Engineering a DPI Powder to Improve Therapeutic Outcomes

As previously discussed, the efficient respiratory deposition of the API powder will be dependent on the physico-chemical nature of the particulate system and, in addition, the physical and environmental conditions to which they are exposed. At this point it is important to state that there are limited products presently available which contain engineered excipients or drugs. However, there has been much research activity into the modification of the powder and material components of DPIs.

Carrier Modification

One of the most commonly studied areas in DPI formulation design is that of carrier modification. Difficulties (both technical and regulatory) in altering the physical properties of micron sized drug particulates has led to the more popular approach of modifying excipient carrier materials to achieve improvements in blend uniformity and delivered drug dose. It must be stated, however, that in general, this approach is still only led to limited empirical observations concerning a material descriptor and formulation performance, and it is unclear to what degree such observations have impacted pharmaceutical manufacturing processes. A series of approaches have indicated that the optimum performance characteristics of a DPI product require a formulation which exhibits adequate flow (for processing and dosing) and a certain level of excipient fines.

The effect of surface morphology: It is reasonable to expect that the macro-, micro-, and nanoscopic morphology of an excipient carrier will play a major role in efficient drug blending and aerosolization since micron sized particles will regularly encounter adhesive forces that are greater than those required for their liberation. Subsequently, the most common investigated approaches to improve drug removal from carrier particles during inhalation are to (1) reduce the contact area between drug particle and carrier, (2) alter the particle geometry of the carrier, and (3) reduce the surface energy of the contiguous surfaces. Of these three approaches, by far the greatest attention has been focused on modifying the carrier morphology in order to achieve changes in the contact geometry between drug and carrier. A simplistic representation of the ranges of surface geometries which may be encountered is shown in Figure 5. In simple terms, by varying the rugosity of a carrier it becomes possible to vary the degree of adhesion and, thus, alter the efficiency of drug liberation (Fig. 5).

Although roughness is believed to be one of the dominating factors for the performance of such systems, it is generally very difficult to investigate the relationships between one material factor, in this case roughness, and performance without altering another potentially influencing factor, such as particle shape or quantity of intrinsic carrier fines. This makes quantifiable interpretation of any observations difficult. Furthermore, the potential

Aiph Carrier Morphology
Figure 5 Influence of carrier morphology on drug particle adhesion.

therapeutic improvement of altering the carrier roughness has, in general, been investigated via comparison of off-the-shelf lactose excipients with materials produced by some variation in batch or process parameters. However, in general, the hypothesized influence of carrier morphology on aerosolization performance (as represented in Fig. 5) is generally in good agreement with recent literature. For example, recent work by Flament et al. (22) has suggested a linear reduction in the FPF of micronized terbutaline sulphate with increased roughness, measured in this case by microscopic luminescence, of a 63-90 ^m sieve fractioned lactose samples. Earlier work, by Kawashima et al. (23), also related the surface area and roughness parameters of a series of lactose carriers (approximated median diameter 60-65 ^m with similar geometric standard deviations) to the aerosolization performance of micronized pranlukast hydrate (Fig. 6).

In general, as can be seen from Figure 6, an increased carrier roughness and surface area resulted in a reduction in drug aerosolization efficiency. Interestingly, a deviation from linearity was observed for lactose type F, and was attributed to a variation in amorphous content and/or increased drug-carrier contact area (e.g. as in the smooth carrier example shown in Figure 5. Other recent studies have reported similar observations. For example, Zeng et al. (24) reported that when the surface structure of a re-crystallized lactose carrier was modified (by etching with a 95% w/w

Figure 6 Influence of carrier surface area on the aerosolization performance of pranlukast hydrate. SEM images represent the carrier used for the measurements circled. Abbreviation: RP, respirable particle. Source: From Ref. 23.

ethanol solution), the induced surface cavities resulted in a decrease in FPF of blended albuterol sulphate. It is interesting to note, however, that the addition of fine lactose, approximated as 5% (between 5 and 10 ^m), rectified this reduction. In other recent studies, the macroscopic etching of commercial grade lactose via mixing in an ethanolic solution (25-27) or via temperature controlled surface dissolution (28) has been shown to improve the aerosolization of various micronized APIs. As with the studies presented previously, it is envisaged that the improvement is, in part, due to a reduction in macroscopic roughness, limiting the contact geometry between drug and carrier surfaces. This potential for particle entrapment in large pits, crevices or craters is decreased as the macroscopic roughness is reduced, as can be seen by atomic force microscopy (AFM) topographical images of a commercial lactose carrier pre- and post-etching (Fig. 7).

In addition to direct surface modification, significant research has focused on the relationships between carrier geometry, for example, crystal habit, dimensions, and performance. In recent studies, Zeng et al. (29) have suggested that the crystal shape of lactose carriers can have significant impact on the aerosolization performance of attached drug particulates. In general, an increase in elongation (aspect) ratio was reported to increase the aerosolization performance (FPF) of albuterol sulphate, although a decrease in blend uniformity was observed (29). Again in these studies, it is suggested that a reduced carrier roughness resulted in increased fine particle drug. Furthermore, it is interesting to note that during these investigations, another important factor influencing aerosolization performance was noticed; the presence of fines.

Apart from direct morphological and surface roughness parameters, one of the key factors that have been suggested to influence aerosolization performance of adhered drug particulates is the presence of similar sized excipient fines, for example, particles with a volume median diameter <5 ^m.

Figure 7 AFM topographical images of (A) a commercial grade lactose carrier surface and (B) surface-etched carrier. Source: From Ref. 26.

The "positive" effect of excipient fines for drug aerosolization would also be expected since the surface of a commercial grade lactose carrier, as represented in Figure 8, will contain a distribution of "energy" sites that will promote particle adhesion to different degrees (16), and thus affect drug particle liberation in DPI carrier based systems (30). These sites of high adhesion may be attributed to a combination of "particle entrapping" crevices in the surface morphology of the carrier, crystalline phases with higher surface energy and the presence of amorphous material. Recent research, investigating the presence of these "active sites" in carrier systems, has suggested that an energy distribution exists for such sites, which, for low dose formulations, significantly influences drug aerosol performance (31,32). This proposed variation in drug adhesion can be observed when directly measuring the adhesion forces experienced by a single micronized drug particle, over the surface of a commercial lactose carrier (Fig. 8).

Clearly, the distribution of such sites could lead to increased particle adhesion and thus variability in content uniformity and drug aerosolization efficiency. The addition of excipient fines to a simple carrier formulation, may improve the aerosol performance due to "filling" these "active sites"

Distribution Albuterol Drugs
Figure 8 SEM of lactose carrier with an overlaid adhesion map of the interaction between a single micronized albuterol sulphate and carrier surface.

(by displacing existing drug particles), and/or by improving aerosol performance by the formation of fine-drug agglomerates. The presence of both these morphological features can be observed via high resolution Scanning electron micrograph (SEM) of a carrier particle surface (Fig. 9).

The mechanism for improved performance in these systems is dependent on both the previously described formulation factors, and the relative cohesive/adhesive balance between the components involved. Recently, direct measurement of inter-particulate forces in conventional DPI systems has shown that a clear balance may be observed between the adhesion and cohesion profiles of each component in the formulation (33,34), and these factors may be used to predict the performance of the formulation. Such observations are also in good correlation with previous studies that predict ordered mixing in tableting ingredients (35).

Regardless of the mechanism, it has been shown, as discussed previously, that the addition of fine excipient material to an inhalation formulation, results in improvement in performance outcomes (i.e. improved aerosolization efficiency). Recent work by several groups has suggested that the presence of carrier fines, significantly improve drug aerosolization performance by either filing these "active sites" or forming discrete agglomerates (24,36-42). For example, studies by Lucas et al. (42) indicated that, regardless of the mixing order, the addition of fine lactose particulates to a formulation increased the aerosol performance (Fig. 10).

Figure 9 SEM of a fine particulate system in the crevice of a lactose carrier surface (albuterol sulphate-lactose carrier). Source: From Ref. 32.

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Figure 10 The influence of fine-particle lactose (FPL) additive on the aerosolization performance of a protein-carrier formulation. Source: From Ref. 42.

Similar observations were later described by Louey et al. Islam et al., and Adi et al., (37,38,43,44). Of note, Islam et al. (37,38) suggested that, while the carrier size and surface features had an influence on aerosol performance, the addition of fines into these formulations dominated performance. More recently, similar studies, investigating the influence of carrier milling, on aerosolization efficiency of blended APIs, again suggested that the introduction of fines dominated the performance compared to other factors, such as particle size and amorphous content (40,41).

Although not fully understood, the presence of a certain level of fines clearly results in improved drug aerosolization performance and the influence of these small particulates on active site filling and/or spontaneous agglomeration is still under investigation. For a more in-depth review of the influence of fines on DPI performance, the reader is referred to a recent review by Jones and Price (45).

Another approach to improve the aerosolization efficiency of blended drug particulates from carrier based systems is to alter the surface chemistry of the parent carrier. Work by Tee et al. (46) and Steckel and Bolzen (47) have investigated the influence of various sugars and sugar alcohols (from polyols, such as mannitol, to more complex disaccharides, such as lactose) on the aerosol performance of different model drugs. The theory behind this approach is that any particular crystalline system has a finite surface energy. Thus, by changing the nature of the crystalline habit, morphology or surface chemistry, the relative particle adhesion of an API will be altered. For example, Tee et al. (46) reported that, unsurprisingly, different sugar alcohols, such as mannitol, altered the aerosol performance of a micronized albuterol sulphate formulation. Interestingly, these studies also highlighted the positive effect of adding different amounts of sugar or sugar alcohol fines to these formulations. Other studies have investigated the influence of different crystalline carrier materials on drug aerosol performance and have reported that materials such as sugars and sugar alcohols can increase/ decrease aerosol performance (47-49). However, it is important to note, that such observations are difficult to compare, since different drugs, carrier size distributions and analytical techniques are used. Furthermore, other compounding factors may ultimately influence performance when trying to compare alternative carriers. For example, authors such as Steckel et al. (47) have reported significant variability in drug aerosolization performance when evaluating a single carrier material (e.g. lactose or mannitol) from multiple batches or different suppliers (47,50). That is not to say, it is impossible to make comparisons between materials, when certain carrier descriptors are altered, as long as most variables are retained constant. In practice, however, this is very difficult since carbohydrates have different moisture sorption characteristics, important for DPI performance, and it is challenging to produce sieve fractions with identical descriptors to that of the comparator material, namely lactose. One alternative to using different carbohydrate type materials for modifying performance is to alter the surface chemistry of a conventional lactose carrier. This may be achieved by varying the crystallization conditions, to alter the crystal habit or polymorphic form (51), or by the addition of ternary agents that act to control the force of interaction (26,52-55). For example, materials such as magnesium stearate (25,26,52,53,56) and leucine (54) are reported to improve the aerosolization efficiency of carrier based system by modification of the adhesive forces between the drug and the carrier. This change in adhesive behavior can be observed in formulations of beclometasone dipropionate which suggested that the addition of magnesium stearate into the surface of a smoothed lactose surface increased the respirable dose of by a factor of 3.5 (29 and 102 ^g doses for the smoothed and magnesium stearate treated lactose carriers, respectively) (26). Similarly, investigation of the cumulative adhesion energies (measured by colloid probe microscopy, indicated a decrease in the 90th percentile adhesion energy by the same factor (3.5) (from a 112 x 10-9 nJ to 32 x 10-9 nJ for magnesium stearate treated systems). More recent work by Iida et al. (52,57), has reported similar improvements, and, improved performance after storage of lactose-magnesium based formulations at elevated humidities. Recent technologies that incorporate this formulation strategy are Vectura's PowderHale® (58), and Chiesi's beclometasone Pulvinal® product (56).

In general, however, regardless of direct carrier adhesion or agglomeration formation, the ultimate aerosol performance of a DPI powder will be based on the inter-particulate forces acting between drug and carrier before, during and after processing and after aerosolization. As can be seen form the overview above, significant advances have been made in understanding these forces (e.g. recent work using colloid microscopy has been utilized to predict carrier adhesion and/or agglomerate formulation (26,33,34,59-61), and in general, the aerosol efficiencies of recent DPI systems are greatly improved compared to the early devices.

Continue reading here: Modification of the API to Improve Respiratory Deposition

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