21st July 2020 – Considerations when Developing Dry Powder Formulations for Nasal Locally Delivered Drugs


21st July 2020 - Considerations when Developing Dry Powder Formulations for Nasal Locally Delivered Drugs

By 2020, 58% of all therapeutics in development are injectable, 29% oral and 4% inhaled including nasal delivery, and while nasal delivery may not be one of the most explored routes, it has the potential to offer an alternative delivery method for therapeutics with some specific advantages.

Nasal delivery of drugs has traditionally been via liquid filled devices, however recent advances in dry powder nasal devices and the success of the recently approved Aptar device Unidose for Baqsimi have once again increased interest in dry powder nasal delivery.

Nasal delivery has a number of key advantages for those receiving the drug; including its relative ease of use, patient acceptability, compliance and the elimination of injection meaning that it can be easily delivered by the user. Nasal delivery also provides a suitable route for those compounds that are destroyed in gastrointestinal fluids if taken orally, are metabolised in the wall of the GI tract or undergo extensive biotransformation by the liver during their first passage in circulation.

Aptar Dry Powder Nasal Device for dry powder Nasal Delivery. Choosing a device early is important in nasal formulation development.

The nose can often be a primary route of infection for many diseases or ailments such as coronavirus or influenza, or the site of allergies such as hay fever and rhinitis. Therefore, delivering therapeutics or indeed vaccines, directly to the desired location of action can induce an immediate effect before the pathogen / allergen has an opportunity to be exposed within the body.

Despite the advantages that nasal drug delivery can bring, limitations also exist and these limitations must be considered when assessing the potential of nasal administration. Some of these limitations can be reduced with effective nasal formulation development.

In our previous article ‘Nasal Delivery: An Alternative Route’ we discussed a few of the beneficial key applications and advantages of nasal delivery. In this current article we will discuss the varying stages of nasal formulation development and the challenges that need to be overcome when developing a dry powder dosage form suitable for local nasal delivery.

Pre-formulation Development

The first step in the nasal formulation development process is to determine what the matrix of the dry powder particles needs to be and will subsequently make up the bulk of the formulation. Understanding the residence times of the molecule is also important, since the need to retain the molecule in the nasal cavity for sufficient time to enable absorption will guide the choice of excipients and the types of mucoadhesive that will need to be built into the formulation plan.

Typical excipients include sugars (mannitol and lactose) and polymers (PVP) are often used as matrices for stabilising the active ingredients within the dry powder; providing suitable bulking properties to allow aerosolisation of the powder emitted from the metered dose and enhancing drug stability both during production and within the nasal device.

Clearance of formulation by the cilia within the nose to the back of throat is typically 8 to 10 minutes giving a relatively short therapeutic window in which the drug can be absorbed across the nasal mucosa. Mucoadhesives such as alginates, chitosans and hyaluronic acid are useful excipients that have the property of lengthening the residence time.

In addition, other agents such as those that change hyrophilicity (surfactants, bile salts) or aid absorption across the membrane (carbopols) can also be added to the formulation to modify pharmacokinetics.

Spray Drying

A key aspect for a dry powder nasal formulation development is engineering the correct particle size is necessary for good deposition in the nasal cavity. Spray drying is now emerging as the go-to technology for producing powders with the correct aerodynamic properties for nasal delivery. In particular it is possible to engineer particles to be absorbed within the nasal mucosa, but large enough to not reach the deep lung; the ideal size of particle for nasal delivery is 15-30 µm with ideally none below 10 µm.

Particle engineering is not the only benefit of using this highly flexible process. Spray drying creates a dry powder consisting of a single phase and the matrix (including the therapeutic, excipients and polymers etc.) can be produced from a single solution.

Powder Properties

It is critical that particle size within the bulk spray dried powder should be around 15-30 µm in size with few if any particles below 10 µm. Other important powder properties for downstream processing include flow and adhesion.

To produce the optimal powder properties, it is important to begin testing powder properties from the intended device in the early formulation development stages. The powders themselves can appear to have ideal properties, but this may change when filled into a device, or upon longer term storage.

The choice of device will ultimately be driven by a number of factors including cost of goods, formulation / device performance, patient profile and ease of use. With this being said the choice of devices for dry powder local nasal delivery are limited.

As with most dry powder drug formulations, maintaining stability is of the upmost importance. In reality there are several factors that need to be considered when assessing stability during formulation development, these being chemical and physical stability. Chemical stability can be affected by oxidation and degradation of the API that has been formulated. Physical stability of the powder itself is also important, degradation / aggregation of the particles is often driven by moisture uptake and will subsequently impact on delivery performance and emitted dose.

Choice of Device and Device Performance

It has already been noted that there are a relatively small selection of dry powder nasal devices available for practitioners considering this attractive route of administration. Indeed, as already mentioned it is important to choose the device early whilst still in the early stages of formulation development to enable the joint testing of experimental formulations as they are produced in the laboratory.

Questions to consider when choosing a device are:

  • What is the target dose for therapeutic treatment and can the device achieve it?
  • How well is the powder sealed in the device and how is the device packaged?
  • What is the method of ejection?
  • Which area of the nasal cavity does the API need to be delivered?
  • What is the regulatory status of the device?
  • What are device costs expected to be? Is cost prohibitive?

Nasal devices utilise numerous methods to deliver / disperse the powder being delivered from the device, including: actuation by pressure (manually actuated), patients blowing into the device, pressurised systems or propellants.

Ejection of powder is intrinsic to the device, there can be variability of devices where patients have to blow into the device to eject the powder to the nose. Pressurised systems or the use of propellants can result in more reproducible results, although dependent upon device they could create discomfort for the patient during application.

To Conclude

Delivering APIs locally within the nasal cavity offer several unique advantages especially for disease or ailments where the nose is the primary route of infection. However, the formulation development for local acting nasal dosage forms is not straight forward and selection of the right formulation within the best device is critical.

Other factors to consider early in development include stability on storage, reproducibility and size of the emitted dose is sufficient, the powder size distribution is large enough to not be inhaled and the API has a long enough residence time for therapeutic action to take place.

These formulation goals often come with a compromise when considering powder properties and choice of device. The choice of device is vital in meeting these goals and testing device performance has to begin in the early stages of formulation development.

Spray drying is a useful technique for producing dry powder formulations for nasal devices. They offer the advantages of a single-phase process with the potential to adjust processing parameters to engineer particles to achieve optimal powder properties.

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