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Inhalation June 2022 27 Composition e composition of the adhesive mixture, i.e., the rel- ative proportions of API(s) and excipients, is a key factor influencing formulation properties and per- formance. e maximum drug load of an adhesive mixture has been a topic of debate [2]. Increasing the drug load of the formulation will, sooner or later, lead to a segregated system, as the carrier surfaces become overloaded with drug. A conservative view states a limit of approximately 5% drug load w/w, but this may be increased, for instance, with aggregated car- riers where the cavities and clefts can accommodate larger amounts of the API [2]. Given the dose, in terms of the amount of powder to be inhaled, also is limited to approximately 50 mg per inhalation, this sets an upper limit for how large a dose can be admin- istered by adhesive mixture technology to approxi- mately 2.5 mg of API. For drugs such as antibiotics, where much higher inhaled doses are required, adhe- sive blends are therefore not an option [2]. e use of the terms "adhesive" mixture and "ordered" mixture stems from the picture of carrier particles covered with a layer of the fine drug parti- cles on the surfaces. e drug load corresponding to a monolayer of API particles on the carrier surfaces (a surface coverage ratio (SCR) of 1), can be calculated based on the (enveloped) surface area of the carrier and the API [17, 23]. e SCR and the associated "blend state" are therefore key features of the formu- lation. In reality, however, such well-ordered struc- tures are usually not found. Instead, many APIs tend to form small clusters adhering to the carrier surfaces, and with increasing API load, a multi-layer structure is often formed [17, 18]. Many inhalation drugs, including corticosteroids, b-agonists and muscarinic agonists, are highly potent, with doses ranging from single digit µg to a few hundred µg. For such low doses, the formulation challenge is achieving a homogeneous and high per- forming formulation when the drug content is less than one percent. Due to the small particle size, the number of API particles in a dose is still enormously large and homogeneity is usually not an issue, at least down to approximately 0.1% drug load (see the pro- cessing section of this article). However, formulations with a low drug load tend to yield a very low FPF, which means that a large fraction of the drug is not able to reach to the lungs and therefore will not con- tribute to the pharmacological effect. e low dis- persibility is often attributed to the irregular surfaces of the marketed carrier grades. Forces acting between particles during mixing, called "press on forces," have been suggested as another explanation [24], although a strict definition of such forces has not been given. Addition of lactose fines to increase the "total fines" concentration, i.e., the sum of fine particles from API(s) and excipients in the formulation, is a way to improve the FPF [16]. Data on the effect of added Coating agents Excipients that are smeared onto the other constit- uents of the formulation are called "coating agents" in this article. Alternative names in the literature are "lubricants" and "force control agents." Currently, the most common coating agent, used in a number of DPIs, is magnesium stearate (MgSt) [3]. Other materials that can have a similar effect are L- leucine and sodium stearyl fumarate [19], but these have not yet found their way to the market. When preparing an adhesive mixture containing a coating agent, it is common to combine the carrier with the coating agent in a first process step (the coating step) and thereafter add the API(s) and optional fines, but other process schemes may be considered [2]. A recent study demonstrated visualization of the coated layer and quantification of the degree of surface cov- erage for three different coating agents using time-of- flight secondary ion mass spectrometry (TOF-SIMS) [20]. For illustration, the coating of lactose carrier with magnesium stearate is shown in Figure 4. Application of a coating agent is known to signifi- cantly enhance the dispersibility of DPI formula- tions with respect to FPF. e mechanism is not fully understood but is believed to be a combina- tion of lowered surface energy and reduced friction among particles [10, 21]. Both the amount of coat- ing agent and the coating process have been shown to be critical, as is described in the processing sec- tion of this article. In addition, application of coat- ing agents may have implications for formulation stability. On the negative side, chemical incompati- bility between MgSt and some drugs, e.g., acetylsal- icylic acid, has been reported [22]. However, if there is chemical compatibility, physical stability may be improved by the addition of a coating agent, as the moisture sensitivity of the dry powder formulation could be reduced, for instance, by addition of hydro- phobic MgSt. Figure 4 Lactose carrier particles (Respitose SV003) coated with 1.0% magnesium stearate at 5, 15 and 25 minutes of coating time in a high shear mixer. The red color indicates magnesium stearate and the green color indicates lactose. (See reference 20.) Reproduced with permission from Elsevier.