Dosage forms pulmonary delivery

Aerosolized DNase (dornase) is a therapeutic protein designed for alveoli delivery to achieve local effects in the deep lung. Aerosolized DNase is formulated as a pulmonary dosage form, targeted for deep-lung delivery to reduce opportunistic infections due to the increased viscosity of mucus in the lung that affects respiratory function in patients with cystic fibrosis. 

GENERAL CONSIDERATIONS FOR EXCIPIENT SELECTION FOR PULMONARY DOSAGE FORMS EXCIPIENT USE DETERMINED VIA PRINCIPLES OF DELIVERY... 

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. 

Inhalation aerosols have been used for the delivery of drugs to the respiratory system since the mid-1950s. The most common dosage form for inhalation is the metered-dose inhaler (MDI), by which the drug is delivered from a pressurized container using a liquefied gas propellant. Medication delivered via this dosage form has allowed for a quick therapeutic response to the symptoms of asthma, emphysema, and chronic obstructive pulmonary disease (COPD), and has resulted in an improvement in the quality of life for millions of asthma sufferers. 

Wu-Pong and Byron [15] have contributed a review of the issues associated with pulmonary delivery of ASOs. Since ASOs are freely soluble and highly hygroscopic, it would be reasonable to assume that initial dosage forms will rely upon the aerosolization of simple aqueous solutions. Our data indicate that commercially available nebulization devices will generate suitable aerosolizations of ASO solutions at concentrations up to 180 mg/mL [3]. Ultrasonic and jet nebulizations were found to have essentially no effect on the phosphorothioate stability of the ASO over 40 min, which is longer than typical treatment times. 

Those involved with the pulmonary delivery of therapeutic agents are challenged in all three areas, especially the first two. We can now develop new therapies, but we must be certain that we can reproducibly deliver those therapeutic agents to the desired site, in the dosage and form in which they will be most effective. 

Pulmonary delivery of insulin for systemic absorption in the treatment of diabetes has been studied extensively since the early days of insulin discovery almost a century ago. Colthorpe et al. and Pillai et al. demonstrated in rabbit and monkey models, respectively, that the deeper into limg the dose of insulin was delivered, the higher was the bioavailability. The work of Laube, Benedict, and Dobs showed the need to achieve deep pulmonary deposition of this molecule for efficient absorption in humans. Handheld liquid and dry powder delivery systems have been developed to generate insulin-containing aerosols with the majority of the particles in the aerodynamic size range 1-3 pm. The relative bioavailability compared with subcutaneous injection based on the insulin contained in the dosage form was 110/ [52] powder system and for the aqueous-based... 

Around 1990, the pulmonary delivery of liposomes was largely an academic exercise [43-46] and at best at an early stage of commercial development [47]. However, these and earlier efforts demonstrated the utility of liposomes, and interest has continued to flourish. This has been reinforced by greater acceptance of the dosage form, since there are now several injectable liposomal products on the market [e.g., Ambisome , Fungisome , Myocet ]. The specific use of lipid-based vehicles to deliver plasmid-based DN A has attracted much attention [48-51]. These developments have indirectly helped improve the quality and variety of... 

Another issue is reproducibility. The formulation may work perfectly in an in vitro test system, but the dosage form requires aerosolization, and lung deposition is a function of the characteristics of the aerosol (dose, mass concentration, droplet/particle size, etc.) and the nature of the inspiratory maneuver, a factor that the patient has control over. These factors can influence performance to a far greater extent than can be built into a particle, and thus the term controlled does not seem a defensible objective for pulmonary delivery. The vagaries of the deposition profile and of the amount that will deposit also imply that sustaining a certain drug concentration is a difficult proposition, but the loosest definition extended release, seems an acceptable goal within the boundaries set by the clearance mechanisms. 

As it becomes increasingly probable that delivery of drugs as aerosols can be achieved readily, the focus can shift to the nature of the therapeutic agent and its physical and chemical stability in the required dosage forms. New chemical entities can be considered for delivery to the lungs to facilitate the control of pulmonary diseases or diseases that may be treated by pulmonary drug delivery. 

Taylor, K. (2002) Pulmonary drug delivery, in Aulton, M. E. (ed.), Pharmaceutics, the Science of Dosage Form Design (). Churchill Livingston, Edinburgh, 473 98. 

Dosage forms with different mechanisms may bypass the organ of absorption, such as the GI tract. These include, for example, the transdermal testosterone patch. Also capable of bypass is the metered dose inhaler for pulmonary delivery of biological products such as a peptide or protein, with a propellant for lung absorption. 

Apart from oral drug delivery, the drug nanoparticles might have a large potential in pulmonary delivery but also in parenteral dosage forms, in particular, the fad that some nanosuspensions may behave like solutions regarding their pharmacokinetics (3) appears to be a very interesting feature. 

An aerosol dosage form developed by suspending zinc insulin crystals in a propellant together with oleyl alcohol to improve the wetting of the crystals was stated to be chemically stable (Lee and Sciarra, 1976), but as this conclusion was based on immunoassay results, it does not necessarily reflect reality. When insulin is formulated for pulmonary delivery by dry-powder generators (Byron, 1990), it is important to remember that insulin in the dry state, in an amorphous as well as a crystalline form, is hygroscopic, even when it contains 10-20% water, depending on the relative humidity. 

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