Considerations for Dosing Accuracy in a New Carrier for Dry Powder Inhalation

Inhalation drug delivery methods are attractive, noninvasive routes when rapid onset of action, minimal side effects and excellent bioavailability are desired. However, not many drugs are administered this way and accurate dosing can be a challenge.

What makes dosing problematic is the very small amount of dosage and a variety of forms of active pharmaceutical ingredients (APIs) that may be inhaled. Liquids carrying dissolved or suspended APIs may be atomized into small droplets for delivery to the lungs using metered dose inhalers. Solid APIs may be converted to fine powders by mechanical micronization for delivery by dry powder inhaler (DPI) devices.

Formulating for DPI delivery is challenging. API particle sizes affect absorption and must fall within the range of 1-5 μm. Because powders this fine tend to cohere, they are often combined with solid excipient carriers to improve drug stability and dose control. During inhalation, however, the API and carrier particles must separate so that only the API is delivered to the lungs.

Currently, most powder blends for DPI formulations are based on lactose monohydrate as an excipient carrier. Despite the widespread use of this carrier, microdosing these blends into pre-metered DPIs is still a critical step. Furthermore, as a carrier, lactose presents several challenges.

Because of the Maillard reaction, reducing sugars such as lactose are a major threat to the stability of peptides, biomolecules and small-molecule APIs with primary amine groups. Additionally, a significant number of patients are lactose intolerant.

A new, engineered, inert mannitol excipient

Recently, a new carrier based on an inert mannitol (Parteck® M DPI excipient) has become available to improve the flow and release characteristics of APIs in drugs delivered via dry, inhaled powders. Unlike mannitol itself, which – according to pharmacopoeia – still contains up to 0.10% reducing sugar impurities, the Parteck® M DPI excipient is physiologically inert and will not compromise API integrity. A lower specification limit (0.05%) for reducing sugars – with even lower actual values (see Figure 1) – greatly reduces the Maillard reaction’s effect on sensitive APIs. The material’s low water content and non-existent hygroscopicity also reduce the risk of API hydrolysis, promote reliable flow and help minimize bioburden. Its bulk and flow properties are well-suited for optimal blend homogeneity, API delivery to the lungs and constant dose uniformity. Lastly, it is a viable alternative for patients with lactose intolerance and is of non-animal origin.

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Article information: L. Ohrem, K.H. Seyfang. Merck.