Adequate treatment of Parkinson's patients in off periods with orally administered levodopa is hindered by a poor bioavailability and a slow onset of action. Hence, there is a need for a fast and reliable alternative as for instance via pulmonary administration of the drug. We developed a levodopa containing powder formulation for pulmonary delivery by a recently presented high dose dry powder inhaler (Cyclops). The objective was to produce the drug formulation by means of simple techniques such as micronization, either as pure active substance or with a minimum amount of excipients. After an initial screening on dispersion behaviour, the most promising formulation in the Cyclops was characterized in vitro over a range of pressure drops (2-6 kPa) and doses (20, 30 and 40 mg), representative of those to be expected in practice. A co-micronized levodopa formulation with 2% L-leucine appeared to yield the best aerosol properties for inhalation and highest delivered dose reproducibility. The combination of this particular formulation and the Cyclops inhaler seems to meet the basic requirements for satisfactory deposition in the airways. This formulation is therefore expected to be a promising candidate for the treatment of Parkinson's patients in an off period.

Because of its rapid onset of action, pulmonary administration of levodopa is an interesting alternative to oral administration for the rescue treatment of Parkinson’s disease patients in an off period. We studied the ability of Parkinson’s disease patients to operate a dry powder inhaler (DPI) correctly during an off period. We used an instrumented test inhaler with three different resistances to air flow to record flow curves and computed various inhalation parameters. We observed that all (13) patients were able to generate pressure drops > 2 kPa over the highest resistance and 10 out of 13 patients achieved at least 4 kPa. Inhaled volumes (all resistances) varied from 1.2 L to 3.5 L. Total inhalation time and the time to peak inspiratory flow rate both decreased with decreasing inhaler resistance. Twelve out of thirteen patients could hold their breath for at least five seconds after inhalation and nine could extend this time to ten seconds. The data from this study indicate that patients with Parkinson’s disease will indeed be able to use a dry powder inhaler during an off period and they provide an adequate starting point for the development of a levodopa powder inhaler to treat this particular patient group.

Background: Inhaled levodopa may quickly resolve off periods in Parkinson’s disease. Our aim was to determine the pharmacokinetics and tolerability of a new levodopa dry-powder inhaler. Methods: A single-centre, single-ascending, single-dose–response study was performed. Over three visits, eight Parkinson’s disease patients (not in the ‘off state’) received by inhalation 30 mg or 60 mg levodopa, or their regular oral levodopa. Maximum levodopa plasma concentration ( C max ), time to maximum plasma concentration (T max ) and area under the concentration time curve 0–180 min were determined. Spirometry was performed three times at each visit. Results: After inhalation, levodopa T max occurred within 15 min in all participants, whereas after oral administration, T max ranged from 20 min to 90 min. The bioavailability of inhaled levodopa without carboxylase inhibitor was 53% relative to oral levodopa with carboxylase inhibitor. No change in lung-function parameters was observed and none of the patients experienced cough or dyspnoea. No correlation was observed between inhalation parameters and levodopa pharmacokinetic parameters. Conclusion: Inhaled levodopa is well tolerated, absorbed faster than oral levodopa, and can be robustly administered over a range of inhalation flow profiles. It therefore appears suitable for the treatment of off periods in Parkinson’s disease.