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US-12622947-B2 - Pharmaceutical composition for treating levodopa-induced dyskinesia or for suppressing progression thereof

US12622947B2US 12622947 B2US12622947 B2US 12622947B2US-12622947-B2

Abstract

A GLP-1 receptor agonist has effects of reducing serious side effects due to long-term use of levodopa when administered in combination with levodopa, and also effects of alleviating or improving abnormal involuntary movements (AIMs) caused by levodopa. A method for prevention or treatment of levodopa-induced dyskinesia according to an embodiment of the present disclosure includes administering a glucagon-like peptide-1 (GLP-1) receptor agonist to a patient.

Inventors

  • Ho Il Choi

Assignees

  • PEPTRON, INC.

Dates

Publication Date
20260512
Application Date
20200729
Priority Date
20200729

Claims (10)

  1. 1 . A method for treatment of levodopa-induced dyskinesia, the method comprising: subcutaneously administering a composition comprising a therapeutically effective amount of a controlled-release formulation of an exendin-4 or exenatide to a patient with the levodopa-induced dyskinesia, wherein the controlled-release formulation comprises: a core containing the and a biodegradable polymer, wherein the biodegradable polymer comprises at least one selected from the group consisting of: polylactide, polyglycolide, and poly (lactide-co-glycolide) as a copolymer of lactide and glycolide; and a coating layer coated on the core, the coating layer comprising at least one selected from the group consisting of basic amino acid, polypeptide and an organic nitrogen compound, wherein the subcutaneous administration of the composition results in a reduction in abnormal involuntary movements (AIMs) as assessed by an AIMs scoring system.
  2. 2 . The method according to claim 1 , wherein the patient has received administration of levodopa.
  3. 3 . The method according to claim 1 , wherein the composition is administered after administration of levodopa.
  4. 4 . The method according to claim 1 , wherein the therapeutically effective amount ranges from 0.01 μg/kg/day to 100 μg/kg/day.
  5. 5 . The method of claim 1 , wherein the coating layer comprises one or more basic amino acids, wherein the basic amino acid comprises at least one selected from the group consisting of arginine, lysine and histidine.
  6. 6 . The method according to claim 1 , the intrinsic viscosity of the biodegradable polymer is 0.1 to 0.5 dl/g.
  7. 7 . A method for prevention of levodopa-induced dyskinesia in a patient with a Parkinson's disease, the method comprising: subcutaneously administering a composition comprising a prophylactically effective amount of a controlled-release formulation of an exendin-4 or exenatide to the patient who does not involve occurrence of levodopa-induced dyskinesia, wherein the patient has received administration of levodopa, wherein the controlled-release formulation comprises: a core containing the exendin-4 or the exenatide- and a biodegradable polymer, wherein the biodegradable polymer comprises at least one selected from the group consisting of: polylactide, polyglycolide, and poly (lactide-co-glycolide) as a copolymer of lactide and glycolide; and a coating layer coated on the core, the coating layer comprising at least one selected from the group consisting of basic amino acid, polypeptide and an organic nitrogen compound, wherein the subcutaneous administration of the composition results in a reduction in abnormal involuntary movements (AIMs) as assessed by an AIMs scoring system.
  8. 8 . The method of claim 7 , wherein the composition is administered simultaneously with levodopa or after administration of levodopa.
  9. 9 . The method of claim 7 , wherein the prophylactically effective amount ranges from 0.01 μg/kg/day to 100 μg/kg/day.
  10. 10 . The method according to claim 7 , the intrinsic viscosity of the biodegradable polymer is 0.1 to 0.5 dl/g.

Description

CROSS REFERENCE TO RELATED APPLICATIONS AND CLAIM OF PRIORITY This application claims benefit under 35 U.S.C. 119(e), 120, 121, or 365(c), and is a National Stage entry from International Application No. PCT/KR2020/010023 with an International Filing Date of Jul. 29, 2020, which claims the benefit of U.S. Application No. 62/879,574 filed on Jul. 29, 2019 and Korean Patent Application No. 10-2020-0094783 filed on Jul. 29, 2020 at the Korean Intellectual Property Office, the disclosures of which are incorporated by reference herein in their entirety. BACKGROUND 1. Technical Field The present invention relates to a pharmaceutical composition for treating or inhibiting progression of levodopa-induced dyskinesia, and a method for treating or inhibiting progression of levodopa-induced dyskinesia using the pharmaceutical composition. 2. Background Art Parkinson's disease (PD) is a neurological disorder caused by degeneration of the dopaminergic neuron of the striatum-black substance (“nigrostriatal”) of the cerebral basal ganglia, and a disease involving symptoms of behavior dysfunctions such as slow behavior, stiffness of the body, tremor and unstable posture (Fahn, 2003). As a primary drug therapy for Parkinson's disease, L-3,4-dihydroxyphenylalanine (L-DOPA) therapy as a dopamine agonist or dopamine precursor is mainly selected and implemented (Olanow et al., 2001). However, long-term L-DOPA therapy in animal models of Parkinson's disease has caused neurotoxicity due to formation of reactive oxygen species (ROS) and changes in downstream gene/protein expression, and long-term administration of L-DOPA in Parkinson's disease patients has not only decreased drug efficacy but also caused dyskinesia, motor fluctuation and other complications (Jankovic, 2005). Dyskinesia is a side effect of abnormal movement caused by confusion due to reflux waves in motor muscles, and it has been reported that 40% of patients who have L-DOPA treatment for 4 to 5 years and 90% of patients who have the same treatment for 9 to 15 years exhibited the above symptom (Nutt, 1990; Quinn, 1995). This dyskinesia is called peak-dose dyskinesia because it responds and is exhibited when the concentration of L-DOPA in the brain is highest (Olanow et al., 2004). The mechanism of levodopa-induced dyskinesia (LID) is not known exactly, but results of increased sensitivity to dopamine D1 and D2 receptors in striatum due to dopamine reduction are suggested as one cause. This increase in dopamine D1 and D2 receptor sensitivity causes a rapid change in dopamine concentration. Long-term administration of dopamine D1 and D2 agonists causes expression of dyskinesia in the animal model of Parkinson's disease (Berke et al., 1998). Further, levodopa-induced dyskinesia is related to the expression of genes and proteins in the striatum in which the dopamine nerve is destroyed. In particular, several studies have reported that ΔFosB protein expression and phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) are highly correlated (Andersson et al., 2001; Pavσn N. et al., 2006). There is a study reporting that long-term administration of L-DOPA to a Parkinson's disease animal model using 6-hydroxydopamine (6-OHDA) results in dyskinesia along with ΔFosB protein expression (Andersson et al., 1999). Recently, studies have reported that phosphorylation of ERK1/2 is associated with an increase in the expression of ΔFosB protein due to dyskinesia (Pavσn N. et al., 2006). Further, there is a study reporting that administration of a physiological saline solution in 6-OHDA-induced Parkinson's disease animal models did not affect ERK1/2 phosphorylation, whereby ERK1/2 phosphorylation by L-DOPA administration was related to the expression of abnormal involuntary movements (AIMs), which indicates a degree of dyskinesia. (Westin et al., 2007). Meanwhile, a GLP-1 receptor is present in both the rodent brain (Jin et al., 1988; Shughrue et al., 1996; Jia et al., 2016) and the human brain (Wei, Mojsov 1995; Satoh et al., 2000). According to the chemical structure, it generally appears that the distribution is mainly confined to the area postrema, that is, the hypothalamus, thalamus, brainstem, lateral septum and subformical organ, and all circumventricular areas where most of peptide receptors are present. Further, even with a lower density, specific binding sites for GLP-1 were detected throughout the caudate, putamen, cerebral cortex and cerebellum (Campos et al., 1994; Calvo et al., 1995; Goke et al., 1995). In prior literatures, it was demonstrated that GLP-1 receptors are expressed in the amygdala, cerebellum, frontal cortex, hippocampus, hypothalamus, midbrain, medulla, pons, striatum, thalamus and temporal cortex of the ferrets (Mustela putorius furo) (Lu et al., 2014). The expression level of the GLP-1 receptor in the brain is not affected by aging. Further, GLP-1 has been shown to be related to cognition and behavior (During et al., 2003). A number of stu