Drug-delivery systems pulmonary

A composition based on diketopiperazine derivatives (3,6-bis (N-fumaryl-N-(n-butyl) amino-2, 5-diketopiperazine) has been investigated as a pulmonary drug delivery system, termed Technospheres (Pharmaceutical Discovery Corp., Elmsford, NY) (Pohl et al. 2000 Steiner et al. 2002). The diketopiperazine derivatives self-assemble into microparticles at low pH with a mean diameter of approximately 2 pm. During self-assembly, diketopiperazine derivatives microencapsulate peptides present in the solution. Insulin incorporated in diketopiperazine derivatives (TI) was administered to five healthy humans by the use of a capsule-based inhaler with a passive powder deagglomeration mechanism. Relative and absolute bioavailability of TI in the first 3 hours (0-180 min) were 26 12% and 15 5%, and for 6 hours (0-360 min) 16 8% and 16 6%, respectively (Steiner et al. 2002). The time to peak action for glucose infusion rates was shorter with both IV (14 6 min) injection and inhalation (39 36 min), as compared to SC administration (163 25 min). This rapid absorption of insulin would be beneficial for diabetic patients who need to rapidly affect their glucose levels. 

Intimately related to these factors is the design of the device, formulation, and the interface with the patient. Much of the discussion below will focus on the implications of excipients on formulation challenges for inhaled aerosol products. This chapter summarizes excipients for pulmonary formulations from several perspectives (i) excipient selection based on principles of delivery, (ii) physicochemical requirements for excipients, and (iii) specific challenges for formulations faced with aerosol drug delivery systems, including (a) biological aspects, (b) microbiological aspects, (c) analytical issues, and (d) future prospects. 

One of the main drivers for the development of new pulmonary drug delivery systems has been the potential for noninvasive systemic delivery of protein and peptide compounds. The systemic delivery of macromolecules via the airways would overcome the inconvenience and cost associated with current methods of administration (injection), and appears likely given the large surface area of the airways and the thin pulmonary epithelium. Most research has concentrated on pulmonary delivery of insulin for the treatment of diabetes. Recently, one insulin product has completed phase three studies and is now undergoing review by European regulatory agencies for marketing approval. 

Courrier HM, Butz N, Vandamme TF. Pulmonary drug delivery systems recent developments and prospects. Crit Rev Ther Drug Carrier Syst. 2002 19 425-498. 

Pharmacokinetic Considerations in the Design of Pulmonary Drug Delivery Systems for Glucocorticoids... 

F. Modulation of Pulmonary Selectivity by Sustained-release Drug Delivery Systems... 

Table 3 Selected Studies of Sustained Drug Delivery Systems for Pulmonary Delivery... 

D. Meisner, Liposomes as a pulmonary drug delivery system, Pharmaceutical Particulate Carriers, (A. Rolland, ed.), Marcel Dekker, New York, 1993, p. 31. 

The lung comprises about 40 different cell types, amongst which type I and type II alveolar epithelial cells are the major types targeted by pulmonary drug delivery systems. Type I cells play an important role in the absorption process of proteins, while type II cells produce surfactant, regulate the immune response, and serve... 

Initial studies of continuous intravenous prostacyclin infusion in patients with primary pulmonary hypertension have shown sustained improvement in pulmonary artery pressure, exercise capacity, and survival compared with historical controls (31,32). Minor complications (diarrhea, jaw pain, flushing, photosensitivity, and headache) were dose-related. Serious complications were related to problems with the drug delivery system, including catheter thrombosis, sepsis, and temporary interruption of the infusion, resulting in abrupt deterioration (31). 

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