February 1, 2010 (Vol. 30, No. 3)

NanoCluster Technology Emulates Natural Aerosols to Deliver Drugs to the Deep Lung

Inhalable therapeutics offer a new formulation option and delivery route for existing drugs that are losing patent protection or need to become more efficient. Inhaled drugs should ideally be one to three microns in diameter, the best size for delivery into the deep lung for local and systemic absorption.

Savara has designed a next-generation pulmonary delivery platform by starting with drug nanoparticles, then assembling them to micron-sized clusters to reach the optimal size. “We want to move completely away from the current manufacturing processes and build aerosols that emulate natural aerosols,” says CSO Cory Berkland, Ph.D., who, with George Laurence, invented the company’s NanoCluster technology in his laboratory at the University of Kansas in Lawrence in 2007.

A major obstacle to inhaled therapeutics is the inability to efficiently deliver large quantities of a drug to the deep lung. Dr. Berkland looked to Mother Nature for inspiration—in particular, soot and mold spores, whose size and structure allows them to fly efficiently into the lungs. These natural aerosols are composed of underlying nanostructures that join together to form microparticles. “We thought that we could make something that looks like soot or mold spores, yet is primarily or entirely a drug.” The NanoCluster technology resulted from this reasoning.

So far, Dr. Berkland has yet to find a class of drugs that cannot be formulated into aerosols using the NanoCluster technology. He reports that Savara’s platform can be used with drugs for asthma and respiratory illnesses, cancer, tuberculosis, hypertension, nausea, diabetes, migraines, and hormone replacement therapy.

“We are not aware of anyone else tailoring the size of microparticles by using nanoparticle building blocks as we do,” he says. The method improves aerosol efficiency and potentially allows two to three times more drug to reach the lung compared to competing technologies, Dr. Berkland adds.

According to the company, current dry powder drugs have several disadvantages. Their manufacturing process requires large spray-drying facilities. The pulverized drugs are blended with excipients, which are materials added to improve the flow and handling of dry powders. The drug must separate from the excipient before reaching the lung.

The inhaled drugs are often too large or too small, causing them to settle in the throat or be exhaled. Even when patients use delivery devices optimally, just 15% to 30% of the inhaled dose reaches the lung, with just 20% of that reaching the deep lung. Moreover, some dry powder drugs can only be delivered with expensive devices that vibrate or use other techniques to move the powder into the lungs.

In contrast, the dry powders generated by Savara’s NanoCluster technology are manufactured without excipients or spray drying. The nanoparticles are made in suspension at room temperature using water-based chemistry, then they are concentrated, dried, and engineered into microparticles. In some cases, a tiny amount of an amino acid or salt may be added to improve the aerosol properties. The manufacturing process, performed in large tanks, is reportedly simple and easy to scale up. When NanoCluster-formulated drugs are tested in animal inhalation models, the majority of the drug reaches the deep lung, says Rob Neville, executive chairman at Savara.

Savara’s dry powder formulations can be delivered with affordable, off-the-shelf oral or nasal inhalers, which could reduce the cost of entry into the market, Neville adds. The NanoCluster technology delivers drugs locally or systemically, including small molecules, peptides, and biological therapeutics.

Drugs with poor water solubility, such as chemotherapy drugs, antibiotics, antifungals, and analgesics, improve their dissolution when formulated into NanoCluster aerosols. Additionally, two or more different drugs can be combined into one microparticle. “The technology allows us to create defined particle sizes, which fly in different ways. For example, larger particles are deposited in the upper airways and smaller particles travel further into the deep lung,” Dr. Berkland explains.

Savara says that its NanoCluster technology achieves the particle size and design for optimal dosing of inhaled therapeutics.

External and Internal Programs

The NanoCluster technology can extend the lifecycle for a drug by increasing the patent life. Savara’s first goal is to dramatically improve the aerosol formulations of existing drugs such as budenoside for asthma. “If you improve the efficiency, you can cut the dose and possibly remove side effects,” adds Dr. Berkland.

Savara offers its dry powder formulation services to other companies. The first step typically starts with a feasibility study, during which Savara researchers formulate an aerosol version of the drug and return it to the customer. If the customer evaluates it and is satisfied, a license is negotiated. Savara can manufacture compounds at scale to support preclinical and clinical trials.

“We are gaining momentum in this service and have a healthy line of customers,” Neville says. Savara has a number of agreements ongoing, including some with top 10 pharmaceutical companies, to make aerosol formulations of existing and new drugs.

Savara is also evaluating a few drugs to develop internally. “We’ve made progress in the proof-of-concept stage and preclinical studies on some products as we assess the business risks and where to proceed,” Neville continues.

The initial focus is on drugs for respiratory diseases, such as asthma, chronic obstructive pulmonary disease, bacterial infections, and tuberculosis. Aerosolized chemotherapy for lung cancer may be another option. Dr. Berkland has converted paclitaxel and cisplatin into aerosols using the NanoCluster platform. When tested alone or in combination, the drugs show desirable aerodynamic properties for inhalation, and they dissolve three to four times faster than micronized particles in the simulated environment of the lungs, he notes.

Savara recently moved its headquarters to the Austin Technology Incubator in Texas, while its laboratory facilities remain in Lawrence, Kansas. “Our objective for moving the company to Texas is to explore relationships with the University of Texas, M.D. Anderson, and other leading healthcare institutions in the state,” Neville says.

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