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Many drugs against lung diseases are administered through the lungs. The advantages are that lower doses can be used, fewer side effects are experienced and the medicine takes effect more quickly. This route of administration is increasingly used for systemic drug application, especially where injection is the only alternative. The traditional dosage form for inhalation is the MDI (metered dose inhaler). From these devices, the drug is dispersed by CFCs followed by the inhalation. However, CFCs are no longer permitted because of the depletion of the ozone layer. This is whyMDIs are being replaced by DPIs (dry powder inhalers), which contain a powder consisting of an active ingredient and a carrier. The powder is packed in capsules or blisters containing one dose. Thisis called a single-dose system. Another possibility is that the powder is packed in a reservoir – the multi dose system. By far the most popular carrier is lactose. Toxicology data on this material after administration to the lung are favourable. Moreover, lactose is readily available and compatible with most active ingredients. Lactose has been used in DPIs for more than twenty years.
Requirements for DPIs
DPIs have to meet the following requirements:
| 1. |
Drug content uniformity. In order to guarantee that the patient gets the same dose every time, it is important that each capsule or blister in a single-dose system contain the same amount of powder and medication, while, in a multi-dose system, the reservoir must release the same amount of powder and drug every time. |
| 2. |
Drug delivery from a DPI depends on the patient’s breathing pattern. This implies that the dose has to be released in exactly the same way at low breathing and at a high breathing rate. Content uniformity at different airflows is therefore extremely important for a DPI. |
| 3. |
Stability of powder against humidity and temperature. Because the particle size distribution of lactose is extremely important for the action of a DPI, the lactose must be protected against particle size growth. The main property responsible for particle size growth is an undesired combination of temperature and relative humidity. Controlling the temperature and relative humidity followed by storage in the correct packaging are important for stability. |
| 4. |
Flowability: this property needs to be sufficient in order to obtain a DPI with the correct amount of powder. Because almost all active ingredients have poor flowability, the good flow has to be supplied by the carrier.
These four requirements concern the powder to be inhaled, to which lactose makes an important contribution. Therefore, lactose for inhalation has to meet the properties explained below. |
Key properties regarding lactose for inhalation
| 1. |
As will be discussed in the next section, the particle size distribution is of key importance for the action of a DPI. This means that for each new combination of active ingredient and DPI device a new type of lactose has to be developed, where particle size distribution is an important characteristic. Consequently, lactose for inhalation has to be customised in close co-operation between the DPI manufacturer and the lactose supplier. The regulation authorities will check particle size specifications more strictly than they have done in the past. The most important technique to measure particle size distribution in inhalation lactose is laser diffraction, which increasingly replaces sieve analysis. |
| 2. |
Surface characteristics. Apart from particle size distribution, the following surface characteristics are important for inhalation lactose:
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The specific surface area (mostly measured by gas adsorption) is an important property for those inhalation powders working according to the principle of adhesive mixtures (see also the next section). For these systems, a monolayer of active particles on lactose is formed. If a surface area is not sufficiently specific, drug particles will form more than one layer and the drug delivery to the lungs will be less.
Particle shape is important because of aerodynamics of the powder when it leaves the DPI. Current DPIs are formulated with a tomahawk-shaped lactose particle. Changing this shape will change the aerodynamics and separation of drug from lactose and delivery to the lungs.
Amorphous content and surface moisture content are important to prevent changes in particle size and adsorption behaviour. |
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Inhalation through a DPI
From a DPI, the medication will reach the lungs by the following route:
| 1. |
Emptying of the capsule or blister (in case of a single-dose system) or taking a dose from the reservoir (multi-dose systems). These actions are carried out mechanically on the DPI device, for example by pushing a button. |
| 2. |
The user breathes while the DPI is being emptied. Inhalation provides the airstream for the further transport of the powder. |
| 3. |
After emptying, the medication separates from the lactose. |
| 4. |
Since the active ingredient particles are smaller than lactose particles, the medication enters the body earlier than the lactose. |
| 5. |
Generally, the lactose particles are too large to enter the respiratory system. They will remain in the throat. Only for systems in which the lactose particles are as small as the active ingredient particles will the lactose also enter the lungs. |
| 6. |
The active ingredients will enter the respiratory system. |
The position in the respiratory tract where the active ingredient is delivered depends on its particle size. Active ingredient particles of 2-5 μm are delivered in the alveolar region. Larger particles are deposited less deep in the respiratory system, whereas particles finer than 2 μm are exhaled. Most active ingredient particles of 2-5 μm tend to (re)agglomerate when they are not formulated with a carrier, and will not reach the lungs then. To prevent this re-agglomeration, the medicine is formulated with a carrier, mostly lactose. Three different principles can be used: adhesive mixtures, adhesive mixtures with fine particles and agglomerates.
Adhesive mixtures
Re-agglomeration of micronised active ingredients is caused by the hydrophobic character and large surface area of their particles. They are attracted to each other, which results in an agglomerate. Blending with a carrier prevents this agglomeration. The micronised active ingredient particles are attached to the surface of the carrier lactose. A prerequisite for the formation of such blends is that the particle size of the lactose is a few factors higher than the particle size of the active ingredient. The amount of lactose should be at least five times as high as that of the medication. The lactose particles are very suitable for this purpose because of their regular shape and smooth surface. The most appropriate lactose types are the non-milled crystalline types, especially the finer products. Most drug-DPI device combinations require a customer-specific lactose with a narrow particle size distribution . The micronised active ingredient particles form a monolayer on the lactose. When there are too many active ingredient particles, or not enough lactose particles, or when the specific surface area of lactose is insufficient, active ingredient particles may form more than one layer on the lactose. At places where there is more than one layer, the active ingredients will agglomerate and fail to reach the lungs.
Adhesive mixtures must be ‘strong’ enough to form a stable mixture: during storage over a longer period in the DPI device, the active ingredient should stay attached to the surface of the lactose. However, when the blend is too ‘strong’ no separation of active ingredients and lactose will occur on inhalation. This system can be applied for many different medicines. However, extremely low-dose medicines, which are insufficiently separated from the lactose, are not suitable for this application. For these medicines the following system – adhesive mixtures with fine lactose particles – may be useful.
Adhesive mixtures with fine lactose particles
The surface of particles has a certain energy called the surface energy. For lactose particles, this energy is not equally divided, but concentrated in a few locations. As a result, lactose particles contain areas with high surface energy and areas with low surface energy. When mixed with micronised active ingredient particles, the active ingredients will tend to agglomerate in the high-energy places. Active ingredient material concentrated in the high-energy areas will not be separated from the carrier sufficiently during inhalation, and will not reach the lungs. Consequently, drug delivery to the lungs will be less than expected. This impact is especially dramatic for extremely low-dose medicines, which will completely concentrate in the high-energy areas and show no lung deposition at all. This problem can be overcome by the addition of micro-fine lactose particles to the lactose carrier. The micro-fine lactose particles occupy the high-energy places of the larger lactose particles and when the drug is blended it will not be able to adhere to these places.
Lactose for this type of application can be produced in two ways. Micro-fine lactose can be added by blending to non-milled lactose. The alternative is gently milled lactose, which still mainly consists of undamaged crystals but also contains the small lactose particles needed.
Agglomerates for inhalation
As the two principles explained above require an excess of lactose , they cannot be applied for extremely high-dose medicines, because that implies that the powder quantities to be inhaled would have to be too large. To prevent re-agglomeration of the active ingredient particles, they are reworked into very porous and soft agglomerates. These agglomerates must be strong enough for storage in a DPI, but not too strong, to avoid insufficient separation from the carrier during inhalation.
Agglomerates can be formulated with or without lactose. Regarding the drug-lactose ratio, the complete range varying from 0% to almost 100% lactose is possible. Because the most stable agglomerates are obtained when the particle size of the drug and lactose are similar, micronised lactose is the most efficient material for this application.
For information on propellants for MDI please go to: www.zephex.com
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