Pulmonary Residence Time

It has been suggested by Gerhard Levy that the absorption rate from the target organ is essential for successful drug targeting. It is now recognized that a distinct pulmonary residence time of inhaled drugs is not only beneficial for a prolonged activity but also for increased pulmonary targeting [12, 21]. By use of an integrated PK/PD model of pulmonary targeting, it could be shown that for the upper portion of the lung, an optimal release rate (dissolution rate, release rate from a carrier) exists for which optimal pulmonary targeting is observed [12]. Very fast pulmonary absorption, such as that observed for a glucocorticoid in solution does not result in any pulmonary targeting. The sole reason for this is that fast pulmonary absorption (equivalent to a short pulmonary residence time) results in identical free drug levels in both the systemic circulation and the lung after the termination of the short absorption phase. For delivery systems with reduced pulmonary absorption (e.g., because of a slow pulmonary dissolution rate of the deposited glucocorticoid), the lung is continuously supplied with drug over a prolonged period, resulting in pulmonary drug concentrations being higher than those in the systemic circulation. This results in improved pulmonary targeting. If the release or dissolution rate is too slow, the mucociliary transporter of the upper respiratory tract removes undissolved drug before it is able to interact with the receptor. Consequently, this portion of the pulmonary deposited drug is removed from the lung before it can induce the desired pulmonary effects, and pulmonary selectivity is reduced. Thus, theoretically an optimal pulmonary release or dissolution rate can be defined for the upper respiratory tract [12]. However, a long pulmonary residence time is not easy to achieve because of the physiological characteristics of the lung, including high blood flow, which favors efficient absorption. At present, the following mechanism might be used to prolong the pulmonary residence time: (1) slow dissolution rate of drug particles (e.g., drug lipophilicity or crystal structure), (2) slow release from drug delivery systems (e.g., liposomes or microcapsules), (3) initiation of a biological interaction resulting in prolonged pulmonary residence time (e.g., ester formation or ''capturing'' in membrane structures).

1. Dissolution Rate

The pulmonary absorption rate and, consequently, the degree of pulmonary targeting will depend on the dissolution rate of a given inhalation drug. Once dissolved, most low-molecular weight drugs will be absorbed relatively quickly [62-66], especially from the alveolar region [66]. Indeed, by use of an animal model for pulmonary targeting, it could be shown that the pulmonary targeting achieved with triamcinolone acetonide (TA) (delivered intratracheally to rats) will differ when the pulmonary dissolution rates differ. Figure 2 compares the pulmonary and systemic receptor occupancy for a TA solution, a micronized TA dry powder, and a TA crystal suspension used for treatment of arthritis. The comparison shows that the degree of pulmonary targeting (difference between pulmonary and systemic receptor occupancy) increases from solutions to mi-cronized particles to crystal suspension, which is in in agreement with its anticipated dissolution behavior. This indicates that the biopharmaceutical properties ofMDIs and DPIs are important determinants of pulmonary selectivity. Similarly, pharmacokinetic profiles obtained for beclomethasone dipropionate (BDP) DPI and MDI devices differed significantly, with a significantly longer terminal halflife obtained for the DPI device. This argued for a much slower pulmonary dissolution from the dry powder-delivered drug, whereas BDP delivered through a MDI resulted in a faster drug dissolution in the lung [56]. The identification of drug preparations with optimized physicochemical properties (e.g., slow dissolution rate caused by the selection of certain crystal modifications) and the selection of the right device might therefore be one way of further improving inhalation performance. By the same token, it will be crucial to assess the pharmacokinetic absorption profiles of drugs in the developmental stage, because studies for commercially available drugs have shown significant differences in the absorption profiles [67]. In addition, with newer devices delivering more to the alveolar

Triamcinolone Acetonide Crystals

Figure 2 Lung and liver glucocorticoid receptor occupancy after administration of 100 |g/kg triamcinolone acetonide (TA): intravenous administration (A) and intratracheal (B) administration of a triamcinolone acetonide solution, micronized TA powder (C) and Ken-alog TA crystal suspension (D). Data taken from Ref. (133) and (134).

Figure 2 Lung and liver glucocorticoid receptor occupancy after administration of 100 |g/kg triamcinolone acetonide (TA): intravenous administration (A) and intratracheal (B) administration of a triamcinolone acetonide solution, micronized TA powder (C) and Ken-alog TA crystal suspension (D). Data taken from Ref. (133) and (134).

region of the lung, the goal of ensuring a slow absorption from these regions of the lung will be even more challenging.

Was this article helpful?

0 0
Natural Arthritis Pain Remedies

Natural Arthritis Pain Remedies

It's time for a change. Finally A Way to Get Pain Relief for Your Arthritis Without Possibly Risking Your Health in the Process. You may not be aware of this, but taking prescription drugs to get relief for your Arthritis Pain is not the only solution. There are alternative pain relief treatments available.

Get My Free Ebook


Post a comment