Pulsatile drug delivery system for treating morning akinesia

Abstract

Provided herewith is a pharmaceutical composition comprising, separately or together, a pulsatile release component comprising levodopa and a DOPA decarboxylase inhibitor for the management of OFF-time episodes in patients with Parkinson's disease.

1 . A pulsatile release pharmaceutical composition comprising
 i) levodopa and a DOPA decarboxylase inhibitor, and   ii) a pulsatile release component providing for a predetermined lag time followed by a pulse release of said levodopa and said DOPA decarboxylase inhibitor.   
     
     
         2 . A pulsatile release pharmaceutical composition comprising, separately or together,
 i) a first pulsatile release component comprising levodopa, said first pulsatile release component providing for a predetermined lag time followed by a pulse release of levodopa, and   ii) a second pulsatile release component comprising a DOPA decarboxylase inhibitor, said second pulsatile release component providing for a predetermined lag time followed by a pulse release of said DOPA decarboxylase inhibitor.   
     
     
         3 . A pulsatile release pharmaceutical composition comprising, separately or together,
 i) a first pulsatile release component comprising levodopa, said first pulsatile release component providing for a predetermined lag time followed by a pulse release of levodopa, and   ii) a second pulsatile release component comprising a DOPA decarboxylase inhibitor, said second pulsatile release component providing for a predetermined lag time followed by a pulse release of said DOPA decarboxylase inhibitor,   
       wherein the lag time of said first pulsatile release component comprising levodopa is longer than the lag time of said second pulsatile release component comprising a DOPA decarboxylase inhibitor. 
     
     
         4 . The pharmaceutical composition according to any of the preceding claims, wherein said DOPA decarboxylase inhibitor is selected from the group consisting of carbidopa, benserazide, methyldopa and DFMD (α-Difluoromethyl-DOPA), or a pharmaceutically acceptable derivative thereof. 
     
     
         5 . The pharmaceutical composition according to any of the preceding claims, wherein said levodopa comprises pharmaceutically acceptable derivatives of levodopa, including but not limited to levodopa pro-drugs such as levodopa methyl ester and XP21279; and modified levodopa such as deuterated levodopa. 
     
     
         6 . The pharmaceutical composition according to any of the preceding claims, wherein said pulsatile release composition is a time controlled pulsatile release system, including bulk-eroding systems and surface-eroding systems. 
     
     
         7 . The pharmaceutical composition according to any of the preceding claims, wherein said pharmaceutical composition is a pharmaceutical dosage form. 
     
     
         8 . The pharmaceutical composition according to any of the preceding claims, wherein said pharmaceutical dosage form is a solid dosage form, an oral dosage form, and/or an oral solid dosage from. 
     
     
         9 . The pharmaceutical composition according to any of the preceding claims, wherein said pharmaceutical composition is a multiparticulate dosage form. 
     
     
         10 . The pharmaceutical composition according to any of the preceding claims, wherein said pharmaceutical composition is a multiparticulate dosage form comprising, separately or together, two dosage forms:
 i) a first dosage form providing for a predetermined lag time followed by a pulse release of levodopa, and   ii) a second dosage form providing for a predetermined lag time followed by a pulse release of a DOPA decarboxylase inhibitor,   
       wherein optionally the lag time of said first dosage form comprising levodopa is longer than the lag time of said second dosage form comprising a DOPA decarboxylase inhibitor. 
     
     
         11 . The pharmaceutical composition according to any of the preceding claims, wherein said multiparticulate dosage form is packaged in a capsule, a pouch a sachet or a stick pack. 
     
     
         12 . The pharmaceutical composition according to any of the preceding claims, wherein
 i) the lag time for the pulsatile release component is adjusted to release said levodopa and said DOPA decarboxylase inhibitor in the small intestine, such as the lower part of the small intestine, and/or   ii) the lag time for the first pulsatile release component comprising levodopa, and the lag time for the second pulsatile release component comprising a DOPA decarboxylase inhibitor, is adjusted to release said levodopa and said DOPA decarboxylase inhibitor in the small intestine, such as the lower part of the small intestine.   
     
     
         13 . The pharmaceutical composition according to any of the preceding claims, wherein
 i) the lag time for the pulsatile release component comprising levodopa and a DOPA decarboxylase inhibitor is between 2 to 8 hours; such as 2 to 3 hours, such as 3 to 4 hours, such as 4 to 5 hours, such as 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours,   ii) the lag time for the first pulsatile release component comprising levodopa is between 2 to 8 hours; such as 2 to 3 hours, such as 3 to 4 hours, such as 4 to 5 hours, such as 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours, and/or   iii) the lag time for the second pulsatile release component comprising a DOPA decarboxylase inhibitor is between 2 to 8 hours; such as 2 to 3 hours, such as 3 to 4 hours, such as 4 to 5 hours, such as 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours.   
     
     
         14 . The pharmaceutical composition according to any of the preceding claims, wherein the lag time of the first dosage form comprising levodopa is 5 minutes to 90 minutes longer than the lag time of the second dosage form comprising a DOPA decarboxylase inhibitor; such as 5 to 10 minutes longer, such as 10 to 15 minutes longer, such as 15 to 20 minutes longer, such as 20 to 25 minutes longer, such as 25 to 30 minutes longer, such as 30 to 35 minutes longer, such as 35 to 40 minutes longer, such as 40 to 45 minutes longer, such as 45 to 50 minutes longer, such as 50 to 55 minutes longer, such as 55 to 60 minutes longer, such as 60 to 65 minutes longer, such as 65 to 70 minutes longer, such as 70 to 75 minutes longer, such as 75 to 80 minutes longer, such as 80 to 85 minutes longer, such as 85 to 90 minutes longer than the lag time of the second dosage form comprising a DOPA decarboxylase inhibitor. 
     
     
         15 . The pharmaceutical composition according to any of the preceding claims, wherein the lag time of the first dosage form comprising levodopa is at least 5 minutes longer than the lag time of the second dosage form comprising a DOPA decarboxylase inhibitor, such as at least 10 minutes longer, such as at least 15 minutes longer, such as at least 20 minutes longer, such as at least 25 minutes longer, such as at least 30 minutes longer, such as at least 35 minutes, such as at least 40 minutes longer, such as at least 45 minutes, such as at least 50 minutes longer, such as at least 55 minutes, such as at least 60 minutes longer than the lag time of the second dosage form comprising a DOPA decarboxylase inhibitor. 
     
     
         16 . The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical composition releases 70 to 100% of the drug load measured at 2 to 5 hours after the lag phase, i.e. releases 70 to 100% of the levodopa and/or the DOPA decarboxylase inhibitor measured at 2 to 5 hours after the lag phase. 
     
     
         17 . The pharmaceutical composition according to any of the preceding claims, wherein said pharmaceutical dosage form is selected from the group consisting of a tablet, a mini-tablet, a micro-tablet, a sphere, a pellet, a granule and a capsule. 
     
     
         18 . The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical dosage form comprises a coating. 
     
     
         19 . The pharmaceutical composition according to any of the preceding claims, wherein said pharmaceutical dosage form is selected from the group consisting of a coated tablet, a coated mini-tablet, a coated micro-tablet, a coated sphere, a coated pellet, a coated granule and a coated capsule. 
     
     
         20 . The pharmaceutical composition according to any of the preceding claims, wherein the pharmaceutical dosage form comprise a soluble core, such as a soluble and swellable core, and a coating. 
     
     
         21 . The pharmaceutical composition according to any of the preceding claims, wherein the coating is a film coating. 
     
     
         22 . The pharmaceutical composition according to any of the preceding claims, wherein the coating is an insoluble coating, such as
 i) a semi-permeable insoluble coating, or   ii) a rupturable insoluble coating.   
     
     
         23 . The pharmaceutical composition according to any of the preceding claims, wherein the insoluble coating comprises a film-forming polymer and/or a water-insoluble polymer. 
     
     
         24 . The pharmaceutical composition according to any of the preceding claims, wherein the semi-permeable insoluble coating comprises a water-insoluble polymer and a pore-former, such as a hydrophilic pore former. 
     
     
         25 . The pharmaceutical composition according to any of the preceding claims, wherein the ratio in the coating of the film-forming or water-insoluble polymer and the hydrophilic pore-former is approx. 10/90, 15/85, 20/80, 25/75 or 30/70. 
     
     
         26 . The pharmaceutical composition according to any of the preceding claims, wherein the film-forming polymer and/or a water-insoluble polymer is selected from the group consisting of ethylcellulose, hydroxypropyl cellulose, cellulose acetate, acrylic polymers, enteric polymers, hypromellose acetate succinate, shellac, vax and ethylcellulose dispersions. 
     
     
         27 . The pharmaceutical composition according to any of the preceding claims, wherein the pore-former is selected from the group consisting of polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG). 
     
     
         28 . The pharmaceutical composition according to any of the preceding claims, wherein the coating is a soluble coating. 
     
     
         29 . The pharmaceutical composition according to any of the preceding claims, wherein said pharmaceutical dosage form comprises coated tablets comprising levodopa and/or a DOPA decarboxylase inhibitor providing for a predetermined lag time followed by a pulse release of said levodopa and said DOPA decarboxylase inhibitor. 
     
     
         30 . The pharmaceutical composition according to any of the preceding claims, wherein said pharmaceutical composition is a multiparticulate dosage form comprising, separately or together,
 i) coated tablets comprising levodopa providing for a predetermined lag time followed by a pulse release of levodopa, and   ii) coated tablets comprising a DOPA decarboxylase inhibitor providing for a predetermined lag time followed by a pulse release of a DOPA decarboxylase inhibitor,   
       wherein optionally the lag time of said coated tablets comprising levodopa is longer than the lag time of said coated tablets comprising a DOPA decarboxylase inhibitor. 
     
     
         31 . The pharmaceutical composition according to any of the preceding claims, wherein said coated tablets are coated mini-tablets. 
     
     
         32 . The pharmaceutical composition according to any of the preceding claims, wherein said coated mini-tablets are compressed to form a tablet. 
     
     
         33 . The pharmaceutical composition according to any of the preceding claims, wherein said dosage form comprises or consists of a core and a coating, said core comprising
 i) levodopa and/or a DOPA decarboxylase inhibitor,   ii) a superdisintegrant,   iii) one or more excipients, and   iv) optionally an anti-adherent.   
     
     
         34 . The pharmaceutical composition according to any of the preceding claims, wherein said first pulsatile release component is a coated mini-tablet comprising
 a mini-tablet core comprising or consisting of
 i) 25 to 75% w/w levodopa; such as 25 to 30%, such as 30 to 35%, such as 35 to 40%, such as 40 to 45%, such as 45 to 50%, such as 50 to 55%, such as 60 to 65%, such as 65 to 70%, such as 70 to 75% w/w levodopa, 
 ii) 15 to 50% w/w superdisintegrant; such as 15 to 20%, such as 20 to 25%, such as 25 to 30%, such as 30 to 35%, such as 35 to 40%, such as 40 to 45%, such as 45 to 50% w/w superdisintegrant, 
 iii) 10 to 50% w/w excipients; such as 10 to 15%, such as 15 to 20%, such as 20 to 25%, such as 25 to 30%, such as 30 to 35%, such as 35 to 40%, such as 40 to 45%, such as 45 to 50% w/w excipients, and 
 iv) 0 to 2% w/w anti-adherent; such as 0.25 to 0.50% w/w anti-adherent, such as 0.50 to 0.75%, such as 0.75 to 1.0%, such as 1.0 to 1.25, such as 1.25 to 1.50, such as 1.50 to 1.75%, such as 1.75 to 2.0% w/w anti-adherent, and 
   a coating.   
     
     
         35 . The pharmaceutical composition according to any of the preceding claims, wherein said mini-tablet core comprises 1 to 5 mg levodopa, such as 1 to 1.25 mg, such as 1.25 to 1.5 mg, such as 1.5 to 1.75 mg, such as 1.75 to 2 mg, such as 2 to 2.25 mg, such as 2.25 to 2.5 mg, such as 2.5 to 2.75 mg, such as 2.75 to 3 mg, such as 3 to 3.25 mg, such as 3.25 to 3.5 mg, such as 3.5 to 3.75 mg, such as 3.75 to 4 mg, such as 4 to 4.25 mg, such as 4.25 to 4.5 mg, such as 4.5 to 4.75 mg, such as 4.75 to 5 mg levodopa. 
     
     
         36 . The pharmaceutical composition according to any of the preceding claims, wherein said second pulsatile release component is a coated mini-tablet comprising
 a mini-tablet core comprising or consisting of
 i) 25 to 75% w/w DOPA decarboxylase inhibitor; such as 25 to 30%, such as 30 to 35%, such as 35 to 40%, such as 40 to 45%, such as 45 to 50%, such as 50 to 55%, such as 60 to 65%, such as 65 to 70%, such as 70 to 75% w/w DOPA decarboxylase inhibitor, 
 ii) 15 to 50% w/w superdisintegrant; such as 15 to 20%, such as 20 to 25%, such as 25 to 30%, such as 30 to 35%, such as 35 to 40%, such as 40 to 45%, such as 45 to 50% w/w superdisintegrant, 
 iii) 10 to 50% w/w excipients; such as 10 to 15%, such as 15 to 20%, such as 20 to 25%, such as 25 to 30%, such as 30 to 35%, such as 35 to 40%, such as 40 to 45%, such as 45 to 50% w/w excipients, and 
 iv) 0 to 2% w/w anti-adherent; such as 0.25 to 0.50% w/w anti-adherent, such as 0.50 to 0.75%, such as 0.75 to 1.0%, such as 1.0 to 1.25, such as 1.25 to 1.50, such as 1.50 to 1.75%, such as 1.75 to 2.0% w/w anti-adherent, and 
   a coating.   
     
     
         37 . The pharmaceutical composition according to any of the preceding claims, wherein said superdisintegrant is selected from the group consisting of Crosslinked starch such as sodium starch glycolate, Crosslinked Cellulose such as croscarmellose sodium and low-substituted hydroxypropylcellulose (L-HPC), Crosslinked PVP (polyvinylpyrrolidone) such as crospovidone, Crosslinked alginic acid, Soy polysaccharides, Calcium silicate, Gellan gum and Xanthan gum. 
     
     
         38 . The pharmaceutical composition according to any of the preceding claims, wherein said excipients comprise of or more of the group consisting of a binder, wet binder, filler, solid carrier, diluent, flavouring agent, solubilizer, lubricant, glidant, suspending agent, preservative, anti-adherent, wetting agent, disintegrating agent and sorbent or combinations thereof. 
     
     
         39 . The pharmaceutical composition according to any of the preceding claims, wherein said binder is selected from the group consisting of acacia, alginic acid, carbomers, carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, chitosan, copovidone, dextrate, dextrin, dextrose, ethylcellulose, gelatin, guar gum, hydroyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hydroxypropylmethylcellulose (HPMC or hypromellose), methylcellulose, microcrystalline cellulose (MCC), poloxamer, polydextrose, polyethylene oxide, povidone, sodium alginate, sucrose, starch, pregelatinized starch and maltodextrin. 
     
     
         40 . The pharmaceutical composition according to any of the preceding claims, wherein said excipients comprise a wet binder selected from the group consisting of pregelatinized starch, hydroxypropylmethylcellulose (HPMC), methylcellulose and gelatin. 
     
     
         41 . The pharmaceutical composition according to any of the preceding claims, wherein said excipients comprise a binder and a wet binder, such as microcrystalline cellulose (MCC) and pregelatinized starch. 
     
     
         42 . The pharmaceutical composition according to any of the preceding claims, wherein said excipients comprise
 i) 5 to 25% w/w binder, such as 5 to 7.5%, such as 7.5 to 10%, such as 10 to 12.5%, such as 12.5 to 15%, such as 15 to 17.5%, such as 17.5 to 20%, such as 20 to 22.5%, such as 22.5 to 25% w/w binder, and   ii) 1 to 20% w/w wet binder, such as 1 to 2.5%, such as 2.5 to 5%, such as 5 to 7.5%, such as 7.5 to 10%, such as 10 to 12.5%, such as 12.5 to 15%, such as 15 to 17.5%, such as 17.5 to 20% w/w wet binder.   
     
     
         43 . The pharmaceutical composition according to any of the preceding claims, wherein said anti-adherent is selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, glyceryl monostearate, hydrogenated castor oil, hydrogenated vegetable oil, medium chain glycerides, palmitic acid, poloxamers, polyethylene glycols, stearic acid and talc. 
     
     
         44 . The pharmaceutical composition according to any of the preceding claims, wherein said mini-tablet core comprises or consists of
 i) 40 to 60% w/w, such as 45 to 55% w/w levodopa,   ii) 20 to 40% w/w, such as 25 to 35% w/w sodium starch glycolate,   iii) 5 to 25% w/w, such as 10 to 20% w/w microcrystalline cellulose,   iv) 1 to 20% w/w, such as 5 to 10% w/w pregelatinized starch, and   v) 0.5 to 1.5% w/w, such as 1% w/w Mg stearate.   
     
     
         45 . The pharmaceutical composition according to any of the preceding claims, wherein the coating is applied to increase the weight of a mini-tablet core by 10 to 40% w/w, such as 10 to 12.5%, such as 12.5 to 15%, such as 15 to 17.5%, such as 17.5 to 20%, such as 20 to 22.5%, such as 22.5 to 25%, such as 25 to 27.5%, such as 27.5 to 30%, such as 30 to 32.5%, such as 32.5 to 35%, such as 35 to 37.5%, such as 37.5 to 40% w/w. 
     
     
         46 . The pharmaceutical composition according to any of the preceding claims, wherein the coating is applied to increase the weight of a tablet core by 1 to 20% w/w, such as 1 to 2.5%, such as 2.5 to 5%, such as 5 to 7.5%, such as 7.5 to 10%, such as 10 to 12.5%, such as 12.5 to 15%, such as 15 to 17.5%, such as 17.5 to 20% w/w. 
     
     
         47 . The pharmaceutical composition according to any of the preceding claims, wherein the weight increase of the coating of the tablet core comprising levodopa, and the weight increase of the coating of the tablet core comprising a DOPA decarboxylase inhibitor, are adjusted in order to release levodopa before the DOPA decarboxylase inhibitor. 
     
     
         48 . The pharmaceutical composition according to any of the preceding claims, wherein said composition further comprises, separately or together, one or more further active pharmaceutical ingredients. 
     
     
         49 . The pharmaceutical composition according to any of the preceding claims, wherein said further active pharmaceutical ingredient is selected from the group consisting of dopamine; dopamine receptor agonists such as bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, lisuride, and derivatives thereof; catechol-O-methyl transferase (COMT) inhibitors such as for example tolcapone and entacapone; apomorphine such as apomorphine injection; NMDA antagonists such as amatidine (Symmetrel); MAO-B inhibitors such as selegiline and rasagiline; serotonin receptor modulators; kappa opioid receptors agonists such as TRK-820 ((E)-N-[17-cyclopropylmethyl)-4, 5α-epoxy-3, 14-dihydroxmorphinan-6β-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride); GABA modulators; modulators of neuronal potassium channels such as flupirtine and retigabine; glutamate receptor modulators; an immediate release product comprising levodopa and a controlled release product comprising levodopa. 
     
     
         50 . The pharmaceutical composition according to any of the preceding claims, wherein said pharmaceutical composition and said further active pharmaceutical ingredient are administered simultaneously, separately or sequentially. 
     
     
         51 . The pharmaceutical composition according to any of the preceding claims for use in the treatment of morning akinesia in a patient with Parkinson's disease. 
     
     
         52 . The pharmaceutical composition according to any of the preceding claims for use in the treatment of morning akinesia in a patient with Parkinson's disease, wherein said composition is administered prior to sleep. 
     
     
         53 . The pharmaceutical composition according to any of the preceding claims for use in the treatment of morning akinesia in a patient with Parkinson's disease, wherein said composition is administered in combination with an immediate release levodopa-product and/or a sustained release levodopa-product.