Proteins pulmonary administration

Table 3.2. Absorption data after pulmonary administration of peptides and proteins. Data from reference [32].

Insulin is the protein that has been most investigated for pulmonary administration. Insulin levels are not maintained in diabetic patients, and precise control over blood glucose levels is needed. Insulin is a small protein, 5.8 kDa, which is composed of two chains that are covalently linked by an interchain disulfide bond. Currently, insulin is administered by injection, several times a day for many diabetics. The ability to deliver insulin via a noninvasive route would free diabetics from inconvenient, invasive insulin delivery methods and possibly eliminate secondary problems associated with diabetes, such as diabetic retinopathy. 

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. 

The major expansion in this present volume concerns the subjects of proteomics and gene therapy, both of which offer so much promise for the future. Pulmonary administration is another likely route of delivery for the future and this is reviewed separately. Conventional wisdom suggests that proteins cannot be delivered orally but there is strong evidence suggesting that this is not always true and this is another exciting area that is reviewed here. The earlier review of vaccines has been expanded considerably since this is another area of current interest with potential for wider future application. 

The feasibility of pulmonary administration for a wide variety of proteins and peptides has been evaluated in animal models and some human proof-of-concept studies, and the results of this work have been reviewed. A wide range of bioavailabilities (commercial development is progressing in earnest for most of the molecules examined due to a lack of published information appearing in the peer-reviewed scientific... 

Fig. 5 Bioavailability of proteins and peptides upon pulmonary administration.

Therapeutic proteins and peptides have gained a significant market interest owing to their increased development and applicability to multiple disease conditions (Chin et al., 2012 Park et al., 2011). For the systemic delivery of therapeutic peptides and proteins, parenteral administration is currently believed to be the most efficient route and also the delivery method of choice to achieve therapeutic activity compared with transdermal, pulmonary, nasal, oral, and buccal delivery routes (Fig. 11.4) (Muranishi, 1985 Lennemas, 1995 Ghilzai, 2004). But, for the usually faced chronic conditions, patients find the use of daily injections both unpleasant and difficult to be self-administered. 

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. 

In rats, the administration of fullerene by inhalation, as nano- and microparticles generated by aerosol, does not lead to lesions and only a little increase of protein concentration in bronchoalveolar lavage fluid was obtained (Baker et al., 2007). Recently, Sayes et al. (2007) analyzed in vivo pulmonary toxicity of C60 and C60(OH)24, after intratracheal instillation in rats. They verified only transient inflammatory and cell injury effects, 1 day postexposure, without differences from water-instilled controls. No adverse lung tissue effects were measured, and the results demonstrated little or no differences in lung toxicity effects between the C60 and fiillerols, compared to controls. 

The pulmonary lymphatic system contributes to the clearance of fluid and protein from the lung tissue interstitium and helps to prevent fluid accumulation in the lungs [108], The lymphatic endothelium allows micron-sized particles (e.g. lipoproteins, plasma proteins, bacteria and immune cells) to pass freely into the lymph fluid [103], After administration of aerosolised ultrafine particles into rats, particles were found in the alveolar walls and in pulmonary lymph nodes [135], which suggests that drainage into the lymph may contribute to the air-to-blood transport of the inhaled particles. 

Many studies have been carried out regarding the absorption of peptides and proteins after pulmonary drug dehvery. The perspectives of a non-parenteral route of administration for larger proteins led to studies on the pulmonary absorption of proteins of different size. To date, over 30 different proteins have been evaluated with regard to absorption rate and... 

With regard to the systemic administration of smaller proteins (<20 kDa), the development of insulin for inhalation has shown that the pulmonary route is a feasible route of administration. However, advanced inhalation devices and formulations were required to obtain a reproducible lung deposition. It will be especially necessary to deal with the problems that occur when drugs with a small therapeutic window are administered. To enable widespread use of the lung as port of entry for these small proteins, future developments should be directed towards more simple inhalation devices which still give a high and reproducible lung deposition. The formulations that will be required for these proteins are likely to be much more complex and advanced than those that are currently used. Examples are formu-... 

Liposome-encapsulated immunomodulators are currently under investigation in different patient groups although this development has certainly not advanced as far as that with the liposomal anthracyclines. MLV-MTP-PE (multilamellar vesicles-muramyl tripeptide-phos-phatidylethanolamine) was studied in several clinical trials in osteosarcoma patients who developed pulmonary metastases during adjuvant chemotherapy [108], The intravenous administration of MLV-MTP-PE induced tumouricidal properties in monocytes as well as increase in serum IL-1 shortly after intravenous infusion. Furthermore elevations in C-reactive protein, 32-microglobulin and ceruloplasmin were frequently observed. Even higher anti-tumour activity was observed in combination with ifosfamide. These preliminary results suggests that liposome-encapsulated immunomodulators in combination with chemotherapy may be an appropriate treatment for recurrent disease. 

The pneumotoxicity of MCT in rats was compared with that of manganese methylcy-clopentadienyl carbonyl by subcutaneous administration of 0.5, 1.0, or 2.5 mg/kg of both compounds. MCT was twice as potent in causing large increases in pulmonary lavage albumin and protein content. 

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