to a compartment within the body (such as the vasculature), and the stability and favorable biodistribution of targeted nanoparticles. The nanoparticles are 50 to 100 nanometers in size and are believed to attach to multiple receptors due to the high density of small molecules on the surface of the nanoparticle.

This design allows even a somewhat poorly binding small molecule compound presented at a high density on the surface of the nanoparticle to have an "on-off" rate on upregulated receptors such that multiple binding events occur at any given moment. "Think of Velcro fasteners," says Ms. Brunke. "They work because of the density of hoops and loops on the respective surfaces not because any single hoop and loop binds that tightly," she explains. By attaching these small molecules to nanoparticles, the efficacy of the small molecule is significantly enhanced in animal tumor models.

The company has an active internal chemistry and nanoparticle development program. In addition, Targesome collaborates with universities such as Stanford in testing its materials in animal models of disease. Ms. Brunke says Targesome is positioned to be both a pharmaceutical and drug delivery company. Its first product is in co-development with a pharmaceutical company.

Soliqs was set up as a drug delivery business unit in 1997 and is part of Abbott GmbH & Co. KG. Soliqs' NanoMorph technology produces amorphous nanoparticles that can greatly enhance the bioavailability of water-insoluble drug substances, says Jon Lewis, head of business development. NanoMorph technology is a co-precipitation technology that results in an amorphous drug substance stabilized in a polymer matrix. After spray-drying, the NanoMorph powder can be directly compressed into tablets or reconstituted in water as a stable dispersion.

"Because NanoMorph formulations contain the drug substance in an amorphous form, they not only enhance bioavailability, but they also circumvent bioavailability/stability problems associated with crystalline nanoparticles, such as polymorphism," notes Mr. Lewis. NanoMorph formulations can be delivered by a variety of routes, not just orally.

Soliqs aims to be a leader in the enhancement of bioavailability of poorly water-soluble drug substances. It has also developed Meltrex extrusion technology for the enhancement of bioavailability (by producing solid solutions of drug substance in polymer) linked to controlled release profiles. Soliqs currently has confidential ongoing projects with a number of third parties involving both Meltrex and NanoMorph technologies.

Novagali was founded in 2000 by Yissum, the research development company of the Hebrew University, and Professor Simon Benita. The company's first round of financing was completed in September 2000, and to date  3.78 million have been raised.

Novagali's lead proprietary technology platform includes cationic submicron emulsions and cationic self-emulsifying drug delivery systems to improve the bioavailability of oral, ophthalmic, dermal and intravenous dosage forms of lipophilic drugs. Today, 50 to 60 percent of new chemical entities (NCEs) and 40 to 50 percent of existing chemical entities are lipophilic and therefore suitable for this technology. In general, such drugs are poorly soluble in water, which seriously limits their bioavailability and clinical efficacy.

With Novagali's technology, the emulsion droplets are surrounded by positive charges. As all the cell membranes are negatively-charged, the droplets can easily penetrate them by electrostatic attraction, allowing a better permeation and therefore an increased bioavailability or a prolonged residence time in target organs like the skin and eyes.

Extensive research has shown that when injected intravenously, cationic submicron emulsions modify the biodistribution of highly lipophilic drugs, increase plasma half-life and target active substances into the lung, which opens new perspectives in the field of lung cancer treatment and pneumonic therapy.

Gregory Lambert, development manager with Novagali, says the benefits and advantages of the cationic emulsions include solubilization of large doses of lipophilic drugs; better penetration through membranes resulting in enhanced bioavailability; degradation protection in the gastrointestinal tract; applicable to injectable, topical, ocular and oral administration; the potential for controlled drug release; and stability, including under sterilization conditions.

"These cationic emulsions offer the opportunity for addition of effective novel routes of administration to existing marketed drugs, expansion of markets and indications, and the extension of product life cycles," says Mr. Lambert. They are also relatively inexpensive to manufacture.

Novagali has several projects underway to evaluate the use of the submicron cationic emulsions. The company is collaborating with Hebrew University of Jerusalem and University of Paris/INSERM 450 to design cationic submicron antisense oligonucleotide emulsion delivery systems for ophthalmic gene therapy to treat and cure corneal and choroidal neovascularisation, which are aspects of age-related macular degeneration (ARMD).

In collaboration with Professor Patrick Couvreur of Chƒtenay Malabry University, Novagali is investigating new bi-compartment systems as drug delivery systems for water soluble actives. This research and development could lead to a new generation of colloidal delivery systems. The company is also developing emulsion formulations applied to NCEs in collaboration with major pharmaceutical groups.

Novagali is developing advanced cationic self-emulsifying delivery systems for oral administration of well-known injectable cytotoxic drugs resulting in novel dosage forms capable of improving the therapeutic effects and patient compliance while diminishing markedly the overall cost of healthcare treatment. To date, increase in oral bioavailability of the drug, physical properties, stability and safety of an oral paclitaxel formulation were optimized using pseudo-ternary diagrams and experimental design. In March 2002 Novagali filed a new patent for this formulation.

Cyclosporin A has been found to be effective in treating the immune-mediated keratoconjunctivitis sicca ( KCS or dry eye disease), by enhancement or restoration of lachrymal gland tearing in patients suffering from this syndrome. Novagali is developing a cationic submicron emulsion containing cyclosporin A to treat moderate and severe dry eye. The new formulation and the dry eye application were patented and filed in November 2001. A cationic emulsion system is also being developed to treat common dry eye.

Elan Drug Delivery Inc. has investigated the application of its Nano-Crystal technology to poorly water soluble drugs to increase oral bio- availability, increase the onset of action, decrease the fed/fasted effect on bioavailability of the active ingredients and improve dose proportionality. "Application of this technology to poorly water soluble parenteral drugs can eliminate the need for solubility enhancing excipients (cremophor, solvents, etc.) that can cause undesirable side effects," says Mr. Vickers.

Elan's technology is based on a high energy milling process to generate an aqueous dispersion of nanoparticles that are stabilized against aggregation and precipitation using generally recognized as safe (GRAS) stabilizers. The company has also developed stabilizers and processes that allow conversion of the aqueous dispersions into dry powders, which can then be incorporated into solid oral dosage forms. When reconstituted with water, nanoparticulate dispersions are regenerated.

Elan's NanoCrystal technology is used for the product Rapamune, which is marketed by Wyeth. A new drug application for a second product will be filed this year by another major pharmaceutical company. Elan's manufacturing process for nanoparticulate dispersions has been reviewed, inspected and approved by the FDA. Elan is currently in the process of divesting its NanoCrystal Technology drug delivery business.

Skyepharma Canada Inc. was originally founded in 1991 as RTP Pharma Inc. and was acquired in March 2002 by SkyePharma. The company's technology is based on surface-stabilized microparticles and nanoparticles of water-insoluble and poorly water-soluble drugs and bioactive compounds in solid and liquid form. The primary surface stabilizers are pharmaceutically acceptable and preferably comprise a phospholipid material or a lecithin.

The microparticles are in the form of solid particles in aqueous and sometimes in non-aqueous suspension or are in the form of liquid particles usually in aqueous suspension. Skyepharma Canada's competitive advantage is related, in part, to the technology developed to prepare suspensions of nanoparticles and microparticles with particle size distributions that do not substantially increase over their useful lifetimes. Other advantages include the ability to form sterilizable suspensions of these particles when needed and to prepare dried particles that can be further formulated and/or rehydrated without agglomeration and aggregation.

The company has patents for proprietary compositions comprising particles and droplets that are stabilized with phospholipid and other membrane-forming surface as well as patents claiming formulations that overcome the difference between fed and fasted conditions for oral drug uptake, compositions that contain phospholipid and sugars but are anti-microbial, and formulations that contain fish oils with unexpected properties.

"The company is evolving as a pharmaceutical science-based company wherein research focuses on support of product development formulations to optimize processes and stability," says Mr. Ford. "This also applies to formulation work done with new chemical entities under contract with other companies where the object is to discover the optimum set of formulation drug plus excipients and stabilizers and particle-formation conditions to provide a specific formulation with a specified set of properties for formulation stability and bioavailability evaluation."

Skyepharma Canada has several products that are in late stage development and a veterinary product awaiting FDA approval. The company hopes to have a product commercialized within two years. "We will continue to apply our technology to drugs that become available to us in some manner for formulation or for reformulation, where such drugs can benefit in a unique way from our technology," says Mr. Ford.

He adds that the technology can also be leveraged to allow expansion beyond passive drug delivery and into active delivery, and targeted delivery, as well as into other non-drug areas such as food additives, nutraceuticals, cosmetics and baby foods.

Nanopharma is a privately held spinoff from Massachusetts General Hospital, founded to develop advanced drug delivery systems to provide fully biodegradable nanoscpopic drug delivery vehicles based on proprietary molecular constructs and 'biological stealth' materials. Skypharma offers nanoparticle drug delivery technologies (nanosuspensions, solid lipid nanoparticles and solid polymer nanoparticles) for delivery of poorly water soluble compounds.

NanoBiotec has several nanotechology-based products for drug and topical delivery applications. Pathfinder nanoparticles are used for targeted drug delivery by modifying the surface of the particles such that they bind to specific proteins in the body that direct the particles to the appropriate location. Nanosphere is developing proprietary microparticle formulations for improved drug delivery of macromolecules that will allow for deposition deep in the lung. Controlled particle sizes, morphology and surface properties improve handling, and the system provides increased shelf-life and sustained release of the active.

Pharmasol has developed lipid drug conjugates (LDCs) as an alternative to polymeric nanoparticulate drug delivery systems. With LDCs, the release of the active ingredient is controlled by degradation. Poorly water soluble conjugates of drugs have been reduced and transferred to lipid nanoparticles via high pressure homogenization. The company also offers nanostructured lipid carriers (NLCs), which are produced by mixing special lipid blends. The internal structure of an NLC is a highly disordered matrix with nano-oil compartments in the solid matrix and the lipid particles themselves are amorphous. Due to this amorphous nature of the particles and the cavities within, higher drug loading is possible and the particles have increased stability over time.

Ntera offers its NanoPart Tech-nology, which is a nanocrystallization technology applicable to universal drug classification, from small organic molecules through large proteins. The technology provides targeted drug delivery of sparingly soluble small molecules and proteineous drugs.

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