Most dry powder inhalers (DPIs) on the market deliver formulations in which the active pharmaceutical ingredient (API) is blended with relatively large inert carrier particles, most commonly lactose. In these mixtures, the API makes up only a small fraction of the total powder. The larger carrier particles, which are coated with API, help ‘bulk out’ the formulation improving how well it flows and making it easier to handle and fill in manufacturing. Because the carrier particles are relatively large, they aren’t able to reach deep into the lungs, so provided the inhaler’s aerosolisation process can detach the API from the carrier surface during inhalation, only the API will reach the lungs to exert a therapeutic effect.
Traditionally, this carrier-based approach has been used for ‘small-molecule’ APIs that typically require only microgram‑scale doses. However, the landscape is shifting: DPIs are increasingly being investigated for delivering biologic drugs (including proteins, peptides, and oligonucleotides) as a more patient‑friendly, and potentially targeted, alternative to needle injection systems. Because biologics often have low potency, achieving therapeutic concentrations in the lung usually requires much higher powder payloads.
Traditional DPIs can deliver high powder payloads to the lung in only two ways: either via a carrier-free formulation (e.g. pure API or spray dried material with high concentration of API) or via multiple inhalations of a carrier-based formulation to avoid overwhelming the patient with large quantities of powder that could trigger coughing.
This raises a fundamental question: is it better for inhaled biologics to be delivered without a carrier, or can newer inhaler technologies make it possible to use a carrier but, importantly, only deliver the API to the patient, negating the need for multiple patient inhalations? (see Figure 1).
Figure 1: Options for delivering high powder doses to the lung (e.g. > 5 mg)
This blog further explores these two strategies, as well as outlining new developments in inhaler design that may offer a best‑of‑both‑worlds solution for delivering inhaled dry powder biologic formulations.
Because biologic drugs can be structurally complex and fragile, they need to be incorporated into carefully engineered formulations for delivery by a DPI. These formulations help protect the molecules from environmental degradation, so they remain stable during long‑term storage (at the right conditions) and ensure they deagglomerate efficiently during inhalation by the patient. Controlled deagglomeration and aerosolisation is essential for producing a high proportion of respirable particles, allowing the biologic to reach the region of the lungs where it can be most effective.
Spray drying and other related particle‑engineering techniques can be used to manufacture ‘carrier-free’ biologic formulations suitable for inhalation. The delicate biologic molecule is effectively encapsuled within a protective excipient matrix, rather like the coloured swirl in the middle of a glassy marble, which physically and chemically protects it from environmental stressors (e.g. heat, moisture, and enzymatic actions) through manufacturing and its shelf life.
Manufacturing spray dried biologics can be expensive and complex; the right conditions are needed to ensure the biologic entity is effectively encapsulated inside its protective excipient matrix. Extensive process optimisation may be required to achieve optimal particle size distribution while ensuring the biologic molecules remain viable at the end of the manufacturing process.
Furthermore, the relatively small particle size of respirable spray-dried biologics means the powder can be poorly flowable and difficult to handle during filling, while also presenting a deagglomeration challenge to candidate DPIs.
However, if delivered by a DPI which effectively deagglomerates the powder, the lack of a carrier fraction comprising large non-respirable particles can help improve deposition of the biologic in the lung while reducing mouth, throat and upper airways deposition.
Using a carrier to deliver biologics can improve powder flowability for easier handling during processing and filling while also presenting opportunities for easier deagglomeration and aerosolisation.
In carrier-based DPI technologies for biologics, spray dried encapsulated biologic molecules are blended with carrier particles as they would be in traditional small molecule dry powder formulations. However, choosing a suitable carrier can be problematic here. Lactose reacts with many biologics via the Maillard reaction, leading to formulation degradation, making it unsuitable for most spray‑dried materials. Alterative carriers such as mannitol can avoid this issue but may induce cough in many patients (more so than lactose does).
For any carrier to be widely acceptable in this application, ‘classification’ (the separation of fine particles of API from the carrier and retention of the carrier particles in the DPI) will be important to prevent the carrier fraction from entering the mouth and throat where it could induce a cough reflex. You can find out more about dry powder classification here and why it can eliminate the need for transition to carrier-free formulations.
To address these challenges, the candidate DPI needs to have an effective deagglomeration and aerosolisation engine to strip the biologic from the carrier and deliver it to the lungs. This will stop the biologic being deposited where it is not needed, reducing loss of these often high value treatments, while also providing a higher therapeutic dose without the need for multiple patient inhalations.
Both carrier-based and carrier free formulations can be viable options for pulmonary delivery of dry powder biologics provided the candidate DPI is optimised for the application and required payload and able to effectively deagglomerate and aerosolise the powder. Novel DPI platforms are being developed to ensure these conditions are met.
CHI is developing a family of novel DPI platforms, including QuattriiTM and AeolusTM which can both be used to effectively deliver carrier-based and carrier free formulations across a broad range of fill masses. Quattrii is already available for pharmaceutical companies to start using in Phase 1 clinical trials.
Quattrii is a novel foil blister-based DPI platform of two related implementations: Quattrii CF for carrier-free formulations and Quattrii CB for carrier-based formulations. Both are designed specifically to handle medium to high fill masses of both traditional drug formulations and sensitive biologics. Quattrii is also intended to be flexible to, where needed, allow for easy customer-specific customisation of the powder deagglomeration engine to give optimal performance for their formulation.
Quattrii offers industry leading performance by being able to deliver a high proportion of fine particles to the lungs with each inhalation across a wide range of fill masses, all in one patient inhalation. This offers a clear advantage over existing inhalers which are often dose size limited and unable to achieve the high lung doses required by new biologic formulations 1
Quattrii CB uses the principle of powder classification by actively detaching the API from the carrier particles, retaining >80% of the carrier within the blister and emitting >80% of the API1. This novel approach avoids excessive throat deposition while reducing the need for multiple inhalations to receive a therapeutic dose (see Figure 2, which compares the impact on the patient).
Quattrii CF releases all of the formulation from the blister2, providing class leading efficiency and a high lung dose across a range of fill masses from 15 mg to over 50 mg.
While both carrier‑based and carrier‑free approaches could be used to successfully deliver inhaled dry powder biologics, their success hinges on whether the DPI can effectively deagglomerate and aerosolise the formulation while delivering a suitably high dose, ideally in a single inhalation. CHI’s DPI platforms, which are designed for high payloads and compatibility with both carrier-based and carrier-free formulations, offer a versatile option to deliver the next generation of inhaled biologic therapies.
References
[1] Jameson H & Harris D. High Delivered Dose in a Single Inhalation for Carrier-Based Formulations by Retaining Carrier-Fraction in DPI Blister. Poster presented at RDD2025.