Methods for treatment of Parkinson's disease
Inventors
Birnberg, Tal • Eliahu, Shmuel Ben • Vostokova, Natalia • BEKER, DANIT FINKELSHTEIN • Adar, Liat • Perlstein, Itay
Assignees
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Publication Number
US-11844754-B2
Publication Date
2023-12-19
Expiration Date
Abstract
Disclosed is a method for the treatment of a neurological or movement disorder, e.g., Parkinson's disease, in an individual in need thereof, by parenteral administration of levodopa, a levodopa salt, a levodopa prodrug, or any combination thereof, and a dopa decarboxylase inhibitor (DDCI), such as carbidopa, a carbidopa salt, a carbidopa prodrug, benserazide or any combination thereof, concomitantly with oral administration of levodopa, a DDCI, such as carbidopa, benserazide, or any combination thereof.
Core Innovation
The invention relates to treatment of Parkinson's disease by administering a levodopa prodrug and carbidopa or a carbidopa prodrug. A first pharmaceutically acceptable liquid composition is subcutaneously administered over a subcutaneous infusion time course of about 24 hours or more to deliver up to about 4260 mg of levodopa over the course of about 24 hours, and at least one oral dosage form comprising levodopa is administered before or during the subcutaneous infusion time course.
The regimen further defines delivered carbidopa or carbidopa prodrug amounts up to about 220 to 227 mg over about 24 hours, a levodopa prodrug to carbidopa prodrug weight ratio of about 20:1, and a volume of between about 1 mL to about 30 mL per site per day over the course of about 24 hours. The oral dosage forms may include a COMT inhibitor and may be administered as a morning oral dose.
The document also describes levodopa prodrug compositions based on levodopa amino acid conjugates and levodopa-lanthionine conjugates, with general structural formulas and allowed substitution patterns. It further provides salt forms, formulation aspects intended to prevent diketopiperazine impurity formation, and DKP measurement methods using HPLC/LC-MS.
Claims Coverage
The consolidated claim coverage identifies two independent method claims. The inventive features center on subcutaneous infusion of a first pharmaceutically acceptable liquid composition comprising a levodopa prodrug and carbidopa or a carbidopa prodrug over about 24 hours or more, together with oral administration of levodopa before or during the infusion; the claims also include quantitative limitations for delivered levodopa amounts or per-site daily volume.
Subcutaneous infusion of levodopa prodrug plus carbidopa with oral levodopa during the infusion
Subcutaneously administering to the patient, over a subcutaneous infusion time course of about 24 hours or more, a first pharmaceutically acceptable liquid composition comprising a levodopa prodrug and carbidopa or a carbidopa prodrug, where the levodopa prodrug is present in an amount to deliver up to about 4260 mg of levodopa to the patient over the course of about 24 hours; and orally administering to the patient, before or during the subcutaneous infusion time course, at least one oral dosage form, each comprising levodopa.
Subcutaneous per-site daily volume for levodopa prodrug plus carbidopa with oral levodopa during the infusion
Subcutaneously administering to the patient, over a subcutaneous infusion time course of about 24 hours or more, a first pharmaceutically acceptable liquid composition comprising a levodopa prodrug and carbidopa or a carbidopa prodrug, at a volume of between about 1 ml to about 30 ml per site per day to the patient over the course of about 24 hours; and orally administering to the patient, before or during the subcutaneous infusion time course, at least one oral dosage form, each comprising levodopa.
Across the independent claims, the inventive coverage is the combined subcutaneous infusion and oral levodopa regimen for Parkinson's disease, with the subcutaneous liquid composition containing a levodopa prodrug plus carbidopa or a carbidopa prodrug over about 24 hours or more, and the oral component comprising levodopa before or during the infusion. The claim scope also includes quantitative limitations for delivered levodopa amounts and per-site daily volume over the infusion period.
Stated Advantages
higher-than-additive levodopa exposure (AUC) when oral levodopa/carbidopa is given concomitantly with subcutaneous infusion of LD/CD prodrugs
lower-than-expected carbidopa AUC in the combined regimen
enhanced LD exposure with oral add-on to SC prodrug
Prevention of diketopiperazine impurity formation.
Documented Applications
treatment of Parkinson's disease in a patient in need thereof
pharmacokinetic evaluation in crossover studies
nonclinical support using an LD-Tyr pig study
Treatment of Parkinson's disease in a patient in need thereof using subcutaneous administration of a levodopa prodrug with carbidopa or a carbidopa prodrug over about 24 hours or more combined with oral administration of levodopa before or during the subcutaneous infusion time course.
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