DPI for treating off periods symptoms of parkinson...

1. A levodopa dry powder inhaler for
the treatment of Parkinson’s
disease patients in off periods
BY VISHAKHA TAMBE
MS PHARMACEUTICS
NIPER AHEMEDABAD

2. PURPOSE
 DPI OF LEVODOPA is being developed as an adjunctive, as-needed therapy to
provide rapid and reliable relief from intermittent debilitating motor
fluctuations, known as OFF episodes, suffered by Parkinson’s disease patients.
 Approximately 50% of people using L-dopa experience off episodes.
 These episodes can be very disruptive to the lives of people with Parkinson’s
disease, their families and caregivers.
 Off episodes increase in frequency and severity during the course of the
disease

3. Characterization of starting
material(levodopa and L-leucine)
Scanning electron microscopy
•Laser diffraction analysis
Dynamic vapour sorption analysis
•Differential scanning calorimetry

4. CHARACTERIZATION OF STARTING
MATERIAL
 SEM Results before micronization
Crystalline
nature of
unmicronized
levodopa
Plate shape
crystals of L-
leucine

5.  Sem results after micronization
SEM images of (A) micronized levodopa (3000), (B) co-micronized levodopa and (2%) L-leucine (3000),
(C) co-micronized levodopa and (2%) L-leucine (250).

6. DYNAMIC VAPOUR SORPTION ANALYSIS
Results
 Increase in mass of 0.075% of
levodopa between 0% to 90%
relative humidity (before
micronization)
 increase in mass of 0.543%
between 0% to 90% relative
humidity(after micronization)
conclusions
 Levodopa is nonhygroscopic
powder in crystalline state(before
micronization)
 Mass increase is more compared to
before micronization due to
increase in specific surface area

7. Differential scanning calorimetry

8. Particle size distribution
 Laser diffraction analysis  Cascade impaction analysis

9. LASER diffraction analysis results
Batch Supplier %L-
Leucine
X10(µm) X50(µm) X90(µm) <5(µm)(%)
1 D 0 0.66 1.46 3.06 99.77
2 D 1 0.62 1.19 2.54 98.85
3 D 1 0.65 1.45 84.22 83.57
4 D 2 0.61 1.13 2.34 100.00
5 D 2 0.62 1.22 3.16 92.37
6 D 2 0.66 1.44 15.46 89.82
7 D 2 0.63 1.29 3.76 90.52
8 D 5 0.63 1.24 2.82 96.16
9 D 6.4 0.62 1.20 2.55 99.96
10 S 2 0.61 1.12 2.31 100.0
11 S 2 0.64 1.29 2.86 97.41
12 S 2 0.62 1.18 2.76 94.88
13 S 2 0.63 1.24 2.57 100
14 S 5 0.62 1.21 3.03 92.58

10. POWDER PREPARATION BY
COMICRONIZATION
Instrument used
 50 AS jet mill
 Applied nozzle pressure 6 bar
 Milling pressure of water free
nitrogen 2 bar
Formulation prepared
 Only micronized levodopa
 Levodopa+1% L-leucine
 Levodopa+2% L-leucine
 Levodopa+5% L-leucine
 Levodopa+6.5% L-leucine

11. 50 AS JET MILL 50 AS JET MILL

12. Dispersion of pure micronized levodopa in
cyclops
Effect of levodopa dose on
FPF <5µm as % of the
metered dose
conclusion
 FPF(fine particle fraction)<5µm as
percent of the metered dose was
only approximately20–30% for all
three doses tested.

13. Dispersion of pure micronized
levodopa in cyclops (contd….)
X50-value of the aerosol
from the Cyclops conclusions
 Dose affects dispersion efficiency

14. Dispersion of pure micronized
levodopa in cyclops (contd….)
inhaler retention for pure
micronized levodopa conclusion
 More dose less is the inhaler
retention

15. The effect of L-leucine on the dispersion of
micronized levodopa in the Cyclops(contd…)
FPF <5 µm as % of the
metered dose (levodopa +L-
leucine)
result
FPF was increased to 60 to 70 %due to
addition of L-leucine in different
proportion except for 6.4%

16. The effect of L-leucine on the dispersion of
micronized levodopa in the Cyclops(contd…)
X50-value of the aerosol
from the Cyclops results
 Decrease in X50 value compared
to only micronized levodopa
except for 6.4%

17. The effect of L-leucine on the dispersion of
micronized levodopa in the Cyclops(contd…)
inhaler retention (levodopa +L-
leucine) results
 Inhaler retention was
approximately 20% of the metered
dose between 1 % to 5%

18. conclusion
1 % and
2 % L-
leucine
Decrease
in X50
Decrease
in inhaler
retention
Increase
FPF
Only 2% L-leucine was taken further

19. Optimization of formulation
micronized
Levodopa
Levodopa with
different L-leucine
concentration
Levodopa with
different L-leucine
concentration+
effect of pressure
drop

20. AEROSOL CHARACTERIZATION FROM
INHALER
Laser diffraction analysis
Cascade impaction analysis
Consistency of delivered dose

21. AEROSOL CHARACTERIZATION FROM
INHALER
Emission time analysis
Inhaler retention

22. EFFECT OF PRESSURE DROP AND METERED
DOSE ON DISPERSION OF 2% L-LEUCINE

23. Gravimetric analysis results
CONCLUSION
Pressure drop is directly proportional
to FPF and inversely proportional to
inhaler retention and X50

24. Cascade impaction analysis (results)

25. Cascade impaction analysis (results)

26. Emission time data
 Discharge of dose from the inhaler
should be within first 1 to 1.5 L of
inhaled air
 Tem 50% and Tem 80%: times
needed to emit 50% and 80% of the
delivered dose.
 (IV = inhaled volume, IV80%:
inhaled volume for 80% dose
∆P
(kPa)
Dose
(mg)
Tem
50%(s
)
Tem
80%(s
)
IV80%
(L)
2 30 1.9 3.5 1.4
3 30 1.5 2.9 1.4
4 20 1.0 1.8 1.0
4 30 1.3 2.5 1.4
4 40 1.4 2.6 1.5
6 30 0.7 1.3 0.9

27. Consistency of delivered dose…
procedure
 30 mg micronized levodopa with
2%L-leucine was taken
 Pressure drop of 4kPa
 Inhalation time=inhaled volume of
4L
 10 measurements were done
 UV analysis
results
 Mean delivered dose
=22.3mg(74.2%) with a spread of
21.3mg to 22.8mg
 requirements in the Pharmacopeia
(at least 9 out of 10 delivered
doses should be between 75% and
125% of the average, whereas all
should bebetween 65% and 135%).

28. LEVODOPA FROM
SIGMA
LEVODOPA FROM DUCHEFA
SPRAY
DRIED
LEVODOPA
MICRONIZED
LEVODOPA
ONLY
LEVODOPA
LEVODOPA
WITH L-
LEUCINE
1 % L-
leucine
2% L-
Leucine
4% L-
Leucine
6.5% L-
leucine
4kPa
/6kPa
pressure
drop

29. CONCLUSION
 a dry powder inhalation formulation of levodopa was developed with a simple
micronization technique and minimal use of excipients.
 The use of laser diffraction technique allowed the fast screening of the
dispersion performance of candidate formulations, in the Cyclops, of which
only the most promising formulation (with 2% L-leucine) was characterized
more extensively with CIA to assess the delivered fine particle µm as per cent
of the metered mass).

30. CONCLUSION
 Levodopa comicronized with only 2% L-leucine and dispersed with the
Cyclops high dose dry powder inhaler appears to be a promising candidate for
the treatment of patients suffering from Parkinson’s disease in an off period.
 The combination of this particular formulation and inhaler meets the basic in
vitro requirements regarding emission rate, dispersion efficiency and
consistency of delivered dose for satisfactory drug delivery to the lung.

31. ARCUS® inhaler by Acorda
therapeutics

32. Data from civitas