No more needles

Developments in valve technology could lead to the development of inhalable therapies that make daily insulin injections a thing of the past for many diabetics

Type 1 diabetes is an auto-immune disease occurring most often in children and young adults, requiring daily insulin injections. Patients usually start with two injections of insulin per day of two different types of insulin and generally progress to three or four injections per day of insulin of different types.

While it is an effective therapy, it gives rise to a series of problems, including the storage of insulin for the patient as well as concerns with injection technique, syringe reuse and syringe disposal. These issues are a major concern with diabetic children.

For many years, the search has been on for alternatives to injection for the non-invasive delivery of macromolecules such as peptides and proteins. Oral, transdermal and nasal routes of delivery have typically not worked: due to their large sizes, therapeutic amounts of most macromolecule drugs, including insulin, cannot naturally pass through the skin or nasal membranes without the use of penetration enhancers, such as detergents or electrical impulses. Oral delivery of macromolecules does not work because proteins are digested before they can reach the blood stream.

inhalable drugs

However, many molecules can be absorbed naturally through the alveoli in the lung into the bloodstream with high drug absorption and without the need for enhancers used by other non-invasive routes. This high bioavailability makes the lung a natural target for peptides, proteins and small molecules that would benefit from pulmonary delivery. A further advantage is that inhalables also provide for very rapid onset, typically quicker than is achieved by subcutaneous injections.

Inhale Therapeutic Systems, of San Carlos, California, is pioneering systems to deliver a range of inhalable drugs, including peptides, proteins and small molecules, to the deep lung. Its Inhance drug delivery platform is said to combine innovations in powder technology and inhalation devices to enable efficient and reproducible delivery of inhalable drugs. The company has developed and completed the initial scale-up needed for commercial production of pulmonary products and has tested eight different drugs in human clinical trials.

Innovations in biotechnology and recombinant techniques have led to a large increase in the number of macromolecule drugs in recent years. To be delivered to the deep lung, the particle size needs to be far smaller (1-5µm) than that traditionally produced for pharmaceutical products. A major challenge is to produce these fine powders at a high enough yield and without degrading the delicate macromolecule. In addition, each drug poses different formulation challenges due to varying chemical and physical characteristics and dosing requirements. This requires significant optimisation work for each specific drug.

blister packaging

Such small particles need to be processed precisely, captured efficiently and handled appropriately. Inhale has modified standard powder processing equipment and developed custom techniques to enable it to produce fine dry powders consistently with particle diameters of 1-5µm without drug degradation or significant loss of expensive bulk drug. The company has scaled up powder processing to levels sufficient for producing test powders necessary for late stage clinical trials and small volume marketed products. Long-term stability of its processed powders is achieved partially by using individual blister packaging to provide a strong moisture barrier. Unit-dose packaging also enables very precise dosing and the ability to deliver blister-packed doses of different strengths, important for certain drugs such as insulin.

ITT Engineered Valves has worked closely with engineers at Inhale Therapeutics and Bechtel, its design team, since 1997 when Inhale began its first phase of expansion and scale-up for clinical trial production. At the time, ITT provided special Pure-Flo divert valves modified to fit in a 0.25in line for the low volume processing required for the trial quantities.

processing facility

Now in Phase 6 of the project, ITT Engineered Valves has provided hundreds of Pure-Flo diaphragm valves, including divert valves for the same process scaled up to 1.5in line size. In addition, 40 Pure-Flo zero-static valves, which eliminate dead legs in the WFI system, were used. With the input of Inhale process engineer, Jeff Boesiger, ITT designed these zero-static valves into multiple valve assemblies, or clusters. These cluster valves enabled the customer to install several valves together as a single unit, reducing hold-up volume, and saving time and money on the piping fabrication.

For the processing facility, ITT also delivered 14 shell-in-tube heat exchangers, one plate-and-frame heat exchanger, two custom-fabricated sample cooler carts, and a 25l process vessel. The facility at Inhale Therapeutics is currently being validated to be ready for production as soon as the FDA approves the inhalable insulin product.