AEROSOL THERAPY: THE PRACTICALITIES

Transcription

1 AEROSOL THERAPY: THE PRACTICALITIES Lester I. Harrison, PhD Section Head, Clinical Pharmacokinetics, 3M Pharmaceuticals, 3M Center 270-3S-05, St. Paul, MN, USA Introduction: Horses, like humans, suffer from an asthma-like chronic airway inflammation disease that can significantly reduce their ability to perform during physical exercise. In humans, asthma can be effectively treated by eliminating the offending agents if possible and by combination drug therapy. Asthma guidelines suggest that a corticosteroid and a beta-agonist are the first choice, followed by a mast-cell stabilizer, parasympatholytic agent or leukotriene antagonist. Some of these same classes of medication are available to the horse and appear to have similar effectiveness in the equine. Human experience has shown that the preferred route to deliver asthma medications is through inhalation. Aerosol administration delivers high concentrations of the drug directly to the target receptor sites in the airways so that lower dosages are required. Inhalation therapy also minimizes the amount of drug absorbed and available to produce systemic adverse effects. Aerosol Devices: Several systems are currently available to deliver medications in aerosol form. These include the jet nebulizer, ultrasonic nebulizer, the pressurized metered-dose inhaler and the dry powder inhaler. In order to make these medications available to the horse, a coupling or spacer device is currently needed. The ideal coupling device should be comfortable to the horse, easy to use, portable, washable, robust, and inexpensive. In addition, the ideal coupling device should allow efficient drug delivery, trapping only those particles that are too big to be respirable by the horse. 1

2 One popular coupling device uses the Aeromask to link the drug delivery system to the horse s nose (1). The Aeromask can accommodate most inhalers and nebulizers and does not require any coordination with the horse s breathing pattern. A more recent device developed by 3M, the equine aerosol drug delivery system (EADDS), combines the metered-dose inhaler with a unique spacer anatomically designed for drug delivery to the horse s nose in a single disposable device (2). The EADDS thus maximizes drug delivery for a single medication, and is dependent on the horse s breathing pattern during administration. The delivery of albuterol (salbutamol) in the EADDS is soon to be approved in the USA and will be marketed by Boehringer-Ingelheim Vetmedica. Efficiency of drug delivery varies greatly between the drug delivery devices (Table 1). Using technetium labeled solutions and the technique of gamma scintigraphy, the jet nebulizer was shown to deliver more material and more deeply into the equine lung than the ultrasonic nebulizer does (3, 4). A metered-dose inhaler coupled with the Aeromask delivered approximately 5 times more material to the horse lung than did the most efficient jet nebulizer (4). In a separate study which used the same techniques, the EADDS delivered about three times more material than that reported in the MDI/Aeromask study (5). To better understand the reasons for the different efficiencies of material delivery to the equine lung, one needs to examine the role of particle size in drug deposition. Table 1: Efficiencies of Various Aerosol Drug Delivery Devices as Reported in the Literature to Deliver a Radiolabelled Solution to the Horse Device % in Lungs from Reference Number: (No. of Animals:) (5) (4) (6) Ultrasonic nebulizer Jet Nebulizer MDI + Aeromask 6.1 EADDS

3 Drug Deposition: For an aerosolized drug to be effective, it must be deposited at its intended site of action in the airways. Experience with humans and horses has taught us that the most important characteristics for drug deposition are the physicochemical properties of the aerosol drug particles, primarily the particle size, and the inspiration velocity of these particles (6). Large particles, greater than 5 microns, tend to be deposited in the nasal passages and trachea and only in the largest airways. This is the reason why nebulizers, which tend to generate large droplets, manage to deposit relatively little drug in the equine lung. The metered-dose inhaler has the potential to produce particles in the range of 1-5 microns, which is associated with lung deposition. It is assumed that particles less than 2 microns can penetrate into the alveoli. The researcher has a valuable in vitro tool to size aerosol particles in the laboratory - the multistage Andersen cascade impactor or similar device. The entrance to the Andersen cascade impactor is bent to simulate a throat, followed by seven plate screens that are designed to sort the particles on the basis of their sizes. The cascade impactor can therefore define a particle size distribution for an aerosol product that is both unique and reproducible for the product and can be used for quality control. More importantly, the cascade impactor allows the scientist to mimic the expected deposition of a drug during inhalation in the equine. Beclomethasone Dipropionate: The aerosol administration of the anti-inflammatory corticosteroid beclomethasone dipropionate (BDP) in the human is an excellent example to highlight the contributions of particle size and delivery device on drug deposition. BDP is currently available in many countries as both chlorofluorocarbon (CFC) containing and CFC-free metered-dose inhalers for human use. 3M developed the most widely used CFC-free product QVAR. There is a major difference between the CFC products and QVAR in the particle size generated (7). The CFC products generate large particles with a mass median aerodynamic diameter (MMAD) of 3.5 to 3.9 microns and leave a significant amount of material on the entrance to the impactor device that is 3

4 bent to simulate a throat. QVAR in contrast generates smaller particles with a MMAD of 1.1 microns and leaves less material on the simulated throat. These particle size differences between products translate into significant deposition differences in the patient. Using technetium labelled products, drug deposition was quantitated in the oropharanyx and lungs of humans (7). The CFC product delivered only 5-10 % of radiolabelled drug to the lungs and the rest was swallowed. This efficiency is typical of most metered-dose inhalers in humans. QVAR delivered almost 60% to the lungs, 30 % to the oropharanyx, and approximately 10% was exhaled. The distribution of the radiolabel within the lungs was also different, with the CFC product reaching only the central airways, whereas QVAR was distributed throughout the peripheral airways. Most importantly, the difference in particle size resulted in a difference between the products in efficacy. Approximately half the dose of QVAR was observed to give comparable efficacy to that of the CFC products (7). A similar difference was also observed in the pharmacokinetics. In the human following a dose of QVAR, BDP is rapidly converted to beclomethasone 17- monopropionate (17-BMP) with a plasma half-life of less than10 minutes. Some of the 17-BMP is further metabolised to beclomethasone free base. Utilizing a LC/MS/MS assay that measures the contributions of BDP and metabolites, the plasma levels of BDP derived material was measured following equivalent doses of CFC product and QVAR (8). Absorption was faster and about twice as great with QVAR. This increased systemic absorption from QVAR was not associated with an increase in side effects, probably because of the non-linear relationship between pharmacokinetics and safety parameters (7). To make this human data applicable to the equine, one needs to consider the deposition effects of the inclusion of a spacer device such as the Aeromask. The Aeromask, besides having a functional purpose of coupling the metered-dose inhaler to the horse, serves to remove the largest particles and eliminate oropharyngyl deposition. In our laboratory, it has been shown that a large 4

5 volume spacer removes about 50% of the dose from a CFC product but may also increase the number of particles in the respirable range, perhaps by breaking up some of the large particles. The drug delivery profile, however, is not changed and the product still has the same MMAD. Because of the relatively small air volume in the adapter and because of its rapid mode of drug delivery, the EADDS should hold up less drug than the Aeromask. The EADDS uses the same QVAR metered-dose canister and, using the dose relationship analogy from the human, should require less medication than the CFC product with the Aeromask. This appears to be the case as the equine development program for the QVAR EADDS is using less than half the puffs recommended for use of CFC BDP with the Aeromask. Salbutamol: Salbutamol is a simpler example. 3M developed Airomir as a CFC-free metered-dose inhaler of salbutamol that was bioequivalent to the CFC product (9). The cascade impactor particle size distributions of both products are comparable. The only difference to be expected between the products in the equine is in the coupling device. Since a large volume spacer would remove about half the dose, more actuations should be required for a CFC product with the Aeromask that with the Airomir EADDS. Examining the dosing recommendations in the USA for use with both devices confirms these predictions. The absorption of salbutamol in humans is rapid, within minutes of inhalation, and is also eliminated quickly, with a half-life of less than 2 hours. Therefore, administration at least twice daily is needed. 3M conducted a preliminary pharmacokinetic study with the salbutamol EADDS in the horse. Results show a similar absorption profile of aerosolized drug in the horse and human. An interesting observation was that despite the seven-fold difference in body weight between the horse and human, only a two-fold difference in dosage was needed to give comparable salbutamol plasma levels. 5

6 Summary: A simple hand-held inhalation delivery device that contains drug as a single unit has been developed by 3M for the administration of aerosol medications to horses. It is convenient and practical to use, requiring less drug to achieve efficacy than other methods. This device meets most of the desirable attributes for an ideal equine inhalation drug delivery device. It soon will be available for use with a beta 2 agonist in the USA, and then for a corticosteroid. References: 1. Tesarowski DB, Viel L, McDonell WN, Newhouse MT: The rapid and effective administration of a β 2 -agonist to horses with heaves using a compact inhalation device and metered-dose inhalers. Can Vet J 1994; 35: Derksen FJ, Olszewski M, Robinson NE, Berney C, Lloyd JW, Hakala J, Matson C, Ruth, D: Use of a hand-held, metered-dose aerosol delivery device to administer pirbuterol acetate to horses with heaves. Equine Vet J 1996; 28: Votion D, Ghafir Y, Munsters K, Duvivier DH, Art T, Lekeux P: Equine Vet J 1997; 29: Viel L, Tesarowski DB: Radioaerosol deposition in equids. In Proceedings of the 40 th Annual American Equine Practitioners Convention, Vancouver, BC, 1994, pp Geor R, Johnston G: Deposition of radiolabelled aerosols within the equine respiratory tract. In Proceedings of the 12 th Veterinary Respiratory Symposium, Kennett Square, PA, Duvivier DH, Votion D, Vandenput S, Lekeux P: Aerosol therapy in the equine species. Vet J 1997; 154: Shaw RJ: Inhaled corticosteroids for adult asthma: impact of formulation and delivery device on relative pharmacokinetics, efficacy and safety. Respir Med 1999; 93: Seale JP, Harrison LI: Effect of changing the fine particle mass of inhaled beclomethasone dipropionate on intrapulmonary deposition and pharmacokinetics. Respir Med 1998; 92 (suppl. A):

7 9. Ross DL, Gabrio BJ: Advances in metered dose inhaler technology with the development of a chlorofluorocarbon-free drug delivery system. J Aerosol Med 1999; 12: