The choice of dosage form is one of the first decisions facing drug development scientists. For most drugs, the answer is simple: formulate as a tablet. For other drugs, injection is the method of choice – there is just no other way to get them into the blood stream. Some drugs are best delivered via inhalation to the lungs or nose due to targeted local activity and ease of use for the patient. We’re all familiar with the variety of nasal sprays available at the pharmacy to treat cold or hay fever symptoms1.Although orally inhaled and nasal spray drugs have traditionally been developed to treat respiratory diseases, an increasing number are targeting systemic delivery of drugs, or even delivery directly to the brain, through the olfactory membranes, thus bypassing the blood-brain-barrier.
Traditionally, drugs delivered to or through the nose have been formulated as liquids. However, the availability of nasal powder devices to deliver a powder to the nose has opened up new opportunities for drug developers. Formulating as a powder can improve product stability, provide for a wider range of doses, improve bioavailability, improve the delivery of drug directly to the brain, improve the chances of obtaining formulation patents, and provide for product differentiation from competitors.
The glucagon story provides an excellent example of many of these advantages. Glucagon is a 29 amino acid peptide that is used as a rescue medication to treat diabetic patients with severe hypoglycemia – acute instances of low glucose that can be life threatening. Being a peptide, it has no bioavailability when delivered orally, so it was traditionally formulated as an injection. In this regard it was much like an EpiPen®, and was often to be administered by a parent to an unconscious child. Unlike epinephrine, however, glucagon is not stable in a liquid formulation, a fact that stymied drug developers for decades. This meant the injection had to be presented as a vial of lyophilized glucagon powder that was reconstituted (dissolved) immediately prior to use. Imagine trying to do this while your child was passed out on the floor beside you – first reconstitute the drug properly, then give the injection. It is a difficult and stressful procedure, and one that was not always done properly.
Enter Baqsimi®, a nasal powder formulation of glucagon developed by Eli Lilly3. By formulating the glucagon as a powder rather than a liquid, the stability problem was overcome. By formulating the drug with enhancing excipients, the scientists at Lilly were able to improve the bioavailability from zero for unformulated drug to an astounding 28% when delivered intranasally, and the bioavailability is unaffected by congestion associated with a common cold. Due to the innovative nature of the formulation and delivery device, Lilly obtained patents on both, part of a robust patent portfolio that will protect Baqsimi® for years to come. And finally, the presentation is far easier to use than the two-part injection, providing robust product differentiation from marketed products.
An astounding feature of nasal drug delivery is the existence of a direct nose-to-brain pathway. This is advantageous if the site of action is the brain – it bypasses the blood brain barrier, not to mention first pass metabolism in the liver. Many small molecule drugs, including antipsychotics, are poorly water soluble, so the prospect of formulating as a liquid can be daunting, especially when the dose is taken into consideration. Formulating as a nasal powder may provide a way forward.
Many biologic drugs, including peptides, antibodies, vaccines and nucleic acids, are being developed for nasal administration for local indications, including prophylactic treatments for airborne and respiratory viruses. Although typically soluble in water, drugs of this sort are notoriously unstable for long periods of time in solution, and may require refrigeration to maintain potency. The chances of developing a dry powder formulation that is stable are much better when compared to a liquid, especially if room temperature stability is the goal.
Nasal powders are typically amorphous solids, consisting of the drug plus excipients. The excipients are present to improve the physiochemical characteristics of the powder, the stability of the active pharmaceutical ingredient, and the absorption of the drug in the nasal cavity. Manufacturing process such as spray drying and lyophilization are used to create the powders, and secondary processing steps are often needed to fine tune powder properties. The properties of the particle affect where it is deposited in the nasal cavity, how long the particle resides there before being cleared, and the permeability of the drug. Particle engineering can tailor the physical attributes of the formulation such as particle size, shape, density, and surface area, to allow for precise targeting of certain nasal regions through optimized aerosol properties. Controlling moisture content is also a critical aspect of the process in order to both protect the drug and to maintain the ability to aerosolize the powder from the device. Selection of the device and the associated secondary packaging should not be overlooked, and indeed Baqsimi® uses a special secondary vial that controls the moisture ingress in lieu of any traditional desiccant.
Finally, the excipients often used in particle engineering are commonly the same excipients used in liquid nasal sprays, so precedence of use provides assurance of safety. Novel excipients can also be used with appropriate safety data. The challenge is determining which of the many excipients available, and in what ratios, will work to generate a powder formulation that can be made efficiently, and that exhibits the many favourable properties needed for the drug to be successful. This is no mean feat, and it requires a combination of expertise and experience working with these formulations. The benefits of success are many, however, especially for the high value systems that are typically under development.
