The second area of dry powder development is dry powder formulation. At the start of the 1990s the need for new powder technologies was evident from the generally poor performance of micronized, spheronized, or blended powders. It was also apparent that, with a few notable exceptions [14], device technology alone could not dramatically improve the performance characteristics of DPI products. That is, with improved powder technology the need for deviceengineering solutions to aerosol dispersion problems are somewhat mitigated. Over the years there has been some reluctance to develop new excipients for pulmonary use (because this can be as arduous as developing a new pharmacologically active molecule), and early attempts at improving powders focused on existing generally-regarded-as-safe pulmonary excipients. However, recent advances have clearly demonstrated that new excipients are an essential component of high-performance dry powder delivery technologies. Figure 5 summarizes the route that powder formulation development has been taking since the early 1990s.

Figure 5 Progress toward new excipients and new manufacturing technology for dry powder formulations.

The basic problem that developers have been trying to solve is the need for a dry powder to flow, for dosing and emptying purposes, yet disperse adequately to make an "inhalable' aerosol. In terms of conventional powder technology these two requirements are usually mutually exclusive. Coarse powders flow well but contain very little "respirable" material. Fine powders possess a high "respirable" content but generally exhibit very poor flow properties. The focus then has been on trying to find ways to make these contradictory requirements compatible.

Progress with formulation innovation has focused on two areas. In chronological order they are improving existing blending techniques, followed by new excipients and particle-engineering methods to produce particles that do not require blending.

Blend improvements began with passivation and corrosion of the lactose carrier surface [15]. The idea was to reduce the number of high-energy binding sites on the lactose carrier surface and hence to reduce the energy required to remove the drug particles from the carrier. This approach generally produces modest improvements in performance. However, one of its major advantages is that "fine" excipient particles (small enough to reach the lung) are not required, and hence there are no major toxicology issues. The next step in blend improvement was to use "force additives" and to manufacture blends with multiple components. Conventional powder blends utilize fine drug particles and large sugar carrier particles. With this new "force additive" technology, a third component is added to the blend, with the intent of its occupying the active binding sites on the carrier and acting as a "breakable" bridge between the carrier and the drug. The data suggest this technique can be very effective [16], although a second excipient with a particle size in the range capable of reaching the lung is required, and this has obvious consequences from a toxicology perspective. Blends using magnesium state are now marketed in Europe, and blends using leucine and other amino acids have been reported in the literature [17].

Published data suggest that the fine-particle "engineering" approach is proving successful from a performance perspective and that it is capable of addressing both overall delivery efficiency and the flowrate-dependence issues without the need for carrier particles or active devices. However, products based on these techniques have yet to reach the market. The approach has been to manufacture particles that include active drug and excipient. By choice of appropriate excipients and judicious selection of manufacturing techniques and conditions, particles with low surface energies and advantageous morphologies and densities can be obtained. The techniques for manufacturing range form coprecipitation to spray-drying. The excipients used include sugars, amino acids, and lipids. The sugar-based systems have been used as both powder-dispersion aids and stabilizers for protein inhalation powders. The most widely reported examples of the lipid-based systems are AIR particles [18], which are ultralow-density particles made by spray-drying lipid and albumin in solution with active drugs, and Pulmospheres [19], where a blowing agent is used to "inflate" particles to produce spongelike structures. These technologies have been extremely successful in generating powders with the required properties for dry powder inhalers. For Pulmospheres, lung deposition as high as 57% of the nominal dose has been reported for a simple passive inhaler [20,21]. However, as stated earlier, these second-generation powder formulations have yet to demonstrate commercial viability.

Dealing With Asthma Naturally

Dealing With Asthma Naturally

Do You Suffer From ASTHMA Chronic asthma is a paralyzing, suffocating and socially isolating condition that can cause anxiety that can trigger even more attacks. Before you know it you are caught in a vicious cycle Put an end to the dependence on inhalers, buying expensive prescription drugs and avoidance of allergenic situations and animals. Get control of your life again and Deal With Asthma Naturally

Get My Free Ebook

Post a comment