Respiratory tract delivery of levodopa and dopa decarboxylase inhibitor for treatment of parkinson's disease

Abstract

A dry pharmaceutical composition is provided that is suitable for respiratory tract delivery of levodopa and DDI for treatment of Parkinson's disease or Parkinson syndrome. The dry pharmaceutical composition comprises levodopa, a dopa decarboxylase inhibitor (DDI) and at least one excipient. A unit dosage form of the dry pharmaceutical composition and a method of treating a patient with Parkinson's disease or Parkinson syndrome by administering the dry pharmaceutical composition are also provided.

What is claimed is: 
     
         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.