Formulation of Lactose for Inhaled Delivery Systems

November 1, 2002
Rudie Damhuis, Paul Diepenmaat, Henk te Wierik
Pharmaceutical Technology Europe

Volume 14, Issue 11

Dry powder inhalers (DPIs) contain a powder which, when required, is discharged and inhaled. The therapeutic drug is manufactured in powder form as small particles a few micrometres in diameter. In many DPIs, the drug is mixed with much larger sugar crystals, such as lactose, and the smaller drug particles attach to these excipient particles, improving entrainment of the drug upon inhalation. This article examines how the application and combination of versatile processes such as milling, micronizing, sieving and air classification can be used to manufacture dedicated lactose products for practically every possible combination of active and excipient blend in DPIs.

Many of the drugs used to treat lung diseases are administered to the patient through the lungs. The advantages of this route include the ability to use lower doses, fewer side-effects and the early onset of drug activity. This method of drug administration is increasingly being used for systemic drug applications, particularly when injection is the only alternative.

The traditional dosage form for inhalation was the metered dose inhaler (MDI). In these devices, the drug was dispersed by chlorofluorocarbons (CFCs) followed by inhalation. Because of environmental implications, however, CFCs were banned,1,2 leading to MDIs partly being superceded by dry powder inhalers (DPIs). DPIs contain a powder consisting of a drug and a carrier.3-7 In some systems, the powder is packed in capsules or blisters containing one dose, and are therefore referred to as single-dose systems. Other devices contain a powder reservoir, known as a multi-dose system. The most popular carrier used is lactose. Toxicology data of lactose after administration to the lungs are favourable.8 Moreover, lactose is readily available and well established, having been used in DPIs for more than 20 years.

Requirements of DPIs

DPIs have to meet the following requirements: Drug content uniformity. In a single-dose system, each capsule or blister needs to contain the same amount of powder/drug. In a multi-dose system, the same amount of powder/drug must be released every time it is administered, to guarantee that the patient receives the same dose each time. The presence of a carrier, such as lactose, promotes content uniformity in what is generally a low-dosage medication.

Figure 1: Gentle milling: the influence of grinding rotor speed of the air classifier mill on the percentage of particles smaller than 15 µm.

Drug delivery. Drug delivery depends on the breathing behaviour of the patient.9 Regardless of a patient's breathing action, it is essential that the dose is released in exactly the same way every time. Consistent delivery at different airflows is therefore essential for a DPI and is assisted by the presence of a carrier in the formulation.

Flowability. Generally, DPI powders have to flow well. The flowability has to be sufficient both for the correct manufacture of the DPI and for dosing from the DPI.

These three requirements dictate the formulation of the powder to be inhaled, of which lactose is a major constituent. Therefore, lactose for inhalation has to meet some basic requirements, which are discussed in this article.

Inhalation using a DPI

From a DPI, the drug will reach the lungs by the following route:

  • The drug is discharged from the capsule or blister (single-dose system) or a dose is taken from the reservoir (multi-dose system). This action is done mechanically, by pushing a button on the DPI, for example.

  • The user inhales during discharge. The action of breathing provides the airstream for the further transport of the powder.

  • The drug separates from the lactose, and the drug particles enter the respiratory system.

  • Typically, the lactose particles are too large to enter the respiratory system. They will remain in the throat. Only when lactose particles are as small as the drug particles will they enter the lungs.

Formulation of inhalation powders

The location in the respiratory tract where the drug is delivered depends upon its particle size. Drug particles of 2-5 mm are delivered to the lungs. Larger particles do not fully penetrate the respiratory tract, whereas particles smaller than 2 mm are exhaled. Most drug particles between 2-5 mm tend to agglomerate when they are not formulated with a carrier and will not, therefore, reach the lungs. To prevent this agglomeration, the drug is formulated with lactose (or another carrier) to form an adhesive mixture.10

Table I: Relationship between the percentage of fine lactose particles and lung deposition (expressed as a percentage of particles