Inhalational administration

Domase-oc, which is indicated for the treatment of cystic fibrosis, is another example of a protein drug successfully administered through the inhalation route. 

In a multi-center, two-year clinical study, inhaled domase-oc was shown to significantly improve lung function and reduce the risk of respiratory exacerbations in pediatric cystic fibrosis patients [25]. 

---

A number of other peptide molecules are currently being explored for delivery via inhalation (6). Very recently, a much smaller peptide (leuprolide, about 9 amino acid residues) has been delivered by metered dose inhaler (MDI) in a characterized fashion to humans (7). This work revealed that about 50% of a dose deposited in the lung could be bioavailable. This value is much greater than those reported for nasal bioavailabilities of this and similar molecules (8). These results, and ours in the rat lung (9), imply that inhalation administration of some peptide and polypeptide molecules is perfectly feasible. 

H-oximes used in combination with atropine sulfate against a background of the intramuscular or inhalation administration of soman are able to protect animals (dogs, monkeys) from 4-5 DL50 of this poison [9],... 

To confirm their results and check for methodological problems, some studies have been carried out. As there was a probability that hypothermic conditions during temporary removal from dam may have affected the results, Pauluhn and Schmuck administered S-bioallethrin and deltamethrin to neonatal mice from postnatal day 10 to 16 under a hypo-, normo-, or hyperthermic environment, and measured the MAChR density at the age of 17 days [51]. Increase in MAChR in Cortex at PND 17 in animals treated with S-bioallethrin was observed. Meanwhile, no changes were observed in animals treated with deltamethrin. In addition, an enormous influence of environmental temperature on the density of MAChR receptors in the crude synaptosomal fraction of the cerebral cortex was ascertained. Tsuji et al. exposed mouse dams with their litters to D-allethrin by inhalation for 6 h from postnatal day 10 to 16. The inhalation administration method is the most relevant route of exposure for humans, including babies and infants, after indoor use of D-allethrin. The neonatal exposure to D-allethrin by inhalation did not induce effects either on the brain MAChR density or motor activity at 17 days and 4 months of age, or on performance in the leaming/memory test at 11 months of age [52]. Other unpublished studies with D-allethrin, S -bioallethrin, or deltamethrin were examined to confirm the results of Eriksson et al. and showed inconsistent results [53]. The reasons for discrepancy among these findings are unknown. 

Very toxic by acute exposure (by oral, dermal or inhalation administration)... 

The route of administration of an NCE is typically the intended clinical route of administration. However, an alternative route may be used if this leads to an increase in systemic exposure of parent drug or major metabolites or if this alternative route satisfies another important objective of the study. For example, it is common to increase the exposure following inhalation administration by associating a subcutaneous administration of the NCE. 

Inhalation Administration Aerosol particles of drug can be inhaled into the lungs. Because of the large surface area of the alveoli, absorption is rapid and effective. As the lungs are richly supplied with capillaries, distribution of inhalational drugs is very quick (refer to Exhibit 4.14 on inhalable insulin). 

For the 28-/90-day studies, separate guidelines are available for studies using oral administration, dermal application, or inhalation. The principle of these study protocols is identical although the updated protocols for oral administration includes additional parameters compared to those for dermal and inhalation administration, see Table 4.12. The 28-day inhalation test guideline is currently undergoing revision, see Table 2.4. 

Methyl iodide is considered a potent methylating agent it methylates hemoglobin in experimental animals and humans. In DNA binding studies in rats, adducts were found in all organs examined, with the highest levels in the stomach and forestomach, after both oral and inhalation administration. It is mutagenic... 

Administration Iloprost is intended for inhalation administration only via the Prodose AAD system, a pulmonary drug delivery device. It has not been studied with any other nebulizers. 

Improvement in asthma control following inhaled administration of budesonide can occur within 24 hours of treatment initiation, although maximum benefit may not be achieved for 1 to 2 weeks or more. 

Budesonide respules - Administer by the inhaled route via jet nebulizer connected to an air compressor in asthmatic patients 12 months to 8 years of age. Improvement in asthma control following inhaled administration of budesonide can occur within 2 to 8 days of initiation of treatment, although maximum benefit may not be achieved for 4 to 6 weeks. It is desirable to downward-titrate to the lowest effective dose once asthma stability is achieved. In symptomatic children not responding to nonsteroidal therapy and in patients who require maintenance therapy of their asthma, a starting dose of 0.25 mg once daily may also be considered. 

There is more rapid onset of action following inhalation administration. 

The P2 selective adrenergic agonists are most widely used drugs for the treatment of asthma. They are effective after oral and inhaled administration and have a longer duration of action. Albuterol (salbutamol), salmeterol, bitolterol, pir-buterol are available as aerosol pack in metered dose. 

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. 

Table 3 indicates the preclinical safety studies for CAPTISOL (25) conducted as of 2005. The strategic safety plan for CAPTISOL was designed based on the guidelines discussed in the 1990s by the International Pharmaceutical Excipients Council which resulted in the May 2005 issuance of the FDA Guidance (26) Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients. These studies and others in the CAPTISOL Drug Master File have delineated the safety of CAPTISOL (SBE7-P-CD) for parenteral, ophthalmic, oral, nasal, and inhalation administration. 

Target Tissues. The Travis model successfully predicted the total amount of benzene in expired air and total metabolite produced in 48 hours following gavage administration in mice and rats, and inhalation administration in mice, but slightly overestimated these parameters in rats after inhalation exposure. 

---