Levodopa dosing regimen

Abstract

The invention is a method for treating patients diagnosed with Parkinson's disease (PD), including post-encephalitic parkinsonism, parkinsonism that may follow carbon monoxide intoxication in adults, or parkinsonism that may follow manganese intoxication in adults by orally administering a controlled release muco-adhesive levodopa formulation and the method provides an improvement of a patient's total post-dose "Off" time compared to post-dose of treatment regimens with oral immediate release levodopa tablets administered with one or more COMT inhibitors, and / or FDA approved controlled release CD-LD product.

Description

[0001] LEVODOPA DOSING REGIMEN

[0002] CROSS REFERNCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Serial No. 63 / 733,682 filed on December 13. 2024 and U.S. Serial No. 63 / 896.413 filed on October 9. 2025, the contents of which are hereby incorporated by reference in their entireties into the present application.

[0004] FIELD OF THE INVENTION

[0005] The present invention relates to oral dosing regimens of levodopa (hereinafter “LD”) and specifically oral dosing regimens that employ controlled release pharmaceutical compositions of LD. The dosing regimens are useful for the treatment of conditions such as neurological diseases associated with reduced or impaired dopamine levels and are particularly useful in treating patients with Parkinson’s disease (hereinafter “PD”), including primary parkinsonism / idiopathic parkinsonism, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication in adults. The dosing regimens are useful for PD patients receiving treatment with LD, salts or esters thereof, and catechol-O-methyltransferase (COMT) inhibitors; and for PD patients receiving FDA approved controlled release CD-LD dosage forms such as SINEMET® CR (controlled release matrix tablets) or RYTARY® (multiparticulate controlled release dosage form comprising CD, LD, and tartaric acid). The dosing regimens are particularly useful in long term treatment of patients diagnosed with PD and for advanced PD patients.

[0006] BACKGROUND OF THE INVENTION

[0007] Patients suffering from neurological diseases associated with reduced or impaired dopamine levels, e.g., patients with PD including primary parkinsonism / idiopathic parkinsonism, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication in adults, frequently have periods in which their mobility becomes difficult, often resulting in an inability to move. Abnormally low levels of dopamine, a neurotransmitter that affects mobility and control of the skeletal-muscular system, are commonly believed to be the main cause of reduced motor symptoms in PD patients. However, administration of dopamine is not effective in treating the motor symptoms of PD because dopamine does not cross the blood-brain barrier. To resolve this problem, PD patients are administered LD, the metabolic precursor of dopamine, but LD is not without its issues.

[0008] Over time patients treated with LD exhibit symptoms of “wearing off,” where a single dose of LD no longer lasts as long as in the early days of LD therapy (usually 5-10 years after start of LD therapy). Such patients may develop motor fluctuations characterized by end-of-dose failure, peak dose dyskinesia, and akinesia. The advanced form of motor fluctuations (also commonly referred to as the ‘on-off’ phenomenon) is characterized by unpredictable swings from mobility to immobility. Although the causes of these motor fluctuations are not completely understood, advanced patients generally benefit from treatment regimens that produce steady plasma levels of LD, such as through intestinal infusion of LD as such delivery method may mimic normally tonic endogenous dopamine. However, intestinal infusion of LD is restrictive, invasive and cumbersome. Oral delivery of LD is preferred, but plasma concentration levels remain difficult to control via oral delivery.

[0009] Combinations of LD and a decarboxylase inhibitor (typically carbidopa (hereinafter “CD”)) to treat PD are known in the pharmaceutical arts. CD prevents LD from breaking down prematurely in the body. Currently, several oral formulations containing a combination of LD and CD are commercially available, e.g., SINEMET®, SINEMET® CR, STALEVO®, RYTARY® and their corresponding generic products. In addition, a decarboxylase inhibitor approved for use outside of the United States, is benserazide, which may be given in combination with LD.

[0010] Catechol-O-methyltransferase inhibitors ("COMT inhibitors") are compounds that inhibit the enzyme catechol-O-methyltransferase. This enzyme methylates LD to 3-O-methyldopa. Inhibiting this enzyme reduces the breakdown or methylation of LD in the periphery thereby allowing more LD to reach the brain. COMT inhibitors when co-administered with LD increase the bioavailability of LD. Some of the known commercially available COMT inhibitors are entacapone (STALEVO® and COMTAN®), opicapone (ONGENTYS®) and tolcapone (TASMAR®).

[0011] Although many oral LD dosage forms are described in the literature, the successful development of a controlled, sustained or extended release oral dosage form of LD has been difficult because LD is rapidly metabolized, with a plasma half-life of about 50 minutes when orally administered without CD and a plasma half-life of about 1.5 hours when orally administered with CD. Tn addition, oral LD dosing is extremely difficult due in part to absorption issues with LD from a patient’s gastrointestinal tract. A majority of LD is only absorbed from a very small portion of the patient’s upper gastrointestinal tract. If the LD is not released from the dosage form in this narrow absorption window, the dosage form passes through the narrow window and the LD is released in the lower gastrointestinal tract with very low absorption. Not only is the absorption of LD limited to a small portion of the patient’s upper gastrointestinal tract, LD competes with other compounds, such as dietary amino acids, at the absorption site. Even if the LD is released in the patient’s narrow absorption window, the absorption could be prevented by other molecules interacting with the absorption site. This competition may cause the released LD to move past the narrow absorption window via normal gastric motility and be excreted without reaching a patient’s bloodstream.

[0012] There remains a need for oral controlled release LD dosage forms and dosing regimens using oral controlled release LD dosage forms that can provide predictable, rapid and long term efficacy in the treatment of PD symptoms in PD patients being treated with immediate release LD with a COMT inhibitor and / or PD patients being treated with marketed controlled release LD dosage forms, such as SINEMET® CR or RYTARY®.

[0013] SUMMARY OF THE INVENTION

[0014] The present invention accomplishes the forgoing need and other needs.

[0015] The present invention provides a dosing regimen that will allow for 2, 3, 4 or 5 times a day oral dosing of a controlled release LD dosage form to PD patients with minimum number of dose adjustments (increase or decrease in amount of drug administered) to obtain a dosing amount and schedule that will provide rapid efficacy and avoid adverse effects that can occur with the administration of excess drug. In certain aspects of this embodiment, the dosing regimen will reduce the burden on the patient, caregiver, healthcare provider and / or prescriber to administer the correct dose and correct dosing frequency of the controlled release oral LD dosage form to provide safe and effective treatment of PD, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication in adults.

[0016] The present invention also provides an oral dosing regimen of a controlled release LD dosage form to PD patients that will allow for dosing every 4-12 hours, preferably every 6-12 hours, i.e., dosing 2, 3, 4 or 5 times a day, with reduced “Off’ time between doses compared to post dose “Off’ time between doses of immediate release LD dosage forms with COMT inhibitors; and controlled release LD dosage forms such as SINEMET® CR or RYTARY®.

[0017] The present invention further provides an oral dosing regimen of a controlled release LD dosage form to PD patients that will allow for dosing every 4-12 hours, preferably every 6-12 hours, i.e. dosing 2, 3, 4 or 5 times a day, with an increased "On" time or increased "Good On" time with each dose, per day and / or per waking hours in a day compared to post dose “On” time or “Good On” time per day or per waking hours of immediate release LD dosage forms with COMT inhibitors and controlled release LD dosage forms such as SINEMET® CR or RYTARY®.

[0018] In certain embodiments of the present invention, the oral dosing regimen will convert a PD patient, being treated with an oral immediate release LD dosage form and a COMT inhibitor to an oral treatment comprising the administration of a controlled release LD dosage form, preferably a muco-adhesive controlled release LD dosage form, wherein the treatment with the controlled release dosage form exhibits one or more of the foregoing benefits such as rapid efficacy, avoidance or reduced adverse events, reduced "Off" time between doses, increased "On" time or increased "Good On" time with each dose, per day and / or per waking hours in a day compared to the prior treatment with an oral immediate release LD dosage form and a COMT inhibitor. In certain embodiments, the prior oral immediate release LD dosage form contains a COMT inhibitor. In certain embodiments, the prior oral immediate release LD dosage form is concurrently administered with a COMT inhibitor.

[0019] In certain aspects of this embodiment, the present invention comprises the steps of:

[0020] (i) selecting a patient diagnosed with Parkinson’s disease and being treated with oral immediate release LD and a COMT inhibitor;

[0021] (ii) determining the highest and most frequent LD dose received daily by the patient from step (i);

[0022] (iii) discontinuing the administration of the oral immediate release LD and COMT inhibitor of step (i); and

[0023] (iv) orally administering a controlled release levodopa dosage form 2, 3, 4, or 5 times a day to the patient of step (iii) wherein the amount of LD administered with each administration of the controlled release LD dosage form is about 1.2 to about 1.8 times, preferably about 1.25 to about 1.7 times, and more preferably about 1 .3, 1 .4, 1.5 or 1 .6 times the most frequent LD dose received daily by the patient as determined from step (ii).

[0024] In certain aspects of the forgoing embodiment, the oral immediate release LD of step (i) is administered as an immediate release CD-LD tablet such as SINEMET® or a U.S. FDA approved AB rated generic CD-LD tablet co-administered with a separate COMT inhibitor dosage form. The separate COMT inhibitor dosage form may be administered in a dosage form that does not contain LD such as COMTAN®, ONGENTYS® or TASMAR® or a U.S. FDA approved AB rated generic of the foregoing. In another embodiment, the oral immediate release LD of step (i) is an immediate release tablet containing CD-LD and a COMT inhibitor such as entacapone. An example of a commercially available dosage form comprising immediate release CD-LD and COMT inhibitor is STALEVO® or a U.S. FDA approved AB rated generic which is an immediate release tablet comprising CD-LD and entacapone. hr certain aspects of the foregoing embodiment, the controlled release LD dosage form of step (iv) is a muco-adhesive controlled release LD dosage form as described herein. In certain further aspects, the controlled release dosage form of step (iv) comprises one or more immediate release components comprising LD and CD and the one or more controlled release components comprising LD, a controlled release material, a mucoadhesive material and an enteric material.

[0025] In certain embodiments of the present invention, the oral dosing regimen will convert a PD patient, being treated with a first oral controlled release LD dosage such as form RYTARY® or a U.S. FDA approved AB rated generic to an oral treatment comprising the administration of an oral muco-adhesive controlled release LD dosage form, preferably a muco-adhesive controlled release LD dosage form as described herein, wherein the treatment with the muco-adhesive controlled release dosage form exhibits one or more of the foregoing benefits such as rapid efficacy, avoidance or reduced adverse events, reduced "Off" time between doses, increased "On" time or increased "Good On" time with each dose, per day and / or per waking hours in a day compared to the prior treatment with an oral controlled release LD dosage form such as RYTARY® or a U.S. FDA approved AB rated generic.

[0026] In certain aspects of this embodiment, the present invention comprises the steps of:

[0027] (i) selecting a patient diagnosed with Parkinson’s disease and being treated orally with a first controlled release LD dosage form administered 3, 4, or 5 times a day; (ii) determining the frequency and amount of LD administered to the patient with each administration of the first controlled release LD dosage form of step (i);

[0028] (iii) discontinuing the administration of the first controlled release LD dosage form of step (i); and

[0029] (iv) orally administering to the patient of step (iii) a second controlled release LD dosage form at the same frequency, i.e., 3, 4 or 5 times a day, and containing a similar amount of LD as the first controlled release dosage form from steps (i) or (ii); wherein the first controlled release LD dosage form is a multi-particulate capsule dosage form comprising LD, CD, and tartaric acid and the second controlled release LD dosage form is a muco-adhesive controlled release LD dosage form as described herein. In certain aspects of this embodiment, the first controlled release LD dosage form is free or substantially free of muco- adhesive materials. In certain aspects of this embodiment, the second controlled release LD dosage form comprises one or more immediate release components comprising LD and CD and the one or more controlled release components comprising LD, a controlled release material, a mucoadhesive material and an enteric material.

[0030] In certain aspects of this embodiment, the most frequent single LD dose of the first controlled release LD dosage form of step (ii) comprises 95 mg - 145 mg LD and the second controlled release LD dosage form comprises 140 mg LD administered at the same dosing frequency as the first controlled release LD dosage form.

[0031] In certain aspects of this embodiment, the most frequent single LD dose of the first controlled release LD dosage form of step (ii) comprises 190 mg - 245 mg LD and the second controlled release LD dosage form comprises 210 mg LD administered at the same dosing frequency as the first controlled release LD dosage form.

[0032] In certain aspects of this embodiment, the most frequent single LD dose of the first controlled release LD dosage form of step (ii) comprises 285 mg - 290 mg LD and the second controlled release LD dosage form comprises 280 mg LD administered at the same dosing frequency as the first controlled release LD dosage form.

[0033] In certain aspects of this embodiment, the most frequent single LD dose of the first controlled release LD dosage form of step (ii) comprises 335 mg - 390 mg LD and the second controlled release LD dosage form comprises 350 mg LD administered at the same dosing frequency as the first controlled release LD dosage form.

[0034] In certain aspects of this embodiment, the most frequent single LD dose of the first controlled release LD dosage form of step (ii) comprises 435 mg - 440 mg LD and the second controlled release LD dosage form comprises 420 mg LD administered at the same dosing frequency as the first controlled release LD dosage form.

[0035] In certain aspects of this embodiment, the most frequent single LD dose of the first controlled release LD dosage form of step (ii) comprises 485 mg - 490 mg LD and the second controlled release LD dosage form comprises 490 mg LD administered at the same dosing frequency as the first controlled LD release dosage form.

[0036] In certain aspects of this embodiment, the most frequent single LD dose of the first controlled release LD dosage form of step (ii) comprises 535 mg - 585 mg LD and the second controlled release LD dosage form comprises 560 mg LD administered at the same dosing frequency as the first controlled release LD dosage form or three times a day.

[0037] In certain aspects of this embodiment, the most frequent single LD dose of the first controlled release LD dosage form of step (ii) comprises 590 mg - 685 mg LD and the second controlled release LD dosage form comprises 700 mg LD administered at the same dosing frequency as the first controlled release LD dosage form or three times a day.

[0038] In certain embodiments, the first controlled release LD dosage form is FDA approved dosage form marketed under the trade name RYTARY® or a U.S. FDA approved AB rated generic.

[0039] In certain embodiments of the present invention, the oral dosing regimen will convert a PD patient, being treated with (a) oral controlled release LD matrix tablets such as SINEMET CR® or a U.S. FDA approved AB rated generic or (b) an oral controlled release LD matrix tablet such as SINEMET CR® or a U.S. FDA approved AB rated generic at bedtime in combination with oral immediate release LD dosage forms during waking hours, to an oral treatment comprising the administration of an oral multi-particulate muco-adhesive controlled release LD dosage form, preferably a multi-particulate muco-adhesive controlled release LD dosage form as described herein, wherein the treatment with the oral multi-particulate muco-adhesive controlled release LD dosage form exhibits one or more of the foregoing benefits such as rapid efficacy, avoidance or reduced adverse events, reduced "Off" time between doses, increased "On" time or increased "Good On" time with each dose, per day and / or per waking hours in a day compared to the prior treatment with an oral controlled release LD matrix tablets such as SINEMET® CR or a U.S. FDA approved AB rated generic.

[0040] In certain aspects of this embodiment, the present invention comprises the steps of:

[0041] (i) selecting a patient diagnosed with Parkinson’s disease and being treated with (a) at least one oral controlled release LD matrix tablet administered 1, 2, 3, 4, or 5 times a day for a total daily LD dose of 500 mg or less or (b) an oral controlled release LD matrix tablet at bedtime in combination with one or more oral immediate release LD dosage forms during waking hours for a total daily LD dose of 500 mg or less;

[0042] (ii) determining (a) the frequency and amount of LD administered to the patient with each administration of the controlled release LD matrix tablet or (b) the frequency and amount of LD administered to the patient with the bedtime administration of the controlled release LD matrix tablet and each immediate release LD dosage form administered during waking hours of step (i);

[0043] (iii) discontinuing the administration of the oral controlled release LD matrix tablets and the immediate release LD dosage forms of step (i); and

[0044] (iv) orally administering a multi-particulate muco-adhesive controlled release LD dosage form 2 or 3 times a day to the patient of step (iii) wherein the amount of LD administered with each administration of the oral multi-particulate muco-adhesive controlled release LD dosage form is about 2.8 times the amount of the most frequent LD dose from step (ii).

[0045] In certain aspects of this embodiment, the multi-particulate muco-adhesive controlled release LD dosage form comprises one or more immediate release components comprising LD and CD and the one or more controlled release components comprising LD, a controlled release material, a mucoadhesive material and an enteric material.

[0046] In further aspects of this embodiment, the present invention comprises the steps of:

[0047] (i) selecting a patient diagnosed with Parkinson’s disease and being treated with (a) at least one oral controlled release LD matrix tablet administered 1, 2, 3, 4, or 5 times a day for a total daily LD dose of 500 mg or more or (b) an oral controlled release LD matrix tablet at bedtime in combination with one or more oral immediate release LD dosage forms during waking hours for a total daily LD dose of 500 mg or more;

[0048] (ii) determining (a) the frequency and amount of LD administered to the patient with each administration of the controlled release LD matrix tablets or (b) the frequency and amount of LD administered to the patient with the bedtime administration of the controlled release LD matrix tablet and the immediate release LD dosage forms administered during waking hours of step (i);

[0049] (iii) discontinuing the administration of the oral controlled release LD matrix tablets and the immediate release LD dosage forms of step (i); and

[0050] (iv) orally administering a multi-particulate muco-adhesive controlled release LD dosage 3, 4 or 5 times a day to the patient of step (iii) wherein the amount of LD administered with each administration of the multi-particulate muco-adhesive controlled release LD dosage form is about 2.8 times the amount of the most frequent LD dose from step (ii).

[0051] In certain aspects of this embodiment, the multi-particulate muco-adhesive controlled release LD dosage form comprises one or more immediate release components comprising LD and CD and the one or more controlled release components comprising LD, a controlled release material, a mucoadhesive material and an enteric material.

[0052] In still further aspects of this embodiment, the present invention comprises the steps of:

[0053] (i) selecting a patient diagnosed with Parkinson’s disease and being treated with (a) at least one oral controlled release LD matrix tablet administered 1, 2, 3, 4, or 5 times a day for a total daily LD dose of 500 mg or more or (b) an oral controlled release LD matrix tablet at bedtime in combination with one or more oral immediate release LD dosage forms during waking hours for a total daily LD dose of 500 mg or more;

[0054] (ii) determining (a) the frequency and amount of LD administered to the patient with each administration of the controlled release LD matrix tablet or (b) the frequency and amount of LD administered to the patient with the bedtime administration of the controlled release LD matrix tablet and the immediate release LD dosage forms administered during waking hours of step (i);

[0055] (iii) if the most frequent amount LD dose of step (ii) is more than 200 mg, discontinuing the administration of the oral controlled release LD matrix tablets and the immediate release LD dosage forms of step (i): and (iv) orally administering to the patient of step (iii) one or more multi-particulate muco- adhesive controlled release LD dosage form at a dose of 700 mg LD per administration 3 times a day for a total dose of 2,100 mg LD per day.

[0056] In certain aspects of this embodiment, the multi-particulate muco-adhesive controlled release LD dosage form comprises one or more immediate release components comprising LD and CD and the one or more controlled release components comprising LD, a controlled release material, a mucoadhesive material and an enteric material.

[0057] In certain aspects of all the foregoing embodiments, the controlled release dosage form used in step (iv) of the oral dosing regimens is a solid multi-particulate dosage form comprising one or more immediate release components comprising an immediate release amount of LD and one or more modified or controlled release components that release LD in a modified or controlled release manner. The one or more modified or controlled release components may be present in the dosage form as a bead, pellet, granule or mini-tablet, comprising a core containing LD that is mixed, coated or layered with a controlled release material and / or a muco-adhesive material and may optionally be coated with an enteric material, preferably an enteric polymer. In certain aspects the controlled release dosage forms used step (iv) of all forgoing oral dosing regimens may also comprise a decarboxylase inhibitor, such as CD. The decarboxylase inhibitor, such as CD, may be present in an immediate release form, a modified or controlled release form or both. Examples of controlled release oral LD dosage forms of step (iv) that are useful in dosing regimens described herein are described in U.S. Patent Nos. 10,098,845; 10,292,935; 10,987,313 and 11,986,449 which are incorporated herein by reference.

[0058] BRIEF DESCRIPTION OF THE FIGURES

[0059] FIGURE 1 is a schematic of the study described in Example 8.

[0060] FIGURE 2 is a graph showing the CD-LD dose frequency from pre-study drug regimen though optimization of the interim data set reported in Example 8.

[0061] FIGURE 3 is a graph showing the dose frequency before and after optimization by pre-study drug regimen for the interim data reported in Example 8.

[0062] FIGURE 4 is a graph showing the number of titration steps to stable dose regimen by prestudy drug regimen for the interim data set reported in Example 8. FIGURE 5 is a graph showing the conversion ratio of stable Total Daily Dose (TDD) to prestudy LD TDD in patients who achieved a stable dosing regimen dose frequency before and after optimization by pre-study drag regimen for the interim data set reported in Example 8.

[0063] FIGURE 6 is a graph showing the change from baseline to Visit 4 in mean “GOOD ON” time per day for the interim data set reported in Example 8.

[0064] FIGURE 7 is a graph showing the change from baseline to Visit 4 in mean “GOOD ON” time per day based on pre- study drug regimen for the interim data set reported in Example 8.

[0065] FIGURE 8 is a graph showing the change from baseline to Visit 4 in mean “GOOD ON” time per dose for the interim data set reported in Example 8.

[0066] FIGURE 9 is a graph showing the change from baseline to Visit 4 in mean “GOOD ON” time per dose based on pre-study drug regimen for the interim data set reported in Example 8.

[0067] FIGURE 10 is a graph showing the change from baseline to Visit 4 in mean “OFF” time per day for the interim data set reported in Example 8.

[0068] FIGURE 11 is a graph showing the change from baseline to Visit 4 in mean “OFF” time per day based on pre-study drug regimen for the interim data set reported in Example 8.

[0069] FIGURE 12 is a graph showing the change from baseline to Visit 4 in mean “ON” time with troublesome dyskinesia (“WTD”) per day for the interim data set reported in Example 8.

[0070] FIGURE 13 is a graph showing the change from baseline to Visit 4 in mean “ON” time with troublesome dyskinesia per day based on pre-study drag regimen for the interim data set reported in Example 8.

[0071] FIGURE 14 is a graph showing the change from baseline to Visit 4 in mean asleep time per day for the interim data set reported in Example 8.

[0072] FIGURE 15 is a graph showing the increased “GOOD ON” time as a result of decreased “OFF” time with no impact to sleep for the interim data set reported in Example 8.

[0073] FIGURE 16 is a graph showing the change from baseline to Visit 4 in mean duration of continuous “GOOD ON” time interval per day for the interim data set reported in Example 8. FIGURE 17 is a graph showing the change from baseline to Visit 4 in mean duration of continuous “GOOD ON” time interval per day based on pre-study drug regimen for the interim data set reported in Example 8.

[0074] FIGURE 18 is a graph showing the change from baseline to Visit 4 in mean MDS-UPDRS total score for the interim data set reported in Example 8.

[0075] FIGURE 19 is a graph showing the change from baseline to Visit 4 in mean MDS-UPDRS total score based on pre- study drug regimen for the interim data set reported in Example 8.

[0076] FIGURE 20 is a graph showing the change from baseline to Visit 4 in mean MDS-UPDRS Part III score for the interim data set reported in Example 8.

[0077] FIGURE 21 is a graph showing the change from baseline to Visit 4 in mean MDS-UPDRS Part III score based on pre-study drug regimen for the interim data set reported in Example 8.

[0078] FIGURE 22 is a graph showing the change from baseline to Visit 4 in mean MDS-UPDRS Part II score for the interim data set reported in Example 8.

[0079] FIGURE 23 is a graph showing the change from baseline to Visit 4 in mean MDS-UPDRS Part II score based on pre- study drug regimen for the interim data set reported in Example 8.

[0080] FIGURE 24 is a graph showing the change from baseline to Visit 4 in “Much or Very Much Improved” PGI-C scores for the interim data set reported in Example 8.

[0081] DETAILED DESCRIPTION OF THE INVENTION

[0082] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs.

[0083] It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a formulation” includes a plurality of formulations.

[0084] As used herein, the term “about” when used before a numerical designation, e.g., temperature, time, amount, concentration, and such other, including a range, indicates approximations which may vary by ( + ) or (-) 10%, 9%, 8%, 7&, 6%, 5%, 4%, 3%, 2%, or 1%. As used herein, the term "substantially free" means 15% or less of the total amount of ingredient is present in the composition, dosage form or treatment regimen, preferably 10% or less, 9% or less, 8% or less, 7% or less. 6% or less, 5% or less. 4% or less, 3% or less, 2% or less, or 1% or less of the ingredient.

[0085] As used herein, the term “Parkinson’s disease” includes primary parkinsonism / idiopathic parkinsonism with an unknown cause, post- encephalitic parkinsonism, parkinsonism following manganese intoxication in adults, and parkinsonism following carbon monoxide intoxication in adults.

[0086] As used herein, the term “Parkinsonism” means a group of movement disorders, that can cause motor symptoms, such as bradykinesia (slowness in starting or carrying out movements), tremors or involuntary shaking of muscles, rigidity or muscle stiffness, postural instability or problems with balance, and / or freezing or being unable to move when trying to walk.

[0087] As used herein, the term “post-encephalitic parkinsonism” means a secondary movement disorder / condition caused by a previous brain inflammation (encephalitis), typically following a viral infection.

[0088] As used herein, the term “parkinsonism following manganese intoxication” means a secondary movement disorder / condition caused by manganese exposure.

[0089] As used herein, the term “parkinsonism following carbon monoxide intoxication” means a secondary movement disorder / condition caused by exposure to carbon monoxide poisoning.

[0090] As used herein, the term “immediate release” refers to a dosage form, composition or component that releases the specified amount of the active ingredient such as LD and / or CD within 30 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less following administration to a patient or subject or when tested in a United States Pharmacopeia Type I or Type II dissolution apparatus using 500-900 ml of an aqueous media. A representative example of an immediate release LD dosage form is the U.S. Food and Drug Administration (FDA) approved and commercially available tablet product, SINEMET®, sold by Merck Sharpe & Dohme Corp, or a U.S. FDA "AB" rated generic to SINEMET® such as the U.S. FDA approved tablets sold by Actavis Elizabeth, LLC, Apotex Inc., Mayne Pharma LLC, Mylan Pharmaceuticals Inc., Sciegen Pharmaceuticals Inc. or Sun Pharmaceutical Industries, Inc. As used herein the term "COMT inhibitor" refers to a catechol-o-methyltransferase inhibitor such as entacapone, opicapone, tolcapone and the like.

[0091] As used herein the term “component” is used in its broadest conventional interpretation unless dictated by context or specifically stated. More specifically, a component may be an element, a constituent part, a single ingredient or a mixture of ingredients. For example, an immediate release component may include a single ingredient such as a drug itself or it may be a combination of a drug and one or more pharmaceutically acceptable excipients provided the “immediate release component” will release the drug immediately upon administration.

[0092] As used herein the term "LD naive patient" or "levodopa naive patient" refers to a patient diagnosed with PD, including PD patients with primary parkinsonism / idiopathic parkinsonism, post-encephalitic parkinsonism, parkinsonism that may follow carbon monoxide intoxication in adults, or parkinsonism that may follow manganese intoxication in adults and that have not been treated with LD.

[0093] As used herein the term "COMT inhibitor naive patient" or "catechol-o-methyltransferase inhibitor naive patient" refers to a patient diagnosed with PD, including PD patients with primary parkinsonism / idiopathic parkinsonism, post-encephalitic parkinsonism, parkinsonism that may follow carbon monoxide intoxication in adults, or parkinsonism that may follow manganese intoxication in adults and that have not been treated with a COMT inhibitor.

[0094] As used herein the term "newly diagnosed PD patient" is a patient diagnosed with PD, including PD patients with primary parkinsonism / idiopathic parkinsonism, post-encephalitic parkinsonism, parkinsonism that may follow carbon monoxide intoxication in adults, or parkinsonism that may follow manganese intoxication in adults wherein the PD diagnosis occurred about 1 year or less, about 6 months or less or about 3 months of less prior to initiation of the dosing regimens of the present invention. In certain embodiments the newly diagnosed PD patient is treated with a total daily dose of about 700 mg or less, preferably 600 mg or less and more preferably 500 mg or less of LD and in certain embodiment without a concomitant COMT inhibitor.

[0095] As used herein the term "advanced PD patient" is a patient diagnosed with PD, including PD patients with primary parkinsonism / idiopathic parkinsonism, post-encephalitic parkinsonism, parkinsonism that may follow carbon monoxide intoxication in adults, or parkinsonism that may follow manganese intoxication in adults wherein the PD diagnosis occurred more than 1 year, such as 2, 3, 4 or 5 years prior to initiation of the dosing regimens of the present invention. In certain embodiments the advanced PD patient is treated with a total daily dose of about 700 mg or more, preferably 800 mg or more and more preferably 900 mg or more of LD, with a maximum daily dose of 2100 mg.

[0096] DOSING REGIMEN

[0097] The present disclosure provides controlled release oral LD compositions comprising capsules or tablets comprising about 95 mg to about 390 mg ± 10% of levodopa and in certain embodiments, about 23.75 mg to about 97.5 mg ± 10% of carbidopa, based on the anhydrous weight of carbidopa. In certain embodiments the compositions are tablets or capsules comprising: (i) about 35 mg CD and about 140 mg LD; (ii) about 52.5 mg CD and about 210 mg LD; (iii) about 70 mg CD and about 280 mg LD; and (iv) 87.5 mg CD and about 350 mg LD. In a preferred embodiment, the disclosure provides LD compositions comprising capsules comprising: (i) about 35 mg CD and about 140 mg LD; (ii) about 52.5 mg CD and about 210 mg LD; (iii) about 70 mg CD and about 280 mg LD; and (iv) 87.5 mg CD and about 350 mg LD. In certain embodiments one or more of the forgoing capsules or tablets may be administered to the PD patient per dosing period to obtain the desired LD dose. For example, two capsules comprising 87.5 mg CD and about 350 mg LD in each capsule maybe administered to a PD patient three times a day for total amount of 700 mg of LD per dose and a total daily dose of 2,100 mg of LD.

[0098] The present disclosure allows 2, 3, 4 or 5 times a day oral dosing of LD to a PD patient to control the patient’s PD symptoms. More specifically, the dosing will control or manage the patient’s motor fluctuations symptoms and in certain embodiments will reduce the patient’s total “Off’ time to less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours, less than 1 hour and less than 0.5 hours a day. The dosing will control or manage the patient’s motor fluctuations symptoms and in certain embodiments will also reduce the patient’s total “Off’ time per dose, per day and / or during waking hours to less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours, less than 1 hour and less than 0.5 hours per dose, per day and / or during waking hours in a 24 hour period. The dosing will control or manage the patient’s motor fluctuations symptoms and in certain embodiments will increase the patient’s total “On” time to at least about 5 hours, e.g., more than 5 hours, more than 6 hours, more than 7 hours, more than 8 hours, more than 9 hours, more than 10 hours or more than 1 1 hours during the 12 hour dose interval (i.e., per dose). The dosing will control or manage the patient’s motor fluctuations symptoms and in certain embodiments will also increase the patient’s total “Good On” time to at least about 5 hours, e.g., more than 5 hours, more than 6 hours, more than 7 hours, more than 8 hours, more than 9 hours, more than 10 hours or more than 11 hours during the 12 hour dosing time interval (per dose). The terms "Off’, “On” and “Good On” time with respect to PD patients are well known terms to those skilled in the treatment of PD patients and a general description is provided in Example 8 of U.S. Patent No. 11,986,449 which is incorporated herein by reference.

[0099] The controlled release oral LD dosage form of the present disclosure may be administered at a total daily dose of LD of about 280 mg to about 2500 mg of LD, preferably about 420 mg to about 2400 mg, about 560 mg to about 2400 mg, or 700 mg to 2400 of LD. This total daily LD dose may be divided into 2, 3, 4 or 5 equal or unequal doses administered 2, 3, 4, or 5 times a day wherein the dose taken or administered every six to twelve hours is from about 140 mg LD to about 700 mg of LD. The LD will be taken by or administered to the PD patient in the form of an oral controlled release dosage form, preferably a multi-particulate dosage form comprising one or more immediate release LD components and one or more controlled release LD components as described in greater detail below. The oral controlled release LD dosage form may be free of or substantially free of a COMT inhibitor. The oral controlled release LD dosage form may be administered with a separate dosage form comprising a COMT inhibitor, i.e. co-administered. Alternatively, the oral controlled release LD dosage form may be administered without a separate dosage form comprising a COMT inhibitor.

[0100] In certain embodiments, the oral controlled release LD dosage form described herein may be taken or administered 2, 3. 4 or 5 times a day and will comprise about 140 mg of LD, 210 mg of LD, 280 mg of LD, 350 mg LD, 420 mg, 490 mg, 560 mg, 630 mg, or 700 mg of LD. In certain embodiments, the oral controlled release LD dose form taken or administered 2, 3, 4, or 5 times a day will comprise one or more tablets or capsules comprising: (i) about 35 mg CD and about 140 mg LD; (ii) about 52.5 mg CD and about 210 mg LD; (iii) about 70 mg CD and about 280 mg LD; and / or (iv) 87.5 mg CD and about 350 mg LD. In a preferred embodiment, the oral controlled release LD dose form comprises capsules comprising: (i) about 35 mg CD and about 140 mg LD; (ii) about 52.5 mg CD and about 210 mg LD; (iii) about 70 mg CD and about 280 mg LD; and (iv) 87.5 mg CD and about 350 mg LD. The tablets or capsules may be swallowed whole or alternatively, the tablets may be crushed and sprinkled onto food, such as yogurt or applesauce or the contents of the capsule may be sprinkled onto food such as yogurt or applesauce and the food swallowed by the patient.

[0101] The dosing regimens of the present invention allow the PD patient to experience improved therapeutic benefits after dosing and before the next dose (a) compared to the patient’s symptoms without the administration of the oral controlled release LD dosage forms described herein, (b) compared to treatment with an immediate release CD-LD oral dosage form with the coadministration of a COMT inhibitor, and / or (c) compared to treatment with an oral controlled release LD dosage forms such as multi-particulate capsules comprising CD, LD and tartaric acid commercially available under the tradename RYTARY® or a U.S. FDA approved AB rated generic or an oral controlled release LD matrix tablet commercially available under the tradename SINEMET CR® or a U.S. FDA approved AB rated generic. An improved therapeutic benefit may be:

[0102] (i) an improvement or increase of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or any range within the aforementioned values, in the patient's motor state as determined by a qualified clinician;

[0103] (ii) an improvement or increase of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or any range within the aforementioned values, in the patient's motor state as determined by a patient’s PD diary;

[0104] (iii) a reduction of the Movement Disorders Society version of the Unified Parkinson’s Disease Rating Scale (“MDS-UPDRS”) scores by 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15. 16, 17, 18, 19 20 or more points or any range within the aforementioned values;

[0105] (iv) an increase of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or any range within the aforementioned values, in the patient's total "On" time per dose, per day or during waking hours (a) compared to a comparable total immediate release CD-LD doses with COMT inhibitors per dose, per day or per waking hours or (b) compared to a comparable total oral controlled release LD doses provided by dosage forms such as multi-particulate capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets per dose, per day or per waking hours; (v) an increase of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or any range within the aforementioned values, in the patient's total "Good On" time per dose, per day or during waking hours (a) compared to a comparable total immediate release CD-LD doses with COMT inhibitors per dose of LD, per day or per waking hours or (b) compared to a comparable total oral controlled release LD doses provided by dosage forms such as multi-particulate controlled capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets per dose, per day or per waking hours;

[0106] (vi) an increase of at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110. 115, 120, 125, 130, 135, 140. 145, 150, 155, 160, 165, 170. 175, 180 minutes or any range within the aforementioned values or longer, of the patient's "On" time per dose, per day and / or during waking hours per day (a) compared to a comparable total immediate release CD-LD doses with COMT inhibitors per dose, per day or per waking hours or (b) compared to a comparable total oral controlled release LD doses provided by dosage forms such as multiparticulate controlled release capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets per dose, per day or per waking hours;

[0107] (vii) an increase of at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180 minutes or any range within the aforementioned values or longer of the patient's "Good On" time per dose, per day and / or during waking hours per day (a) compared to a comparable total immediate release CD- LD doses with COMT inhibitors per dose, per day or per waking hours or (b) compared to a comparable total oral controlled release LD doses provided by dosage forms such as multiparticulate controlled release capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets per dose, per day or per waking hours;

[0108] (viii) a decrease of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%. 40%, 45%, 50% or any range within the aforementioned values in the patient's total "Off" time per dose, per day or during waking hours (a) compared to a comparable total immediate release CD-LD doses with COMT inhibitors per dose, per day or per waking hours or (b) compared to a comparable total oral controlled release LD doses provided by dosage forms such as multi-particulate controlled release capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets per dose, per day or per waking hours; (ix) a decrease of at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180 minutes or any range within the aforementioned values or longer of the patient's "Off" time per dose, per day and / or during waking hours per day (a) compared to a comparable total immediate release CD-LD doses with COMT inhibitors per dose, per day or per waking hours or (b) compared to a comparable total oral controlled release LD doses provided by dosage forms such as multiparticulate controlled release capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets per dose, per day or per waking hours;

[0109] (x) an increase of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or any range within the aforementioned values in the patient's Patient Global Impression of Change ("PGI-C") score, and / or Clinical Global Impression of Change ("CGI-C") score (a) compared to a comparable total immediate release CD-LD doses with COMT inhibitors per dose, per day or per waking hours or (b) compared to a comparable total oral controlled release LD doses provided by dosage forms such as multi-particulate controlled release capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets per dose, per day or per waking hours;

[0110] (xi) a decrease of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50% or any range within the aforementioned values in the average number of motor fluctuations per day (a) compared to a comparable total immediate release CD-LD doses with COMT inhibitors per day or per waking hours or (b) compared to a comparable total oral controlled release LD doses provided by dosage forms such as multi-particulate controlled release capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets per day or per waking hours;

[0111] (xii) a decrease of at least 5%, 10%, 15%. 20%, 25%, 30%, 35%. 40%, 45%, 50% or any range within the aforementioned values in the perceptual problems and / or hallucinations per day (a) compared to a comparable total immediate release CD-LD doses with COMT inhibitors per day or per waking hours or (b) compared to a comparable total oral controlled release LD doses provided by dosage forms such as multi-particulate controlled release capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets per day or per waking hours; or

[0112] (xiii) any combination of the foregoing. In certain embodiments the improved therapeutic benefit includes at least 3%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%, improvement in MDS-UPDRS Part III scores or ranges within the aforementioned values.

[0113] A more detailed explanation of the motor states, PD diaries, MDS-UPDRS, PGI-C, and CGIC from administration of controlled release dosage form of the present disclosure such as Example 7 herein compared to oral dose of immediate release CD-LD dosage forms and RYTARY® are provided in Examples 8, 9 and 11 of U.S. Patent No. 11,986,449 incorporated herein by reference.

[0114] The dosing regimens of the present invention comprises orally administering to a PD patient one or more oral controlled release muco-adhesive dosage forms described herein about every 6 to 12 hours, about every 6 to 9 hours, about every 7 to 8 hours or about every 12 hours to control or manage the patient’s motor fluctuations symptoms and in certain embodiments to reduce the patient’s total “Off’ time during in a 24 hour period to less than about 5 hours, less than about 4 hours, less than about 3 hours, less than about 2 hours, less than about 1 hour, less than about 0.5 hours, or any intermediate periods therein. The dosing regimen may also comprise orally administering to the PD patient one or more of the controlled release muco-adhesive dosage forms described herein about every 6 to 12 hours, about every 6 to 9 hours, about every 7 to 8 hours or about every 12 hours to control or manage the patient’s motor fluctuations symptoms and in certain embodiments to also reduce the patient’s total “Off’ time during waking hours to less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours, less than 1 hour and less than 0.5 hours during waking hours in a 24 hour period.

[0115] The dosing regimen of the present invention also comprises orally administering to a PD patient the controlled release muco-adhesive dosage forms described herein about every 6 to 12 hours, about every 6 to 9 hours, about every 7 to 8 hours or about every 12 hours to control or manage the patient’s motor fluctuations symptoms and in certain embodiments to increase the patient’s total “On” time to at least about 5 hours, e.g., more than 5 hours, more than 6 hours, more than 7 hours, more than 8 hours, more than 9 hours, more than 10 hours, or intermediate periods therein per day. The dosing regimen also comprise orally administering to the PD patient the controlled release muco-adhesive dosage forms described herein about every 6 to 12 hours, about every 6 to 9 hours, about every 7 to 8 hours or about every 12 hours to control or manage the patient’s motor fluctuations symptoms and in certain embodiments to also increase the patient’s total “Good On” time to at least about 5 hours, e.g., more than 5 hours, more than 6 hours, more than 7 hours, more than 8 hours, more than 9 hours, more than 10 hours, or intermediate periods therein, per day.

[0116] The dosing regimen of the present invention further comprise orally administering to the PD patient the controlled release muco-adhesive dosage forms described herein about every 6 to 12 hours, about every 6 to 9 hours, about every 7 to 8 hours, or about every 12 hours to control or manage the patient’s motor fluctuations symptoms and in certain embodiments to increase the patient’s total “On” time per dose, per day and / or during waking hours per day by at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 1 10, 1 15, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175 180 minutes or any range within the aforementioned values or longer (a) compared to a comparable total immediate release CD-LD doses with COMT inhibitors per dose, per day or per waking hours, (b) compared to comparable total immediate release CD- LD doses during waking hours and one or more controlled release LD matrix tablets at bedtime per dose, per day or per waking hours, or (c) compared to a comparable total oral controlled release LD doses provided by dosage forms such as multi-particulate controlled release capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets per dose, per day or per waking hours. In certain aspects of this embodiment, the controlled release muco-adhesive dosage forms described herein are administered 2, 3 or 4 times a day compared to the immediate release CD-LD dose administered 4, 5 or 6 times a day. In certain aspects of this embodiment, the controlled release muco-adhesive dosage forms described herein are administered 3 or 4 times a day compared to the immediate release CD-LD dose administered 4, 5 or 6 times a day.

[0117] The dosing regimen of the present invention also comprises orally administering to the PD patient the controlled release muco-adhesive dosage forms described herein about every 6 to 12 hours, about every 6 to 9 hours, about every 7 to 8 hours or about every 12 hours to control or manage the patient’ s motor fluctuations symptoms and in certain embodiments to also increase the patient’s total “Good On” time per dose, per day and / or during waking hours per day by at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135. 140, 145, 150, 155, 160. 165, 170, 175 180 minutes or any range within the aforementioned values or longer (a) compared to a comparable total immediate release CD-LD doses administered with a COMT inhibitor per dose, per day or per waking hours (b) compared to comparable total immediate release CD-LD doses during waking hours and one or more controlled release LD matrix tablets at bedtime per dose, per day or per waking hours or (c) compared to a comparable total oral controlled release LD doses provided by dosage forms such as multi-particulate controlled release capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets per dose, per day or per waking hours. In certain aspects of this embodiment, the controlled release muco-adhesive dosage forms described herein are administered 2, 3 or 4 times a day compared to the immediate release CD-LD dose administered 4, 5 or 6 times a day. In certain aspects of this embodiment, the controlled release muco-adhesive dosage forms described herein are administered 3 or 4 times a day compared to the immediate release CD-LD dose administered 4, 5 or 6 times a day.

[0118] The dosing regimen of the present invention may also comprise orally administering to the PD patient the controlled release muco-adhesive dosage forms described herein about every 6 to 12 hours, about every 6 to 9 hours, about every 7 to 8 hours, or about every 12 hours to control or manage the patient’s motor fluctuations symptoms and in certain embodiments will also decrease the patient’s total “Off’ time per dose, per day and / or during waking hours per day by at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175 180 minutes or any range within the aforementioned values or longer (a) compared to a comparable total immediate release CD-LD doses administered with a COMT inhibitor per dose, per day or per waking hours (b) compared to comparable total immediate release CD-LD doses during waking hours and one or more controlled release LD matrix tablets at bedtime per dose, per day or per waking hours or (c) compared to a comparable total oral controlled release LD doses provided by dosage forms such as multi-particulate controlled release capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets per dose, per day or per waking hours. In certain aspects of this embodiment, the controlled release muco-adhesive dosage forms described herein are administered 2, 3 or 4 times a day compared to the immediate release CD-LD dose administered 4, 5 or 6 times a day. In certain aspects of this embodiment, the controlled release muco-adhesive dosage forms described herein are administered 3 or 4 times a day compared to the immediate release CD-LD dose administered 4, 5 or 6 times a day. In certain embodiments the improved therapeutic benefits experienced by the PD patients may include a substantial reduction in total “Off’ time during waking hours, which may range from about 12 to about 16 hours in a 24 hour period. As used herein substantial reduction in total “Off’ time during waking hours may mean at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% or 50% reduction in the total “Off’ time during waking hours (or any range within the aforementioned values), which may be about 12-18, 13-17 or 14-16 hours during a 24 hour time period, compared to (a) treatment with an immediate release CD-LD oral dosage form administered with COMT inhibitor(s) (b) ) treatment with one or more immediate release CD-LD dosage forms during waking hours and one or more controlled release LD matrix tablets at bedtime or (c) treatment with oral controlled release LD dosage forms such as multi-particulate controlled release capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets.

[0119] In certain embodiment the improved therapeutic benefits experienced by the PD patients may include a total “Off’ time / dosing period of 240 minutes or less, 180 minutes or less, 160 minutes or less, 140 minutes or less, 120 minutes or less. 100 minutes or less, 90 minutes or less, 75 minutes or less, 60 minutes or less. 50 minutes or less, 45 minutes or less, 40 minutes or less, 35 minutes or less, 30 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less, 10 minutes or less. 5 minutes or less, 0 minutes, or any intermediate periods therein.

[0120] In certain embodiments the improved therapeutic benefits experienced by the PD patients may include a substantial increase in “On” and “Good On” time during waking hours, which may range from about 12 to about 18 hours or about 14 to about 16 hours in a 24 hour period. As used herein substantial increase in total “On” and “Good On” time during waking hours may mean at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% or 50% increase in the total “On” or “Good On” time during waking hours (i.e., about 12-18, 13-17 or 14-16 hours during a 24 hour time period) compared to (a) treatment with an immediate release CD-LD oral dosage form administered with one or more COMT inhibitors, (b) treatment with one or more immediate release CD-LD dosage forms during waking hours and one or more controlled release LD matrix tablets at bedtime, or (c) treatment with oral controlled release LD dosage forms such as multi-particulate controlled release capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets. In certain embodiments the improved therapeutic benefits experienced by the PD patients may include a substantial increase in “On” and “Good On” time during waking hours, which may range from about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70. 75. 80. 85. 90, 95, 100. 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180 minutes or longer (or any range within the aforementioned values) during the dosing time interval (i.e. per dose), (a) compared to a comparable dose of an oral immediate release CD-LD composition administered with one or more COMT inhibitors (b) the total immediate release CD-LD doses administered with one or more COMT inhibitors per waking hours, (c) compared to a comparable dose of a controlled release LD dosage forms such as multi-particulate controlled release capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets or (d) the total LD doses administered with one or more controlled release LD dosage forms such as multi-particulate controlled release capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets per waking hours.

[0121] In certain embodiments the improved therapeutic benefits experienced by the PD patients may include a substantial decrease in “Off’ time during waking hours, which may range from about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175 180 minutes or longer (or any range within the aforementioned values) during the dosing time interval (i.e. per dose), (a) compared to a comparable dose of immediate release CD-LD administered with one or more COMT inhibitors during waking hours, (b) compared to comparable dose of immediate release CD-LD administered during waking hours and one or more controlled release LD matrix tablets administered at bedtime, or (c) compared to a comparable dose of an oral controlled release LD dosage form such as multiparticulate controlled release capsules comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets during waking hours.

[0122] In certain embodiments the improved therapeutic benefits experienced by the PD patients may include a substantial increase in “On” and “Good On” time during waking hours, for e.g., from about 12 to about 18 hours or about 14 to about 16 hours in a 24 hour period, with thrice daily administration of the controlled release dosage forms disclosed herein compared to four or five times daily administration of immediate release CD-LD oral dosage form administered with one or more COMT inhibitor(s), compared to three, four or five times daily administration of immediate release CD-LD oral dosage forms and one or more controlled release LD matrix tablets at bedtime, or compare to three or four times a day administration of an oral controlled release LD dosage form such as a multi-particulate controlled release capsule comprising CD, LD and tartaric acid or oral controlled release LD matrix tablets. In certain embodiments the improved therapeutic benefits experienced by the PD patients may include a similar or improved LD pharmacokinetic parameter when the controlled release muco-adhesive dosage forms described herein are: (i) administered under fed conditions and compared to an administration under fasting conditions; (ii) administered under fed conditions and compared to an administration under fasting conditions wherein the components of the controlled release muco-adhesive dosage forms described herein are sprinkled onto a food substance such as yogurt or a fruit preparation, puree or compote and the sprinkled composition is administered; (iii) administered under fasting conditions and compared to an administration under fasting conditions wherein the components of the controlled release dosage forms described herein are sprinkled onto a food substance such as yogurt or a fruit preparation, puree or compote and the sprinkled composition is administered; or (iv) a combination of (i), (ii) and / or (iii). The similar or improved LD pharmacokinetic parameters include, but are not limited to, Cmax and AUCO-t (ng.h / mL). A similar LD pharmacokinetic parameter as used herein means the geometric mean ratio of the target parameter value obtained from administration under fed or sprinkle conditions is within 80-120 of the target parameter value obtained from administration under fasting conditions. An improved LD pharmacokinetic value means the target parameter value obtained from administration under fed or sprinkle conditions exhibits a higher or larger value compared to the target parameter value obtained from administration under fasting conditions. For example, PD patients may take the controlled release muco-adhesive dosage form as described herein with food and the LD Cmax and / or LD AUCO-t (ng.h / mL) values will be at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18% 19%, 20%, 21%, 22%, 23%. 24% or 25% or greater than the LD Cmax and / or LD AUCO-t (ng.h / mL) values obtained when the same amount of the controlled release dosage form is administered under fasting conditions, preferably after at least ten hours of fasting and more preferably after an overnight fasting.

[0123] DOSAGE FORMS

[0124] Dosage forms that are useful in the dosing regimens of the present invention are controlled release oral solid muco-adhesive formulations of LD and provide a relatively steady LD plasma or serum concentration profile over a prolonged period of time and enhancing absorption of the active agents in the gastrointestinal tract of a subject.

[0125] The dosage forms may comprise at least two components: (i) a first component or immediate release component that provides immediate release of LD; and (ii) a second component or controlled release component that provides for a controlled or sustained release of LD. In certain embodiments, the second component or controlled release component comprises a core comprising LD that is mixed, coated or layered with a muco-adhesive material, preferably a muco-adhesive polymer and externally coated with an enteric material, preferably an enteric polymer. The second component or controlled release component may also contain a rate controlling material that will contribute to the controlled release of the LD. The rate controlling material may be part of the controlled release component. For example, the rate controlling material may be a rate controlling polymer applied to the drag containing core and as an undercoating to a coating or layer containing a muco-adhesive material or the rate controlling material may be mixed with the LD to form a controlled release matrix or controlled release core of the controlled release component. The second or controlled release component is essential to provide extended absorption, thereby providing prolonged and steady therapeutic coverage.

[0126] The oral dosage forms useful in the present invention may also comprise a decarboxylase inhibitor, such as CD. The decarboxylase inhibitor, such as CD, may be present in the first or immediate release LD component, the second or controlled release LD component or in both the first or immediate release LD component and second or controlled release LD component. The decarboxylase inhibitor, such as CD, may also be present in a component that is separate and distinct from the first or immediate release LD component and / or the second or controlled release LD component. More specifically, one embodiment of the controlled release oral dosage form of the present invention may comprise: (i) a first or immediate release component comprising LD; and (ii) a second or controlled release component comprising LD. Another embodiment may comprise: (i) a first or immediate release component comprising LD and CD; and (ii) a second or controlled release component comprising LD. A further embodiment may comprise: (i) a first or immediate release component comprising LD; and (ii) a second or controlled release component comprising LD and CD. A still further embodiment may comprise: (i) a first or immediate release component comprising LD and CD; and (ii) a second or controlled release component comprising LD and CD. Another embodiment may comprise (i) a first or immediate release component comprising LD; and (ii) a second or controlled release component comprising LD. (iii) a third or immediate release component comprising CD; and / or (iv) a fourth or controlled release component comprising CD. The first, second, third and / or fourth components may be separate and distinct components or may be combined to form distinct parts or regions of a larger combined component.

[0127] In another embodiment, first or immediate release component may comprise a powder or granules comprising LD and / or CD and optionally one or more pharmaceutically acceptable excipients and the powder or granules are a separate and distinct composition from the second or controlled release component however, both may be incorporated into a capsule for administration to a patient.

[0128] In another embodiment, the first or immediate release component comprises immediate release granules comprising CD and LD with a disintegrant to allow for rapid dissolution.

[0129] Alternatively, the first or immediate release component may comprise a coating or layer comprising LD and / or CD and optionally one or more pharmaceutically acceptable excipients wherein the coating or layer is applied to or part of the second or controlled release component. In this alternative embodiment, the first or immediate release component is combined with the second or controlled release component to form a distinct part or component of the larger combined component. It will be appreciated by the skilled artisan that the location, structure and / or placement of the first or immediate release component with respect to the second or controlled release components in the final dosage form is not critical provided the first or immediate release component allows for the immediate release of the drug such as LD and / or CD following administration of the dosage form to a patient and the second or controlled release component has the controlled-release and / or muco-adhesive properties described herein.

[0130] In another embodiment, the first or immediate release component comprises immediate release granules comprising CD and LD with a disintegrant to allow for rapid dissolution; and the controlled release component comprises controlled release beads comprising LD cores coated with a sustained release / controlled release polymer to allow for slow release of the drug (e.g., LD), a mucoadhesive polymer to keep the beads adhered to the patient’s area of absorption longer and an enteric coating to prevent the beads from disintegrating too early in stomach. In some embodiments, the controlled release component comprises a rate controlling material, which may be the same or different from the muco-adhesive material. The rate controlling material and / or the muco-adhesive material slows or prolongs the release of active agent(s) or drug(s) from the controlled release component, thereby further extending the release and absorption of drug(s), preferably LD and optionally CD. The controlled release component should release the drug(s) such as LD or CD over a four to ten hour period preferably a five to eight hour period.

[0131] The immediate release component should provide fast release of the drug(s) such as LD and CD and thereby a rapid absorption of the drug(s) such as LD and CD. The rapid absorption is important for PD patients in need of a fast “on.” As a result, controlled release dosage forms useful in the present invention can provide LD plasma levels that rise quickly, preferably to therapeutic levels, and extend for a prolonged period of time.

[0132] In certain embodiments the amount of immediate release LD should range from about 10% to about 40% based on the total amount of LD in the oral dosage forms, preferably about 15% to 35%, and most preferably about 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 35%, or 35%.

[0133] In certain embodiments, the controlled release oral dosage form of the present invention may comprise: (i) a first or immediate release component comprising LD; and (ii) a second or controlled release component comprising LD. In certain embodiments, the ratio of LD in the immediate release component to that in the controlled release component can be in the range of 0.15 to 0.49. For example, a ratio in weight of LD in the controlled release component: immediate release component is at least about 2:1, most preferably 3:1.

[0134] Decarboxylase inhibitors such as CD are often provided with LD formulations in order to inhibit decarboxylation of LD, thereby increasing the LD bioavailability. In the controlled release dosage forms useful in the present invention, a decarboxylase inhibitor may be included in the immediate release component, the controlled release component, both the immediate release and controlled release component or in separate immediate release and / or controlled release components as described previously. Preferably, the decarboxylase inhibitor is CD and is included only in an immediate release form such as in the immediate release component with the LD or in a separate immediate release component from the LD. In alternative embodiments, the decarboxylase inhibitor, preferably CD, is included in both an immediate release form as previously described and a controlled release form such as in the controlled release component with the LD or in a separate controlled release component that does not contain LD. In the various embodiments, the amount of immediate release decarboxylase inhibitor, preferably CD, should range from about 75% to about 100% based on the total amount of decarboxylase inhibitor in the oral dosage forms, preferably about 80% to 100%, and most preferably about 81%, 82%, 83%, 84%, 85%. 86%, 87%, 88%. 89%. 90%, 91%, 92%. 93%, 94%, 95%. 96%, 97%, 98%, 99% or 100%. In a most preferred embodiment, the amount of immediate release decarboxylase inhibitor ranges from 95% to 100% based on the total amount of decarboxylase inhibitor in the oral dosage forms.

[0135] In one embodiment of the invention, the oral dosage forms comprise (1) one or more controlled release components comprising LD and (2) one or more immediate release components comprising LD. The one or more controlled release components may be formulated as a tablet, mini-tablet, bead, pellet, granule or combination thereof. The controlled release components may comprise a core containing LD coated with a layer comprising a muco-adhesive material or polymer and further coated with an outer layer comprising an enteric material or polymer. In certain embodiments, the drug-containing core of the controlled release component will comprises a rate controlling material, which may be mixed with the drug to form a controlled release matrix core, coated onto the drug containing core to form an undercoat below the coating or layer comprising the muco-adhesive material, incorporated into the coating or layer comprising the muco-adhesive material or polymer, or a combination thereof. In some embodiments, the controlled release material and muco-adhesive material may be mixed together with the LD to form a controlled release / muco-adhesive core.

[0136] The immediate release component may be formulated as a powder, coating, tablet, minitablet, bead, pellet, granule or combination thereof that is separate from or part of the controlled release component. In certain embodiments, the immediate release component is in the form of a powder, tablet, mini-tablet, pellet, bead or granule that is separate from the controlled release component. In alternative embodiments the immediate release component may also be applied as an immediate release coating or layer onto one or more of the controlled release components. In certain embodiments, the immediate release component may be applied to or surround the enteric coating of the controlled release component. In another embodiment of the invention, the oral controlled release dosage forms comprise (1) one or more controlled release components comprising a LD and (2) one or more immediate release components comprising LD and (3) a decarboxylase inhibitor component, preferably a CD component. The decarboxylase inhibitor component may be formulated as a powder, coating, tablet, mini-tablet, bead, pellet, granule or combination thereof. The decarboxylase component may be in an immediate release form, a controlled release form or immediate release and controlled release forms. The decarboxylase inhibitor may be co-formulated with (1) one or more of the controlled release components comprising LD and / or (2) with one or more of the immediate release components comprising LD. Alternatively, the decarboxylase inhibitor may be formulated separately from the one or more controlled release components comprising a LD and / or the one or more immediate release components comprising LD.

[0137] The controlled release component may comprise drug-containing cores containing both LD and a decarboxylase inhibitor such as CD, or the LD may be in separate controlled release components from that containing the decarboxylase inhibitor. In one embodiment of the invention, the controlled release component comprises an LD-containing core free or substantially free of a decarboxylase inhibitor such as CD. In this embodiment, “substantially free” means 15% or less of the total amount of decarboxylase inhibitor in the dosage form is in the controlled release component(s), preferably 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less. The immediate release component of this embodiment may comprise a combination of LD and a decarboxylase inhibitor. The LD may also be in a separate immediate release component from the decarboxylase inhibitor.

[0138] In some embodiments, the controlled release dosage forms used in the dosing regimens described herein are free or substantially free of a COMT inhibitor. In this embodiment, “substantially free” means less than a therapeutic amount of COMT inhibitor or 10% or less. 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% of the total weight of the controlled release dosage form. In this embodiment the term “free” means 0%.

[0139] In some embodiments, the controlled release dosage forms used in the dosing regimens described herein are free or substantially free of an organic acid such as tartaric acid. In this embodiment, “substantially free” means the amount of organic acid present in the controlled release component and / or the controlled release dosage form is 15% or less, 14% or less, 13% or less, 12% or less, 11% or less, 10% or less, 9% or less, 8% or less, 7% or less, 6% or less, 5% or less, 4% or less, 3% or less. 2% or less, or 1% of the total weight of the controlled release dosage form. In this embodiment the term “free” means 0%. In certain aspects of this embodiment, the controlled release component and / or the controlled release dosage form may contain an organic acid in an amount that does not alter the absorption profile of LD released from the controlled release dosage form by more than 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less.

[0140] In a preferred embodiment of the invention, the oral dosage forms comprise (1) one or more controlled release components comprising LD and (2) one or more immediate release components comprising LD and CD. In this embodiment, the controlled release component may comprise a drug-containing core coated with a first layer comprising a rate controlling material or polymer, a second layer comprising a muco-adhesive material or polymer surrounding or applied to the first layer and an outer or third layer comprising an enteric material or polymer surrounding or applied to the second layer. Additional coatings or layers such as cosmetic coatings or nonfunctional coatings such as water soluble seal coatings can also be added to separate the core, first, second and / or third layers or to overcoat the third layer. These cosmetic or non-functional coatings may also be used to separate an immediate release component from the controlled release component as well as to apply or adhere an immediate release component to the controlled release component. As used herein a non-functional or cosmetic coating should dissolve within 30 minutes, 25 minutes, 20 minutes. 15 minutes, 10 minutes or 5 minutes when the component with the non-functional or cosmetic coating as the outermost coating is placed in a USP dissolution apparatus, either a Type I or II with 500-900 ml of an aqueous media with a pH of 1-7. In accordance with the practice of the invention, the components of the invention may be obtained by any methods commonly used in the art such as blending, mixing, granulation and / or coating processes, including, but not limited to, wet-granulation, fluid bed granulation / coating, or extrusion / spheronization, as are well-known in the pharmaceutical arts. The compositions may also be formed with other conventional formulation techniques such as compression and / or slugging. In addition to drugs such as LD and CD, the controlled release components and / or the immediate release components may further contain conventional pharmaceutically acceptable excipients such as lubricants, fillers, binders, disintegrants, glidants, surfactants (sometimes referred to as wetting agents), pH adjusting agents, antioxidants or mixtures of the foregoing. In an embodiment of the invention, the controlled release and / or immediate release components are multi-particulates that are encapsulated, preferably in a hard gelatin capsule. The multi-particulates may be in a form that can be sprinkled directly onto food or liquids for easy ingestion.

[0141] The active agents, such as CD and LD, may be combined and dispersed throughout a drugcontaining core. In another embodiment, the active agents may be present in the center of the drugcontaining core or layered / coated on an inert core such as a sugar sphere, microcrystalline cellulose sphere, glass sphere, plastic sphere or combination thereof.

[0142] The muco-adhesive material employed in the present invention may be a homogenous muco-adhesive material, i.e., a single type of muco-adhesive material or polymer or may comprise multiple types of muco-adhesive materials and / or polymers. The muco-adhesive material or polymer may possess certain characteristics such as being hydrophilic, hydrophobic, cationic, anionic and / or biocompatible and include multiple hydrogen bonding groups, hydrophobic surfaces, positively charged groups and / or negatively charged groups for adhesion to a mucosal surface so that the controlled release component can be held, prolonged or slowed at the site of absorption, thereby allowing the release of the LD from the controlled release component at the desired absorption site and thereby increase bioavailability.

[0143] Alternatively, the muco-adhesive material or polymer is a material capable of forming a positive ionic charge at the pHs present in the human gastro-intestinal tract. It is believed that the positive charge may allow the muco-adhesive material to interact with the negative charge of the intestinal walls and thereby slow or delay the gastrointestinal transit time of the controlled release component.

[0144] Further, the muco-adhesive material or polymer may be natural, synthetic or from a biological source. Further still, the muco-adhesive material or polymer may be composed of a single polymer or a combination of two or more different polymers. In one embodiment, the polymers may range in size from 10,000 daltons to 1,000,000 daltons more preferably 20,000 daltons to 200,000 daltons, and most preferably 20,000 daltons to 100,000 daltons.

[0145] An example of a muco-adhesive polymer includes, but is not limited to, a basic methacrylate copolymer, such as an amino methacrylate copolymer. A preferred example of a methacrylate copolymer is a basic butylated methacrylate copolymer, such as Eudragit® E100 (poly(butyl methacrylate-co-(2- dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1; CAS number: 24938-16-7; Evonik Industries). EUDRAGIT® E100 is a cationic copolymer made up of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate with a ratio of 2:1:1.

[0146] Other examples of muco-adhesive materials or polymers include, but are not limited to, a glyceride, steroidal detergent, polycarbophil (CAS Number 9003-97-8; Noveon® AA-1; Lubrizol Corp.), carbomer, cellulosics, chitosan, diethylaminodextran, diethylaminoethyldextran, polygalactosamine, polylysine, polyomithine, prolamine, polyimine, hyaluronic acid, sodium alginate, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC). sodium carboxymethylcellulose (sodium CMC) and alginate or combination thereof.

[0147] The muco-adhesive material or polymer may constitute about 1-50% of the mass of the controlled release component, preferably about 1-10% of the mass of the controlled release component, most preferably about 2-10% of the mass of the controlled release component. Preferably, the muco-adhesive material or polymer is Eudragit® E 100 alone or combined with at least one additional muco-adhesive material. The muco-adhesive material or polymer percentages of mass stated above are based on a multi-particulate with a bead size between 0.8 to 1.2 mm. If the bead size is larger or smaller than 0.8 to 1.2 mm, the skilled artisan will understand that the mass percentage described above should be adjusted accordingly.

[0148] Enteric coating materials or polymers are known in the art. In general, enteric coating polymers are designed to prevent drug release from an oral solid dosage form in the low pH environment of the stomach, thereby delaying drug release until the dosage form reaches the small intestine. As such, the controlled release components of the invention have an in vitro release profile with minimal release of the active agent at pH 1.0. In the controlled release formulations of the invention, it is believed the second, third or outer enteric coating layer provides an additional advantage in preventing agglomeration of the controlled release components. That is, the enteric coat layer prevents the controlled release muco-adhesive components from sticking together in the low pH environment of the stomach.

[0149] The preferred enteric materials are shellac (esters of aleurtic acid), zein, cellulose acetate phthalate (CAP), poly (methacrylic acid-co-methyl methacrylate), poly (methacrylic acid-co-ethyl methacrylate), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinates. The preferred enteric polymers release at a pH of greater than or equal to pH 5.5. Examples include Eudragit® L100 or Eudragit® L100-55. The enteric polymers may constitute about 1-40% of the mass of the controlled release component, preferably about 1.5-30%, most preferably about 1.5-10%. The enteric-coated polymer percentages stated above are based on a multi-particulate bead size between 0.8- 1.2 mm. If the bead size is smaller or larger, the skilled artisan will understand that the mass percentage described above should be adjusted accordingly.

[0150] The second, third or outer enteric coating should be designed to dissolve at a pH greater than 5.0, at a pH of 5.5 or higher, at a pH of 6.0 or higher or a pH of 6.5 or higher. In certain embodiments, the second, third or outer enteric coating should be designed to dissolve at a pH in the range of 5.0 to 6.4, preferably in the range of 5.0 to 6.0.

[0151] The enteric coating polymer may comprise a methacrylic acid copolymer or multiple types of methacrylic acid copolymers. The methacrylic copolymer may comprise any of Eudragit® L 30 D-55 (poly(methacrylic acid-co-ethyl acrylate) 1:1; Eudragit® L 100-55 (poly(methacrylic acid- co-ethyl acrylate) 1:1; Eudragit® L 100 (poly(methacrylic acid-co-methyl methacrylate), Eudragit® L 12,5 (poly (methacrylic acid-co-methyl methacrylate); Eudragit® S 100 (poly(methacrylic acid-co-methyl methacrylate) 1:2; Eudragit® S 12,5 (poly(methacrylic acid-co- methyl methacrylate) 1 and Eudragit® FS 30 D (poly(methyl acrylate-co-methyl methacrylate-co- methacrylic acid) 7:3:1 ; or a combination thereof.

[0152] In a preferred embodiment of present invention, the controlled release component comprises a first rate controlling coating over the drug-containing core (i.e. applied to or surrounding the drug containing core with or without a seal coating), a second coating comprising a muco-adhesive material that is applied to or surrounding the rate controlling coating (with or without a seal coating) and a third coating comprising an enteric material that is applied to or surrounding the second coating (with or without a seal coating). The first rate controlling coating may comprise a controlled release material or polymer such as ethylcellulose, cellulose acetate, Eudragit® E, Eudragit® RS, Eudragit® RL, and Eudragit® NE, or mixtures thereof. Preferably, the controlled release materials are not soluble in water at neutral pH. Additional controlled release materials or polymers that may be used are described in United States Patent No. 5,002,776 which is incorporated herein by reference. In certain embodiments the controlled release material or polymer is cellulose acetate, ethylcellulose or a mixture thereof. The first or rate controlling coating may further comprise a pore forming agent or a flux enhancer to adjust the release rate of the drug from the core. Preferably, the pore forming agent or flux enhancer is a water soluble material such as a salt, i.e., NaCl, KC1, a sugar, i.e., lactose, sucrose, mannitol, povidone, copovidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcelluose or combinations thereof. If the pore forming agent or flux enhancer is a water soluble polymer, it should have a low molecular weight such as below 100,000, preferably below 50,000 and / or should rapidly dissolve in water, i.e., 2 wt% of the water soluble polymer should dissolve in 100 ml of water within 15 minutes or less, preferably 10 minutes or less, and most preferably 5 minutes or less at 25°C.

[0153] The controlled release component may also comprise a hydrophobic controlled release material in addition to or in place of the controlled release materials described above. Examples of hydrophobic materials that can be used include beeswax, white wax, emulsifying wax, hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, cetyl alcohol, stearyl alcohol, free wax acids such as stearic acid, esters of wax acids, propylene glycol monostearate, glycerol monostearate, carnauba wax, palm wax, candelilla wax, lignite wax, ozokerite, ceresin wax, lardaceine, China wax and mixtures thereof. Other possible controlled release excipients useful in the present invention include saturated hydrocarbons having from 25 to 31 carbon atoms, saturated alcohols having from 25 to 31 carbon atoms, saturated monocarboxylic acids having from 25 to 31 carbon atoms, esters obtained from said alcohols, and monocarboxylic acids which are described in United States Patent No. 6,923,984, incorporated herein by reference.

[0154] In an alternate embodiment, the controlled release component comprises a matrix core comprising a mixture of a controlled release material, which may be the afore-described controlled release materials and / or hydrophobic materials and the drug, i.e., CD and / or LD. The matrix core may further comprise one or more pharmaceutically acceptable excipients such as lubricants, fillers, binders, disin tegrants, glidants, surfactants (sometimes referred to as wetting agents). pH adjusting agents, antioxidants or mixtures of the foregoing. In this embodiment, the matrix core may be further coated with a rate controlling coating or polymer before being coated with the muco-adhesive coating and the outer enteric coating. In another alternate embodiment, the controlled release component may incorporate a controlled release material, which may be the afore-described controlled release materials and / or hydrophobic material, into the muco-adhesive coating. The muco-adhesive material may also function as the controlled release material or contribute to the controlled release of the drug form the controlled release component.

[0155] The controlled release material may constitute about 1-35% of the mass of the controlled release component, preferably about 1-25% and most preferably about 1-20%.

[0156] The muco-adhesive coating or layer and enteric coating or layer employed in the present invention may further comprise one or more pharmaceutically acceptable excipients such as plasticizers, lubricants, fillers, binders, disin tegrants, glidants. surfactants (sometimes referred to as wetting agents), pH adjusting agents, antioxidants, or mixtures of the foregoing in addition to the muco-adhesive material and enteric material.

[0157] Some commonly known plasticizers include adipate, azelate, enzoate, citrate, stearate, isoebucate. sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citric acid esters, and those described in the Encyclopedia of Polymer Science and Technology, Vol. 10 (1969), published by John Wiley & Sons. The preferred plasticizers are triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate, diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate and combinations thereof. Depending on the particular plasticizer, amounts from about 0% to about 15%, and preferably about 0.5% to about 10%, of the plasticizer can be used based upon the total weight of the controlled release, muco-adhesive and / or enteric coating.

[0158] Lubricants useful in pharmaceutical formulations are known in the art. Examples of a suitable lubricant include, but are not limited to, stearic acid, lauric acid, myristic acid, palmitic acid, fatty acid, magnesium stearate, calcium stearate, zinc stearate, sodium stearate, Stear-O- Wet®, sodium stearyl fumarate, salt of a fatty acid, metallic salt of fatty acid, glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate, Compritol® 888 ATO, glyceride ester, sorbitan monostearate, sucrose monopalmitate, sugar ester, fatty acid ester, talc, hydrated magnesium silicate, PEG 4000, boric acid, Carbowax (PEG) 4000 / 6000, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate, Sterotex, wax, or mixture thereof.

[0159] Examples of fillers that may be employed in the composition of the present invention include sugars, such as lactose, sucrose, mannitol, dibasic calcium phosphate, microcrystalline cellulose, calcium carbonate, magnesium carbonate, calcium sulfate, powdered cellulose, silicified microcrystalline cellulose, magnesium carbonate, magnesium oxide, starch, and mixtures thereof. The filler may constitute about 1-50% of the mass of the controlled release component, preferably about 2-45% and most preferably about 5-40%. Similarly, the filler may constitute about 0-50% of the mass of the immediate release component.

[0160] Examples of binders that may be employed in the compositions of the present invention include acacia, povidone, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyethylene oxide, polymethacrylates, methyl cellulose, ethyl cellulose, pregelatinized starch, gelatin, tragacanth, zein, or mixtures thereof. Preferably, the binder is selected from povidone, hypromellose, hydroxypropyl cellulose, hydroxyethyl cellulose, polymethacrylates, methyl cellulose, gelatin and ethyl cellulose, or mixtures thereof. Especially preferred binders include water soluble binders such as povidone, hypromellose, hydroxypropyl cellulose, gelatin and mixtures thereof. The binder may constitute about 0.1-15% of the mass of the controlled release component, preferably about 0.2-10% and most preferably about 0.5-5%. The binder may constitute about 0.1-15% of the mass of the immediate release component, preferably about 0.2- 10% and most preferably about 0.5-5%.

[0161] Examples of disintegrants that may be employed in the compositions of the present invention include croscarmellose sodium, starch, crospovidone, sodium starch glycolate. alginic acid, calciumcarboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, powdered cellulose, chitosan, guar gum, magnesium aluminum silicate, methylcellulose, sodium alginate, and mixtures thereof. The disintegrant may constitute about 0.1- 15% of the mass of the immediate release component, preferably about 0.2-10% and most preferably about 0.5-10%.

[0162] Examples of glidants that may be employed in the compositions of the present invention include colloidal silicon dioxide, cornstarch, talc or mixtures thereof. One or more surfactants may also be employed in the compositions of the present invention. The surfactant may be a non-ionic surfactant or an ionic surfactant. Examples of nonionic surfactants include polyethoxylated castor oil, a polyoxyethylene alkyl ester, a polyglycolyzed glyceride, a sorbitan fatty acid ester, a glycerin fatty acid ester, a fatty acid polyglyceride, a fatty acid alcohol polyglycol ether, acetylene glycol, acetylene alcohol, an oxyalkylene block polymer, a polyoxyethylene alkyl ether, a polyoxyethylene alkylaryl ether, a polyoxyethylene styrylaryl ether, a polyoxyethylene glycol alkyl ether, a polyoxyethylene fatty acid ester, a polyoxyethylene sorbitan fatty acid ester, a polyoxyethylene glycerin fatty acid ester, a polyoxyethylene hydrogenated castor oil, a polyoxypropylene fatty acid ester, or a mixture of the foregoing. A further listing of possible non-ionic surfactants can be found on pages 1243-1249 of Martindale, The Extra Pharmacopoeia 29th ed. which is incorporated herein by reference.

[0163] In certain embodiments, the non-ionic surfactants may comprise fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates alkyl polyglycosides, mixtures thereof, and the like. Certain non-ionic surfactants include polyoxyethylene derivatives of polyol esters, such as Polysorbate 20 (TWEEN 20®), Polysorbate 40 (TWEEN 40®) Polysorbate 60 (TWEEN 60®), and Polysorbate 80 (TWEEN 80®).

[0164] In certain embodiments, the non-ionic surfactant may also comprise d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), nonoxinols, poloxamers, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, tyloxapol, and mixtures of the foregoing.

[0165] Any variety of ionic surfactants may also be incorporated into the compositions of the present invention. Suitable ionic surfactants include, but are not limited to, carboxylates such as soaps, acyl lactylates, acyl amides of amino acids, esters of sulfuric acid such as alkyl sulfates and ethoxylated alkyl sulfates, sulfonates such as alkyl benzene sulfonates, acyl isethionates, acyl taurates and sulfosuccinates, phosphates, quaternary ammonium salts, and ethoxylated amines. An example of a preferred ionic surfactant is sodium lauryl sulfate.

[0166] The surfactant may constitute about 0.1-15% of the mass of the controlled release component or the immediate release component, preferably about 0.2-10% and most preferably about 0.5-5%. Examples of pH adjusting agents that may be employed in the compositions of the present invention include pharmaceutically acceptable acids or bases which may be present to adjust the pH of intermediate compositions leading up to the final compositions and to adjust the pH of the drug environment of final compositions to a desired or optimum pH range. Representative examples of pharmaceutically acceptable acids that may be used include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, and mixtures thereof. Representative examples of pharmaceutically acceptable bases that may be used include but are not limited to ammonia, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium hydroxide, trolamine, and mixtures thereof. In certain embodiments the pH adjusting agent is an acid, preferably an organic acid and will constitute about 0.5-20% of the mass of the controlled release component, preferably about 0.75-15% and most preferably about 1-10%. Alternatively, the pH adjusting agent is an acid, preferably an organic acid and will be present in the controlled release component in a molar ratio of acid to levodopa of about 1:4 to about 4:1, preferably about 1:3 to about 3:1 and most preferably about 1:2 to about 2:1. In preferred embodiments of the present invention, the immediate release components, the controlled release components and / or the final oral dosage forms are free or substantially free of a pH adjusting acid, preferably a pH adjusting organic acid and most preferably a pH adjusting carboxylic acid such as acetic acid, citric acid, fumaric acid, malic acid, propionic acid, tartaric acid, and mixtures thereof

[0167] Examples of antioxidants that may be employed in the compositions of the present invention include ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfate, propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfate, sodium sulfate, sodium thiosulfate, sodium dioxide, tocopherol, and mixtures thereof.

[0168] In a preferred embodiment of the invention, the oral dosage forms comprise 1) one or more controlled release components comprising LD and (2) one or more immediate release components comprising LD and CD. The immediate release component comprises immediate release granules and the extended release component comprises extended release beads. The immediate-release granules comprise carbidopa and levodopa with a disintegrant polymer to allow for rapid dissolution. The extended release beads comprise levodopa, coated with a sustained-release polymer to allow for slow release of the drug, a muco-adhesive polymer to keep the beads adhered to the patient’s area of absorption longer and an enteric coating to prevent the beads from disintegrating too early in the stomach. The inactive ingredients are cellulose acetate, copovidone, croscarmellose sodium, amino methacrylate copolymer, methacrylic acid and methyl methacrylate copolymer, magnesium stearate, mannitol, microcrystalline cellulose, povidone, sodium lauryl sulfate, talc, and triethyl citrate.

[0169] In an embodiment of the invention, the CD and the LD are present in the dosage form of the invention in a weight ratio of about 1:1 to about 1:10, preferably about 1:3 to about 1:5 and most preferably about 1:4. Certain embodiments comprise CD and LD in a ratio of about 1:4 and wherein all or substantially all of the CD is in the immediate release component.

[0170] Examples of useful amounts of LD to CD include: (a) about 140 mg LD and about 35 mg of CD; (b) about 210 mg LD and about 52.5 mg of CD; (c) about 280 mg LD and about 70 mg of CD; and (d) about 350 mg LD and about 87.5 mg of CD. The foregoing values are based on the weight of anhydrous CD. If a monohydrate form of CD is employed the amounts will be slightly higher. For example, 35 mg of anhydrous CD is equivalent to 37.79 mg of CD monohydrate; similarly, 70 mg of anhydrous CD is equivalent to 75.58 mg of CD monohydrate.

[0171] In an embodiment of the invention, the immediate release component may comprise less LD than the controlled release component. For example, the ratio of LD in the immediate release component to that in the controlled release component can be in the range of 0.15 to 0.49. For example, a ratio in weight of LD in the controlled release component: immediate release component is at least about 2: 1, most preferably 3:1. Preferably the amount of LD in the immediate release component should provide a therapeutic dose of LD within one hour or less after administration of the dosage form, preferably within 45 minutes or less after administration and most preferably about 30 minutes or less after administration.

[0172] As discussed above, in certain embodiments comprising a decarboxylase inhibitor such as CD, all or substantially all of decarboxylase inhibitor should be in the immediate release component. The amount of immediate release decarboxylase inhibitor, preferably CD, in the immediate release component(s) should range from about 75% to about 100% based on the total amount of decarboxylase inhibitor in the oral dosage forms, preferably about 80% to 100%, and most preferably about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99 or 100%. In a most preferred embodiment, the amount of immediate release decarboxylase inhibitor ranges from 95% to 100% based on the total amount of decarboxylase inhibitor in the oral dosage forms.

[0173] In one embodiment of the invention, the controlled release component comprises one or more, beads, pellets, tablets, mini-tablets or granules having a size that passes through 12, 14, or 16 mesh but may be retained on 18, 20 or 25 mesh screens. Further, the beads, pellets, tablets, mini-tablets or granules may have a size that passes through 14 mesh but may be retained on 18 or 25 mesh screens. In certain embodiments, the controlled release component comprises one or more, beads, pellets, tablets, mini-tablets or granules having a size that passes through 12 mesh screen and retained on 24 mesh screen. In certain embodiments, the dosage forms of the invention comprise a plurality beads, pellets, tablets, mini-tablets or granules having a size that passes through 12, 14, or 16 mesh but may be retained on 18, 20 or 25 mesh screens. In certain embodiments, the dosage forms of the invention comprise a plurality beads, pellets, tablets, minitablets or granules having a size that passes through 12 mesh screen but may be retained on 24 mesh screen.

[0174] The controlled release component will have an in vitro dissolution profile showing minimal release of the LD at pH 1.0 and extended release of the LD near neutral pH, for example at or near pH 7. For example, minimal release may entail less than 20% release of LD, preferably less than 10%, most preferably less than 5% using United States Pharmacopeia (USP) I dissolution method at agitation speed of 75 rpm in Simulated Gastric Fluid (pH 1.0, without enzyme) for 2 hrs. Further, extended release may involve release at over at least four and up to an additional 8 hours at or near pH 7, upon changing to Simulated Intestinal Fluid (pH 7.0, without enzyme) after first 2 hrs. in Simulated Gastric Fluid (pH 1.0, without enzyme) using USP I dissolution method at agitation speed of 75 rpm. Further still, as used here, at or near pH 7 includes a pH at or about pH 6.5. 6.6, 6.7, 6.8 6.9, 7.1, 7.2, 7.3, 7.4, 7.5 or 7.6.

[0175] The oral controlled release dosage forms useful in the present invention should comprise one or more immediate release components and one or more controlled release components wherein following administration to a human patient the immediate release component(s) should provide a therapeutic dose of LD within one hour or less after administration of the dosage form, preferably within 45 minutes or less after administration and most preferably about 30 minutes or less after administration. To obtain this therapeutic level, the controlled release component(s) should exhibit the following in vitro release profiles when tested using a USP Type I or II apparatus, at 37°C, with a rotational speed of 75 rpms and 900 ml of an aqueous media with a pH between 6.8 and 7.4 and preferably at a pH of 7:

[0176] The amount of LD released in the above table is based on the total amount of LD present in the controlled release component(s). In certain embodiments the controlled release component(s) should also release less than 25% of the LD, preferably less than 20% and most preferably less than 15% when tested using a USP Type I or II apparatus, at 37°C. with a rotational speed of 75 rpms and 900 ml of an aqueous media with a pH of 1 for 2 hours.

[0177] In certain embodiments the oral controlled release dosage forms useful in the present invention comprises: (i) one or more immediate release components comprising LD and CD and (ii) one or more controlled release components, i.e., controlled release particles such as beads, pellets, tablets, mini-tablets, or granules comprising: (a) a core comprising LD, optionally CD and at least one pharmaceutically acceptable excipient, (b) a layer or coating surrounding the core comprising a muco-adhesive material and (c) an outer coating comprising an enteric material surrounding the muco-adhesive coating (b). This embodiment may also comprise a controlled release material in the core or a coating comprising a controlled release material surrounding the core and beneath the coating comprising the muco-adhesive material as well as cosmetic and / or non-functional seal coatings as previously described. When this embodiment of the dosage form of the present invention is tested using a USP Type I or Type II apparatus with 500-900 mL of an aqueous medium with a pH from about 1 to about 7.5, about 75% to 100% of the CD is released within 30 minutes, preferably about 85% to 100% of the CD is released within 30 minutes and most preferably about 90% to 100% of the CD is released within 30 minutes. In addition, when this embodiment of the dosage form is tested using a USP Type I or Type II apparatus and 500- 900 mL of an aqueous medium with a pH from about 1 to about 4.0, about 15% to 45% of the LD is released within 30 minutes, preferably about 20% to 40% of the LD is released within 30 minutes and most preferably about 25% to 35% of the LD is released within 30 minutes. When this embodiment of the dosage form is tested using a USP Type I apparatus, at 37°C+ 0.5°C, with a rotational speed of 75 rpms and 500-900 ml of simulated gastric fluid for 2 hours and pH 6.8 phosphate buffer thereafter the following LD in vitro profile is exhibited:

[0178] NLT = Not Less Than.

[0179] In a further embodiment, the present invention comprises: a) one or more immediate release components as previously described; b) one or more controlled release components as previously described and c) one or more enteric coated components. The enteric coated component comprises a core comprising LD or ester of LD or salt thereof and / or a decarboxylase inhibitor and at least one pharmaceutically acceptable excipient as previously described and an enteric coating. The enteric coated component will release 100% of the LD and / or a decarboxylase inhibitor within 90 minutes, preferably 60 minutes and most preferably within 45 minutes when tested using a USP Type I or II apparatus, at 37°C, with a rotational speed of 75 rpms and 900 ml of an aqueous media with a pH between 6.8-7.4, preferably at pH 7. The enteric coated component will also release less than 25% of the LD, preferably less than 20% and most preferably less than 15% when tested using a USP Type I or II apparatus, at 37°C, with a rotational speed of 75 rpms and 900 ml of an aqueous media with a pH of 1.

[0180] The LD released from the controlled release component(s) may produce an in vivo LD a plasma profile (e.g., mean in vivo LD plasma profile) comprising a peak occurring not before about two hours after administration to a subject and provides at least three hour duration for LD plasma concentration above 50% the maximum value of the peak concentration (Cmax). In another embodiment, in the plasma profile, the peak occurs after about one and a half hours after administration to the subject and exhibits at least a four-hour duration for LD plasma concentration at or above 50% of Cmax. By way of example, the profile may be achieved under fasting conditions.

[0181] When the composition of the invention comprises an immediate release component and a controlled release component, the in vivo LD plasma profile following oral administration of the dosage form of the present invention to a subject may comprise a time of administration of an oral dosage form; an LD plasma concentration corresponding to Cmax occurring within about 6 hours or 7 hours after administration of the dosage form; a mean time to reach 50% of Cmax within one hour of administration, more preferably within 30 minutes. The time to 50% of Cmax is less than one hour and 50% of Cmax is maintained for at least 4 hours, e.g., about 4.5 hours or more. The time after administration of the dosage form when the maximum plasma concentration is reached (Tmax) is between 30 minutes and 7 hours. Preferably, the LD plasma level is maintained at or above 50% of Cmax for at least about 4.5 hours, more preferably, for at least about 5 hours, even more preferably, for at least about 5.5 hours, and most preferably for at least about 7.0 hours.

[0182] In patients with PD, multiple-dose pharmacokinetics was comparable to single-dose pharmacokinetics, i.e., there was minimal accumulation of levodopa. When the composition of the invention comprises an immediate release component and a controlled release component, the in vivo LD plasma profile following oral administration of the dosage form of the present invention to a subject may comprise an LD fluctuation index that may range from 0.5 to 1.59, preferably about 0.7 to about 1.8 and more preferably about 1.7 compared to about 2.7 for immediate release CD-LD compositions. The fluctuation index can be determined the following formula (Cmax- Cmin) / Cavg, wherein Cmax is the maximum or peak LD concentration, Cmin the minimum LD concentration and Cavg is the average LD concentration over the entire measurement interval. In certain embodiments, the fluctuation index is determined at steady state or about 10 to about 15 days after treatment with the formulations described herein and preferably is measured during the time period beginning from the first morning dose and 6, 7, 8, 9, 10, 11 or 12 hours after the first morning dose. In a preferred embodiment, variation in levodopa peak to trough plasma concentrations at steady-state defined as (Cmax-Cminj / Cavg is about 1.7 for the combination composition compared to approximately 2.7 for immediate-release carbidopa-levodopa. It is understood by those skilled in the art that the pharmacokinetic parameters recited herein may be obtained by single or multidose dose studies to healthy subjects or PD patients unless specifically stated. It is also understood that the pharmacokinetic parameters recited herein may be obtained under fed or fasting conditions. It is further understood that the pharmacokinetic parameters recited herein are mean values, unless specifically stated, obtained from single or multidose studies employing at least 3 or more subjects or patients.

[0183] The combination of immediate release components and controlled release components of the invention provide the near infusion-like profile. The LD Cmax itself is not clinically relevant. What is clinically relevant is the time to reach a therapeutic level of LD (e.g., an LD level of 50% Cmax) and the time maintained at or above the therapeutic level (e.g., 50% Cmax). The short time to reach a therapeutic LD level is associated with a faster “on” time for PD patients, whereas the prolonged period at or above therapeutic levels provides the desired steady “infusion-like” profile.

[0184] It is an advantage of the present invention to provide a sustained LD plasma concentration for a duration greater than 4.5 hrs. and a more consistent duration with percent coefficient of variation (CV) of mean duration of LD plasma concentrations > 50% Cmax of less than 35%, preferably less than 30%.

[0185] In certain embodiments, the dosage forms that are useful in the dosing regimen of the present invention are described in U.S. Patent No. 10,292,935 and U.S. Published Patent Application No. 2020 / 0009062 (U.S. Serial No. 16 / 573,634 filed September 17, 2019) which are incorporated herein by reference.

[0186] Preferred compositions of the present invention include:

[0187] Embodiment A - A multi-particulate composition comprising: a) one or more immediate release component(s) comprising LD and / or CD and optionally at least one pharmaceutically acceptable excipient as previously described and b) one or more controlled release component(s) comprising LD, a muco-adhesive material, a controlled release material and an enteric coating surrounding the controlled release component. The mucoadhesive material may be: i) mixed with the LD in the matrix core, ii) applied as a coating or layer onto the core comprising the LD and at least one pharmaceutically acceptable excipient; iii) incorporated or mixed into the controlled release coating or layer or iii) a combination of (i). (ii), and / or (iii). The controlled release material may be: i) mixed with the LD to form a controlled release matrix core, ii) applied as a coating or layer onto the core comprising the LD and at least one pharmaceutically acceptable excipient; iii) incorporated or mixed into the muco-adhesive coating or layer or iv) a combination of (i), (ii) and / or (iii). Cosmetic and / or seal coatings as previously described may also be employed in immediate release and controlled release components of this embodiment.

[0188] Embodiment B - A multi-particulate composition comprising: a) one or more immediate release component(s) comprising LD and / or CD and optionally at least one pharmaceutically acceptable excipient as previously described and b) one or more controlled release component(s) comprising controlled release beads, pellets, tablets, mini-tablets, or granules wherein the beads, pellets, tablets, mini-tablets, or granules comprise a core of LD free or substantially free of CD and at least one pharmaceutically acceptable excipient as previously described, a muco-adhesive coating or layer applied to and / or surrounding the core and an enteric coating surrounding the muco-adhesive coating or layer wherein the controlled release beads, pellets, tablets, mini-tablets, or granules also comprises a controlled release material. The controlled release material may be: i) mixed with the LD to form a controlled release matrix core, ii) applied as a coating or layer onto the core comprising the LD and at least one pharmaceutically acceptable excipient; iii) incorporated or mixed into the muco-adhesive coating or layer or iv) a combination of (i), (ii) and / or (iii). Cosmetic and / or seal coatings as previously described may also be employed in immediate release and controlled release components of this embodiment. In certain aspects of this multi-particulate composition, the composition is free or substantially free of a COMT inhibitor. In certain further aspects of this multi-particulate composition, the composition is free or substantially free of an organic acid, such as tartaric acid.

[0189] Embodiment C - A multi-particulate composition comprising: a) one or more immediate release component(s) comprising of LD, CD and optionally at least one pharmaceutically acceptable excipient as previously described; b) one or more controlled release component(s) free or substantially free of CD comprising beads, pellets, mini-tablets or granules wherein the beads, pellets, tablets, mini-tablets or granules comprise a core of LD and at least one pharmaceutically acceptable excipient as previously described, a muco-adhesive coating or layer applied to and / or surrounding the core and an enteric coating surrounding the muco-adhesive coating or layer wherein the controlled release beads, pellets, tablets, mini-tablets or granules also comprises a controlled release material and c) an enteric coated component comprising a plurality of enteric coated beads, pellets, mini-tablets or granules comprising a core comprising LD and / or a decarboxylase inhibitor and at least one pharmaceutically acceptable excipient as previously described and an enteric coating surrounding the core. The controlled release material employed in the controlled release component may be: i) mixed with the LD and at least one pharmaceutically acceptable excipient to form a controlled release matrix core, ii) applied as a coating or layer onto the core of the LD and at least one pharmaceutically acceptable excipient; iii) incorporated or mixed into the muco-adhesive coating or layer or iv) a combination of (i), (ii) and / or (iii). In certain aspects of this multi-particulate composition, the composition is free or substantially free of a COMT inhibitor. In certain further aspects of this multi-particulate composition, the composition is free or substantially free of an organic acid, such as tartaric acid.

[0190] Embodiment D - A multi-particulate capsule composition wherein the contents of the capsule comprise (a) plurality of controlled release LD components and (2) one or more immediate release components comprising LD and CD. The plurality of controlled release components comprise, (a) a core comprising levodopa, at least one filler, at least one binder and at least one surfactant, (b) a controlled release layer surrounding or applied to the core wherein the controlled release layer comprises a controlled release material surrounding the core (c) a muco-adhesive layer surrounding or applied to the controlled release layer wherein the muco-adhesive layer comprises a muco-adhesive material and (d) an enteric layer applied to or surrounding the muco- adhesive layer. In certain aspects the amount of levodopa in the capsule is 95 mg to 390 mg ± 10% of levodopa and the amount of carbidopa in the capsule is 23.75 mg to 97.5 mg ± 10%. based on the anhydrous weight of carbidopa. In certain aspects of this multi-particulate composition, the composition is free or substantially free of a COMT inhibitor. In certain further aspects of this multi-particulate composition, the composition is free or substantially free of an organic acid, such as tartaric acid. In certain aspects of this multi-particulate composition, the core comprises at least one filler, at least one binder and at least one surfactant. The filler(s) may comprise about 1 wt% to about 50 wt% of the total weight of the controlled release components, the binder(s) may comprise about 0.1 wt% to about 15 wt% of the total weight of the controlled release components and the surfactant(s) may comprise about 0.1 wt% to about 15 wt% of the total weight of the controlled release components. The controlled release material employed in the controlled release layer is a polymer such as cellulose acetate or ethylcellulose. EXAMPLES

[0191] EXAMPLE 1

[0192] Immediate release granules with the following composition were prepared:

[0193] *monohydrate

[0194] The granules were prepared mixing using the procedure similar to that described above in Example 5, preparation of Component 1 of U.S. Patent No. 10.292,935 which is incorporated herein by reference. Generally, the CD, LD and croscarmellose sodium were mixed in a high shear granulator and wet granulated with a 5 wt% aqueous solution of povidone. After granulation, the wet granules were passed through a Comil with a 0.375 inch screen and dried in a fluidized bed. The dried granules were milled with a Fitzmill equipped with a 30 mesh screen then blended with magnesium stearate.

[0195] EXAMPLE 2

[0196] Controlled release particles (beads) with the following composition were prepared:

[0197] The controlled release beads were prepared by a process similar to that described in Example 5, Preparation of Component II of U.S. Patent No. 10,292,935 which is incorporated herein by reference. Generally, the LD, microcrystalline cellulose, mannitol, and sodium lauryl sulfate were mixed in a high shear granulator and wet granulated with a 5 wt% aqueous solution of povidone. After granulation, the wet granules were extruded using an extruder equipped with a 0.9 mm hole size screen and the extrudate collected and loaded into a spheronizer equipped with a 3 mm cross hatch disc. The wet spheronized beads were dried in a fluidized bed drier. The dried beads were sieved through 16 market grade (MG) and 24 MG mesh screens and the beads passing through the 16 MG screen but remaining on the 24 MG screen were collected.

[0198] The collected beads were coated with a solution comprising cellulose acetate, copovidone, acetone and isopropyl alcohol using a fluidized bed coating apparatus. After the target coating solution was applied, the controlled release coated beads were dried in the fluidized bed. The dried controlled release beads were sieved through 14 MG and 24 MG mesh screens and the beads remaining on the 24 MG screen were collected. The collected controlled release coated beads were coated with a muco-adhesive solution comprising Eudragit E100, talc, acetone and isopropyl alcohol in the fluidized bed. After the target muco-adhesive coating solution was applied to the controlled release coated beads, the muco-adhesive coated beads were dried in the fluidized bed. The dried muco-adhesive coated beads were coated with an enteric coating solution comprising Eudragit L 100, talc triethyl citrate, acetone and isopropyl alcohol in a fluidized bed. After the target enteric coating solution was applied to the muco-adhesive coated beads, the enteric coated beads were dried in the fluidized bed. The dried enteric coated beads were sieved through 14 MG and 24 MG mesh screens and the beads remaining on the 24 MG screen were collected. The collected beads were blended with talc.

[0199] EXAMPLE 3

[0200] The immediate release component of Example 1 and the controlled release beads of Example 2 were blended to create a mixture with 67.49 wt% controlled release beads and 32.51% immediate release granules. The mixture was filled into hard gelatin capsules containing (a) 180 mg LD and 45 mg CD and (b) 270 mg LD and 67.5 mg CD. The CD weight is based on CD anhydrous.

[0201] EXAMPLE 4

[0202] Controlled release particles (beads) with the following composition were prepared according to the procedure of Example 2:

[0203] EXAMPLE 5

[0204] The immediate release component of Example 1 and the controlled release beads of Example 4 were blended to create a mixture with 68.11 wt% controlled release beads and 31.89% immediate release granules. The mixture was filled into hard gelatin capsules containing (a) 180 mg LD and 45 mg CD and (b) 270 mg LD and 67.5 mg CD. The CD weight is based on CD anhydrous.

[0205] EXAMPLE 6

[0206] Controlled release particles (beads) with the following composition were prepared according to the procedure of Example 2:

[0207] EXAMPLE 7

[0208] The immediate release component of Example 1 and the controlled release beads of Example 6 were blended to create a mixture with 67.5 wt% controlled release beads and 32.5% immediate release granules. The mixture was filled into hard gelatin capsules containing (a) 140 mg LD and 35 mg CD; (b) 210 mg LD and 52.5 mg CD; (c) 280 mg LD and 70 mg CD; and (d) 350 mg LD and 87.5 mg CD. The CD weight is based on CD anhydrous. These dosage forms contained approximately 25% of the total LD content in the immediate release component; 75% of the total LD content in the controlled release component and 100% of the total CD content in the immediate release component.

[0209] The 210 mg LD and 52.5 mg CD; 280 mg LD and 70 mg CD; and 350 mg LD and 87.5 mg CD capsules prepared in this Example were tested using a USP Type I apparatus, at 37°C± 0.5°C, with a rotational speed of 75 rpms and 900 ml of simulated gastric fluid for 2 hours and pH 6.8 phosphate buffer thereafter. The 140 mg LD and 35 mg CD capsules prepared in this Example were tested using a USP Type T apparatus, at 37°C+ 0.5°C, with a rotational speed of 75 rpms and 900 ml of simulated gastric fluid for 2 hours and pH 6.8 phosphate buffer thereafter. The results of the in vitro dissolution testing were as follows:

[0210] EXAMPLE 8

[0211] A multi-center, open-label Phase 4 study to evaluate the efficacy and safety of the controlled release dosage form described in Example 7 was conducted to evaluated the controlled release dosage form of Example 7 under real world conditions in PD patients. In the study approximately 220 PD patients who were currently treated with oral CD-LD dosage forms and experience, on average, at least 2.5 hours of "Off" time per day were enrolled. The study will consist of:

[0212] (i) a screening period of up to 28 days:

[0213] (ii) a baseline dose conversion period wherein eligible PD patients will be converted from their current CD-LD therapy to treatment with the multi-particulate CD-LD dosage form of Example 7;

[0214] (iii) a dose optimization period wherein the dose of the CD-LD dosage form of Example 7 is optimized over a period of up to 5 weeks; (iv) a dose stabilization period wherein the patient received the optimized dose of the CD- LD dosage form of Example 7 described in period (iii) for a period of at least one week (7 days);

[0215] (v) a test treatment period wherein the patient receives the optimized dose of the CD-LD dosage form of Example 7 from step (iv) for a period of about 360-365 days.

[0216] These portions of the study are graphically summarized in Figure 1, wherein the dosage form of Example 7 is referred to as CREXONT®

[0217] The Screening Period (i)

[0218] The Screening Period (i) may be from 1 to 28 days wherein the PD patient is evaluated for inclusion in the study. Each patient must meet the following to be included in the study:

[0219] 1. Patients with PD consistent with the United Kingdom Parkinson’s Disease Society Brain Bank Diagnostic Criteria and who are being treated with stable regimens of oral CD-LD;

[0220] 2. Patients with a score of at least 20 units at Screening on the Movement Disorder Society- Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III total score in the “Off’ state;

[0221] 3. Patients with predictable “Off’ periods at Screening defined by a score of 1 or 2 on Item #4.5 (Complexity of Motor Fluctuations) of the MDS-UPDRS Part IV B (Motor Fluctuations);

[0222] 4. By history, for the 4 weeks (28 days) prior to Screening, the patient experiences: a. Daily predictable “wearing-off’ episodes with periods of worsening motor symptoms; b. An average of at least 2.5 cumulative hours per day of “Off’ time, during the hours the patient is awake.

[0223] 5. At Screening, the patient is able to differentiate “On” state from “Off’ state as determined by at least 75% concordance with a trained rater (i.e., investigator or qualified and certified site staff) in “On / Off ’ ratings for 8 ratings over a 4-hour training period. The concordance must include at least one “On” and one “Off’ rating in this 4-hour training period. a. If the concordance is less than 75%, or if it does not include at least one “On” and one “Off’ rating within the first 4-hour training period, a second 4-hour training period should be conducted with the patient before being considered for inclusion in the study; b. If during the second 4-hour training-period a concordance of at least 75% is also not achieved, or if it does not include at least one “On” and one “Off’ rating, the patient cannot be included in the study.

[0224] 6. At baseline (Visit 1), review of the 3-day PD diaries confirms the following: a. The patient is able to properly complete the PD diaries with valid entries. Inability to properly complete the diaries is indicated when more than 1 day of a diary is not returned or if more than 1 day of the diary is not valid (i.e., more than 2 hours [4 half-hour periods] of the 24-hour diary day are missing; and b. The patient has an average of at least 2.5 hours per day of “Off’ time, during the hours the patient is awake, over the 3 PD diary days; and c. The patient has at least 1.5 hours of cumulative “Off’ time, during the hours the patient is awake, on each of the 3 PD diary days.

[0225] 7. The patient is responsive to CD-LD therapy and currently being treated on a stable regimen of oral CD-LD for at least 4 weeks (>28 days) prior to baseline (Visit 1) and meets the following criteria: a. Daily Dose Requirements: i. All patients should be taking at least 100 mg of an immediate release ("IR") CD- LD tablet such as SINEMET® or a U.S. FDA approved AB rated generic, or 195 mg of RYTARY® or a U.S. FDA approved AB rated generic ( RYTARY® is a U.S. FDA approved controlled release CD-LD dosage form as described in Example 9 of U.S. Patent No. 9,463,246) for the first morning dose; ii. For patients taking IR CD-LD (with or without a bedtime dose of a controlled release (“CR”) CD-LD matrix tablet such as SINEMET® CR or a U.S. FDA approved AB rated generic): 1 . Require a total daily dose of at least 300 mg of LD and a maximum total daily dose of <1200 mg LD (from IR CD-LD alone or from IR CD-LD in combination with a single daily bedtime dose of CR CD-LD);

[0226] 2. The maximum individual dose allowed is 250 mg of LD;

[0227] 3. The minimum individual dose should be at least 100 mg of LD. iii. For patients using a COMT inhibitor:

[0228] 1. Require a total daily dose of at least 300 mg of LD and a maximum total daily dose of <1000 mg LD;

[0229] 2. The maximum individual dose is 200 mg of LD. iv. For patients using RYTARY®:

[0230] 1. Require a total daily dose of at least 585 mg of LD and a maximum total daily dose of <2100 mg LD;

[0231] 2. The maximum individual dose is 685 mg of LD. b. Dose Frequency Requirement: i. If a patient is using IR / CR CD-LD alone or in combination with a COMT inhibitor, then the dosing frequency must be 3 to 6 times daily; ii. If a patient is using RYTARY®, then the dosing frequency must be 3 to 4 times daily.

[0232] 8. Patient is able and willing to provide written informed consent prior to the conduct of any study- specific procedures;

[0233] 9. Patient is able and willing to comply with the protocol, including completion of PD diaries, questionnaires, and available for all study visits and telephone calls;

[0234] 10. Patients who have participated in prior CREXONT® clinical studies are allowed to be enrolled in this Phase 4 study.

[0235] Patients meeting any of the following criteria will be excluded from the study: 1. Patient who, in the opinion of the clinical investigator, should not participate in the study based on the U.S. FDA approved CREXONT® Prescribing Information (copy of the U.S. FDA approved CREXONT® Prescribing Information is incorporated herein by reference):

[0236] 2. Patient had a prior neurosurgical treatment for PD (e.g., deep brain stimulation [DBS] surgery or neurosurgical ablation treatment procedures) or if such procedure is planned or anticipated prior to Visit 4 (Day 42) of the study;

[0237] 3. Patient received the following within 4 weeks (<28 days) prior to baseline (Visit 1): a. Any doses of a CR CD-LD apart from a single daily bedtime dose; b. the U.S. FDA approved DUOPA® (CD-LD suspension) or a U.S. FDA approved AB rated generic; c. Nonselective monoamine oxidase inhibitor (MAOI); d. Rescue medication used to treat “Off’ episodes for example: apomorphine or inhaled LD (INBRIJA®); e. Received any investigational drugs within 30 days or 5 times the half-life, whichever is longer, prior to baseline (Visit 1).

[0238] 4. Patient who, in the opinion of the clinical investigator, should not participate in the study (e.g., based on clinical assessment, patient does not adequately comprehend the terminology needed to complete the PD diary and patient-reported outcomes, or any other reason);

[0239] 5. Employees or family members of the investigator, or study site staff, or Sponsor.

[0240] The Baseline-Dose Conversion Period (ii)

[0241] Patients selected during the screening period (i) will be instructed to discontinue their prior oral CD-LD medications and COMT inhibitors. The patients will receive the multi-particulate dosage form of Example 7, i.e. CREXONT®, to begin administration the following day (Day 1). Investigators should follow the dose conversion strategy as appropriate for their condition and guided by the US FDA approved CREXONT® Prescribing Information. The initial dose conversion will be based on the FDA approved CREXONT® Prescribing Information as follows:

[0242] 1. Conversion from Immediate-Release (IR) CD-LD to the dosage form of Example 7 • The dosages of IR CD-LD products are not substitutable on a 1:1 basis with the dosage form of Example 7;

[0243] • To convert patients from IR CD-LD to the dosage form of Example 7, the following steps will be used: a. Determine the patient’s total daily dosage of IR LD; b. Determine the patient’s most frequent single dose of IR LD. If more than one dose corresponds to the most frequent, use the highest of the doses; c. Find the values from ‘a’ and ‘b’ in below table to determine the recommended starting dosage of dosage form of Example 7 and dosing frequency.

[0244] TABLE 1

[0245] 2. Conversion of Controlled-Release (CR) CD-LD to Example 7

[0246] For patients who are on a single bedtime dose of CR CD-LD, the below step will be followed:

[0247] • For conversion of CR CD-LD to Example 7, discontinue the CR CD-LD dose and substitute it with a 1:1 milligram-equivalent dose of IR CD-LD for calculations of conversion; • The patient will be converted as if all their doses were IR CD-LD, as per the steps outlined in above in Period (ii) item 1.

[0248] 3. Conversion of CD-LD + COMT Inhibitor to Example 7

[0249] Patients on CD-LD with a COMT inhibitor will discontinue their COMT inhibitor and will be converted based on an estimation by multiplying the current most frequent single LD dose by 1.33 (if on entacapone), and by 1.5 (if on opicapone) as shown in the Table below. This conversion is based upon the LD-equivalent daily dose for each patient. The appropriate dose may be further determined by the investigator at their discretion.

[0250] TABLE 2

[0251] After 1 to 3 days the dose and / or frequency and / or time of dosing during the day, maybe be adjusted based on the patient’s clinical response and tolerability. Similar adjustments may be between Visit 1 (Baseline) and Visit 2 and between Visit 2 and day 35.

[0252] 4. Conversion from RYTARY® to Example 7

[0253] For patients converting from RYTARY® or a U.S. FDA approved AB rated generic to Example 7 will be initiated on an approximately 1:1 basis (using the LD component for conversion) as shown in the Table below.

[0254] TABLE 3

[0255] After 1 to 3 days the dose and / or frequency and / or time of dosing during the day, maybe be adjusted based on the patient’s clinical response and tolerability. Similar adjustments may be made between Visit 1 (Baseline) and Visit 2.

[0256] The Dose Optimization Period (iii)

[0257] 1. Between Baseline / Visit 1 (Day -1) and Visit 2 (Day 14 ± 3): Telephone Follow-up

[0258] • Between baseline (Visit 1) and Visit 2, the investigator may adjust dosing of Example 7 to achieve the optimal balance of efficacy and tolerability;

[0259] • Patients will begin administration of Example 7 on Day 1 based on the initial dose conversion as outlined above in Period (ii);

[0260] • Between baseline (Visit 1) and Visit 2, the investigator or site staff will be in frequent contact (every 1 to 3 days) with the patient to assess the need for changes in the Example 7 dosing regimen (i.e., changes in dose strength [mg], and / or dosing frequency, and / or time of dosing throughout the day) with the goal of minimizing “Off” time without causing troublesome dyskinesia. Any changes to the dosing regimen should only be made by the investigator or qualified site personnel and will be recorded.

[0261] 2. Visit 2 (Day 14 ± 3): Clinic Visit

[0262] • Patients will continue to take Example 7. If any adjustments to the Example 7 dosing regimen are made, patients will begin the new dosing regimen the same day (Day 14). Investigators can optimize the dosing regimen (i.e.. changes in dose strength [mg], and / or dosing frequency, and / or time of dosing throughout the day) as appropriate for the condition of each patient and guided by the FDA approved CREXONT® Prescribing Information, in order to achieve the optimal balance of efficacy and tolerability for each patient. Any changes to the dosing regimen should only be made by the investigator or qualified site personnel and will be recorded. 3. Between Visit 2 (Day 14 + 3) and Visit 3 (Day 28 ± 3): Telephone Follow-up

[0263] • Between Visit 2 and Visit 3, the investigator may adjust dosing of Example 7 to achieve the optimal balance of efficacy and tolerability;

[0264] • Between Visit 2 and Visit 3, the investigator or site staff will be in contact

[0265] (every 3 to 5 days) with the patient to assess the need for changes in the dosing regimen (i.e., changes in dose strength [mg], and / or dosing frequency, and / or time of dosing throughout the day) with the goal of minimizing “Off’ time without causing troublesome dyskinesia. Any changes to the dosing regimen should only be made by the investigator or qualified site personnel and will be recorded.

[0266] 4. Visit 3 (Day 28 ± 3): Clinic Visit

[0267] • Patients will continue to take Example 7. If any adjustments to the Example 7 dosing regimen are made, patients will begin the new dosing regimen the same day (Day 28). Investigators can optimize the dosing regimen (i.e., changes in dose strength [mg], and / or dosing frequency, and / or time of dosing throughout the day) as appropriate for the condition of each patient and guided by the FDA approved CREXONT® Prescribing Information, in order to achieve the optimal balance of efficacy and tolerability for each patient. Any changes to the dosing regimen should only be made by the investigator or qualified site personnel and will be recorded.

[0268] 5. Between Visit 3 (Day 28 ± 3) and End of 5-week Example 7 Dosing Regimen Optimization Period (Day 35 ± 3): Telephone Follow-up

[0269] • Between Visit 3 and the end of the Example 7 dosing regimen optimization period (Day 35), the investigator or site staff will be in contact (every 3 to 5 days) with the patient to assess the need for changes in Example 7 dosing regimen (i.e., changes in dose strength [mg], and / or dosing frequency, and / or time of dosing throughout the day) with the goal of minimizing “Off’ time without causing troublesome dyskinesia. Any changes to the dosing regimen should only be made by the investigator or qualified site personnel and will be recorded.

[0270] The Dose Stabilization Period (iv)

[0271] • On Day 35 + 3 days, investigator or site staff will contact patients via a telephone call or video call to inform the patient that their Example 7 dosing regimen must remain stable for the next 7 days;

[0272] • However, if during the call, it becomes apparent that any adjustments to the Example 7 dosing regimen (i.e., changes in dose strength [mg], and / or dosing frequency, and / or time of dosing throughout the day) need to be made, patients will begin the new dosing regimen the following day (Day 36 ± 3 days) and remain stable on the new dosing regimen for a minimum of 7 days. Investigators can optimize the dosing regimen as appropriate for the condition of each patient and guided by the FDA approved CREXONT® Prescribing Information, in order to achieve the optimal balance of efficacy and tolerability for each patient. Any changes to the dosing regimen should only be made by the investigator or qualified site personnel and will be recorded;

[0273] • The Example 7 dosing regimen should remain stable between Day 36 ± 3 and Visit 4 (Day 42 + 3) for a minimum of 7 days. Any changes made in this 1-week period will lead to discontinuation of the patient from the study.

[0274] The Test Treatment Period (v)

[0275] During the 12-month (i.e.. 360-365days) of the test treatment period, it is hoped the Example 7 dosing regimen will not require changes for the majority of patients.

[0276] If a change in dosing regimen (i.e., changes in dose strength [mg], and / or dosing frequency, and / or time of dosing throughout the day) is required for a patient, adjustments may be made during the test treatment period as appropriate for the condition of each patient and guided by the FDA approved CREXONT® Prescribing Information to achieve optimal balance of efficacy and tolerability for a patient. Any changes to the dosing regimen should only be made by the investigator or qualified site personnel and will be recorded.

[0277] Patients will continue to take Example 7 as established during the dose stabilization period (iv) and be should report for a clinical visit at one or more of the following time points:

[0278] • Visit 4 (Day 42 ± 3);

[0279] • Visit 5 (Day 132 + 7);

[0280] • Visit 6 (Day 222 ± 7);

[0281] • Visit 7 (Day 312 + 7); and

[0282] • Visit 8 (Day 402 + 7) End of Study (EOS) / Early Termination (ET). Visit 8 (Day 402 ± 7) or ET visit will be the final study visit at which time point:

[0283] • The patients should discontinue study drug (Example 7);

[0284] • The patients will be assessed by the investigator or site staff and receive instructions and / or a prescription for their PD medications post-study; and

[0285] • The post-study PD medication may be Example 7 as prescribed by the investigator or site staff, and as dispensed by the patient’s own pharmacy.

[0286] Once the study is concluded or at appropriate intermediate time points the following efficacy assessments will be evaluated:

[0287] • PD diary;

[0288] • MDS-UPDRS;

[0289] • Patient Global Impression of Change (PGI-C);

[0290] • Patient Global Impression of Severity (PGI-S);

[0291] • Clinical Global Impression of Change (CGI-C);

[0292] • Clinical Global Impression of Severity (CGI-S);

[0293] • 12-item Zarit Burden Interview (ZB I- 12);

[0294] • Change from baseline (Visit 1) to Visit 4 in “Good On” time per the PD diary.

[0295] • Change from baseline (Visit 1) to Visit 4 in “Off’ time per the PD diary.

[0296] • Change from baseline (Visit 1) to Visit 2, Visit 3, Visit 5, Visit 6, Visit 7, and Visit 8 in

[0297] “Good On” time;

[0298] • Change from baseline (Visit 1) to Visit 2, Visit 3, Visit 5, Visit 6, Visit 7. and Visit 8 in “Off’ time;

[0299] • Change from baseline (Visit 1) to Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8 in “Asleep” time;

[0300] • Change from baseline (Visit 1) to Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8 in “On time with non-troublesome dyskinesia”;

[0301] • Change from baseline (Visit 1) to Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8 in “On time with troublesome dyskinesia”;

[0302] • Change from baseline (Visit 1) to Visit 2, Visit 3, Visit 4, Visit 5, Visit 6. Visit 7, and Visit 8 in “On time without dyskinesia”;

[0303] • Change from baseline (Visit 1) to Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8 in MDS-UPDRS total score;

[0304] • Change from baseline (Visit 1) to Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8 in MDS-UPDRS Part II;

[0305] • Change from baseline (Visit 1) to Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8 in MDS-UPDRS Part III;

[0306] • Change from baseline (Visit 1) to Visit 2, Visit 3. Visit 4, Visit 5, Visit 6. Visit 7, and

[0307] Visit 8 in MDS-UPDRS Part II and Part III combined;

[0308] • PGI-C at Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8;

[0309] • Change from baseline (Visit 1) to Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8 in PGI-S;

[0310] • Change from baseline (Visit 1) to Visit 2, Visit 3, Visit 4, Visit 5, Visit 6. Visit 7, and Visit 8 in CGI-S;

[0311] • CGI-C at Visit 2, Visit 3, Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8;

[0312] • Change from baseline (Visit 1) to Visit 3, Visit 4, Visit 5, Visit 6, Visit 7. and Visit 8 in ZBI-12;

[0313] • Change from baseline (Visit 1) to Visit 2, Visit 3, and Visit 4 in Example 7 dosing regimen (i.e., dose strength [mg], dosing frequency, and number of capsules per day);

[0314] • Number of titration steps for Example 7 from baseline (Visit 1) to Visit 2, Visit 3, and Visit 4.

[0315] Once the study is concluded or at appropriate intermediate time points the following efficacy assessments will be evaluated:

[0316] Analysis of the primary efficacy endpoints including but not limited to the change from baseline (Visit 1) in “Good on” time in hours per day, averaged over the PD diary days, at Visit 4. “Good on” time is derived from the 3-day PD diaries. For each day, “Good on” time is calculated by adding the number of half-hour intervals in which either an “On time without dyskinesia” or “On time with non-troublesome dyskinesia” is checked. “Good on” time and its change from baseline (Visit 1) will be analyzed descriptively by visit for the intent-to treat ("ITT") population which consists of all enrolled patients.

[0317] Analysis of the secondary efficacy endpoints including but not limited to the change from baseline (Visit 1) in “Off’ time in hours per day. averaged over the PD diary days, at Visit 4. “Off’ time is derived from the 3-day PD diaries. For each day, “Off’ time is calculated by adding the number of half-hour intervals in which “Off’ is checked. “Off’ time and its change from baseline (Visit 1) will be analyzed descriptively by visit for the ITT population.

[0318] Analysis of exploratory endpoints will include the various PD diary-based endpoints such as the MDS-UPDRS based endpoints will be calculated as the sum of the responses in the appropriate MDS-UPDRS part. Additional exploratory endpoints may include:

[0319] • The PGI-C and CGI-C scores;

[0320] • The ZB I- 12 total score; and

[0321] • Example 7 dosing regimen-related endpoints (total daily dose, daily dosing frequency and daily number of capsules) will be summarized descriptively along with changes from baseline (Visit 1). The number of titration steps will also be summarized.

[0322] Adverse events ("AE") will be summarized by Medical Dictionary for Regulatory Activities (MedDRA) system organ class and preferred term. Serious AEs and AEs leading to study drug discontinuation will be summarized separately. AEs will also be summarized by relationship to the study drug and severity. Relationship between AE rates and duration of exposure, total daily dose and daily dosing frequency will be explored. The Columbia -Suicide Severity Rating Scale ("C-SSRS") may also be employed and may be summarized by providing the number and percentage of patients with any suicidal ideation or any suicidal behavior by visit and overall, in the study.

[0323] The ZBI score described previously is used to assess the perceived burden of family caregivers who provide assistance to patients with long-term progressive neurological disorders, including PD. The 22-item Zarit Burden Interview (ZBI-22) consists of 22 items with 5 ordered frequency-related response categories scored 0 (never) to 4 (nearly always), except for the final item, which has 5 ordered intensity-related response categories (0 = not at all; 4 = extremely). All 22 items are used to calculate a total score that can range between 0 and 88 (88 = more burden). A total score of 21 has been suggested as a burden cut point. The ZB I- 12 is a 12-item short form of the ZBI-22 and has been shown to be reliable and valid and to produce results that are similar to the longer version while minimizing respondent time and burden. See generally Hagell et al., "Assessment of Burden Among Family Caregivers of People with Parkinson's Disease Using the Zarit Burden Interview," J Pain Symptom Manage, 2017;53(2):272-8 and Bedard et al., "The Zarit Burden Interview: A New Short Version and Screening Version," Gerontologist. 2001;41(5):652- 7. An interim analysis of 55 patients (mean age 66.4+8.95 years) completing Week 6 (Day / Visit 4) was conducted and the interim results (IA#1) showed:

[0324] • At baseline, mean daily “Good On” time was 9.58+2.36 hours, “Off’ time was 5.94+2.02 hours;

[0325] • CREXONT® (Example 7) treatment increased daily “Good On” time:+3.13 hours for patients switching from IR CD-LD (n=36), +2.31 hours from IR CD-LD+COMT inhibitor (n=6), +1.80 hours from RYTARY® (n=l l);

[0326] • Corresponding reductions in “Off’ time were -2.82, -2.36, -2.47 hours, respectively;

[0327] • CREXONT® (Example 7) increased “Good On” time per dose by 1.81, 0.77, 0.78 hours, respectively;

[0328] • CREXONT® (Example 7) improved MDS-UPDRS total scores by -14.1, -4.2, -10.8 points, respectively;

[0329] • TEAEs were mild to moderate; most common (>3%) were nausea (5.5%), falls (3.6%), dizziness (3.6%), urinary tract infection (3.6%).

[0330] The following Tables summarize the interim analysis of the 55 patients in IA#1:

[0331] TABLE 4 TABLE 5

[0332] TABLE 6

[0333] TABLE 7 TABLE 8

[0334] TABLE 9

[0335] * An adverse event is defined as treatment-related if its relationship to the study drug is recorded as possibly related or related on the eCFR. fSerious TEAE = Toxicity with dyskinesia and hypotension (hospitalization).

[0336] TABLE 10 Most Common TEAEs in the Safety Population

[0337]

[0338] The nausea and 1 of the dizziness events were determined to be related to the drug treatment, while the fall and urinary tract infection were determined not to be related to the drug treatment.

[0339] A graph showing the CD-LD dose frequency from pre-study drug regimen though Example 7 optimization of the interim data set IA#1 is shown in FIGURE 2.

[0340] A graph showing the Example 7 dose frequency before and after optimization by pre-study drug regimen for the interim data set IA#1 is shown in FIGURE 3.

[0341] A graph showing the number of titration steps to stable Example 7 dose regimen by pre-study drug regimen for the interim data set IA#1 is shown in FIGURE 4. As used herein a stable dosing regimen means no changes to the daily dosing frequencies and doses of LD (mg) taken at each daily dosing time during the 7-day stable dosing regimen period starting on the day after the day 35 follow up, and allowing for changes in time of dosing throughout the day. As used herein “titration step” means a change in the daily dosing frequency or doses of LD (mg) taken at each daily dosing time.

[0342] A graph showing the conversion ratio of stable Example 7 LD Total Daily Dose (TDD) to prestudy LD TDD in patients who achieved a stable dosing regimen dose frequency before and after optimization by pre-study drug regimen for the interim data set IA#1 is shown in FIGURE 5.

[0343] A graph showing the change from baseline to Visit 4 in mean “GOOD ON” time per day for the interim data set IA#1 is shown in FIGURE 6.

[0344] A graph showing the change from baseline to Visit 4 in mean “GOOD ON” time per day based on pre- study drug regimen for the interim data set IA#1 is shown in FIGURE 7.

[0345] A graph showing the change from baseline to Visit 4 in mean “GOOD ON” time per dose for the interim data set IA#1 is shown in FIGURE 8. A graph showing the change from baseline to Visit 4 in mean “GOOD ON” time per dose based on pre-study drug regimen for the interim data set IA#1 is shown in FIGURE 9.

[0346] A graph showing the change from baseline to Visit 4 in mean “OFF” time per day for the interim data set IA#1 is shown in FIGURE 10.

[0347] A graph showing the change from baseline to Visit 4 in mean “OFF” time per day based on pre-study drag regimen for the interim data set IA#1 is shown in FIGURE 11.

[0348] A graph showing the change from baseline to Visit 4 in mean “ON” time with troublesome dyskinesia (“WTD”) per day for the interim data set IA#1 is shown in FIGURE 12.

[0349] A graph showing the change from baseline to Visit 4 in mean “ON” time with troublesome dyskinesia per day based on pre-study drag regimen for the interim data set IA#1 is shown in FIGURE 13.

[0350] A graph showing the change from baseline to Visit 4 in mean asleep time per day for the interim data set IA#1 is shown in FIGURE 14.

[0351] A graph showing the increased “GOOD ON” time as a result of decreased “OFF” time with no impact to sleep for the interim data set IA#1 is shown in FIGURE 15.

[0352] A graph showing the change from baseline to Visit 4 in mean duration of continuous “GOOD ON” time interval per day for the interim data set IA#1 is shown in FIGURE 16.

[0353] A graph showing the change from baseline to Visit 4 in mean duration of continuous “GOOD ON” time interval per day based on pre-study drug regimen for the interim data set IA#1 is shown in FIGURE 17.

[0354] A graph showing the change from baseline to Visit 4 in mean MDS-UPDRS total score for the interim data set IA#1 is shown in FIGURE 18.

[0355] A graph showing the change from baseline to Visit 4 in mean MDS-UPDRS total score based on pre-study drug regimen for the interim data set IA#1 is shown in FIGURE 19.

[0356] A graph showing the change from baseline to Visit 4 in mean MDS-UPDRS Part III score for the interim data set IA#1 is shown in FIGURE 20.

[0357] A graph showing the change from baseline to Visit 4 in mean MDS-UPDRS Part III score based on pre- study drag regimen for the interim data set IA#1 is shown in FIGURE 21.

[0358] A graph showing the change from baseline to Visit 4 in mean MDS-UPDRS Part II score for the interim data set IA#1 is shown in FIGURE 22. A graph showing the change from baseline to Visit 4 in mean MDS-UPDRS Part IT score based on pre-study drug regimen for the interim data set IA#1 is shown in FIGURE 23.

[0359] A graph showing the change from baseline to Visit 4 in “Much or Very Much Improved” PGI- C scores for the interim data set IA#1 is shown in FIGURE 24.

[0360] The interim data reported in the above tables and Figures shows that the controlled release dosage from as described in Example 7 substantially increased “Good On” time, reduced “Off’ time, and improved motor function in PD patients across all therapy groups, confirming that switching patients from other levodopa-based therapies to the controlled release dosage from as described in Example 7 offers meaningful improvements in symptom control through the day. The data also demonstrates a useful, quick, easy and reliable method to convert PD patients receiving LD therapy with or without a COMIT inhibitor to the controlled release mucoadhesive dosage form of Example 7.

[0361] A second interim analysis including the 55 patients of IA#1 and an additional 56 patients completing Week 6 (Day 42 / Visit 4) was conducted and the interim results (IA#2) showed:

[0362] • CREXONT® (Example 7) treatment increased daily “Good On” time:+3.40 hours for patients switching from IR CD-LD, +2.91 hours from IR CD-LD+COMT inhibitor, +3.07 hours from RYTARY® and +3.29 hours for all patients in the IA#2 data set.

[0363] The following Tables summarize the interim analysis of the 111 patients in the second interim analysis, IA#2:

[0364] TABLE 11

[0365] TABLE 12

[0366] TABLE 13 TABLE 14

[0367] TABLE 15

[0368] TABLE 16A

[0369] TABLE 16B

[0370] TABLE 16C TABLE 16D

[0371] TABLE 17A

[0372] TABLE 17B

[0373] TABLE 17C

[0374] TABLE 17D

[0375] TABLE 18A

[0376] TABLE 18B

[0377] TABLE 18C

[0378] TABLE 18D

[0379] TABLE 19A

[0380] TABLE 19B

[0381] TABLE 19C TABLE 19D

[0382] TABLE 20A

[0383] TABLE 20B

[0384] TABLE 20C

[0385] TABLE 20D EXAMPLE 9

[0386] PD patients being treated with an IR CD-LD dosage form and a COMT inhibitor may be converted to treatment with the controlled release multi-particulate muco-adhesive dosage forms described herein, such as the dosage form of Example 7, and without the co-administration of a COMT inhibitor, as shown in the following table:

[0387] TABLE 21

[0388] The conversion factor for the co-administration of opicapone is 1.5 x the most frequent IR LD amount.

[0389] The conversion factor for the co-administration of entacapone is 1.33 x the most frequent IR LD amount.

[0390] After 1 to 3 days the dose and / or frequency of the multi-particulate muco-adhesive dosage form, such as Example 7, may be adjusted if necessary.

[0391] The patients may be converted without further need for dose adjustment, administration frequency adjustment or titration. If a dose adjustment, administration frequency adjustment or titration is required to control the patient’s symptoms or adverse events, the number of dose adjustments, administration frequency adjustments or titrations will be 4, 3, 2, or 1. In certain aspects the patient is converted from the prior IR CD-LD dosage form and a COMT inhibitor dosing regimen to treatment with the controlled release multi-particulate muco-adhesive dosage forms described herein, such as Example 7 within 1, 2, 3, or 4 weeks and preferably without the need for dose adjustment, administration frequency adjustment or titrations, to obtain a stable and effective dosing regimen using controlled release multi-particulate muco-adhesive dosage forms described herein.

[0392] The PD patient may receive the multi-particulate muco-adhesive dosage form 2, 3, or 4 times a day for at least 3 days or longer. In certain aspects the PD patient may receive the multiparticulate muco-adhesive dosage form 2, 3, or 4 times a day for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or longer.

[0393] EXAMPLE 10

[0394] PD patients being treated with a controlled release multi-particulate dosage form without a muco-adhesive material, such as RYTARY® as described in Example 9 of 9,463,246, or a U.S. FDA approved AB rated generic and without a COMIT inhibitor may be converted to treatment with the controlled release multi-particulate muco-adhesive dosage form as described herein such as the dosage form of Example 7 and without the co-administration of a COMT inhibitor, as shown in the following table:

[0395] TABLE 22

[0396] The RYTARY® product is a multi-particulate dosage from comprising immediate release CD-LD beads, two different types of modified release CD-LD beads and modified release tartaric acid beads. The two different modified release CD-LD beads employed in the RYTARY® product do not employ a muco-adhesive layer as described in Examples 5 and 7 above.

[0397] After 1 to 3 days the dose and / or frequency of the multi-particulate dosage form, such as Example 7. may be adjusted if necessary.

[0398] In certain aspects, the PD patient will be converted from a controlled release multiparticulate dosage form without a muco-adhesive material, such as RYTARY® as described in Example 9 of 9,463,246, or a U.S. FDA approved AB rated generic and without a COMIT inhibitor to treatment with the controlled release multi-particulate muco-adhesive dosage form as described herein wherein the LD dose per administration of the controlled release multi-particulate muco- adhesive dosage form is equal to or less than the LD dose of the controlled release multi-particulate dosage form without a muco-adhesive material, such as RYTARY®. For example, a PD patient is receiving RYTARY® at 285-290 mg LD per administration three times a day as described in Table 22, the PD patient will be converted to the controlled release multi-particulate muco-adhesive dosage form as described herein at 280 mg of LD per administration three times a day. Similarly, a PD patient is receiving RYTARY® at 350-390 mg LD per administration three times a day as described in Table 22, the PD patient will be converted to the controlled release multi-particulate muco-adhesive dosage form as described herein at 350 mg of LD per administration three times a day The converted PD patient will exhibit one or more of the benefits described above such as rapid efficacy, avoidance or reduced adverse events, reduced "Off" time between doses, increased "On" time or increased "Good On" time with each dose, per day and / or per waking hours in a day compared to the prior treatment with RYTARY®.

[0399] The patients may be converted without further need for dose adjustment, administration frequency adjustment or titration. If a dose adjustment, administration frequency adjustment or titration is required to control the patient’s symptoms or adverse events, the number of dose adjustments, administration frequency adjustments or titrations will be 4, 3, 2, or 1. In certain aspects the patient is converted from the prior RYTARY® or a U.S. FDA approved AB rated generic dosing regimen to treatment with the controlled release multi-particulate muco-adhesive dosage forms described herein, such as Example 7 within 1, 2, 3, or 4 weeks and preferably without the need for dose adjustment, administration frequency adjustment or titrations, to obtain a stable and effective dosing regimen using controlled release multi -particulate muco-adhesive dosage forms described herein.

[0400] The PD patient may receive the multi-particulate muco-adhesive dosage form 3 or 4 times a day for at least 3 days or longer. In certain aspects the PD patient may receive the multiparticulate muco-adhesive dosage form 3 or 4 times a day for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or longer.

[0401] EXAMPLE 11

[0402] PD patients being treated with (a) an oral controlled release LD matrix tablets such as SINEMET® CR or a U.S. FDA approved AB rated generic or (b) an oral controlled release LD matrix tablet such as SINEMET® CR or a U.S. FDA approved AB rated generic at bedtime in combination with an immediate release LD dosage forms during waking hours, without a COMIT inhibitor, may be converted to treatment with the controlled release multi-particulate muco- adhesive dosage forms described herein, such as Example 7, and without the co-administration of a COMT inhibitor, as shown in the following table as shown in the following table:

[0403] TABLE 23

[0404] The SINEMET® CR product is a compressed sustained release matrix tablet comprising LD, CD, hydroxypropyl cellulose, magnesium stearate and Hypromellose and is gnereally described in U.S. Patent No. 4,900,755. After 1 to 3 days the dose and / or frequency of the multi-particulate dosage form, such as Example 7, may be adjusted if necessary.

[0405] The patients may be converted without further need for dose adjustment, administration frequency adjustment or titration. If a dose adjustment, administration frequency adjustment or titration is required to control the patient’s symptoms or adverse events, the number of dose adjustments, administration frequency adjustments or titrations will be 4, 3, 2, or 1. In certain aspects the patient is converted from the prior SINEMET® CR or U.S. FDA approved AB rated generic treatments with the controlled release multi-particulate muco-adhesive dosage forms described herein, such as Example 7 within 1, 2, 3, or 4 weeks and preferably without the need for dose adjustment, administration frequency adjustment or titrations, to obtain a stable and effective dosing regimen using controlled release multi-particulate muco-adhesive dosage forms described herein.

[0406] The PD patient may receive the multi-particulate muco-adhesive dosage form 3 or 4 times a day for at least 3 days or longer. In certain aspects the PD patient may receive the multiparticulate muco-adhesive dosage form 3 or 4 times a day for at least 1, 2, 3, 4, 5, 6, 7, 8, 9. 10, 11, 12 months or longer.

[0407] The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein, any of the terms “comprising,” “consisting essentially of’ and “consisting of’ may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

Claims

What is claimed is:

1. A method for treating a patient diagnosed with Parkinson’s disease comprising:(i) selecting a patient diagnosed with Parkinson’s disease and being treated with oral immediate release levodopa (LD) tablets and a catechol-O-methyltransferase (COMT) inhibitor;(ii) determining the highest and most frequent LD dose received daily by the patient from step (i);(iii) discontinuing the administration of the oral immediate release LD and COMT inhibitor of step (i); and(iv) orally administering a controlled release levodopa dosage form 2, 3, 4, or 5 times a day to the patient of step (iii) wherein the amount of LD administered with each administration of the controlled release LD dosage form is about 1.2 to about 1.8 times, preferably about 1.25 to about 1.7 times, and more preferably about 1.3, 1.4, 1.5 or 1.6 times the most frequent LD dose received daily by the patient as determined from step (ii).

2. The method of claim 1 wherein Parkison’s disease includes primary parkinsonism, postencephalitic parkinsonism, parkinsonism associated with carbon monoxide intoxication in adults, and parkinsonism associated with manganese intoxication in adults.

3. The method of claim 1 wherein the oral immediate release LD tablets of step (i) comprise LD and a COMT inhibitor.

4. The method of claim 1 wherein the oral immediate release tablets of step (i) comprise LD and are co-administered with a COMT inhibitor.

5. The method of claim 1 wherein the controlled release dosage form administered in step (iv) comprises one or more immediate release components comprising levodopa and carbidopa and the one or more controlled release components comprising levodopa and a controlled release material.

6. The method of claim 5 wherein the controlled release components further comprises a mucoadhesive material.

7. The method of claim 1 wherein the COMT inhibitor of step (i) is entacapone and controlled release levodopa dosage form of step (iv) contains 1.33 times the amount of levodopa the patient was receiving with each administration of the one or more immediate release levodopa tablets and COMT inhibitor of step (i).

8. The method of claim 1 wherein the COMT inhibitor of step (i) is opicapone and controlled release levodopa dosage form of step (iv) contains 1 .5 times the amount of levodopa the patient was receiving with each administration of the one or more immediate release levodopa tablets and COMT inhibitor of step (i).

9. A method for treating a patient diagnosed with Parkinson’s disease comprising: of:(i) selecting a patient diagnosed with Parkinson’s disease and being treated orally with a first controlled release levodopa (LD) dosage form administered 3, 4, or 5 times a day;(ii) determining the frequency and amount of LD administered to the patient with each administration of the first controlled release LD dosage form of step (i):(iii) discontinuing the administration of the first controlled release LD dosage form of step (i); and(iv) orally administering to the patient of step (iii) a second controlled release LD dosage form at the same frequency, i.e., 3, 4 or 5 times a day, and containing a similar amount of LD as the first controlled release dosage form from steps (i) or (ii); wherein the first controlled release LD dosage form is a multi-particulate capsule dosage form comprising LD, CD, and tartaric acid and the second controlled release LD dosage form is a muco-adhesive multi-particulate controlled release LD dosage form comprising LD and at least one muco-adhesive material.

10. The method of claim 9 wherein:(a) the most frequent single LD dose from the first controlled release LD dosage form comprises 95 mg- 145 mg LD and the second controlled release LD dosage form comprises 140 mg LD administered at the same dosing frequency as the first controlled release LD dosage form;(b) the most frequent single LD dose from the first controlled release LD dosage form comprises 190 mg-245 mg LD and the second controlled release LD levodopa dosage form comprises 210 mg LD administered at the same dosing frequency as the first controlled release LD dosage form;(c) the most frequent single LD dose from the first controlled release LD dosage form comprises 285 mg-290 mg LD and the second controlled release LD dosage form comprises 280 mg LD administered at the same dosing frequency as the first controlled release LD dosage form;(d) the most frequent single LD dose from the first controlled release LD dosage form comprises 335 mg-390 mg LD and the second controlled release LD dosage form comprises 350 mg LD administered at the same dosing frequency as the first controlled release LD dosage form;(e) the most frequent single LD dose from the first controlled release LD dosage form comprises 435 mg-440 mg LD and the second controlled release LD dosage form comprises 420 mg LD administered at the same dosing frequency as the first controlled release LD dosage form;(f) the most frequent single LD dose from the first controlled release LD dosage form comprises 485 mg-490 mg LD and the second controlled release LD dosage form comprises 490 mg LD administered at the same dosing frequency as the first controlled release LD dosage form;(g) the most frequent single LD dose from the first controlled release LD dosage form comprises about 535 mg-685 mg LD and the second controlled release LD dosage form comprises 560 mg LD administered at the same dosing frequency as the first controlled release LD dosage form; or(h) the most frequent single LD dose from the first controlled release LD dosage form comprises about 590 mg-685 mg LD and the second controlled release LD dosage form comprises 700 mg LD administered at the same dosing frequency as the first controlled release LD dosage form.

11. The method of claim 9 wherein Parkison’s disease includes primary parkinsonism, postencephalitic parkinsonism, parkinsonism associated with carbon monoxide intoxication in adults, and parkinsonism associated with manganese intoxication in adults.

12. The method of claim 9 wherein the second controlled release LD dosage form administered in step (iv) comprises one or more immediate release components comprisinglevodopa and carbidopa and the one or more controlled release components comprising levodopa a controlled release material, a mucoadhesive material and an enteric material.

13. A method for treating a patient diagnosed with Parkinson’s disease comprising:(i) selecting a patient diagnosed with Parkinson’s disease and being treated with (a) at least one oral controlled release levodopa (LD) matrix tablet administered 1, 2, 3, 4, or 5 times a day for a total daily LD dose of 500 mg or less or (b) an oral controlled release LD matrix tablet at bedtime in combination with one or more oral immediate release LD dosage forms during waking hours for a total daily LD dose of 500 mg or less;(ii) determining (a) the frequency and amount of LD administered to the patient with each administration of the controlled release LD matrix tablet or (b) the frequency and amount of LD administered to the patient with the bedtime administration of the controlled release LD matrix tablet and each immediate release LD dosage form administered during waking hours of step (i);(iii) discontinuing the administration of the oral controlled release LD matrix tablets and the immediate release LD dosage forms of step (i); and(iv) orally administering a multi-particulate muco-adhesive controlled release LD dosage form 2 or 3 times a day to the patient of step (iii) wherein the amount of LD administered with each administration of the oral multi-particulate muco-adhesive controlled release LD dosage form is about 2.8 times the amount of the most frequent LD dose from step (ii) and wherein the multiparticulate muco-adhesive controlled release LD dosage form comprises one or more immediate release components comprising LD and carbidopa and the one or more controlled release components comprising LD, a controlled release material, a mucoadhesive material and an enteric material.

14. A method for treating a patient diagnosed with Parkinson’s disease comprising:(i) selecting a patient diagnosed with Parkinson’s disease and being treated with (a) at least one oral controlled release levodopa (LD) matrix tablet administered 1, 2, 3, 4, or 5 times a day for a total daily LD dose of 500 mg or more or (b) an oral controlled release LD matrix tablet atbedtime in combination with one or more oral immediate release LD dosage forms during waking hours for a total daily LD dose of 500 mg or more;(ii) determining (a) the frequency and amount of LD administered to the patient with each administration of the controlled release LD matrix tablets or (b) the frequency and amount of LD administered to the patient with the bedtime administration of the controlled release LD matrix tablet and the immediate release LD dosage forms administered during waking hours of step (i);(iii) discontinuing the administration of the oral controlled release LD matrix tablets and the immediate release LD dosage forms of step (i); and(iv) orally administering a multi-particulate muco-adhesive controlled release LD dosage 3, 4 or 5 times a day to the patient of step (iii) wherein the amount of LD administered with each administration of the multi-particulate muco-adhesive controlled release LD dosage form is about 2.8 times the amount of the most frequent LD dose from step (ii) and wherein the multi-particulate muco-adhesive controlled release LD dosage form comprises one or more immediate release components comprising LD and CD and the one or more controlled release components comprising LD, a controlled release material, a mucoadhesive material and an enteric material.

15. A method for treating a patient diagnosed with Parkinson’s disease comprising:(i) selecting a patient diagnosed with Parkinson’s disease and being treated with (a) at least one oral controlled release levodopa (LD) matrix tablet administered 1, 2, 3, 4, or 5 times a day for a total daily LD dose of 500 mg or more or (b) an oral controlled release LD matrix tablet at bedtime in combination with one or more oral immediate release LD dosage forms during waking hours for a total daily LD dose of 500 mg or more;(ii) determining (a) the frequency and amount of LD administered to the patient with each administration of the controlled release LD matrix tablet or (b) the frequency and amount of LD administered to the patient with the bedtime administration of the controlled release LD matrix tablet and the immediate release LD dosage forms administered during waking hours of step (i);(iii) if the most frequent amount LD dose of step (ii) is more than 200 mg, discontinuing the administration of the oral controlled release LD matrix tablets and the immediate release LD dosage forms of step (i); and(iv) orally administering to the patient of step (iii) one or more multi-particulate muco- adhesive controlled release LD dosage form at a dose of 700 mg LD per administration 3 times a day for a total dose of 2,100 mg LD per day and wherein the multi-particulate muco-adhesive controlled release LD dosage form comprises one or more immediate release components comprising LD and CD and the one or more controlled release components comprising LD, a controlled release material, a mucoadhesive material and an enteric material.

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