WO2009059242A1

WO2009059242A1 - A controlled-release partial glycine agonist composition for use with levodopa in parkinson's disease and method of use

Info

Publication number: WO2009059242A1
Application number: PCT/US2008/082139
Authority: WO
Inventors: Roberto Fiorentini
Original assignee: Lazarus Therapeutics, Inc.
Priority date: 2007-11-01
Filing date: 2008-10-31
Publication date: 2009-05-07
Also published as: WO2009059242A8

Abstract

A pharmaceutical composition comprises partial glycine agonist in a controlled release formulation for once a day administration to subjects with Parkinson's disease. The composition includes a controlled release material comprising a partial glycine agonist, a sustained release component, and at least one pharmaceutically acceptable excipient, wherein the composition upon initial administration of one dose provides a mean plasma concentration of the partial glycine agonist of at least 10 μg/mL and not more than 30 μg/mL within one hour of administration and continues to provide a mean plasma concentration of the partial glycine agonist of not more than 30 μg/mL for 12 - 16 hours. The partial glycine agonist is administered in a dose effective to enhance the efficacy of the levodopa or to reduce the frequency or severity of side effects of the levodopa. A method for treating Parkinson's disease in a subject comprises administering levodopa to the patient at least once per day and administering to the patient a once daily composition including a partial glycine agonist, formulated to provide a release profile wherein sufficient partial glycine agonist is delivered to the brain of the subject to enhance efficiency or reduce the side effects of each levodopa dose for up to 16 hours after administration of the partial glycine agonist.

Description

A CONTROLLED-RELEASE PARTIAL GLYCINE AGONIST COMPOSITION FOR USE WITH LEVODOPA IN PARKINSON'S DISEASE AND METHOD OF

USE

FIELD OF THE INVENTION

[0001] The present disclosure relates to compositions and methods for the treatment of Parkinson's Disease and Parkinsonian related conditions. The present disclosure is more particularly related to controlled-release compositions which enhance the efficacy and reduce the side effects of levodopa in a controlled manner, and methods for using such compositions to promote stable relief from the symptoms of Parkinson disease.

BACKGROUND OF THE INVENTION

[0002] The statements in this section merely provide background information related to the present disclosure and cannot constitute prior art. Parkinson's disease (PD) belongs to a group of conditions called motor system disorders, which are the result of the loss of dopamine-producing brain cells. The four primary symptoms of PD are tremor, or trembling in hands, arms, legs, jaw, and face; rigidity, or stiffness of the limbs and trunk; bradykinesia, or slowness of movement; and postural instability, or impaired balance and coordination. As these symptoms become more pronounced, patients can have difficulty walking, talking, or completing other simple tasks. PD usually affects people over the age of 50. Early symptoms of PD are subtle and occur gradually. In some people the disease progresses more quickly than in others. As the disease progresses, the shaking, or tremor, which affects the majority of PD patients can begin to interfere with daily activities. Other symptoms can include depression and other emotional changes; difficulty in swallowing, chewing, and speaking; urinary problems or constipation; skin problems; and sleep disruptions.

[0003] Currently, the most effective treatment for PD is the combination of levodopa and carbidopa. Carbidopa delays the conversion of levodopa into dopamine until it reaches the brain. Nerve cells can use levodopa to make dopamine and replenish the brain's dwindling supply. The drug levodopa is the standard treatment for Parkinson's disease. However, after four to five years of taking levodopa, more than 75 percent of patients can experience disabling motor fluctuations due to 1) unpredictable changes in drug effectiveness, called the on-off effect; 2) sudden and unpredictable changes in movement, a side-effect called levodopa-induced dyskinesia; and/or 3) decreasing periods of drug effectiveness, called the "wearing off" effect. These complications compromise long-term treatment. Chronic use of levodopa also causes other serious side-effects, including dystonia, drop in blood pressure, hallucinations and nausea. Levodopa and other PD drugs can be used in combination or in series to prevent and/or ameliorate the symptoms of the disease, including administering dopamine agonists, enzyme inhibitors such as catechol-O-methyl transferase inhibitors, and monoamine oxidase type B (MAO-B) inhibitors and other drug classes, for example antivirals.

[0004] Dopamine agonists are a class of drugs that mimic the effect of dopamine in the brain. Dopamine agonists can be used alone in early Parkinson's disease and also in combination with levodopa. Side effects, for example, dyskinesias and dystonias are similar to those of levodopa although this class of drugs is more likely to cause hallucinations and sleepiness. Furthermore, these drugs have no affect on the therapeutic index of levodopa, i.e. the incidence of side-effects that are detrimental to the PD patient increase for a given levodopa dose over the course of treatment.

[0005] Selegiline is a monoamine oxidase type B (MAO-B) inhibitor, often used in conjunction with levodopa to help prevent the breakdown of naturally produced dopamine and the dopamine produced by levodopa. This drug inhibits the enzyme responsible for metabolizing dopamine in the brain. The efficacy of this inhibitor in the treatment of PD is dubious. Although clinicians believed that selegiline retarded the progression of Parkinson's disease, this now appears not to be true.

[0006] Catechol-O-methyltransferase (COMT) inhibitors are used in combination with levodopa to prevent enzymes from breaking down dopamine in the liver and other organs. Research suggests that some of these drugs, such as tolcapone, can cause liver damage and liver failure. As a result, these drugs are used primarily when the patient is not well responding to other treatments, particularly levodopa.

[0007] Amantadine is an antiviral drug that is often used to treat patients with late-stage Parkinson's disease, especially if they are having difficulty controlling involuntary movements caused by levodopa. Side effects can include swollen ankles and a purple mottling of the skin.

[0008] Various pharmacokinetic and pharmacodynamic effects can lead to fluctuations of response to levodopa. These can include factors that affect gastric emptylng such as acidity, anticholinergics and food. Treatment-related changes in the central nervous system can also affect the pharmacodynamics of levodopa. Such factors can include reduced striatal storage of dopamine, damage to dopaminergic neurons by toxic byproducts of dopamine metabolism or altered dopamine receptors. The most frequent fluctuation a PD patient appears to experience is disruption in levodopa activity characterized by shorter periods of therapeutic benefit following each dose of levodopa. 'Wearing-off' is a regular and mostly predictable phenomenon linked with nigro-striatal system degeneration and reflects the extent of nigro-striatal dopamine system loss.

[0009] During the course of disease, PD patients experiencing further neuronal degeneration, and have relatively predictable 'wearing-off fluctuations. Eventually, these fluctuations become less predictable and can progress to the abrupt and unpredictable 'on/off' phenomenon, which is characterized by sudden and unpredictable shifts between the 'on' and 'off states, together with dyskinesias, dystonias and other adverse side effects of levodopa therapy. During this phase, patients undergoing levodopa treatment can display sensory, psychiatric and autonomic symptoms. They can complain of pain, paresthesias, sweating, constipation or shortness of breath, generally during the 'off times. 'On/off' fluctuations appear to be associated with a lowered threshold for dyskinesias. Management of motor fluctuations can involve delicate balancing of levodopa regimen, doses and adjunct drugs.

[0010] Therefore, sustained-release compositions can be preferred, by optimizing the kinetics of delivery, also increase patient compliance as patients are less likely to miss a dose with less frequent administration, particularly when a once- a-day dosage regimen is possible. This is particularly important for the intended patient population experiencing neurological sequelae in. addition to the Parkinsonian symptoms such as poor motor function. Less frequent administration of medication also increases patient convenience. Additionally, sustained-release formulations can reduce overall healthcare costs. Although the initial cost of sustained-release delivery systems may be greater than the costs associated with conventional delivery systems, average costs of extended treatment over time can be lower due to less frequent dosing, enhanced therapeutic benefit, reduced side-effects, and a reduction in the time required to dispense and administer the drug and monitor patient compliance. Accordingly, the present invention provides advantages over the prior art by allowing patients the freedom in taking as many doses of levodopa as needed without having to continuously take D-cycloserine to reduce the levodopa-induced side affects. As discussed below, sustained-release administration of D-cycloserine decreases the risk of toxicity.

[0011] Schneider (U.S. Pat. No. 6,551,993) discuses the use of partial glycine agonists to treat cognitive dysfunction in a subject having schizophrenia or PD by administering a therapeutically effective dose of a partial glycine agonist to the glycine modulatory site of the NMDA receptor. However, there is no disclosure to suggest the use of a partial glycine agonist to reduce the severity or frequency of long- term side effects of levodopa use.

[0012] U.S. Pat. No. 7,160,913 to Schneider proposes the use of a partial glycine agonist to enhance the efficacy and therapeutic index of levodopa, In some compositions, the partial glycine agonist was administered with levodopa in a single composition.

[0013] D-cycloserine and other partial glycine agonists have been shown to reduce the deleterious symptoms of PD while at the same time reducing the frequency and/or severity of levodopa-induced side effects in Parkinson's disease. However, fluctuations in partial glycine agonist dosing, particularly when blood plasma levels spike above 30 μg/mL, can also induce undesirable side effects such as toxicity and worsening of levodopa side effects. A need exists therefore, to provide a therapeutic regimen to maintain the long-duration levodopa response and reduce or avoid the appearance of daily motor fluctuations including dyskinesias due to long term levodopa therapy using partial glycine agonists.

SUMMARY OF THE INVENTION

[0014] There is now provided a pharmaceutical composition for the treatment of Parkinson's disease in a subject, said composition comprising a controlled release formulation having an immediate release component and a sustained release component. The controlled release formulation is adapted to release a partial glycine agonist according to an in vitro release profile when measured in a standard dissolution test apparatus, where the immediate release component is formulated to release 0 to about 30% of the partial glycine agonist in the composition within about 1 hour and the balance of the total amount of the partial glycine agonist in the composition is released from the sustained release component during a second phase having a duration between 12 to about 24 hours. The partial glycine agonist is present in an amount effective when administered once daily to enhance the efficacy of levodopa concomitantly administered or to reduce the frequency or severity of side effects of the levodopa. The controlled release formulation includes one or more pharmaceutically acceptable excipients.

[0015] In one embodiment, the composition can comprise a controlled release formulation comprising a partial glycine agonist, a sustained release component, and at least one pharmaceutically acceptable excipient. The composition, upon initial administration of one dose, provides a mean plasma concentration of the partial glycine agonist of at least 10 μg/mL and not more than 30 μg/mL within one hour of administration and continues to provide a mean plasma concentration of the partial glycine agonist of not more than 30 μg/mL for 12 - 24 hours. The partial glycine agonist is present in the composition in an amount effective to produce a partial glycine agonist concentration in the brain of a subject at which the partial glycine agonist antagonizes the glycine binding site of the NMDA receptor for at least 12 to about 24 hours.

[0016] There is further provided a method for treating a subject for treating Parkinson's disease in comprising administering levodopa to the patient at least once per day; and administering to the subject a once daily composition comprising a partial glycine agonist, formulated to provide a release profile, such that sufficient partial glycine agonist is delivered to the brain of the subject to enhance efficiency or reduce the side effects of each levodopa dose administered together with or separately for at least 18 hours to about 24 hours after administration of the partial glycine agonist.

[0017] There is still further provided a kit comprising a partial glycine agonist in a controlled release formulation, and instructions for administering a high dose of a partial glycine agonist to a subject for the treatment of Parkinson's disease.

[0018] Further areas of applicability will become apparent from the description provided herein. It should be understood that the description and specific examples are intended for purposes of illustration only and are not intended to limit the scope of the present disclosure.

DETAILED DESCRIPTION

[0019] The present invention provides methods and pharmaceutical compositions for reducing the severity or frequency of levodopa side effects with a once daily composition in patients with Parkinson's disease.

[0020] It has now been found that administering a controlled dose of a partial glycine agonist to subjects undergoing levodopa therapy enhances the duration of effect of levodopa (i.e., prevents the "wearing off" phenomenon), provides a greater therapeutic effect than levodopa alone, and decreases the severity and frequency of side effects that result from long-term use oflevodopa. Treatment of PD patients with a high dose of a partial glycine agonist and levodopa also allows for a decrease in levodopa dosage, which helps delay the wearing-off effect and decreases levodopa-induced side effects as shown by Schneider, J., U.S. Pat. No. 7,160,913, which is incorporated by reference herein.

[0021] Partial glycine agonists acting as antagonists also decrease neuronal excitotoxicity caused by excessive glutamate neurotransmission in the Parkinsonian brain. Decreasing neuronal excitotoxicity has antidepressant and anxiolytic effects, and can also have a positive effect on certain types of cognitive disorders. Depression and anxiety are common complications in subjects with PD. Thus, treatment of these complications is an added advantage to the administration of a partial glycine agonist with levodopa.

[0022] More particularly, methods of the invention are useful in the treatment of PD and Parkinsonian like disorders, wherein the subject in need of such treatment has been prescribed with a therapeutic formulation of levodopa, for example, an immediate release form oflevodopa which is taken three or more times a day. A subject suffering from PD can therefore be treated with levodopa and a once daily formulation of a controlled release form of a partial glycine agonist. Partial glycine agonists are known to those skilled in the art, and include D-cycloserine, 1- aminocyclopropaneearboxylic acid (ACPC) and (+)-3-Amino-1-hydroxypyrrolidin-2- one. As used herein, a partial glycine agonist also includes substances which convert other substances into a partial glycine agonist in the body. A preferred partial glycine agonist is D-cycloserine. [0023] In some embodiments, PD and related levodopa treatment side effects can be modulated by one or more partial glycine agonists formulated in a controlled release formulation, when administered in conjunction with levodopa, either in the same composition or when administered separately. Providing a therapeutic and effective dose of a partial glycine agonist also reduces the possibility of partial glycine agonist toxicity and insufficient dosing levels when compared to immediate release, multi dose regimens.

[0024] The terms "treat", "treating" and "treatment" herein will be understood, except where the context demands otherwise, to encompass prophylactic administration to a patient experiencing symptoms of PD and which is undergoing levodopa therapy for the daily relief of PD symptoms and the frequency or severity of the side effects of levodopa therapy.

[0025] As used herein, an effective dose of a controlled release partial glycine agonist is a dose which produces a partial glycine agonist concentration in the brain of a subject at which the partial glycine agonist antagonizes the glycine binding site of the NMDA receptor or acts as a functional antagonist at the NMDA receptor. Preferably, a controlled release dose of a partial glycine agonist can be greater than 1 mg/kg body weight of the subject to be treated, for example at least 1 mg/kg, at least 2 mg/kg, at least 3 mg/kg, at least 4 mg/kg, at least 5 mg/kg, at least 6 mg/kg, at least 7 mg/kg or at least 8 mg/kg partial glycine agonist made bioavailable over a period of from about 12 to 24 hours. Preferably, at least 8 mg/kg partial glycine agonist is administered to the subject per unit dose, for example 1 to 12 mg/kg partial glycine agonist per unit dose made bioavailable over a period of from about 12 to 24 hours. In some embodiments, the dose administered is one that is sufficient to maintain plasma levels between about 10 μg/mL and about 30 μg/ml for a period of 8 hours, for 12 hours, for 13 hours, for 14 hours, for 15 hours, for 16 hours, for 18 hours and not more than 24 hours.

[0026] As used herein, a "subject" is any mammal suffering from PD or exhibiting symptoms of PD. A subject can be a primate (e.g., human or macaque) or a rodent (e.g., mouse, rat or guinea pig), but most typically is a human subject. One skilled in the art can readily determine if a subject is suffering from PD or exhibiting PD symptoms by performing a standard clinical or neurological assessment; for example, by using the Unified Parkinson's Disease Rating Scale (UPDRS).

[0027] As used herein, "Parkinson's disease" or "PD" includes PD of any etiology, including idiopathic PD, postencephalitic PD, PD resulting from chronic manganese poisoning or carbon monoxide poisoning, parkinsonism-dementia of Guam and hemiparkinsonism. PD also includes any neurological syndrome of undetermined etiology which a subject presents with neurological symptoms associated with a decrease in dopamine production or dopaminergic transmission in the brain.

[0028] The composition to be used according to the present method has specific requirements with respect to its partial glycine agonist release properties. These properties can be defined in part by pharmacokinetic data for the controlled release composition comprising a partial glycine agonist that can be obtained experimentally, for example, from a statistically relevant number of test subjects according to pre-established and accepted pharmacokinetic protocol. The test subjects herein can be of the same species as the patients, i.e. a human, preferably adult, and preferably including a significant number of test subjects that are representative of the patients currently being treated for PD. The protocol can involve a single dose or once daily dosing for several days, usually at least 3-7 days. A dose, unit dosage, or doses used to provide pharmacokinetic data in test subjects should be similar to the once daily dose desired to be administered to the patient By "similar" in the present context is meant equivalent, or sufficiently close that, by reasonable interpolation or extrapolation from the data, pharmacokinetic properties for the desired dose can be reasonable estimated.

[0029] It is preferred mat the composition, following single dose administration of 1 to 12 mg/kg D-cycloserine or a therapeutically equivalent dose of a partial glycine agonist other than D-cycloserine per kg body weight, exhibit a maximum plasma concentration (C_max) of a partial glycine agonist that is not greater than about 30 μg/ml. It is especially preferred that the composition exhibit a pharmacokinetic profile consistent with steady-state plasma concentrations having a fluctuation ratio that is not substantially greater than that of the immediate release formulation of partial glycine agonist. Fluctuation ratio (FR) is defined by the following equation: FR=(C_max-C_min)/C_avg, where C_max, C_min and C_avg are maximum, minimum and average plasma concentrations respectively.

[0030] A composition having the in vitro release and/or in vivo pharmacokinetic parameters specified above is advantageous in having reduced potential to cause undesirable side effects related to partial glycine agonist toxicity that may be related to a combination of high C_max and short T_max, by comparison with other once-daily dosage forms. Preferably, the incidence of side effects is no greater than with an immediate-release dosage form of a partial glycine agonist formulation administered in conjunction with levodopa in a three-five times daily regimen. More preferably, the incidence of levodopa use side effects is even lower than with such an immediate-release partial glycine agonist regimen. It is contemplated that these advantages become more pronounced with increase in daily dosage. In some embodiments, the partial glycine agonist release profile provides sufficient partial glycine agonist in the brain of the subject to enhance efficacy or reduce the side effects of each levodopa dose concomitantly administered together with or separately of the partial glycine agonist for at least 18 to about 24 hours.

[0031] In some embodiments, the composition administered to PD subjects according to the present method provides a 8-24 hour profile of plasma partial glycine agonist concentration, averaged over the test subjects, that does not substantially exceed 30 μg/mL and does not substantially fall below about 10 μg/mL. It is an objective of the present invention to provide an effective dose of partial glycine agonist during the waking hours of the patient concurrently with levodopa administration. The plasma concentration of the partial glycine agonist during the patient's sleeping hours may deviate from the therapeutic range of approximately 10 μg/mL to 30 μg/mL.

[0032] In some embodiments, the plasma partial glycine agonist concentration neither substantially nor protractedly falls below about 1, about 5, about 7, about 9, or about 10 μg/ml. In various embodiments, the plasma partial glycine agonist concentration neither substantially nor appreciably exceeds about 40, about 37, about 35 or about 30 μg/ml. With respect to the terms "substantially" and "appreciably" in the present context, the following situations are illustrative. A concentration that is within about 20%, for example within about 20%, below a stated minimum or above a stated maximum is considered not to "substantially" fall below or exceed the stated minimum or maximum respectively. A concentration that temporarily falls below a stated minimum or exceeds a stated maximum for a period of less than about 2 hours, for example less than about 1 hour, is considered not to "appreciably" fail below or exceed the stated minimum or maximum respectively. [0033] In one particular embodiment, the plasma partial glycine agonist concentration, averaged over the test subjects, does not substantially or appreciably fall below about 10 μg/mL and does not substantially or appreciably exceed about 30 μg/mL.

[0034] In some embodiments, the present invention illustratively provides examples of partial glycine agonist release from a controlled release formulation as measured in a standard in vitro dissolution test. The present invention is designed to be formulated with a specific pharmacokinetic profile wherein, with once daily administration of a controlled release formulation of a partial glycine agonist, plasma concentrations of the aforementioned agonist can remain within a narrow window as described above.

For example, the composition will typically be formulated wherein the release of a partial glycine agonist in an effective dose is still occurring at least about 8 hours, for example at least about 10 hours, at least about 12 hours, at least about 14 hours, at. least about 16 hours, at least about 18 hours, at least about 20 hours, at least about 22 hours, or at least about 24 hours. In some embodiments the pharmaceutical composition upon initial administration of one dose, provides in the subject a mean plasma concentration of the partial glycine agonist of at least 10 μg/mL and not more than 30 μg/mL within one hour of administration and continues to provide a mean plasma concentration of the partial glycine agonist of not more than 30 μg/mL for 12 - 24 hours. The partial glycine agonist can be present in an amount effective to produce a partial glycine agonist concentration in fee brain of a subject at which the partial glycine agonist antagonizes the glycine binding site or acts as a functional antagonist of the NMDA receptor for at least 12 -24 hours. [0035] Such a release profile is an example of a sustained profile or extended release profile. The terms "extended release", "immediate release", etc., have their commonly accepted meanings used in the field of pharmacy and pharmacokinetics. The kinetics of the extended release can be influenced by the choice of the delivery system, amount of the active ingredient, dissolution rate of the drug, compartment in which release occurs (e.g., with oral delivery systems, this is the gastrointestinal tract), absorption of drug from the site of release into the systemic circulation, drug distribution from the systemic circulation, etc.

[0036] In an illustrative example, a once daily pharmaceutical composition can comprise a partial glycine agonist, wherein the composition also includes a controlled release matrix or coating portion comprising a partial glycine agonist, a sustained release carrier, and at least one pharmaceutically acceptable excipient. The composition upon initial administration of one dose can provide a mean plasma concentration of the partial glycine agonist of at least 10 μg/mL and not more than 30 μg/mL within one hour of administration and continues to provide a mean plasma concentration of Hie partial glycine agonist of not more than 30 μg/mL for 12 - 18 hours. The partial glycine agonist is present and upon release, the partial glycine agonist dose effective to enhance the efficacy of the levodopa or to reduce the frequency or severity of side effects of the levodopa.

Pharmaceutical Compositions

[0037] In some embodiments, a once daily pharmaceutical composition for the treatment of PD in a patient is provided. The pharmaceutical composition for the treatment of Parkinson's disease in a subject comprises a controlled release formulation having an immediate release component and a sustained release component. The formulation is adapted to release a partial glycine agonist according to an in vitro release profile when measured in a standard dissolution test apparatus, i.e. in a U.S.P. type I dissolution apparatus in an acidic pH medium at 100 r.p.m., 37°C, where the immediate release component is formulated to release 0 to about 30% of the partial glycine agonist in the composition within about 1 hour and the balance of the total amount of the partial glycine agonist in the composition is released from said sustained release component during a second phase having a duration between 12 to about 24 hours. The partial glycine agonist can be present in an amount effective when administered once daily to enhance the efficacy of levodopa concomitantly administered with or separately or to reduce the frequency or severity of side effects of the levodopa.

[0038] In some embodiments, the controlled release formulation can include one or more pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition can also contain one or more excipients which can include one or more of carriers, wetting agents, emulsifiers, lubricants, coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidant and mixtures or combinations thereof.

[0039] In some embodiments, a controlled release formulation can comprise a partial glycine agonist, a sustained release component, and at least one pharmaceutically acceptable excipient The composition upon initial administration of one dose can provide a mean plasma concentration of the partial glycine agonist of at least 10 μg/mL and not more than 30 μg/mL within one hour of administration and continues to provide a mean plasma concentration of the partial glycine agonist of not more than 30 μg/mL for 12 - 24 hours. The partial glycine agonist dose present in the composition, when released in the subject, can provide an amount effective to produce a partial glycine agonist concentration in the brain of a subject at which the partial glycine agonist antagonizes the glycine binding site of the NMDA receptor or acts as a functional antagonist of the NMDA receptor for at least 12, or about 14, or about 16, or about 18, or about 20, or about 22, or about 24 hours. In some embodiments, the partial glycine agonist is present in a dose that when made bioavailable in the subject, is effective to enhance the efficacy of the levodopa or to reduce the frequency or severity of side effects of the levodopa.

[0040] In some embodiments, the controlled release partial glycine agonist can be administered in conjunction with levodopa, and can be administered together with the partial glycine agonist or taken separately. The controlled release partial glycine agonist can be taken at the same time as the levodopa or before taking levodopa. In some embodiments, the levodopa can be ingested 1 hour, 2 hours, 3 hours or up to 4 hours after the administration of the controlled release partial glycine agonist. In the practice of the present method, the levodopa and partial glycine agonist can optionally be administered with a peripheral dopa decarboxylase inhibitor, such as carbidopa or benserazide. One skilled in the art can readily determine the amount of peripheral dopa decarboxylase inhibitor to be administered to a subject. In general, 10 mg of carbidopa or 15 mg of benserazide can be given 2-3 times daily with levodopa to the average adult human. Carbidopa or benserazide dosage can be adjusted upward daily until the desired effect is seen. Combined carbidopa/levodopa formulations are available commercially, for example, from Bristol Meyers Squibb Co,, Princeton, N.J., as SinemetRTM.

[0041] In another aspect, the present disclosure provides pharmaceutically acceptable compositions which comprise a therapeutically-effective amount of a partial glycine agonist described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents. As described in detail below, the controlled release pharmaceutical compositions of the present invention may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e. g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension of sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; sublingual; ocular; transdermal; or nasal.

[0042] In some embodiments, the compositions of the present invention comprise one or more controlled release components. In some embodiments, the controlled release properties exhibit an extended or sustained release pharmacokinetic profile. In some embodiments, the compositions may contain one or more controlled release materials, illustratively selected from two formulation components having different release characteristics. Thus a composition can comprise a first formulation component comprising a partial glycine agonist exhibiting a first release profile and a second formulation component comprising the same or different partial glycine agonist exhibiting a second release profile. Illustratively, the first release profile can be an immediate release profile and the second release profile can be an extended or sustained release profile.

[0043] The preparation of controlled release formulations and components are well known within the art. U.S. Patent Nos. 2005/0175691, 2004/0242640, 2003/0219488 and WO 2005/097191 describe exemplary formulations useful for preparing controlled release formulations of the present invention and are each incorporated by reference herein. In some embodiments, the composition comprises a partial glycine agonist, a sustained release component, and at least one pharmaceutically acceptable excipient, wherein the composition upon initial administration of one dose provides a mean plasma concentration of the partial glycine agonist of at least 10 μg/mL and not more than 30 μg/mL within one hour of administration and continues to provide a mean plasma concentration of the partial glycine agonist of not more than 30 μg/mL for at least 12 hours to about 24 hours. The partial glycine agonist is present in the pharmaceutical composition in a dose effective to enhance the efficacy of the levodopa or to reduce the frequency or severity of side effects of the levodopa in a Parkinson's subject treated with levodopa.

[0044] In the case of a discrete solid dosage formulation, the immediate and sustained release components can be more or less intimately co-mixed or blended, or alternatively can form spatially distinct zones of the dosage form.

[0045] An illustrative composition has spatially distinct zones comprising a core and a mantle surrounding the core. In such a composition, the mantle can comprise a partial glycine agonist exhibiting an immediate release profile and the core can comprise the same or different partial glycine agonist exhibiting a sustained release profile.

[0046] Another illustrative composition has spatially distinct zones comprising at least two layers. An example of such a composition is a bilayer tablet, wherein one layer, an immediate release component, can comprise a partial glycine agonist exhibiting an immediate release profile and the other sustained release component layer comprises the same or different partial glycine agonist exhibiting an sustained release profile. [0047] In one embodiment, the composition comprises an immediate release and sustained release formulation components as described above, which comprise particles of a first and second kind respectively. For example, the particles of the first kind can exhibit an immediate release profile and the particles of the second kind can exhibit a sustained release profile. Illustratively, the particles of the second kind comprise a core comprising the partial glycine agonist and a sustained and/or delayed release coating comprising the same or different partial glycine agonist surrounding the core.

[0048] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0049] The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, manufacturing aid (e. g., lubricant, talc magnesium, calcium or zinc stearate, or steric acid), or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other components and agents of the formulation and not deleterious to the patient after administration. In some illustratively examples, pharmaceutically-acceptable carriers can include: sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; any polyol, such as, but not limited to, glycerin, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffering agents, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; (19) ethyl alcohol; pH buffered solutions; polyesters, polycarbonates and/or polyanhydrides; and other non-toxic compatible substances employed in pharmaceutical formulations.

[0050] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0051] Examples of pharmaceutically-acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. In some embodiments, a formulation of the present disclosure comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e. g., bile acids, and polymeric carriers, e. g., polyesters and polyanhydrides. In some embodiments, an aforementioned formulation renders orally bioavailable a compound of the present disclosure. [0052] Methods of preparing these formulations or compositions include the step of bringing into association one or more partial glycine agonists with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and mixing with a partial glycine agonist with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product Formulations of the disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges, powders, granules, or as a solution or a suspension in an aqueous or non- aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) each containing an effective amount of a partial glycine agonist as an active ingredient. A controlled release partial glycine agonist formulation of the present disclosure may also be administered as a bolus, electuary or paste.

[0053] In solid dosage forms of the disclosure for oral administration (capsules, tablets, pills, dragees, powders, granules, trouches and the like), the partial glycine agonist is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; humectants, such as glycerol; disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarding agents, such as glycerol and paraffin; absorption accelerators, such as quaternary ammonium compounds and surfactants, such as poloxamer and sodium lauryl sulfate; wetting agents, such as, for example, cetyl alcohol, glycerol monostearate, and non-ionic surfactants; lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid; coloring agents; and controlled release agents such as crospovidone or ethyl cellulose. In the case of capsules, tablets and pills, the pharmaceutical compositions can also comprise buffering agents. Solid compositions of controlled release partial glycine agonist formulations can also be used as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0054] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0055] The tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention, such as capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. In some embodiments, the present controlled release pharmaceutical compositions can be formulated so as to provide immediate, sustained, delayed, pulsed, biphasic release of a partial glycine agonist using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. The compositions may be prepared for immediate release, e.g., freeze-dried. In some embodiments, the compositions can be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use. The compositions can also optionally contain opacifying agents and may be of a composition that they release the partial glycine agonist or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. The partial glycine agonist can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0056] The compositions intended for oral use can be prepared according to any method commonly known in the art. The pharmaceutical compositions of the present disclosure can contain one or more agents selected from the group consisting non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. Such excipients include, for example, an inert diluent such as lactose; granulating and disintegrating agents such as cornstarch; binding agents such as starch; and lubricating agents such as magnesium stearate. The tablets may be uncoated or they may be coated by known techniques for elegance or to delay release of the active ingredients. Formulations for oral use may also be presented as hard gelatin capsules wherein the partial glycine agonist is mixed with an inert diluent and a controlled and/or immediate release matrix or coating.

Liquid Formulations

[0057] Liquid dosage forms for oral administration of the compounds of the disclosure can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0058] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0059] Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The partial glycine agonist can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellents which may be required.

[0060] The ointments, pastes, creams and gels may contain, in addition to an active compound of this disclosure, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0061] Powders and sprays can contain, in addition to a compound of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstitutεd hydrocarbons, such as butane and propane.

[0062] Transdermal patches have the added advantage of providing controlled delivery of a partial glycine agonist of the present disclosure to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

[0063] Pharmaceutical compositions of the present disclosure can be suitable for parenteral administration comprising a partial glycine agonist in a controlled release formulation in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0064] One skilled in the art can readily prepare pharmaceutical compositions comprising a partial glycine agonist, for example by using the principles set forth in Remington's Pharmaceutical Science, 18th Edition (Alphonso Gennaro, ed.), Mack Publishing Co., Easton, Pa, 1990. Preferred pharmaceutical compositions of the present disclosure comprise a partial glycine agonist in a controlled release form.

[0065] The compositions of the present disclosure may be given enterally, illustratively orally, parenterally, topically, or rectally. They are of course provided in forms suitable for each administration route. For example, they can be administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[0066] These the controlled release formulation of a partial glycine agonist may be administered to humans and other animals, including rats, mice, rabbits , dogs, cats, non-human primates, and monkeys for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually. Regardless of the route of administration selected, the compounds of the present disclosure, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present disclosure, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.

[0067] In general, a suitable daily dose of a partial glycine agonist contained within a controlled release formulation will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect i.e. a dose which produces a partial glycine agonist concentration in the brain of a subject at which the partial glycine agonist antagonizes the glycine binding site of the NMDA receptor. In some embodiments, an effective dose can be a dose of a partial glycine agonist wherein the plasma levels of the partial glycine agonist in the patient is between about lOμg/raL and about 30 μg/mL for at least about 12 hours to at least about 24 hours. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous, and subcutaneous doses of the controlled release partial glycine agonist of the present disclosure for a patient, when used for the desired thereapeutic effects, will range from about 1 to about 12 mg per kilogram of body weight per dose of D-cycloserine or a therapeutically equivalent amount of partial glycine agonist other than D-cycloserine. In some embodiments, the dosage of partial glycine agonist can be about 1 mg to about 12 mg of D-cycloserine per kg body weight of the subject per dose or equivalents thereof.

[0068] In some embodiments, the once daily pharmaceutical composition containing the controlled release partial glycine agonist formulation can be concomitantly administered with at least one dose of levodopa. In some embodiments, the effective daily dose of levodopa may be administered as two, three, four, or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing for the levodopa is one or more administrations per day, optionally in combination with carbidopa and/or a peripheral dopa carboxylase such as benserazide.

In some embodiments, the present disclosure provides pharmaceutically acceptable compositions which comprise a controlled release formulation adapted to release a partial glycine agonist according to a single sustained release profile or a dual profile having two different release component phases of dissolution when measured in a U.S.P. type I dissolution apparatus in an acidic pH medium at 100 r.p.m., 37°C, where the immediate release component is formulated to release 0 to about 30% of the partial glycine agonist in the composition within about 1 hour and the balance of the total amount of the partial glycine agonist in the composition is released from the sustained release component during a second phase having a duration between 12 to about 24 hours;

[0069] The partial glycine agonist is administered in a dose effective to enhance the efficacy of levodopa or to reduce the frequency or severity of side effects of the levodopa,

[0070] In some embodiments a method is provided for treating Parkinson's disease in a patient comprising: administering levodopa to the patient at least once per day; and administering to the patient a once daily composition comprising a single unit dose partial glycine agonist, formulated to provide a release profile wherein sufficient partial glycine agonist is delivered to the brain of the subject to enhance efficiency or reduce the side effects of each levodopa dose administered together with or separately for up to 18 hours after administration of the partial glycine agonist.

[0071] Increasing the duration of effect of a levodopa dose with a therapeutic dose of a controlled release partial glycine agonist allows one to give fewer levodopa doses, avoid side effects, reduce the severity of the side effects of levodopa, or to reduce the levodopa standard dose, but still achieve the same therapeutic effect. This is particularly advantageous, because giving fewer or reduced levodopa doses to a subject with PD delays the point at which levodopa becomes ineffective.

[0072] Administering a pharmaceutical composition comprising a controlled release formulation of partial glycine agonist also reduces the frequency or severity of levodopa-induced side effects, such as dyskinesias and dystonias. [0073] One skilled in the art can readily determine whether the frequency or severity of levodopa-induced dyskinesias is reduced by using any suitable technique for the clinical assessment of involuntary movements in subjects with PD. For example, the frequency and severity of levodopa-induced dyskinesias can be assessed using the Abnormal Involuntary Movement Scale (AIMS) or similar rating of dyskinesia.

[0074] For example, assessment of subjects undergoing levodopa therapy with high dose partial glycine agonist are subjected to a six-week trial. During the trial, subjects fill out a detailed diary with regard to the frequency or duration of dyskinesias and severity of any dyskinesias and assess daily function according to the following scales: Dyskinesia Intensity: 0-without dyskinesia; 1-mild dyskinesia; 2- medium dyskinesia; 3-severe dyskinesia. Rating of Daily Function: 1-improvement of daily function as compared to the basic condition; 2-no improvement in daily function; 3-deterioration of daily function as compared to the basic condition.

[007S] A reduction in the daily AIMS scores duration of dyskinseias during the course of the trial indicates that the frequency and severity of dyskinesias are being reduced. Alternatively, AIMS scores obtained after administration of levodopa and high dose partial glycine agonist to a subject can be compared to AIMS (or similar test) scores obtained for the subject prior to treatment with high dose partial glycine agonist.

[0076] One skilled in the art can also readily determine whether the frequency or severity of levodopa-induced dystonias is reduced by using any suitable technique for the clinical assessment of involuntary, sustained muscle contraction in subjects with PD. For example, frequency or severity of dystonias can be determined by clinical observation of the subject, including reflex studies, or by techniques such as electromyography (EMG) or nerve conduction velocity tests.

[0077] The present disclosure also provides a method for increasing the therapeutic index of levodopa in a subject being treated for Parkinson's disease, comprising administering levodopa and a pharmaceutical composition comprising a controlled release formulation comprising partial glycine agonist in an effective dose to the subject.

[0078] As used herein, "therapeutic index" refers to a quantitative measure of the selectivity of a drug when a therapeutic effect ("E") and a toxic effect ("T") are being compared. The therapeutic index can then be calculated as ED₅₀/TD₅₀, at some arbitrary level of response observed in a subject receiving the drug. The ED₅₀ is the dose required to generate the desired intensity of therapeutic effect in 50% of the subjects tested. The TD₅₀ is the dose required to generate the toxic effect in 50% of the subjects tested.

[0079] The therapeutic index is a useful indicator of the benefit versus adverse effect of a drug. Those drugs which have a high therapeutic index can be administered over a wide range of effective doses without incurring significant adverse events. Conversely, drugs having a small therapeutic index can be administered over a small range of effective doses without incurring significant adverse events. The therapeutic index of levodopa lessens over time with chronic administration.

[0080] As discussed above, a pharmaceutical composition comprising a controlled release formulation of partial glycine agonist can increase the efficacy of levodopa while also reducing toxic side effects. Thus, the therapeutic index of levodopa is increased by administration of a controlled release dose of a partial glycine agonist over a period of 12 to about 24 hours. As discussed above, techniques for determining whether the efficacy of levodopa has increased, and whether toxic side effects of levodopa have been reduced, are within the skill in the art. Suitable effective doses of the partial glycine agonist and suitable routes of administration are as described above.

[0081] Substances which inhibit peripheral dopa decarboxylase (e.g., carbidopa or benserazide) can also be administered to the subject with levodopa in order to increase the therapeutic index of levodopa.

[0082] In another embodiment, the present disclosure provides a method of treating PD in a subject, comprising administering to a subject in need of such treatment a partial glycine agonist in a controlled release formulation having an immediate release component and a sustained release component. Without wishing to be bound by theory, it is believed that altered NMDA receptor transmission can be involved in abnormal basal ganglia activity in PD and is involved in levodopa-related treatment complications such as wearing off and dyskinesia. Partial glycine agonists acting as non-selective antagonists of the NMDA receptor can correct this altered NMDA receptor transmission. Suitable and effective doses of the partial glycine agonist and suitable routes of administration are as described above.

[0083] The present disclosure also provides a kit comprising a controlled release formulation comprising a partial glycine agonist and instructions for administering a sustained release or biphasic release profile of the partial glycine agonist to a subject suffering from PD. The instructions can specify mat the partial glycine agonist is administered with or without levodopa. Preferably, the instructions specify that the partial glycine agonist is administered with levodopa, and that more than one dose of levodopa per day is required to maintain thereapeutic benefit of the levodopa. The instructions can also specify that the partial glycine agonist can. be administered with a peripheral dopa decarboxylase inhibitor such as carbidopa or benserazide.

[0084] In one embodiment, the kit further comprises levodopa. in another embodiment, the kit further comprises levodopa and a peripheral dopa decarboxylase inhibitor. Preferably, the kit comprises a controlled release formulation comprising partial glycine agonist and levodopa in separate pharmaceutical compositions, in which the amount of partial glycine agonist is sufficient to sustain a plasma level of 10, 15, 20, 25, or 30 μg/mL partial glycine agonist while the patient is awake for at least 12 hours but no more than 16 hours within a 24 hour period. For example, the single-dose pharmaceutical composition can deliver at least 1 mg/kg, at least 2 mg/kg, at least 3 mg/kg, at least 4 mg/kg, at least 5 mg/kg, at least 6 mg/kg, at least 7 mg/kg or at least 8 mg/kg, for example 8 to 12 mg/kg, partial glycine agonist to the subject over a period of at least 12 hours and generally no more than 24 hours maintaining the plasma concentration of partial glycine agonist in the subject constant or in a dual (immediate and sustained) release profile wherein there is a spike in the concentration of the partial glycine agonist wherein 0-30 % of the total dose of the partial glycine agonist is released in the first 60 minutes and the balance of the total partial glycine agonist present is released in a constant and sustained fashion over a period of 11 to 23 hours.

[0085] Additional embodiments, as well as features, benefits and advantages, of the present invention will be apparent to those skilled in the art, taking into account the foregoing description of preferred embodiments of the invention. It is therefore to be appreciated that the present invention is not to be construed as being ion any way limited by the foregoing description of such preferred embodiments, but that various changes and modifications can be made to the invention as specifically described herein, and that all such changes and modifications are intended to be within the scope of the present invention.

Claims

What is claimed is:

1. A pharmaceutical composition for the treatment of Parkinson's disease in a subject said composition comprising: a controlled release formulation having an immediate release component and a sustained release component, said formulation is adapted to release a partial glycine agonist according to an in vitro release profile when measured in a standard dissolution test apparatus, where said immediate release component is formulated to release 0 to about 30% of the partial glycine agonist in the composition within about 1 hour and the balance of the total amount of the partial glycine agonist in the composition is released from said sustained release component during a second phase having a duration between 12 to about 24 hours, wherein the partial glycine agonist is present in an amount effective when administered once daily to enhance the efficacy of levodopa concomitantly administered or to reduce the frequency or severity of side effects of the levodopa; said controlled release formulation further comprising one or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition of claim 1, wherein the partial glycine agonist is selected from the group consisting of D-cycloserine, 1- aminocyclopropanecarboxylic acid and (+)-3-Amino-1-hydroxypyrrolidin-2-one.

3. The pharmaceutical composition of claim 2, wherein the partial glycine agonist is D-cycloserine.

4. The pharmaceutical composition of claim 1, wherein the effective dose of the partial glycine agonist is sufficient to deliver greater than about 1 mg to about 12 mg of partial glycine agonist per kg body weight of the subject.

5. The pharmaceutical composition of claim 4, wherein the effective dose of partial glycine agonist administered is sufficient to maintain the subject with a blood plasma level of more than 10 μg/mL and less than 30 μg/mL over a 18 hour period.

6. The pharmaceutical composition of claim 4, wherein the effective dose of a controlled release partial glycine agonist is a dose which produces a partial glycine agonist concentration in the brain of a subject at which the partial glycine agonist antagonizes the glycine binding site of the NMDA receptor or acts as a functional antagonist of the NMDA receptor.

7. The pharmaceutical composition of claim 5, wherein the 18 hour period comprises a period during which the subject is awake.

8. The pharmaceutical composition of claim 1, wherein the composition is formulated for enteral or parenteral administration, said composition is selected from the group consisting of an aqueous or oily suspension, emulsions, microemulsions, suspensions, tablet, gel capsule, dispersible powders or granules, emulsions, hard or soft capsules, syrups, eleixirs, suppositories, liposome preparation, microencapsulation preparation, transdermal patch and sprays.

9. The pharmaceutical composition of claim 1 , wherein the composition includes one or more excipients selected from the group consisting of carriers, wetting agents, emulsifiers, lubricants, coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants and combinations thereof.

10. A pharmaceutical composition for the treatment of Parkinson's disease, said composition comprising: a controlled release formulation comprising a partial glycine agonist, a sustained release component, and at least one pharmaceutically acceptable excipient, wherein the composition upon initial administration of one dose provides a mean plasma concentration of the partial glycine agonist of at least 10 μg/mL and not more than 30 μg/mL within one hour of administration and continues to provide a mean plasma concentration of the partial glycine agonist of not more than 30 μg/mL for 12 through 24 hours, the partial glycine agonist is present in an amount effective to produce a partial glycine agonist concentration in the brain of a subject at which the partial glycine agonist antagonizes the glycine binding site of the NMDA receptor for at least 12 through 24 hours.

11. The pharmaceutical composition of claim 10, wherein the partial glycine agonist is selected from the group consisting of D-cycloserine, 1- aminocyclopropanecarboxylic acid and (+)-3-Amino-1-hydroxypyrrolidin-2-one.

12. The pharmaceutical composition of claim 11, wherein the partial glycine agonist is D-cycloserine.

13. The pharmaceutical composition of claim 10, wherein the amount of the partial glycine agonist is sufficient to deliver a unit dose greater than about 1 mg/kg to about 12 mg/kg of D-cycloserine or a therapeutically equivalent unit dose of a partial glycine agonist other than D-cycloserine per kg body weight of the subject.

14. The pharmaceutical composition of claim 13, wherein the amount of partial glycine agonist present in said composition is sufficient to maintain the subject with a blood plasma level of more than 10 μg/mL and less than 30 μg/mL over a 24 hour period.

15. The pharmaceutical composition of claim 14, wherein the 24 hour period comprises a period during which the subject is awake.

16. The pharmaceutical composition of claim 10, wherein the composition is formulated for enteral or parenteral administration, said composition is selected from the group consisting of an aqueous or oily suspension, tablet, gel capsule, dispersible powders or granules, emulsions, hard or soft capsules, syrups, eleixirs, suppositories, liposome preparation, microencapsulation preparation, transdermal patch and sprays.

17. The pharmaceutical composition of claim 1, wherein the composition further comprises one or more agents selected from the group consisting of carriers, wetting agents, emulsifiers, lubricants, coloring agents, release agents, coating agents, sweetening, flavoring arid perfuming agents, preservatives and antioxidants and combinations thereof.

18. A method for treating Parkinson's disease in a subject comprising;

(a) administering levodopa to the patient at least once per day; and

(b) administering to the subject a once daily composition comprising a partial glycine agonist, formulated to provide a release profile wherein sufficient partial glycine agonist is delivered to the brain of the subject to enhance efficiency or reduce the side effects of each levodopa dose concomitantly administered together with or separately for at least 18 to about 24 hours after administration of the partial glycine agonist.

19. The method of claim 18, wherein the partial glycine agonist is selected from the group consisting of D-cycloserine, 1-aminocyclopropanecarboxylic acid and (+)- 3-Amino-1-hydroxypyrrolidin-2-one.

20. The method of claim 19, wherein the partial glycine agonist is D-cycloserine.

21. The method of claim 18, further comprising administering a peripheral dopa decarboxylase inhibitor to the subject.

22. The method of claim 18, wherein the levodopa or partial glycine agonist is administered enterally.

23. The method of claim 18, wherein the levodopa or partial glycine agonist is administered parentally.

24. The method of claim 18, wherein the dose is sufficient to deliver greater than about 1 mg to about 12 mg of partial glycine agonist per kg body weight of the subject.

25. The method of claim 18, wherein the levodopa side effects are dyskinesias, dystonias, deterioration of daily function, depression, and anxiety.

26. The method of claim 18, wherein the subject is selected from the group consisting of humans, non-human primates, monkeys and rodents.

27. The method of claim 27, wherein the subject is human.

28. A kit comprising: a partial glycine agonist in a controlled release formulation; and instructions for administering a high dose of a partial glycine agonist to a subject for the treatment of Parkinson's disease.

29. The kit of claim 29, further comprising instructions for administering the partial glycine agonist in combination with levodopa for the treatment of Parkinson's disease.

30. The kit of claim 28, wherein the kit further comprises levodopa.

31. The kit of claim 28, wherein the partial glycine agonist is selected from the group consisting of D-cycloserine, 1-aminocyclopropanecarboxylic acid and (+)-3- Amino-1-hydroxypyrrolidin-2-one.

32. The kit of claim 28, further comprising a peripheral dopa decarboxylase inhibitor.

33. The kit of claim 32, wherein the peripheral dopa decarboxylase inhibitor is carbidopa or benserazide.