SELECTION OF EXCIPIENTS FOR DRY POWDER INHALERS

Citation: Peters H, Hebbink G, “Selection of Excipients For Dry Powder Inhalers”. ONdrugDelivery Magazine, Issue 72 (Dec 2016), pp 34-36.

Harry Peters and Gerald Hebbink explain how, because dry powder inhalers need a carrier to help with ensuring the drug is effectively delivered, interest has been focused on developing inhalation-grade lactose for this purpose, and examine which selection criteria to use to ensure the best grade of lactose is used for each dry powder inhalation formulation.

Dry powder inhalers (DPIs) have become very popular for dosing of medications to patients, especially those suffering from respiratory diseases. Most DPI formulations contain a carrier to improve the handling of the powder and to control the deposition of the drug into the lungs.1,2

Excipients like lactose, mannitol, sorbitol, erythritol, anhydrous glucose, trehalose and fumaryl diketopiperazine (FDKP) have been investigated as carriers for use in DPI drugs.3,4 Some of these excipients are hygroscopic and are therefore not suitable for combination with every drug.3

“One of the challenges for the formulator is to fill a device with the drug and obtain content dose uniformity…”

Most formulations in the market use alpha-monohydrate lactose, which has been widely accepted by regulatory authorities.5 However, health authorities do require extra testing and controls for some parameters, compared with the use of lactose in oral dosage forms. Therefore, inhalation-grade lactose has been developed and is the preferred excipient for the use in DPI formulations.

During the R&D process for a DPI project, it should be understood what kind of functionality needs to be addressed with the lactose. Also in view of quality by design (QbD) regulations,6,7 the critical attributes of a DPI formulation that determine the functionality should be understood. A number of attributes of excipients have been identified.8 In this article several selection criteria are described that will determine which grade of lactose is optimal for any specific DPI formulation.

DRUG PROCESSING

Most inhaled formulations contain a highly potent pharmaceutical active that has been micronised and is dosed in low concentrations. Handling of micronised actives is a challenge due to agglomeration. To improve the handling, a carrier is added to de-agglomerate the active during blending. Almost all inhalation-grade lactose would give this functionality. The criterion to be evolved is that the surface area of the lactose is sufficient to de-agglomerate the active particles that stick to the lactose surface.9 Furthermore, the amount of powder that can be inhaled should be considered.

DEVICES

Dry powder inhalation devices on the market can roughly be divided into three groups: capsule devices, blister devices and reservoir devices. The first step in a development process of a DPI is the selection of a device. Subsequently, the most important parameters for the selection of the optimal lactose grade are the filling platform, dosing of the drug out of the device and deposition of the drug in the lungs.

Once the device has been selected it has become clearer what the filling platform of the formulation could look like and what type of lactose is needed to fill and empty the device.10

One of the challenges for the formulator is to fill a device with the drug and obtain content dose uniformity. Filling systems nowadays can consistently fill small volumes of approximately 5 mg on commercial production scale. Since dosages of some actives are below 1 mg, the formulator will have to increase the mass of the powder with a carrier to ensure proper filling. Formulations containing more than 95% lactose are therefore quite common.

Filling Reservoir Devices

Reservoir devices are often filled with a good flowing carrier, because the dosing of the formulation is metered by the device. The metering system requires sufficient flow and constant density of the powder to achieve good content dose uniformity. Good flowing lactose grades with constant density are recommended to be used in these types of devices. The mean particle size will mostly be in the range of 100–200 μm. Good flowing lactose grades are obtained mainly by sieving processes.

Filling Blister Devices

Blisters can be filled with different techniques. All techniques require that the powder stays in the pocket of the aluminium-seal of the blister before it is sealed. Therefore, the powder properties of the formulation should be non-dusting and slightly cohesive. Cohesiveness of the lactose can be increased by milling the lactose or by addition of fine lactose grades to the formulation.

Filling Capsule Devices

The type of lactose chosen here is dependent on the filling system. Capsule filling devices, like drum fillers and piston fillers, will require more cohesive, milled-grade lactose grades.11 Tamper filling or other volume filling techniques like the “pepper shaker”, however, require a free-flowing powder.12 Sieved lactose grades will in general meet these criteria.

DRUG DEPOSITION  

Figure 1 - DFE Pharma

Figure 1: Unit operations and combinations thereof for the design of lactose particle size distribution.

Literature describes that for specific devices the amounts of fine lactose particles plays a significant role in the deposition of the drug.13,14 Especially for the generic formulator, it is a challenge to meet the requested deposition with the same dose of drug, particularly when using a different device. The parameters that a formulator can use to optimise the deposition are restrained by the design of the device and expanded by the various lactose grades.15

DESIGN OF EXCIPIENT

From these selection criteria for excipients, it becomes clear that the excipients need to be designed specifically. There are several ways to do this, such as chemical and mechanical surface modifications.16,17 However, the most common technique of manipulating particle size distributions of lactose is through milling and sieving operations. By combining several of these techniques, as illustrated in Figure 1, a plethora of lactose grades can be designed.

CONCLUSION

The selection of the optimal inhalation lactose grade is based on the device, the filling platform, the concentration of the active, processing of the active and the required deposition of the drug in the lungs. Each formulation will therefore need the excipient to be designed to meet the specific requirements mentioned above. Although this selection is often empirical, support of an experienced excipient supplier can speed up the development process.

REFERENCES

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  13. Kinnunen H et al, “Extrinsic lactose fines improve dry powder inhaler formulation performance of a cohesive batch of budesonide via agglomerate formation and consequential co-deposition”. Int J Pharm, 2014, Vol 478, pp 53–59.
  14. Kinnunen H, Hebbink G, Peters H, Shur J, Price R, “An investigation into the effect of fine lactose particles on the fluidization behaviour and aerosolization performance of carrier-based dry powder inhaler formulations”. AAPS PharmSciTech, 2014, Vol 15, pp 898–909.
  15. Grasmeijer F et al, “New mechanisms to explain the effects of added lactose fines on the dispersion performance of adhesive mixtures for inhalation”. PLoS One, 2014, Vol 9, e87825.
  16. Singh DJ et al, “Preparation and evaluation of surface modified lactose particles for improved performance of fluticasone propionate dry powder inhaler”. J Aerosol Med Pulm Drug Deliv, 2015, Vol 28, pp 254-267.
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