Inhalation biopharmaceutics

Shoyele SA, Cawthome S. 2006. Particle engineering techniques for inhaled biopharmaceuticals. Adv. Drug Deliv. Rev. 58(9-10) 1009-1029. 

Pulmonary delivery currently represents the most promising alternative to parenteral delivery systems for biopharmaceuticals. Delivery via the pulmonary route moved from concept to reality in 2006 with the approval of Exubera, an inhalable insulin product (Chapter 11). Although the lung is not particularly permeable to solutes of low molecular mass (e.g. sucrose or urea), macromolecules can be absorbed into the blood via the lungs surprisingly well. In fact, pulmonary... 

Molander L, LuneU E, Andersson SB, Kuylenstiema F (1996) Dose released and absolute bioavaU-abUity of nicotine from a nicotine vapor inhaler. CUn Pharmacol Ther 59 394 00 Murphy JK, Edwards NB, Downs AD, Ackerman BJ, Rosenthal TL (1990) Effects of doxepin on withdrawal symptoms in smoking cessation. Am J Psychiatry 147 1353-1357 Nabi Biopharmaceuticals (2007). Nabi biopharmaceuticals announces positive results of phase Ilb trial of NicVAX. Medical News Today, 3 May 2007. See http //www.medicalnewstoday.com/ articles/69666.php, accessed October 11, 2007... 

The transformation of a drug into a medicinal product is a complex process that is controlled by a range of competing factors. The formulator must amalgamate the preformulation information and the clinical indication, which may suggest a particular route of administration (e.g. inhalation of salbutamol. Table 2.2), with toxicology and biopharmaceutical data determining... 

Although no biopharmaceutical product delivered to the bloodstream via the pulmonary route has been approved to date, several companies continue to pursue active research and development programmes in the area. Amongst the leading product candidates is Exubera , an inhalable dry powder insulin formulation currently being evaluated by Pfizer and Aventis Pharma in Phase III clinical studies. The inhaled insulin is actually more rapidly absorbed than if administered subcutaneously and appears to achieve equivalent glycaemic control. While promising, final approval or otherwise of this product also depends upon additional safety studies which are currently under way. 

Because of the sensitive nature of most biopharmaceuticals, their dosage forms are limited to injectable solutions. Therapeutic proteins cannot pass the acidic milieu of the stomach undamaged, nor are they absorbed through the intestinal wall. Although work on alternatives such as inhalers is underway (the first commercial application is an insulin inhaler), injection remains the predominant option for administering sensible biopharmaceuticals. 

Because most proteins are susceptible to protease degradation and denaturation in biologic fluids, most biopharmaceuticals must be administered by intravenous, intramuscular, or subcutaneous injection (see Table 5.5). High concentrations of proteases are found in the gastrointestinal tract, nasal mucosa, bronchioles, and alveoli, which severely limit the bioavailability of protein pharmaceuticals after oral, intranasal, and inhalation administration. Diffusional barriers to the passage of relatively large macromolecules preclude transdermal and mucosal administration of protein pharmaceuticals. Research is under way to develop methods that will protect protein drugs from proteolysis and improve transmembrane diffusion. 

A small number of biopharmaceuticals are delivered by nonparenteral means. Recombinant DNase is given by inhalation aerosol to reduce the viscosity of mucus in the lungs of patients with cystic hbrosis. A platelet-derived growth factor in the form of a gel is administered topically for wound healing. Several hormones and peptides are administered in solution by the intranasal route. A solution of an antisense drug used for the treatment of cytomegalovirus retinitis is injected directly into the eye. 

Various characteristics of the molecule influence its chances of reaching its target receptor since they influence the nature and extent of the body s effect on it. A drug s pharmacokinetic profile therefore determines the extent of the drug s opportunity to exert its pharmacodynamic effect. While there are various routes for human drug administration (oral rectal intravenous, subcutaneous, intramuscular, and intra-arterial injections topical and direct inhalation into the lungs), the most common for small-molecule drugs is oral administration, and discussions in the first part of this chapter therefore focus on oral administration. (In contrast, biopharmaceuticals are typically administered by injection, often directly into the bloodstream.)... 

Inhalation/nebulization is an alternative method of administration of some biopharmaceuticals, for example insulin and GM-CSF (Anderson... 

A more relevant study for biopharmaceuticals is the repeat-dose study where exaggerated clinical doses are given to an animal model using the intended clinical route of administration. For most biopharmaceuticals this is the intravenous route of administration. Interesting exceptions are Lucentis and Pulmozyme , given intraocularly and by inhalation, respectively, in the pivotal repeat-dose studies. 

Le Bmn PPH, De Boer AH, Mannes GPM, de Fraiture DMI, Brimicombe RW, Touw DJ, Vinks AA, Frijlink HW, Heijerman GM. Dry powder inhalation of antibiotics in cystic fibrosis therapy part 2. Inhalation of a novel colistin dry power formulation a feasibility study in healthy volunteers and patients. Eur J Pharmaceut Biopharmaceut 54 25-32, 2002. 

Steckel, H., and B. W. Muller. 1998. Metered-dose inhaler formulations with beclomethasone-17,21-dipropionate using the ozone friendly propellant 134a. Eur.. Pharmaceut. Biopharmaceut. 46 77-83. 

A third area to consider is the generation of an enhanced product that adds value to the original finished dosage form. Product enhancements include, for example, other forms of dehvery (e.g., transder-mal, nasal, inhalable, etc.) or new formulations. Examples among the biopharmaceuticals are the development of inhaled insulins, e.g., Exubera currently in phase III clinical trials developed by Nektar Therapeutics, Pfizer, and Aventis (admittedly, this work is not driven by a potential generic threat, but primarily by the enormous market potential of an insuhn that does not have to be injected) (see also Part VI, Chapter 2). 

Deposition mechanisms Inhalation manoeuvre Pulmonary administration Pulmonary drug delivery Therapeutic aerosol Biopharmaceutics Particle size Dry powder inhaler Metered-dose inhaler Nebuhser Novel liquid inhaler... 

Ali, M. E., Lamprecht, A. (2014). Spray freeze drying for dry powder inhalation of nanoparticles. European Journal of Pharmaceutics and Biopharmaceutics, 87, 510-517. 

Cordts, E., Steckel, H. (2012). Capabilities and limitations of using powder rheology and permeability to predict dry powder inhaler performance. European Journal of Pharmaceutics and Biopharmaceutics, 82(2), 417-423. 

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