New Developments in Corticosteroids Gu ¨ nther Hochhaus Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida

The goal of inhaled corticosteroid therapy is the targeted delivery of drug into the lung to achieve distinct pulmonary effects with reduced systemic side effects. Pharmacokinetic/pharmacodynamic assessment of pulmonary delivery suggests that an ideal inhaled corticosteroid and/or its delivery system should have the following characteristics: high pulmonary deposition efficiency, low oral bioavailability, high systemic clearance, optimized pulmonary residence time, and selective binding to the glucocorticoid receptor. Therefore, future developments will focus on improved delivery devices with higher pulmonary deposition; drugs or drug formulations providing prolonged pulmonary residence time (e.g., use of liposomes, microspheres, and nanothin coatings, or use of biological systems that achieve prolonged pulmonary residence time by ester formation and reactivation); drugs with efficient systemic clearance (e.g., soft drugs/hydrolyzable drugs); and/or improved pharmacodynamic selectivity. Keywords: oral bioavailability; protein binding; pulmonary deposition; pulmonary residence time; systemic clearance

For the past 30 years, pulmonary drug delivery has been successfully used in asthma therapy, because it controls inflammatory and other asthmatic processes in the lung without producing high systemic drug levels with the concurrent induction of systemic side effects. Direct pulmonary delivery increases pulmonary selectivity. Today, we know that in addition to pulmonary deposition efficiency, pulmonary selectivity depends on a complex interplay of a number of other pharmacokinetic and pharmacodynamic properties: oral bioavailability, systemic clearance, pulmonary residence time, and protein and tissue binding. These properties have been partially incorporated into the development of recent generations of inhaled corticosteroids (ICS) such as budesonide and fluticasone propionate. Because of the high pulmonary selectivity of the currently available corticosteroids, it is clear that further improvement in ICS will not be trivial and will require a rational drug development approach. As indicated in Figure 1, a number of biopharmaceutical, pharmacokinetic, and pharmacodynamic processes are involved in determining pulmonary selectivity in inhalation therapy (1). Based on these relationships, Table 1 indicates that a successful ICS formulation should provide a high pulmonary deposition efficiency, have a low oral bioavailability in order to reduce systemic absorption, be subject to high systemic clearance for efficient removal of systemically absorbed drug (12% for budesonide, and ⬍ 1% for fluticasone propionate), and possess a prolonged pulmonary residence time to maximize the effect (observed for fluticasone propionate and for the esterified fraction of budesonide; see below). Furthermore, the prodrug approach has been revitalized with the development of ciclesonide as lipophilic prodrugs are likely to increase the pulmonary residence

time and also reduce oropharyngeal side effects, because these drugs are not activated in the mouth. In addition, drugs with high plasma protein binding (mometasone furoate, ciclesonide) are currently being evaluated as a means of further reducing systemic side effects of ICS. Recent research in the pharmacodynamic arena suggests that the effect to side effect ratio can be further maximized by optimizing the interaction with the glucocorticoid receptor (Table 1). The current belief is that transrepression reactions (blockage of transcription factors such as activator protein-1 and nuclear factor-␬B) are beneficial, whereas transactivation reactions (induction of the synthesis of side effect–inducing proteins) are not. Currently available ICS, such as fluticasone propionate and budesonide, fulfill a number of the criteria shown in Figure 1 and Table 1 (e.g., low oral bioavailability, high hepatic clearance, prolonged pulmonary residence time). This makes it increasingly difficult to develop new ICS with significantly improved properties. However, current ICS such as budesonide and fluticasone propionate may not be fully optimized with respect to their extent of pulmonary deposition, their pulmonary residence time, and the efficacy with which the systemically absorbed drug is metabolically cleared. Thus, advances in the development of ICS will focus on the following three design strategies: increased pulmonary deposition efficiency; optimized pharmacokinetic properties (e.g., more efficient systemic inactivation, improved pulmonary residence time); and optimized pharmacodynamic profile. However, as improvement of the current ICS will be more and more difficult, one needs to evaluate new developments critically to make sure that drug properties are driven not only by marketing considerations but also by hard science.

INCREASING PULMONARY DEPOSITION Metered-dose inhalers used during the first 2 decades of ICS therapy had relatively small (10%) pulmonary deposition efficiencies (Table 2). The deposition efficiency of dry powder inhalers is equivalent or only somewhat higher (up to 30% for the Turbohaler). It is obvious that improved pulmonary deposition will favor pulmonary selectivity, especially for drugs with high oral bioavailability, such as beclomethasone dipropionate (8), because an increased pulmonary drug deposition will allow the same clinical effects being achieved with a reduced daily dose. Therefore, it was not surprising that the need to design chlorofluorocarbon-free inhalers was used by a number of research groups as an opportunity for innovation (9). Although this research focused on an efficient transition from chlorofluorocarbon to hydrofluoroalkane propellant or other alternatives, developers began to experiment with better device/patient coordination, higher pulmonary and peripheral deposition, and engineered particle design. Consequently, a number of new metered-dose inhalers, dry powder inhalers, and nebulizers are in development.

(Received in original form February 17, 2004; accepted in final form May 20, 2004)

Hydrofluoroalkane Inhalers

Correspondence and requests for reprints should be addressed to Gu¨nther Hochhaus, Ph.D., Department of Pharmaceutics, College of Pharmacy, University of Florida, Box 100494, Gainesville, FL 32610. E-mail: [email protected]

Whereas some research groups decided to develop hydrofluoroalkane formulations that mimicked the characteristics of the old chlorofluorocarbon devices (3), other groups aimed at developing better-performing inhalers. For example, the transition from chlorofluorocarbon- to hydrofluoroalkane-based metered-dose inhal-

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Figure 1. Events involved in pulmonary targeting.

ers for beclomethasone dipropionate and flunisolide resulted in valve and actuator redesigns and the use of solution- rather than suspension-based systems. These changes yielded smaller aerosol particle sizes (10), different aerosol plume characteristics (e.g., soft plume), and higher pulmonary (11) and peripheral deposition (12, 13). Ederle and colleagues showed that patients switching to the more efficient hydrofluoroalkane beclomethasone dipropionate preparations were able to reduce their daily dose by half (14). Use of hydrofluoroalkane flunisolide results in a lower incidence of candidiasis (15). In addition to having more efficient delivery mechanisms, newer hydrofluoroalkane-based inhalers deliver more drug to the peripheral part of the lung, which might be beneficial in asthma as these regions are involved in inflammation and remodeling of the lung (16). As an example, Hauber and co-workers reported that markers of inflammation were reduced in the peripheral lung when flunisolide was given as a hydrofluoroalkane formulation, which showed distinct peripheral deposition (17). Future studies should evaluate the benefits of more peripheral deposition in asthma therapy. However, deposition into the peripheral part of the lung might be a double-edged sword: alveolar deposition might also result in faster pulmonary absorption, faster spillover into the systemic circulation, and reduced pulmonary selectivity.

Nebulizers and Liquid Formulations

Nebulizer technology, often judged as old-fashioned, has also experienced revitalization during the past few years. Recent developments have shown that this delivery mode has the potential to be an alternative to metered-dose inhalers and dry powder inhalers. Some new nebulizers are very similar in size to traditional metered-dose inhalers, so they are mobile and can be used by patients throughout the day. Furthermore, nebulizers do not depend on propellants, and some companies have decided to develop nebulizer technology as an alternative to hydrofluoroalkane technology. More efficient methods of aerosolization include ultrasonic principles, piezoelectric atomization (Aerodose [18]), high-pressure microspray (Respimat [19]), electromechanical extrusion (AERx [9]), and electrohydrodynamic principles (Mystic [20]). In addition, coordination of aerosol particle release with the patient’s breathing has been improved (AERx [19]). Another example of progress is the HaloLite nebulizer (21), which releases drug aerosols only during the first half of the inspiratory cycle, thereby reducing drug wastage and promoting more efficient pulmonary deposition. These and similar developments suggest that nebulizers will be a viable alternative to metered-dose inhalers and dry powder inhalers if their cost can be made more competitive.

TABLE 1. FACTORS RELEVANT FOR PULMONARY TARGETING OF ICS Pharmacodynamics Affinity to pulmonary and systemic receptor: Not relevant Selectivity: Transactivation to transrepression ratio (high transrepression desired) Pharmacokinetics Pulmonary factors Pulmonary deposition efficiency (high) Location of pulmonary deposition (peripheral and central) Residence time in the lung (long) Pulmonary tissue binding (?)

Systemic factors Oral bioavailability (low) Systemic clearance (high) Plasma protein binding (?) General tissue binding (?)

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TABLE 2. PULMONARY DEPOSITION OF SOME INHALATION DEVICES Metered-dose inhaler Diskus dry powder inhaler Diskhaler Metered-dose inhaler with spacer Turbohaler Spiros Qvar Respimat Mystic

Particle Design 10–15% 14–20%* 10–15%* 15–25% 30%† 45%‡ 53%§ 40%
80%¶

* Mackie and coworkers (2). † Thorsson and coworkers (3). ‡ Hochhaus and coworkers (4). § Leach and coworkers (5). 兩兩 Newman and coworkers (6). ¶ http://www.battellepharma.com/mystic.stm. Accessed December 1, 2003 (7).

During the design of newer, more efficient dry powder inhalers and metered-dose inhalers, rational particle design, particularly the design of low-density particles, helped achieve high-efficiency drug delivery to the lung (29–31). Other innovative particle designs, such as critical fluid technology, might also be beneficial (32). The use of additives or nanotechnology to modulate particle surface characteristics might further optimize inhalation therapy.

OPTIMIZING PHARMACOKINETIC PROPERTIES Oral Bioavailability

Dry powder inhalers provide good device-to-patient coordination, because inhalation triggers the release of drug powder. However, this is a disadvantage for some patients with asthma who find it difficult to inhale. Newer developments in this arena provide assistance during inhalation using piezoelectric, pneumetric, or electric (motor plus impeller [22]) principles for drug particle suspension. Metering mechanisms and reusable devices are also in development.

Because a significant portion of any dose of an ICS is swallowed and absorbed systemically, it is important that the drug exhibit low oral bioavailability and high pulmonary selectivity. Oral bioavailability is determined mainly by the degree to which the swallowed drug is inactivated during the first pass through the liver. The hepatic metabolism of newer ICS is very efficient (high intrinsic clearance) and more pronounced than for first- and second-generation ICS, so that almost 100% of the orally absorbed drug is metabolized. The negligible oral bioavailabilities of modern ICS such as fluticasone (33), mometasone furoate (34), ciclesonide (35), and loteprednol etabonate (36) indicate that optimal performance with respect to this parameter has been achieved (Table 3). Although further improvement cannot be expected, it is a must for every new drug development process to achieve comparably low oral bioavailabilities.

Add-on Devices

Systemic Clearance

One of the disadvantages of metered-dose inhalers has been the lack of coordination between drug delivery from the device and the patient’s inhalation pattern. Electronic or mechanical breathactuation mechanisms have therefore been incorporated into some devices or developed as add-on devices (23). Examples are SmartMist (24), Easibreathe (25), and Maxair Autohaler (26). A vast body of literature shows that many patients do not comply with ICS therapy (27). A number of the newer metereddose inhalers, dry powder inhalers, and nebulizers incorporate metering devices that track drug delivery. These approaches range from simple dose-counting devices to fully electronic mechanisms for tracking dose delivery, inhalation time, and pulmonary function. It will be important to further develop these innovations to provide economical ways of improving patient compliance, one of the biggest challenges in asthma therapy. On the other hand, patient education and patient–clinician communication remain vital factors in improving compliance (28).

Assuming that inhalation therapy is able to manage asthma locally, without systemic effects, ICS should induce their effects in the lung, but should be inactivated efficiently once absorbed systemically. It can be seen from pharmacokinetic/pharmacodynamic models of pulmonary targeting that the higher the systemic clearance of an ICS, the better its pulmonary selectivity. Most of the current ICS are cleared efficiently through hepatic metabolism. Because the systemic clearance of these high-extraction drugs is not determined by plasma protein binding, hepatic clearances of almost all ICS, including those of new drugs such as mometasone furoate, are very similar to the liver blood flow. Therefore, further improvement must involve extrahepatic inactivation as a means of increasing systemic clearance (30). Corticosteroids that are enzymatically inactivated by the blood or are subject to nonenzymatic inactivation in the body have been tested. Their development is not a trivial task, however, because the corticosteroids have to be sufficiently stable in the lung,

Dry Powder Inhalers

TABLE 3. SOME PHARMACODYNAMIC AND PHARMACOKINETIC PROPERTIES OF COMMERCIALLY AVAILABLE CORTICOSTEROIDS AND DRUGS IN DEVELOPMENT* Drug Dexamethasone Flunisolide Triamcinolone acetonide Loteprednol etabonate Budesonide Ciclesonide Beclomethasone dipropionate Fluticasone propionate Mometasone furoate

Receptor binding affinity, %

Oral bioavailability, %

Plasma protein binding, %

100 190 233 430* 935 1,200† 1,022 1,800 2,700‡

20 23 ⬍1 12 ⬍1 40§ ⬍1 ⬍1

80 71 88 99† ** 90–99 98–99

Data are from Mobley and coworkers (37) and Hochhaus and coworkers (38, 39), except as otherwise noted. * When related to fluticasone propionate (Druzgela and coworkers [40]). † Rohatagi and coworkers (41). ‡ Smith and coworkers (42). § Dayley-Yates and coworkers (8). ** No data available.

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Figure 2. Biological system for optimizing pulmonary residence time. A glucocorticoid such as budesonide (BUD) enters pulmonary cells, where it is able to interact with the receptor, leave the cell, and enter the systemic circulation or be reversibly trapped as a lipophilic ester, resulting in a prolonged stay in pulmonary cells.

and, ideally, the enzyme systems responsible for the plasmatic inactivation should not be present in lung tissue (43). Two drug candidates, 17 ␤-glucocorticoid butyrolactone and itrocinonide, exhibited instability in the blood and low systemic side effects (33, 44), but development was stopped, presumably because of lack of clinical efficacy. The future will show whether other approaches to enzymatic and/or chemical inactivation (45) will be more successful. Pulmonary Residence Time

The fate of the drug in the lung is another important parameter determining the degree of pulmonary selectivity. Because of leaky pulmonary membranes and the large blood flow through the lungs, drugs in solution are generally absorbed in a relatively short period of time. Strategies suitable to prolong the residence time in the lung are summarized as follows: choice of the right lipophilic drug with optimal dissolution time; use of liposomes with slow release characteristics; use of microspheres with slow release characteristics; use of drug coatings (trehalose, laser-based coatings) with slow release characteristics; and use of biological systems providing slow release characteristics. Drugs with low lipophilicity dissolve in the lung very quickly and, consequently, are rapidly absorbed into the systemic circulation. These drugs are likely to induce only a certain degree of pulmonary selectivity. Drugs with very slow dissolution rates might be removed from the upper part of the lung via the mucociliary transporter and be swallowed before a pulmonary effect and pulmonary selectivity can be achieved. Thus, there seems to be an optimal drug release rate (1), and the potential benefits of using slow-release pulmonary drug formulations have been recognized by a number of research groups. Liposomal encapsulated glucocorticoids have been evaluated experimentally in asthma therapy for quite some time (46–49). The pulmonary selectivity of a number of such formulations has been shown to be superior in animal models to that of unencapsulated drugs. Using optimized stealth liposomes for the encapsulation of budesonide, weekly treatment regimens have been shown to be sufficient in a mouse asthma model (49). However, the use of liposomal formulations is hampered by the potential instability of such formulations, and liposomes will be competitive in the marketplace only if dry powder formulations can be developed. Alternative systems, such as porous low-density microspheres, have been described that have slow drug-release rates (31). Certain additives, such as coadministered oligolactic acid (50), have been used in the design of slow-release metered-dose inhalers. Trehalose-based coatings (51) and nanothin coatings of biodegradable polymers (52) have also been tested. An interesting alternative to prolonging pulmonary residence time is the use of biological systems (53) (Figure 2). 21-OH cortico-

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steroid alcohols form lipophilic esters in pulmonary cells and other regions of the body. These inactive esters are trapped in the cell, but they can be slowly reconverted to active glucocorticoid alcohols, ready to interact with the glucocorticoid receptor (53). It has been suggested that the formation of these esters explains why a once-daily dosing regimen for budesonide can be used in certain patient groups. However, clinical studies are lacking that clearly link ester formation and clinical efficacy. Further optimization of such ester trapping using modified corticosteroids might yield more efficient systems.

OPTIMIZING PHARMACODYNAMIC ACTIVITY Prodrugs

Although most ICS are active drugs that can induce the desired pulmonary effect and undesired side effects, beclomethasone dipropionate and some of the newer drugs (e.g., ciclesonide) are prodrugs with esterifications in position 21 of the molecule. These prodrugs are pharmacologically inactive and need to be activated by esterases to the corresponding 21-alcohols. Because esterases are present throughout the body, including the lung, it is desirable for most of a drug deposited in the lung to be activated in the lung in order to induce its local effects. However, as shown for beclomethasone dipropionate, this cannot generally be assumed. Thus, pulmonary activation should be carefully assessed during drug development. The use of prodrugs might reduce some local side effects, for example in the oropharynx, because the inactivated drug is deposited in these regions and might be swallowed before activation (54). In addition, the higher lipophilicity of prodrugs should be useful in optimizing the pulmonary residence time. Protein/Tissue Binding

Corticosteroids in development tend to be relatively lipophilic. Lipophilic residues in the 16 and 17 positions of the molecule increase the receptor binding affinity and plasma protein binding (Table 3). The plasma protein binding of mometasone furoate (55) and the active principle of ciclesonide (41) have been reported to be between 98 and 99%. The high safety margin observed for these drugs, for example an insignificant degree of plasma cortisol suppression, has been linked to this pronounced plasma protein binding (41). However, pronounced tissue binding in the lung might also reduce the free concentration of the drug at the site of action. More detailed clinical studies are needed to demonstrate whether protein and tissue binding also affect the clinical efficacy of these drugs such that an increased dose is needed. Transactivation and Transrepression

Until recently, it was believed that pharmacodynamic properties do not differ among different steroids, assuming that the same degree of receptor occupancy induces the same therapeutic effects and side effects. Indeed, differences in the relative binding affinities (Table 3) paralleled differences in pharmacokinetic and pharmacodynamic assessments of a number of corticosteroid effects (56). Recent research seems to suggest that even if the same number of receptors have been occupied by two different corticosteroids, those corticosteroids might differ in their activity to affect transactivation and transrepression pathways (57) (Figure 3). Because transactivation pathways are thought to induce undesired side effects, while transrepression of transcription factors is linked to the desired effects of corticosteroids on asthma, it seems important to optimize the transactivation-to-transrepression ratio. The first corticosteroid reported to do so, RU24858, was described by Vayssie`re and coworkers (58). Other corticosteroids, such medroxyprogesterone, and new drugs such as A276575 and

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273 References

Figure 3. Scheme showing transactivation and transrepression pathways. After the glucocorticoid (GC) induces activation of the glucocorticoid receptor (GR), the activated GR dimer can interact with the glucocorticoid response element (GRE), resulting in transactivation of the genes. Alternatively, the activated glucocorticoid receptor can interact directly with other transcription factors (e.g., nuclear factor-␬B [NF-␬B]), inactivating these factors (transrepression). There is evidence that the transrepression activity of the GC-GR complex depends on the structure of the GC and that newer inhaled GC show higher transrepression than transactivation activity. hsp indicates heat shock protein.

AL438, reportedly have improved effect to side-effect ratios (59–61). Now that the crystal structure of the glucocorticoid receptor has become available (62) and the first structural requirements for optimizing the transactivation-to-transrepression ratio have been generated (63), other innovative drugs might be identified. It should be stressed, however, that for now there is no evidence that corticosteroids optimized for transactivation versus transrepression activity have beneficial clinical effects. Animal studies using different models have been inconclusive (64). In vitro and animal models assessing the transrepression and transactivation potencies and their resulting selectivities have been described (65, 66). However, such assays need to be further validated by showing that similar selectivity profiles are obtained in humans. CONCLUSIONS

Although currently available corticosteroids already provide a high safety margin and pronounced pulmonary selectivity, current research and development indicates that improvement is possible by redesigning inhaler devices and enhancing the pharmacokinetic and pharmacodynamic properties of ICS. Because current ICS are already very efficient and safe, it will be difficult to introduce further improved formulations. It is likely that progress in the design of metered-dose inhalers, dry powder inhalers, and nebulizers will result in more efficient pulmonary deposition and an optimized deposition profile (central vs. peripheral). Therefore, more clinical studies should be performed that identify the optimal ratios of central versus peripheral deposition in more detail. Longer-term approaches will incorporate better particle design and engineering into new products. It will also be of interest to show whether new structural entities with affinity to the glucocorticoid receptor and improved effect to side effect ratios are clinically important. Conflict of Interest Statement : G.H. has participated as a speaker in scientific meetings and courses organized by Aventis and GlaxoSmithKline and received consulting fees for Lilly and consulted for AstraZeneca and owns stock in Nanotherapeutics and obtained research grants from Sepracor, AstraZeneca, 3M, IVAX, and West Pharmaceuticals during the last three years, and is involved in a patent on slowrelease coatings for pulmonary delivery.

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