Pulmonary absorption enhancers

Yamamoto, A. Fujita, T. Muranishi, S. Pulmonary absorption enhancement of peptides by absorption enhancers and protease inhibitors. J. Controlled Release 1996, 41, 57-67. 

GIT, is considered to be lost from the absorption site, as is metabolic clearance and sequestration in various cell types and membranes (72,14). It is clear from Scheme I that the relative rates of the various processes will define the bioavailable fraction of the dose and understanding those factors which control pulmonary absorption kinetics is obviously the key to enhancing bioavailability via the lung. In a recent book (75) the molecular dependence of lung binding and metabolism was considered alongside the parallel processes of absorption, clearance and dissolution in the lung (14). Some key features of this work will be repeated as it relates to the systemic delivery of polypeptides. 

Hussain, A., Arnold, J.J., Khan, M.A., and Ahsan, F. 2004. Absorption enhancers in pulmonary drug delivery. Journal of Controlled Release 94(1), 15-24. 

Yamamoto A, Tanaka H, Okumura S, Shinsako K, Ito M, Yamashita M, Okada N, Fujita T, Muranishi S (2001) Evaluation of insulin permeability and effects of absorption enhancers on its permeability by an in vivo epithelial system using Xenopus pulmonary membrane. Biol Pharm Bull 385-389... 

Yamamoto, A., S. Okumura, Y. Fukuda, M. Fukui, K. Takahashi, and S. Muranishi, Improvement of the pulmonary absorption of (Asul,7)-eel calcitonin by various absorption enhancers and their pulmonary toxicity in rats. J Pharm Sci, 1997. 86(10) 1144-7. 

Liposomes were formed from 1,2-dipalmitoylphosphatidylcholine (DPPC) and cholesterol (Choi) and the effect of liposomal entrapment on pulmonary absorption of insulin was related to oligomerization of insulin (Liu et al. 1993). Instillation of both dimeric and hexameric insulin produced equivalent duration of hypoglycemic response. However, the initial response from the hexameric form was slightly slower than that from dimeric insulin, probably due to lower permeability across alveolar epithelium of the hexameric form caused by larger molecular size. The intratracheal administration of liposomal insulin enhanced pulmonary absorption and resulted in an absolute bioavailability of 30.3%. Nevertheless, a similar extent of absorption and hypoglycemic effects was obtained from a physical mixture of insulin and blank liposomes and from liposomal insulin. This suggests a specific interaction of the phospholipid with the surfactant layer or even with the alveolar membrane. 

Several pharmaceutical and physiological barriers must be overcome for the successful pulmonary delivery of peptide and protein drugs [3], For example, many of these macromolecular drugs have relatively low permeability when they are administered without any absorption enhancers [4], Furthermore, the clinical toxicology of peptides/proteins in the lung, especially for chronic disease, should be of some concern [6], Therefore, cost-benefit ratios should be evaluated in the... 

Consequently, absorption enhancers were used in dry powder and liquid formulations to enhance the pulmonary absorption of SCT. Without absorption enhancers, SCT absorption from dry powder or solution was similar to that observed after intratracheal administration. However, the absorption was more improved from dry powder than from solution when absorption enhancers (oleic acid, lecithin, citric acid, taurocholic acid, dimethyl-[5-cyclodextrin, octyl-P-D-glu-coside) were co-administered intratracheally. Such improved absorption could be due to the fact that enhancers added to the dry powder dissolved at high concentration because only a trace volume of fluid lining the alveolar epithelium was available for their dissolution. However, the potential implications of such a mechanism on lung toxicity, especially in lung edema, is yet to be investigated in detail [68]. 

Kobayashi, S., S. Kondo, and K. Juni. 1994. Study on pulmonary delivery of salmon calcitonin in rats effects of protease inhibitors and absorption enhancers. Pharm. Res. 11 1239-1243. 

Penetration enhancers have been investigated for most mucosal and epithelial routes (see Sections 6.7.4, 8.5.3 and 9.7.1 for further details). The major challenge that remains is to find enhancers that will reversibly increase membrane permeability without causing toxicity during long-term use. Various surfactants and protease inhibitors have been reported to increase the pulmonary absorption of peptides and proteins on an experimental basis but their clinical use is not established and the current general consensus seems to be against their inclusion in pulmonary formulations. 

Only a few studies are available related to the effect of known absorption enhancers on the pulmonary absorption of poorly absorbable drugs, including peptides and proteins. 

Sakagami M, Sakon K, Kinoshita W, Makino Y. Enhanced pulmonary absorption following aerosol administration of mucoadhesive powder microspheres. J Control Release 2001 77(1-2) 117-129. 

Enhancement of drug uptake by altered junctional (paracellular) or vesicular (transcellular) transport (Fig. 2) is an active area of research [22,23], The paracellular transport mechanism provides an explanation for the pulmonary absorption of peptides and proteins <40 kDa. 

In order to enhance pulmonary absorption of enoxaparin, a low molecular weight heparin (LMWH), it was complexed with poly(L-arginine) (PLA). The increase in PLA content in the complex resulted in less negative zeta potential and in a decrease of its size. Addition of 0.0125% or 0.0625% PLA to the pulmonary formulations of enoxaparin led to a twofold increase of its bioavailability compared to enoxaparin administered in normal saline. It was concluded that the enoxaparin-PLA complex may be used for pulmonary administration of LMWH. 

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