INTRANASAL DELIVERY OF LEVODOPA POWDER BY PRECISION OLFACTORY DEVICE
Methods are provided for treating OFF episodes in a patient with Parkinson's disease or a Parkinson syndrome, comprising administering to a subject with Parkinson's disease or a Parkinson syndrome experiencing an OFF episode an effective dose of a dry pharmaceutical composition comprising L-DOPA, wherein the dose is administered by an intranasal delivery device that provides, following intranasal administration, (a) a mean peak plasma levodopa concentration (C max ) of at least 200 ng/mL, with (b) a mean time to C max (T max ) of levodopa of less than or equal to 60 minutes. Dry pharmaceutical compositions of levodopa suitable for intranasal administration and unit dosage forms comprising the dry pharmaceutical compositions are also provided.
1 . A method of treating an OFF episode in a patient with Parkinson's disease (PD) or a Parkinson syndrome, the method comprising:
administering to a subject suffering from an OFF episode of either Parkinson's disease or a Parkinson syndrome an effective dose of levodopa (L-DOPA) by delivering a dry pharmaceutical composition comprising levodopa (L-DOPA) using an intranasal delivery device, thereby providing:
(a) a mean peak plasma levodopa concentration (C max ) of at least 200 ng/mL, with
(b) a mean time to C max (T max ) of levodopa of less than or equal to 60 minutes, wherein the intranasal delivery device is configured to deliver the dry pharmaceutical composition.
2 . The method of claim 1 , wherein the mean peak plasma levodopa concentration (C max ) provided by the dose is at least 400 ng/mL.
3 . The method of claim 1 , wherein the intranasal administration of levodopa is adjunctive to oral administration of a DDI, optionally wherein the oral DDI is benserazide or carbidopa.
4 . The method of claim 3 , wherein the intranasal administration of levodopa is adjunctive to oral treatment with a DDI and oral treatment with levodopa, optionally wherein the oral treatment with a DDI and oral treatment with levodopa is with an oral dosage form containing a fixed dose combination of a DDI and levodopa.
5 . The method of claim 1 , wherein the patient has PD or a Parkinson syndrome selected from the group consisting of post-encephalitic parkinsonism, symptomatic parkinsonism following carbon monoxide intoxication, or symptomatic parkinsonism following manganese intoxication.
6 . The method of claim 1 , wherein the dry pharmaceutical composition is a powder, optionally wherein the median diameter of the levodopa particle size distribution (D50) in the powder is 5 μm-500 μm, 5 μm-250 μm, 5 μm-100 μm, 5 μm-75 μm, 5 μm-50 μm, 10 μm-50 μm or 20 μm-40 μm.
7 . The method of claim 1 , wherein the dry pharmaceutical composition comprises levodopa (i) in a crystalline form, (ii) in an amorphous form, optionally wherein the amorphous form is obtained by spray-drying, or (iii) in a partially crystalline and partially amorphous form.
8 . The method of claim 1 , wherein the dry pharmaceutical composition comprises no more than 80 wt % levodopa, 50-80 wt % levodopa, 50-70 wt % levodopa, or 65-70 wt % levodopa.
9 . The method of claim 1 , wherein the dry pharmaceutical composition further comprises a nonionic surfactant, optionally wherein the nonionic surfactant is an alkyl maltoside, optionally wherein the alkyl maltoside is n-dodecyl β-D-maltoside.
10 . The method of claim 1 , wherein the dry pharmaceutical composition further comprises HPMC.
11 . The method of claim 1 , wherein the dry pharmaceutical composition further comprises a salt of a monovalent inorganic cation, optionally wherein the salt is NaCl.
12 . The method of claim 1 , wherein the dry pharmaceutical composition comprises 68 wt % levodopa, 2 wt % NaCl, 29 wt % HPMC, and 1 wt % n-dodecyl β-D-maltoside, optionally wherein the composition is a spray dried composition.
13 . The method of claim 1 , wherein the effective dose is a dose of dry pharmaceutical composition containing levodopa in an amount effective to reverse an OFF episode within 60 minutes.
14 . The method of claim 13 , wherein the effective dose of levodopa is 25-150 mg, 35 -140 mg, 35 mg, 70 mg, 105 mg, or 140 mg.
15 . The method of claim 1 , wherein the effective dose is administered (i) as a single undivided dose or (ii) as a plurality of equally divided sub-doses.
16 . The method of claim 1 , wherein the intranasal delivery device is (i) a handheld, manually actuated, metered-dose intranasal administration device or (ii) a manually actuated, propellant-driven, metered-dose intranasal administration device.
17 . The method of claim 16 , wherein the levodopa composition is, prior to device actuation, (i) encapsulated within a capsule present in the device or (ii) stored within a dose container that is removably coupled to the device.