Dosage forms and therapeutic uses of L-4-chlorokynurenine
Inventors
Snodgrass, H. Ralph • CATO, Allen E. • HICKLIN, Jack S.
Assignees
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Publication Number
US-10980758-B2
Publication Date
2021-04-20
Expiration Date
Abstract
Compositions of L-4-chlorokynurenic are provided, as are methods for the treatment of neurological dysfunction.
Core Innovation
The invention relates to pharmaceutical unit dose forms consisting essentially of L-4-chlorokynurenine for treating depression. The compositions are presented as unit dose forms comprising L-4-chlorokynurenine in an amount of about 360 mg to about 1440 mg together with a pharmaceutically acceptable ingredient, and the unit-dose approach targets therapeutic use for depression.
The described mechanism is downregulating NMDA-R signaling by conversion to 7-chlorokynurenic acid in activated astrocytes. The invention associates the formation of 7-chlorokynurenic acid with targeted plasma levels of about 15–550 ng/mL, in the context of neurological dysfunction including depression.
The partial content also describes clinical and pharmacokinetic characterization in a Phase 1b randomized double-blind placebo-controlled study using oral administration of AV-101, with reported pharmacokinetic measures such as Cmax, Tmax, half-life, and AUC for L-4-chlorokynurenine and/or 7-chlorokynurenic acid. Pain evaluation is described using a capsaicin-induced hyperalgesia model with decreases in measures such as allodynia and heat/mechanical hyperalgesia for a 1,080 mg cohort.
In addition, L-4-chlorokynurenine (AV-101) may be combined with L-DOPA to reduce dyskinesias associated with L-DOPA. The described outcomes include decreases in pain measures in an experimental model and exploratory mood-related effects in active-treated subjects versus none in placebo, consistent with the therapeutic intent for depression.
Claims Coverage
The independent claim (clm-00001) is directed to a pharmaceutical unit dose form consisting essentially of L-4-chlorokynurenine in an amount of 360 mg to 1440 mg for treating depression, including a pharmaceutically acceptable ingredient. The dependent claims refine the unit dose form to oral and further narrow the dosage form to tablet or capsule, and they specify particular dose amounts within the claimed range (360 mg, 1080 mg, 1440 mg).
Pharmaceutical unit dose form consisting essentially of 360 mg to 1440 mg L-4-chlorokynurenine for treating depression
A pharmaceutical unit dose form consisting essentially of 360 mg to 1440 mg L-4-chlorokynurenine therapeutically effective to treat depression, including a pharmaceutically acceptable ingredient.
Oral unit dose form
The pharmaceutical unit dose form is a pharmaceutical oral unit dose form.
Tablet or capsule dosage form
The pharmaceutical unit dose form is a tablet or a capsule.
360 mg L-4-chlorokynurenine unit dose
The pharmaceutical unit dose form contains 360 mg of L-4-chlorokynurenine.
1080 mg L-4-chlorokynurenine unit dose
The pharmaceutical unit dose form contains 1080 mg L-4-chlorokynurenine.
1440 mg L-4-chlorokynurenine unit dose
The pharmaceutical unit dose form contains 1440 mg L-4-chlorokynurenine.
Overall claim coverage focuses on a depression-treating pharmaceutical unit dose form comprising L-4-chlorokynurenine within 360 mg to 1440 mg, optionally limited by oral administration and by tablet/capsule form, with dependent claims specifying 360 mg, 1080 mg, or 1440 mg unit dose strengths.
Stated Advantages
Treat depression using a therapeutically effective amount of L-4-chlorokynurenine in a unit dose form.
Downregulate NMDA-R signaling via conversion to 7-chlorokynurenic acid in activated astrocytes.
Target plasma levels of 7-chlorokynurenic acid (about 15–550 ng/mL) are described.
Exploratory anti-depressive activity is described for “well-being” responses in active-treated subjects versus none in placebo.
Decreases in pain measures are described in a capsaicin-induced hyperalgesia pain evaluation, including allodynia/mechanical hyperalgesia/heat hyperalgesia for a 1,080 mg cohort.
Possible reduction of L-DOPA-associated dyskinesias when combined with L-DOPA is described.
Documented Applications
Treatment of depression using a pharmaceutical unit dose form of L-4-chlorokynurenine (AV-101/VistaGen AV-101).
Neurological dysfunction context including downregulation of NMDA-R signaling via conversion to 7-chlorokynurenic acid in activated astrocytes.
Capsaicin-induced hyperalgesia pain evaluation, including decreases in measures of allodynia/mechanical hyperalgesia/heat hyperalgesia for a 1,080 mg cohort.
Exploratory anti-depressive activity based on “well-being” responses in active-treated subjects versus none in placebo.
Combination use with L-DOPA to reduce dyskinesias associated with L-DOPA.
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