Nebulizer labeling

A wide variety of nebulizers are now available. They all have their own physicochemical properties. In the absence of the ability to quantitate lung deposition, the Food and Drug Agency (FDA) has now said that it will approve only combinations of new drugs with specified nebulizers labeling for a-dornase is the first to exhibit this change in policy. This requires that the clinical development plan be implemented, as early as possible, with the nebulizer that is intended to be marketed. 

To measure lung deposition by imaging, the aerosol must be first labelled or tagged with a suitable radionuclide. Radiolabelling techniques have been developed for current inhalation products including nebulizers, propellant-driven metered dose inhalers, and dry powder inhalers. 

Tobramycin solution for inhalation has approval from the Food and Drug Administration (FDA) for maintenance therapy in patients with cystic fibrosis and who are colonized with Pseudomonas aeruginosa. The commercially available formulation is a 300 mg per 5mL. It is a sterile, preservative-free product that is pH adjusted to 6.0. According to the labeling, this product should be used with a specific nebulizer, the Pari C Plus. 

In the studies conducted in support of the commercially available inhaled tobramycin product, aerosol therapies were delivered using a PARI LC Plus nebulizer and a Pulmo-Aide compressor. Currently, the commercial product is labeled for use with the PARI LC Plus nebulizer. 

The Tc-DTPA complex may also be used as an aerosol however, the kit composition suitable for nebulization differs from the renal agent. TechneScan DTPA/Aerosol contains 1.25 mg of DTPA and 0.12 mg tin(II)-chloride as dihydrate. Gentisic acid (0.25 mg) is used for stabilization. Labeling is performed by injecting less than 0.1 ml of Tc eluate, corresponding to at least 550 MBq (15 mCi) of radioactivity into the TechneScan DTPA/Aerosol vial, and then water for injection is added to obtain 1 ml of solution. After 15 min at room temperature, 0.5 ml of ethanol (98%) is added to the labeled product. The labeling yield is >95%. The kit TechneScan DTPA/Aerosol must not be used for intravenous injection. 

Fractionated elution of the generator is required to obtain a high activity concentration of Tc eluate for labeling. Tc eluate used for labeling should be obtained from a generator that is eluted daily (Van Duzee and Bugaj 1981). Not more than 0.5 ml (1,110 MBq 30 mCi) of the labeled product should be used for nebulization (to deliver 150 MBq (4 mCi) to the lung). 

Figure 10.2-4. Scintigraphic biodistribution study. A plasmid encoding the reporter protein luciferase was labeled with Tc. The lipoplexes, resulting from the association of the phosphonolipid GLB43 with the radiolabeled plasmid, was administrated to mice either by intravenous injection or endotracheal nebulization. The animals were imaged using a gamma camera dedicated to small animals. Reprinted from Ref. 15, with permission from Nature Publication Group. (This figure is available in full color at ftp //ftp.wiley.com/public/sci tech med/pharmaceutical biotech/.)...

Laube et al. administered a Tc-labeled aerosol (MMAD = 1.12 pm GSD = 2.04), generated by a jet nebulizer, on two different study days to five patients with cystic fibrosis (CF) who had a mean FEVj of 35% of predicted (112). Dis-... 

X. Labeling Pharmaceutical Nebulizer Solutions for Bench Testing and Deposition Studies... 

Because loading of the device with dmg requires merely pouring an aqueous formulation into the reservoir, off-label use of jet nebulizers is common. Jet nebulizers are also the oldest modem aerosol delivery device for limg delivery [17]. 

Donohue JF, Hanania NA, Fogarty C, Campbell SC, Rinehart M, Denis-Mize K. Long-term safety of nebulized formoterol results of a twelve-month open-label clinical trial. Ther Adv Respir Dis 2008 2(4) 199-208. 

The off-flavors due to the Maillard reaction are most typically labeled as being stale in character. Stale is one of the more nebulous terms used in sensory evaluation. Stale is a rather nondescript term denoting a lack of fresh character. Benzothiazole and 0-aminoacetophenone are two compounds believed to be formed via Maillard browning, which are responsible for this stale flavor. These compounds were found in stale, dry milk by Parks et al. [88]. 0-aminoacetophenone along with some furans were also found to be partially responsible for the gluey flavor of old casein [89]. There is also some work in this area related to fruit juices. 

Adrenaline can be administered in a nebulized form, but should be aware that inhalation route causes a systemic consequence. A randomized study was performed to explore pharmacokinetics and pharmacodynamics of two nebulized inhalative adrenaline doses (4 and 8mg in aqueous solution) using a mobile pocket inhaler relative to i.m. administration (0.3 mg) and placebo. This randomized, open-label, change-over pilot study involved eight young healthy men and women. Results indicated that adrenaline concentrations obtained following the 8 mg inhalative dose were not inferior to those after 0.3 mg i.m, showing that relevant fraction of most inhalation adrenaline doses is absorbed and mediates systemic effects [271. 

Vidgren and co-workers (219) studied six normal volunteers who inhaled 20 breaths of beclomethasone dipropionate liposomes labeled with technetium in the presence of SnCU as a reducing agent. Particles were inhaled from each of two nebulizers Aerotech II nebulizer and Spira nebulizer. Pulmonary deposition was 17 7% for Aerotech II and 14 3% for Spira nebulizer. At 3 hr, 93% of the deposited activity was detected in the volunteers breathing from the... 

Thomas and co-workers (221) have studied deposition of technetium-labeled human serum albumin particles, administered through a Siemens Servo 945 nebulizer system and a system 22 Acorn nebulizer unit. Total pulmonary deposition by percentage of the dose in the nebulizer was on the average 2.2%. There was considerable variability between subjects, with a coefficient of variation of 46%, but within subjects reproducibility was close, with a coefficient of variation of 15%. 

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