Novel pharmaceutical agents containing carbohydrate moieties and methods of their preparation and use

Abstract

Hydrophilic N-linked pharmaceutical compositions, methods of their preparation and use in neuraxial drug delivery comprising a glycosyl CNS acting prodrug compound covalently N-linked with a saccharide through an amide or an amine bond and a formulary consisting of an additive, a stabilizer, a carrier, a binder, a buffer, an excipient, an emollient, a disintegrant, a lubricating agent, an antimicrobial agent or a preservative, with the proviso that the saccharide moiety is not a cyclodextrin or a glucuronide.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. application Ser. No. 09 / 547,501 filed Apr. 12, 2000, which is hereby incorporated herein by reference in its entirety.FIELD OF THE INVENTION [0002] The invention relates generally to compositions and methods for treating peripheral and central neurological dysfunctions including e.g. infectious diseases, epilepsy, impaired motor dysfunction, schizoprenia, cognition, depression, behavior and mood disorders. BACKGROUND OF THE INVENTION [0003] It is estimated that mental disorders account for 10 percent of the global burden of disease with four disorders ranking among the 10 leading causes of disability worldwide: namely, unipolar major depression, bipolar disorder, schizophrenia and obsessive-compulsive disorder (National Institute of Mental Health, Report of the National Advisory Mental Health Council Behavioral Science Workgroup, March 2000). Unfortunately, the fundamental basis by which neuro...

AI Technical Summary

Benefits of technology

[0021] Methods are disclosed for preparing and using hydrophilic prodrug N-linked glycosyl-amine and glycosyl-amide compounds, including cyclic and heterocyclic compounds having good aqueous solubility and pharmacokinetic half-life in blood, but which are also transportable by saccharide transporters in the gastrointestinal tract and in endothelial cells at the blood brain barrier. Compounds produced according to the methods of the invention find a variety of uses in therapeutic methods for treating symptoms of neurologic dysfunction e.g., in inf

Problems solved by technology

Unfortunately, the fundamental basis by which neurobiologic function translates into behaviors such as cognition, emotion, motivation, development, personality and social interaction are (at present) largely unknown.

The blood brain barrier effectively limits access of many classes of known and potentially useful pharmaceutical agents.

For instance, in Parkinson's disease it has long been understood that the disease results from a defect in dopamine biosynthesis, but it has proven exceptionally difficult to effect proper delivery of therapy across the blood brain barrier into affected nigrostriatal tissues.

Although metabolic replacement therapy in Parkinson's might theoretically be effected with L-Dopa, the precursor of dopamine and a compound, which readily crosses the blood-brain barrier, the compound is highly unstable and rapidly inactivated in blood.

L-dopa, Levodopa, Cardiodopa (an inhibitor of dopa decarboxylase), Deprenyl (inhibiting dopamine degrading monoamine oxidase), Sinemet (a controlled release form of Levodopa) and their combinations and derivatives suffer from many major disadvantages common also in certain other drugs which might be used in neuraxial therapies, e.g. poor aqueous solubility, poor brain penetrability, relatively short half-lives, dosing fluctuations and numerous side effects.

Often after 3-5 years of treatment patients reportedly develop complex dose-related unpredictable response fluctuations leading to a progressive decrease in therapeutic efficacy and also possible onset of serious side effects such as abnormal involuntary movements, end-of-dose deterioration and abrupt near instantaneous on-off changes in patient disability.

In addition to these neurologic side effects, metabolism of oral dopa compounds to dopamine in the stomach and gastrointestinal tract (even in the presence of decarboxylase inhibitors) can often lead to unwanted side effects including severe nausea and hypotension.

Levodopa methyl and ethyl esters given orally suffer many of these same problems.

Oral delivery of drugs constitutes special chemical challenges, i.e., general simultaneous requirements for intestinal penetration, blood borne delivery, blood-brain-barrier penetrability and maintenance of functional (receptor binding and / or metabolic) utility.

CNS active drugs constitute yet additional special and challenging problems, i.e., low pH stability (or protection) and intestinal transport.

Missense mutations in SGLT1 reportedly result in potentially lethal inability to transport glucose and galactose (Martin et. al., 1996).

While agonists are theoretically superior to Levodopa (i.e., because they should not be dependent on enzymatic conversion), in clinical use they have been shown to lack the therapeutic potency of Levodopa.

Direct acting D2 agonists (e.g., bromocriptine, lisuride and pergolide) have also shown limited efficacy in monotherapy and are primarily used as add-on therapy to L-Dopa.

However, it's utility is also limited by bioavailability problems.

Success in development of a candidate neuropharmaceutical agent may often turn on issues of whether receptor binding activity can be retained while optimizing for intestinal transport, pharmacologic half-life in blood and blood brain barrier penetrability.

Unfortunately, even within a class, receptors may be structurally (and functionally) heterogeneous.

Unlike systemic treatments, neuraxial delivery of pharmaceutical agents may be complicated by endogenous mechanisms for recycling, scavenging and transporting neural mediators.

Pointing out the essential nature of this transport, missense mutations in SGLT1 result in a potentially lethal inability to transport glucose and galactose (Martin et al., 1996).

However, these approaches suffer from various different disadvantages including poor pharmacokinetic half-life, poor neuraxial bioavailability, variable dosing and side effects.

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