Proteins, pulmonary delivery

As pharmaceutical scientists gain experience and tackle the primary challenges of developing stable parenteral formulations of proteins, the horizons continue to expand and novel delivery systems and alternative routes of administration are being sought. The interest in protein drug delivery is reflected by the wealth of literature that covers this topic [150-154]. Typically, protein therapeutics are prepared as sterile products for parenteral administration, but in the past several years, there has been increased interest in pulmonary, oral, transdermal, and controlled-release injectable formulations and many advances have been made. Some of the more promising recent developments are summarized in this section. 

J. S. Patton and R. M. Platz, Routes of drug delivery case studies (2) pulmonary delivery of peptides and proteins for systemic action, Adv. Drug Deliv. Rev, 8, 179 (1992). 

Dry powder inhalers have initially found their application in inhalation therapy as a CFC-free alternative for the older MDIs. However, nowadays they seem to have a much larger potential [14,53], because of the high lung deposition that can be attained and also because they are suitable for the pulmonary delivery of therapeutic peptides and proteins [2,10,16]. 

ITABLE 13.12. Aerosolized proteins and peptides tested in humans with portable devices for pulmonary delivery... 

Pulmonary administration of PNAs has great potential for the same reasons that pulmonary protein and peptide delivery have been successful. Predominantly, the distance for transport and ease of administration of agents are the advantages of pulmonary delivery, but the formulation of labile molecules for eventual pulmonary administration as lipid-based aerosols may be problematic. 

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. 

Protein-based drugs have been formulated mainly as stable liquids or in cases where liquid stability is limiting as lyophilized dosage forms to be reconstituted with a suitable diluent prior to injection. This is because their delivery has been limited primarily to the parenteral routes of intravenous (IV), subcutaneous (SC), or intramuscular (IM) administration. There are a few drugs that have been developed for pulmonary delivery, such as rhDNase (Pulmozyme ) and an inhalable formulation of insulin (e.g., Exubra ). However, even such drugs have been formulated as either liquid or lyophilized or spray-dried powders. This chapter will focus only on excipients that are applicable to liquid and lyophilized protein formulations. 

Biopharmaceutical Challenges Pulmonary Delivery of Proteins and Peptides... 

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... 

Table 9.1 Summary of peptide and proteins used for pulmonary delivery.

In this chapter, we will discuss the biophysical basis and recent advances in pulmonary delivery of peptides and proteins. 

Mechanisms of Protein Absorption after Pulmonary Delivery... 

In conclusion, the pulmonary delivery of insuhn offers an efficient and convenient therapy for diabetic patients. The feasibility of inhaled insuhn is based mainly on the lungs large absorption area of alveoli and their extremely thin walls full of intercellular spaces that make them more permeable than other mucosal sites to large proteins. Generally, inhaled insuhn showed a more rapid absorption than insulin administered by SC injection [59]. One major concern for pulmonary insuhn delivery is the unknown long-term effects of inhaled insuhn within the respiratory tract. Thus, possible long-term problems should be considered when insuhn is administered in this manner [66]. 

BiopharmaceuticaI Challenges Pulmonary Delivery of Proteins and Peptides 9.6.3.3.2 Detirelix (LHRH Antagonist)... 

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