RESPIRATORY TRACT DELIVERY OF LEVODOPA AND DOPA DECARBOXYLASE INHIBITOR FOR TREATMENT OF PARKINSON'S DISEASE

1 . A dry pharmaceutical composition, comprising:

L-DOPA (levodopa),

a dopa decarboxylase inhibitor (DDI), and

at least one excipient,

wherein the dry pharmaceutical composition is suitable for delivery to the respiratory tract.

2 . The dry pharmaceutical composition of claim 1 , wherein the dry pharmaceutical composition is a powder suitable for intranasal administration.

3 . The dry pharmaceutical composition of claim 1 , wherein the dry pharmaceutical composition is a powder suitable for administration by oral inhalation.

4 . The dry pharmaceutical composition of any of claims 2 - 3 , wherein the powder comprises (i) a plurality of separate levodopa and DDI particles, and/or (ii) a plurality of particles that comprise both levodopa and DDI.

5 . The dry pharmaceutical composition of claim 4 , wherein the median diameter of the plurality of particles (D50) is 1 μm-500 μm.

6 . The dry pharmaceutical composition of claim 5 , wherein the median diameter of the plurality of particles (D50) is 1 μm-250 μm.

7 . The dry pharmaceutical composition of claim 6 , wherein the median diameter of the plurality of particles (D50) is 1 μm-100 μm.

8 . The dry pharmaceutical composition of claim 7 , wherein the median diameter of the plurality of particles (D50) is 1 μm-75 μm.

9 . The dry pharmaceutical composition of claim 8 , wherein the median diameter of the plurality of particles (D50) is 1 μm-50 μm.

10 . The dry pharmaceutical composition of claim 9 , wherein the median diameter of the plurality of particles (D50) is 1 μm-40 μm.

11 . The dry pharmaceutical composition of claim 10 , wherein the median diameter of the plurality of particles (D50) is 1 μm-5 μm.

12 . The dry pharmaceutical composition of claim 11 , wherein the median diameter of the plurality of particles (D50) is 1 μm-3 μm.

13 . The dry pharmaceutical composition of claim 10 , wherein the median diameter of the plurality of particles (D50) is 10 μm-40 μm.

14 . The dry pharmaceutical composition of claim 13 , wherein the median diameter of the plurality of particles (D50) is 10 μm-30 μm.

15 . The dry pharmaceutical composition of claim 13 , wherein the median diameter of the plurality of particles (D50) is 20 μm-40 μm.

16 . The dry pharmaceutical composition of claim 13 , wherein the median diameter of the plurality of particles (D50) is 15 μm-35 μm.

17 . The dry pharmaceutical composition of any one of claims 4 - 16 , wherein the plurality of particles are in a crystalline or amorphous form.

18 . The dry pharmaceutical composition of claim 17 , wherein the plurality of particles are in an amorphous form.

19 . The dry pharmaceutical composition of any of claims 4 - 18 , wherein the plurality of particles are obtained by spray-drying.

20 . The dry pharmaceutical composition of any one of claims 4 - 16 , wherein the plurality of particles are in a partially crystalline and partially amorphous form.

21 . The dry pharmaceutical composition of any one of claims 1 - 20 , wherein the dry pharmaceutical composition comprises no more than 95 wt % levodopa.

22 . The dry pharmaceutical composition of claim 21 , wherein the composition comprises no more than 80 wt % levodopa.

23 . The dry pharmaceutical composition of claim 22 , wherein the composition comprises 50-80 wt % levodopa.

24 . The dry pharmaceutical composition of claim 23 , wherein the composition comprises 50-70 wt % levodopa.

25 . The dry pharmaceutical composition of claim 24 , wherein the composition comprises 60-70 wt % levodopa.

26 . The dry pharmaceutical composition of any of claims 1 - 25 , wherein the DDI is carbidopa or benserazide.

27 . The dry pharmaceutical composition of claim 26 , wherein the DDI is carbidopa.

28 . The dry pharmaceutical composition of claim 26 , wherein the DDI is benserazide.

29 . The dry pharmaceutical composition of any of claims 1 - 28 , wherein the dry pharmaceutical composition comprises no more than 30 wt % DDI.

30 . The dry pharmaceutical composition of claim 29 , wherein the composition comprises 5-20 wt % DDI.

31 . The dry pharmaceutical composition of claim 30 , wherein the composition comprises 5-15 wt % DDI.

32 . The dry pharmaceutical composition of any of claims 26 - 31 , wherein the weight ratio between levodopa and the DDI is between 1:1 and 12:1.

33 . The dry pharmaceutical composition of claim 32 , wherein the weight ratio between levodopa and the DDI is between 4:1 and 11:1.

34 . The dry pharmaceutical composition of claim 33 , wherein the weight ratio between levodopa and the DDI is 10:1 or 4:1.

35 . The dry pharmaceutical composition of any of claims 1 - 34 , further comprising a nonionic surfactant.

36 . The dry pharmaceutical composition of claim 35 , wherein the nonionic surfactant is an alkyl maltoside.

37 . The dry pharmaceutical composition of claim 36 , wherein the alkyl maltoside is n-dodecyl β-D-maltoside.

38 . The dry pharmaceutical composition of any of claims 35 - 37 , wherein the nonionic surfactant is present at 0.1-10 wt %.

39 . The dry pharmaceutical composition of claim 38 , wherein the nonionic surfactant is present at 0.8-5 wt %.

40 . The dry pharmaceutical composition of claim 39 , wherein the nonionic surfactant is present at 0.9-1 wt %.

41 . The dry pharmaceutical composition of any of claims 1 - 40 , further comprising HPMC.

42 . The dry pharmaceutical composition of any of claims 1 - 41 , further comprising DSPC.

43 . The dry pharmaceutical composition of any of claims 1 - 42 , further comprising a salt of a monovalent inorganic cation.

44 . The dry pharmaceutical composition of claim 43 , wherein the salt is NaCl.

45 . The dry pharmaceutical composition of claim 44 , wherein the dry pharmaceutical composition comprises 1-5 wt % NaCl.

46 . The dry pharmaceutical composition of claim 45 , wherein the dry pharmaceutical composition comprises 1-3 wt % NaCl.

47 . The dry pharmaceutical composition of any of claims 1 - 46 , wherein the dry pharmaceutical composition comprises 68 wt % levodopa, 2 wt % NaCl, 7 wt % benserazide, 16 wt % HPMC, and 7 wt % DSPC.

48 . The dry pharmaceutical composition of any of claims 1 - 46 , wherein the dry pharmaceutical composition comprises 68 wt % levodopa, 2 wt % NaCl, 6.8 wt % carbidopa, 22.2 wt % HPMC, and 1% n-dodecyl β-D-maltoside.

49 . The dry pharmaceutical composition of any of claims 1 - 46 , wherein the dry pharmaceutical composition comprises 63.35 wt % levodopa, 1.86 wt % NaCl, 6.34 wt % carbidopa, 27.02 wt % HPMC, and 0.93% n-dodecyl β-D-maltoside.

50 . The dry pharmaceutical composition of any of claims 47 - 49 , wherein the dry pharmaceutical composition is a spray dried composition.

51 . A unit dosage form containing the dry pharmaceutical composition according to any one of claims 1 - 50 .

52 . The unit dosage form of claim 51 , wherein the unit dosage form contains 25-150 mg of levodopa.

53 . The unit dosage form of claim 52 , wherein the unit dosage form contains 35-140 mg of levodopa.

54 . The unit dosage form of claim 53 , wherein the unit dosage form contains 35 mg of levodopa.

55 . The unit dosage form of claim 53 , wherein the unit dosage form contains 50 mg of levodopa.

56 . The unit dosage form of claim 53 , wherein the unit dosage form contains 70 mg of levodopa.

57 . The unit dosage form of claim 53 , wherein the unit dosage form contains 100 mg of levodopa.

58 . The unit dosage form of claim 53 , wherein the unit dosage form contains 140 mg of levodopa.

59 . The unit dosage form of any of claims 51 - 58 , wherein the unit dosage is individually encapsulated in a capsule.

60 . A method of treating a patient with Parkinson's disease (PD) or a Parkinson syndrome, the method comprising the step of:

delivering an effective amount of the dry pharmaceutical composition of any of claims 1 - 50 to the patient's respiratory tract.

61 . The method of claim 60 , wherein the dry pharmaceutical composition is administered by intranasal administration.

62 . The method of claim 60 , wherein the dry pharmaceutical composition is administered by oral inhalation.

63 . The method of any of claims 60 - 62 , wherein the patient has PD.

64 . The method of any of claims 60 - 62 , wherein the patient has a Parkinson syndrome selected from post-encephalitic parkinsonism, symptomatic parkinsonism following carbon monoxide intoxication, or symptomatic parkinsonism following manganese intoxication.

65 . The method of any of claims 60 - 64 , wherein the patient is also being treated with an oral DDI.

66 . The method of any of claims 60 - 64 , wherein the patient is also being treated with an oral DDI and oral levodopa.

67 . The method of any of claims 60 - 64 , wherein the patient is not being treated with an oral DDI and oral levodopa.

68 . The method of any of claims 60 - 67 , wherein the step of delivering is performed when the patient is experiencing an OFF episode.

69 . The method of claim 68 , wherein the effective dose is a dose of levodopa effective to reverse the OFF episode within 60 minutes.

70 . The method of any of claims 60 - 69 , wherein the effective dose is sufficient to provide, following administration,

(a) a mean peak plasma levodopa concentration (C max ) of at least 400 ng/mL, with

(b) a mean time to C max (T max ) of levodopa of less than 60 minutes.

71 . The method of any of claims 60 - 70 , wherein the effective dose is 25-150 mg levodopa.

72 . The method of claim 69 , wherein the effective dose is 35-140 mg levodopa.

73 . The method of claim 72 , wherein the effective dose is 35 mg levodopa.

74 . The method of claim 72 , wherein the effective dose is 50 mg levodopa.

75 . The method of claim 72 , wherein the effective dose is 70 mg levodopa.

76 . The method of claim 72 , wherein the effective dose is 100 mg levodopa.

77 . The method of claim 72 , wherein the effective dose is 140 mg levodopa.

78 . The method of any of claims 60 - 77 , wherein the effective dose is administered as a single undivided dose.

79 . The method of any of claims 60 - 77 , wherein the effective dose is administered as a plurality of equally divided sub-doses.

80 . The method of claim 60 - 79 , wherein the step of delivering is performed using a delivery device, wherein the delivery device is an intranasal administration device or an oral inhalation administration device.

81 . The method of claim 80 , wherein the delivery device is a handheld, manually actuated, metered-dose administration device.

82 . The method of claim 80 , wherein the delivery device is a manually actuated, propellant-driven, metered-dose administration device.

83 . The method of claim 80 , wherein the delivery device is a breath-actuated inhaler.