Levodopa Dosing Regimen

Abstract

The present invention provides an oral dosage regimen of a controlled release levodopa composition for use in treating patients with Parkinson's disease.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Patent Application No. 63 / 129,063, filed December 22, 2020, U.S. Patent Application No. 63 / 150,121, filed February 17, 2021, U.S. Patent Application No. 63 / 236,403, filed August 24, 2021, and U.S. Patent Application No. 63 / 247,639, filed September 23, 2021, the contents of all of which are incorporated by reference in their entireties into this application.

[0002] The present invention relates to oral dosing regimens for levodopa (hereinafter "LD"), and in particular to oral dosing regimens using controlled release pharmaceutical compositions of LD. The dosing regimens are useful in the treatment of conditions such as neurological disorders associated with reduced or impaired dopamine levels, and are particularly useful in the treatment of patients with Parkinson's disease (hereinafter "PD"). [Background technology]

[0003] Patients suffering from PD often have periods of difficulty in mobility and are often unable to move. Abnormally low levels of dopamine, a neurotransmitter that affects the mobility and control of the skeletal musculoskeletal system, are generally believed to be the main cause of these motor symptoms in PD patients. However, dopamine does not cross the blood-brain barrier, so administration of dopamine is not effective in treating the motor symptoms of Parkinson's disease. To solve this problem, PD patients are administered levodopa, a metabolic precursor of dopamine, but levodopa is not without problems.

[0004] Over time, patients treated with LD exhibit symptoms of "wearing off," in which a single dose of levodopa does not last as long as it did initially (usually 5-10 years after initiation of levodopa therapy). Such patients may develop motor fluctuations characterized by dose termination failure, peak-dose dyskinesia, and akinesia. Advanced forms of motor fluctuations (also commonly referred to as the "on-off" phenomenon) are characterized by unpredictable switching from mobility to immobility. Although the causes of these motor fluctuations are not fully understood, advanced patients generally benefit from treatment regimens that produce steady plasma levels of LD, such as by enteral infusion of LD, because such delivery methods can mimic the normally tonic endogenous dopamine. However, enteral infusion of LD is restrictive, invasive, and cumbersome. Oral delivery of LD is preferred, but plasma concentration levels remain difficult to control with oral delivery.

[0005] The combination of LD and a decarboxylase inhibitor, typically carbidopa (hereinafter "CD"), for treating PD is known in the pharmaceutical art. Currently, several formulations containing a combination of LD and CD are commercially available, such as SINEMET®, SINEMET® CR, STALEVO®, PARCOPA®, RYTARY® and their corresponding generic products. In addition, a decarboxylase inhibitor approved for use outside the United States is benserazide, which may be given in combination with LD.

[0006] Although many oral LD ​​dosage forms have been described in the literature, successful development of a once or twice daily oral dosage form of LD has been difficult. LD is rapidly metabolized. LD has a plasma half-life of about 50 minutes when administered orally without CD and about 1.5 hours when administered orally with CD. Due to this short plasma half-life, many efforts have been made to provide sustained release forms of LD that would allow for once or twice daily oral dosing. Although in vitro data suggests that LD can be released from oral controlled release dosage forms in a manner that may allow for once and twice daily dosing, in vivo data demonstrates that once and twice daily oral dosing is extremely difficult to obtain, due in part to problems with absorption of LD from the patient's gastrointestinal tract. LD is absorbed only from a small portion of the patient's upper gastrointestinal tract. If LD is not released from the dosage form in this narrow absorption window, the dosage form will pass through the narrow window and LD will be released into 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, but LD also competes with other compounds, such as dietary amino acids, for the absorption site. Even if LD is released in a patient's narrow absorption window, absorption may be hindered by other molecules that interact with the absorption site. This competition allows the released levodopa to pass through the narrow absorption window via normal gastric motility and be excreted without reaching the patient's bloodstream.

[0007] There remains a need for oral LD ​​dosage forms and dosing regimens that can provide two or three times daily dosing, that can provide stable plasma concentrations of LD with minimal "peak-to-trough" fluctuations during daily dosing, and that provide a longer duration of effect than commercially available oral dosage forms of LD.

[0008] There also remains a need for oral LD ​​dosage forms and dosing regimens that reduce or eliminate the amount of "off" time or increase the amount of "on" time and "good on" time, especially when administered every 6, 7, 8, 9, 10, 11 or 12 hours in a 24 hour period.

[0009] Additionally, there remains a need for oral LD ​​dosage forms and dosing regimens that reduce or eliminate the amount of "off" time, or increase the amount of "on" time and "good on" time per dose, per day, and / or per waking hour of the day, especially when administered every 6, 7, 8, 9, 10, 11, or 12 hours over a 24 hour period, as compared to commercially available oral LD ​​dosage forms, such as immediate release CD-LD tablets.

[0010] There also remains a need for oral LD ​​dosage forms and dosing regimens that can be administered prior to bedtime and provide therapeutic benefit throughout the patient's sleep, and that continue to provide therapeutic benefit upon awakening 7-9 hours after the bedtime dose. Summary of the Invention [Problem to be solved by the invention]

[0011] The present invention fulfills the above-mentioned needs and other needs. [Means for solving the problem]

[0012] The present invention provides a dosing regimen that allows twice-daily dosing of PD patients, preferably taking 500 mg or less LD per day from an immediate release LD formulation. The dosing regimen allows twice-daily dosing of an oral controlled release LD formulation, i.e., once about every 12 hours, where each dose contains about 140 to about 700 mg LD, preferably about 210 mg LD to about 450 mg LD, and most preferably about 280 mg to about 420 mg LD. The doses administered about every 12 hours can be administered as a single dosage form or multiple dosage forms. For example, a total daily dose of 560 mg levodopa can be administered twice-daily, i.e., every 12 hours, as a single dose of 280 mg LD, where each single 12-hour dose of 280 mg LD can be administered as two capsules per dose, each capsule containing 140 mg LD, or as one capsule per dose containing 280 mg LD. In certain embodiments, the total daily dose for a twice daily regimen is about 400 mg to about 500 mg LD or about 200 mg to about 250 mg every 12 hours.

[0013] The present invention also provides a dosing regimen that allows for twice or three times daily dosing for newly diagnosed PD patients who have not started LD treatment or are LD naive patients. The dosing regimen for newly diagnosed PD patients or LD naive patients allows for twice daily dosing of the oral controlled release LD formulation, i.e., once every about 12 hours or 8 hours, where each dose contains about 140 to about 700 mg of LD, preferably about 210 mg of LD to about 450 mg of LD, most preferably about 280 mg to about 420 mg of LD. One dose may be administered about every 12 hours or 8 hours as a single dosage form or multiple dosage forms. For example, a total daily dose of 560 mg levodopa can be administered twice daily, i.e., every 12 hours, as a single dose of 280 mg LD, where each single 12 hour dose of 280 mg LD can be administered as two capsules per dose, each capsule containing 140 mg LD, or as one capsule per dose containing 280 mg LD. In certain embodiments, the total daily dose of the twice daily regimen is about 400 mg to about 500 mg LD or about 200 mg to about 250 mg doses every 12 hours.

[0014] The present invention also provides a dosing regimen that allows for administration every 4-12 hours, preferably every 6-12 hours, i.e., 2, 3, 4 or 5 times per day, with no or substantially no "off" time between doses.

[0015] The invention further provides a dosing regimen that allows for dosing every 4-12 hours, preferably every 6-12 hours, i.e., 2, 3, 4 or 5 times per day, with increased "on" hours or increased "good on" hours per day and / or per waking hour of the day with each dose compared to an oral immediate release CD-LD dose or a total immediate release CD-LD dose per day or per waking hour.

[0016] The present invention also provides a dosing regimen that allows the controlled release dosage forms described herein to be taken before bedtime, thereby providing therapeutic benefit to the patient upon awakening 6-9 hours, preferably 7-8 hours, after administration. In certain embodiments, the controlled release dosage forms useful in the present invention are administered every 6-7 hours or 7-8 hours in a 24 hour period, such that after 7-15 days of continuous treatment, the patient obtains a steady state minimum LD plasma level of at least 250 ng / mL, preferably at least 300 ng / mL, and most preferably at least 330 ng / mL between doses, and exhibits therapeutic benefit for 7-8 hours prior to administration of the next dose.

[0017] The invention further provides dosing regimens that allow for dosing every 6-12 hours, i.e., 2, 3, or 4 times per day, and reduce the number of motor fluctuations per dose, per day, and / or per waking hour of the day, compared to oral immediate release CD-LD doses or total immediate release CD-LD doses per day or per waking hour.

[0018] The present invention also provides a dosing regimen that allows for dosing every 6-12 hours, i.e., 2, 3, or 4 times per day, and increases the patient's mental well-being per dose, per day, and / or per waking hour of the day, compared to oral immediate release CD-LD doses or total immediate release CD-LD doses per day or per waking hour.

[0019] The present invention also provides a dosing regimen that allows for dosing every 6-12 hours, i.e., 2, 3, or 4 times per day, and further provides for a reduction in the patient's perception problems and / or hallucinations per dose, per day, and / or per waking hour of the day, as compared to an oral immediate release CD-LD dose or a total immediate release CD-LD dose per day or per waking hour.

[0020] In certain embodiments, the controlled release dosage form used in the dosing regimen of the present invention is a multiparticulate dosage form comprising an immediate release amount of LD and a modified or controlled release amount of LD. The modified or controlled release amount of LD may be present as a modified or controlled release component such as beads, pellets, granules or mini-tablets, comprising a core containing LD, which may be mixed with, coated or layered with a controlled release material and / or a mucoadhesive material, and optionally coated with an enteric material, preferably an enteric polymer.

[0021] The controlled release dosage forms used in the present invention may also include a decarboxylase inhibitor, such as CD. The decarboxylase inhibitor, such as CD, may be in immediate release form, modified or controlled release form, or both. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows in vivo levodopa plasma profiles on day 1 under fasting conditions for the formulations tested in Example 8. [Diagram 2] FIG. 1 shows dose-normalized in vivo levodopa plasma profiles on day 1 under fasting conditions for the formulations tested in Example 8. [Diagram 3] FIG. 1 shows the in vivo carbidopa plasma profile on day 1 under fasting conditions for the formulations tested in Example 8. [Figure 4] FIG. 15 shows the in vivo levodopa plasma profile at day 15 for the formulations tested in Example 8. [Diagram 5] FIG. 15 shows the in vivo carbidopa plasma profile at day 15 for the formulations tested in Example 8. [Figure 6] FIG. 1 shows the mean MDS-UPDRS part III scores on day 1 for the formulations tested in Example 8. [Figure 7] 1 shows the time course of mean LD plasma concentrations and mean change from baseline in MDS-UPDRS part III scores on Day 1 by treatment for the formulations tested in Example 8. [Figure 8]1 shows the time course of mean LD plasma concentrations and mean change from baseline in MDS-UPDRS part III scores on Day 15 by treatment for the formulations tested in Example 8. [Figure 9] FIG. 1 shows the in vivo levodopa plasma profile of the formulations tested in Example 9. [Figure 10] FIG. 1 shows the in vivo carbidopa plasma profile of the formulations tested in Example 9. [Figure 11] 1 shows a summary of investigator motor assessment scores for the formulations tested in Example 9. [Figure 12] FIG. 1 shows the mean change from mean pre-dose MDS-UPDRS part III scores for the formulations tested in Example 9. [Figure 13] FIG. 13 shows least squares mean time to 4, 7, or 13 point improvement in MDS-UPDRS part III score for the formulations tested in Example 9. [Figure 14] 1 shows the mean LD plasma concentration over time and the mean change from baseline in MDS-UPDRS part III scores by treatment for the formulations tested in Example 9. [Figure 15] FIG. 1 shows the in vivo levodopa plasma profile of Formulations A and E tested in Example 10. [Figure 16] FIG. 1 shows the in vivo carbidopa plasma profile of Formulations A and E tested in Example 10. [Figure 17] FIG. 13 shows improvement in "good on" time from baseline to end of study as described in Example 11. [Figure 18] 1 shows improvement in "good on" time per dose at Visit 7 in the study described in Example 11. [Figure 19] FIG. 13 shows the reduction in "off" time from baseline to the end of the study as described in Example 11. [Figure 20] 1 shows the mean LD plasma concentrations for the administrations described in Example 12. [Figure 21] 1 shows the mean CD plasma concentrations for the administrations described in Example 12. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] Detailed Description of the Invention Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0024] It should be noted that as used in this specification and 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.

[0025] As used herein, the term "about," when used prior to a numerical designation, e.g., temperature, time, amount, concentration, etc., including a range, indicates an approximation that may vary by (+) or (-) 10%, 5% or 1%.

[0026] As used herein, the term "immediate release" refers to a dosage form or composition that releases a specified amount of active ingredient, such as LD and / or CD, within 30 minutes, 25 minutes, 20 minutes, 15 minutes, or within 500-900 ml of aqueous medium after administration to a patient or subject when tested in a United States Pharmacopoeia Type I or Type II dissolution apparatus. Representative examples of immediate release LD dosage forms are the U.S. Food and Drug Administration (FDA) approved and commercially available tablet product, SINEMET®, sold by Merck Sharpe & Dohme Corp., or the U.S. FDA "AB" grade generic of SINEMET®, such as 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 "component" is used in its broadest conventional interpretation unless dictated by the context or specifically stated. More specifically, a component may be an element, a component, a single component, or a mixture of components. For example, an immediate release component may include a single component, such as the drug itself, or may be a combination of the drug and one or more pharma- ceutically acceptable excipients, provided that the "immediate release component" releases the drug immediately after administration.

[0027] Target Patient Population The present invention is useful for all PD patients. The present invention is also useful in specific target patient populations.

[0028] The first target patient population includes (a) PD patients currently being treated with a total daily dose of LD of 500 mg or less, the total daily dose of 500 mg or less being administered in three, four or more divided doses of LD over a 24 hour period. In some embodiments, the PD patients in the first target patient population are administered an immediate release oral LD ​​composition, such as an immediate release oral tablet containing about 100 mg of LD and 25 mg of CD, three, four or five times a day. In another embodiment, the PD patients in the first target patient population are administered a combination of an immediate release oral LD ​​composition and a controlled release oral LD ​​composition for a total daily LD dose of 500 mg or less. In yet another embodiment, the PD patients in the first target patient population are newly diagnosed PD patients and / or PD patients who have not started treatment with LD.

[0029] The second target patient population includes LD-experienced PD patients with motor fluctuations. A subset of the second target patient population includes PD patients who have been on LD therapy for at least 4, 5, 6, 7, 8 years or more and who experience motor complications or motor fluctuations while on LD therapy, particularly immediate release oral LD ​​therapy. This subset of the second target patient population may be referred to as advanced PD patients.

[0030] The third target patient population includes all PD patients, including patients in the first and second target patient populations as well as patients with advanced PD, unless otherwise specified.

[0031] Medication Regimen The present invention allows for twice-daily oral dosing of LD to the first target patient population described above, thereby controlling the patient's PD symptoms. More specifically, twice-daily dosing controls or manages the patient's motor fluctuation symptoms, and in certain embodiments, reduces 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 per day. Twice-daily dosing controls or manages the patient's motor fluctuation symptoms, and in certain embodiments, also reduces 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 per dose, per day, and / or during waking hours within a 24-hour period. Twice-daily dosing controls or manages the patient's motor fluctuation symptoms, and in certain embodiments, increases the patient's total "on" time to 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 a 12-hour dosing interval (i.e., per dose). Twice-daily dosing controls or manages the patient's motor fluctuation symptoms, and in certain embodiments, also increases the patient's total "good on" time to 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 a 12-hour dosing interval (per dose). The terms "off", "on" and "Good On" time in relation to PD patients are terms well known to those skilled in the art of treating PD patients, and a summary is provided in Example 8 below.

[0032] The first target patient population is administered or taken a total daily dose of about 400 mg to about 1000 mg LD, preferably about 400 mg to about 800 mg, and most preferably about 400 mg to about 600 mg LD. This total daily LD dose may be divided into two equal or unequal doses administered about every 12 hours, where the dose administered or taken every 12 hours is about 200 mg LD to about 500 mg LD, preferably about 200 mg to about 450 mg LD, and most preferably about 200 mg LD to about 400 mg LD every 12 hours. The LD is administered or taken by the PD patient in the form of an oral controlled release dosage form, preferably a multiparticulate dosage form comprising an immediate release LD component and a controlled release LD component, as described in more detail below.

[0033] In certain embodiments, the LD dose taken or administered every 12 hours by the first target patient population comprises about 140 mg LD, 210 mg LD, 280 mg LD, 350 mg LD, 410 mg LD, or 420 mg LD. In certain embodiments, the LD dose taken or administered every 12 hours comprises 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 (iv) about 87.5 mg CD and about 350 mg LD. The tablet or capsule may be swallowed whole, or the tablet may be crushed and sprinkled on a food such as yogurt or applesauce, or the contents of the capsule may be sprinkled on a food such as yogurt or applesauce, and the food may be swallowed by the patient.

[0034] Certain embodiments of the dosing regimens of the invention for the first target patient population should provide an LD plasma level of at least 300 ng / mL, 325 ng / mL, 350 ng / mL, 375 ng / mL, 400 ng / mL or 425 ng / mL within 0.25 to 1 hour, preferably 0.25 to 0.75 hours, after administration, based on single or multiple doses. The administered dosage form should also provide CD plasma levels of at least 30ng / mL, 40ng / mL, 50ng / mL, 60ng / mL, 70ng / mL, 75ng / mL, 80ng / mL, 85ng / mL, 90ng / mL, 95ng / mL or 100ng / mL within 0.25 to 1 hour, preferably 0.25 to 0.75 hours, after administration, and should maintain CD plasma levels greater than 75ng / mL, 85ng / mL, 95ng / mL, 100ng / mL, 110ng / mL, 120ng / mL, 125ng / mL, 130ng / mL, 135ng / mL, 140ng / mL, 145ng / mL, 150ng / mL from 1 hour after administration up to 7 or 8 hours after administration, based on single or multiple doses.

[0035] Certain embodiments of the dosing regimens of the invention for the first target patient population should provide a steady state minimum LD plasma level of at least 250ng / mL, 275ng / mL, 285ng / mL, 290ng / mL, 300ng / mL, 310ng / mL, 320ng / mL or 330ng / mL 7-8 hours after dosing. The dosing regimens of the invention should also provide a steady state minimum CD plasma level of at least 40ng / mL, 45ng / mL, 50ng / mL, 55ng / mL, 60ng / mL, 65ng / mL, 70ng / mL or 75ng / mL 7-8 hours after dosing.

[0036] The dosing regimen of the present invention allows PD patients in the first target patient population to experience an improved therapeutic benefit after dosing and before the next dosing, compared to the patient's condition without administration of a controlled release dosage form or compared to treatment with an immediate release CD-LD oral dosage form. The improved therapeutic benefit can be: (i) At least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% improvement or increase in the patient's motor status as determined by a competent clinician; (ii) at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% improvement or increase in the patient's motor status as determined by the patient's PD diary; (iii) at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% improvement or increase in the subject's tremor, dyskinesia and / or mobility as measured by the Kinesia 360 sensor; (iv) a reduction in Movement Disorder Society Unified Parkinson's Disease Rating Scale ("MDS-UPDRS") score of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 points or more; (v) an increase of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% in the patient's total "on" time per day or per waking hour compared to an equivalent total immediate release CD-LD dose per day or per waking hour; (vi) an increase of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% in the patient's total "good on" time per day or per waking hour compared to an equivalent total immediate release CD-LD dose per day or per waking hour; (vii) an increase in patient “on” time 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 more per dose, per day, and / or per awake hour per day compared to a comparable oral dose of an immediate release CD-LD dosage form, or a total immediate release CD-LD dose per day or per awake hour; (viii) an increase in the patient's "good on" time 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 more per dose, per day, and / or per awake hour per day compared to a comparable oral dose of an immediate release CD-LD dosage form, or a total immediate release CD-LD dose per day or per awake hour; (ix) at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% reduction in the patient's total "off" time per day or per waking hour compared to an equivalent total immediate release CD-LD dose per day or per waking hour; (x) a reduction in patient “off” time 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 more per dose, per day, and / or per awake hour per day compared to a comparable oral dose of an immediate release CD-LD dosage form, or a total immediate release CD-LD dose per day or per awake hour; (xi) at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% increase in the patient's Patient Global Impression of Change ("PGI-C") score, Clinical Global Impression of Change ("CGI-C") score and / or 39-item Parkinson's Disease Questionnaire ("PDQ-39") score compared to a comparable oral dose of an immediate release CD-LD dosage form, or the total immediate release CD-LD dose per day or per waking hour; (xii) at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% reduction in the average number of motor fluctuations per day compared to an equivalent oral dose of an immediate release CD-LD dosage form, or the total immediate release CD-LD dose per day or per waking hour; (xiii) at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% reduction in perceptual problems and / or hallucinations per day compared to an equivalent oral dose of an immediate release CD-LD dosage form, or a total immediate release CD-LD dose per day or per waking hour; or (xiv) any combination of the foregoing.

[0037] In certain embodiments, the improved therapeutic benefit comprises at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% improvement in MDS-UPDRS Part III score.

[0038] A more detailed description of motor status, PD diary, MDS-UPDRS, PGI-C, CGIC and PDQ-39 is provided in Examples 8, 9 and 11 herein below.

[0039] The invention also provides a dosing regimen for treating subjects with PD or primary Parkinsonism in the second or third target patient populations, the dosing regimen comprising orally administering to a patient in need of such treatment a controlled release dosage form as described herein to provide an effective amount of LD for treating the symptoms of PD or primary Parkinsonism for at least 6-9 hours, preferably 7-8 hours.

[0040] In certain embodiments of the invention, the dosing regimen for the second or third target patient population comprises orally administering to the subject a controlled release dosage form described herein every 6, 7 or 8 hours over a 24 hour period (i.e., day) to provide an effective amount of LD to treat symptoms of PD or primary parkinsonism. The administered controlled release dosage form should provide an LD plasma level of at least 300ng / mL, 325ng / mL, 350ng / mL, 375ng / mL, 400ng / mL or 425ng / mL within 0.25 to 1 hour, preferably 0.25 to 0.75 hours, after administration, based on single or multiple doses. The administered controlled release dosage form should also provide CD plasma levels of at least 30ng / mL, 40ng / mL, 50ng / mL, 60ng / mL, 70ng / mL, 75ng / mL, 80ng / mL, 85ng / mL, 90ng / mL, 95ng / mL or 100ng / mL within 0.25 to 1 hour, preferably 0.25 to 0.75 hours, after administration, and should maintain CD plasma levels greater than 75ng / mL, 85ng / mL, 95ng / mL, 100ng / mL, 110ng / mL, 120ng / mL, 125ng / mL, 130ng / mL, 135ng / mL, 140ng / mL, 145ng / mL, 150ng / mL from 1 hour after administration through 7 or 8 hours after administration, based on single or multiple doses.

[0041] In certain embodiments of the invention, a dosing regimen for a second or third target patient population comprises orally administering a controlled release dosage form described herein to a subject every 6-9 hours, preferably about every 7-8 hours, for at least 7, 8, 9, 10, 11, 12, 13, 14, or 15 days to obtain a steady state minimum LD plasma level of at least 250 ng / mL, 275 ng / mL, 285 ng / mL, 290 ng / mL, 300 ng / mL, 310 ng / mL, 320 ng / mL, or 330 ng / mL 6-9 hours, preferably about 7-8 hours, after dosing and prior to the next dose. The controlled release dosage form should also be administered every 6 to 9 hours, preferably about 7 to about 8 hours, for at least 7, 8, 9, 10, 11, 12, 13, 14, or 15 days to obtain a steady state minimum CD plasma level of at least 40 ng / mL, 45 ng / mL, 50 ng / mL, 55 ng / mL, 60 ng / mL, 65 ng / mL, 70 ng / mL or 75 ng / mL 6 to 9 hours, preferably about 7 to about 8 hours, after dosing and before the next dose.

[0042] The dosing regimens of the present invention for the first, second and third target patient populations may further comprise orally administering a controlled release dosage form as described herein such that at least one of the administrations of the controlled release dosage form occurs within 30 minutes, 15 minutes, 10 minutes, 5 minutes prior to or at bedtime and provides a therapeutic benefit upon awakening 6, 7 or 8 hours after bedtime administration, and by about 7, 8, 9, 10, 11 or 12 hours after bedtime administration in the first target patient population. In certain embodiments of this bedtime treatment method, after dosing with a controlled release dosage form described herein every 6, 7, 8, 9, 10, 11, or 12 hours in a 24 hour period for at least 7, 8, 9, 10, 11, 12, 13, 14, or 15 days, the waking LD plasma level, i.e., the LD plasma level before the next dose, should be at least 250 ng / mL, 275 ng / mL, 285 ng / mL, 290 ng / mL, 300 ng / mL, 310 ng / mL, 320 ng / mL, or 330 ng / mL, and the waking CD plasma level should be at least 40 ng / mL, 45 ng / mL, 50 ng / mL, 55 ng / mL, 60 ng / mL, 65 ng / mL, 70 ng / mL, or 75 ng / mL.

[0043] The dosing regimen of the present invention allows the second and third target patient populations to experience an improved therapeutic benefit 6, 7, or 8 hours after dosing and prior to the next dose, compared to the patient's condition without administration of the controlled release form described herein, or compared to treatment with an immediate release CD-LD oral dosage form. The improved therapeutic benefit can be: (i) At least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% improvement or increase in the patient's motor status as determined by a competent clinician; (ii) at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% improvement or increase in the patient's motor status as determined by the patient's PD diary; (iii) at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% improvement or increase in the subject's tremor, dyskinesia and / or mobility as measured by the Kinesia 360 sensor; (iv) reduction in MDS-UPDRS score of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 points or more; (v) an increase of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% in the control total "on" time per day or per waking hour compared to an equivalent total immediate release CD-LD dose per day or per waking hour; (vi) an increase of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% in the patient's total "good on" time per day or per waking hour compared to an equivalent total immediate release CD-LD dose per day or per waking hour; (vii) an increase in patient “on” time 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 more per dose, per day, and / or per awake hour per day compared to a comparable oral dose of an immediate release CD-LD dosage form, or a total immediate release CD-LD dose per day or per awake hour; (viii) an increase in the patient's "good on" time 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 more per dose, per day, and / or per awake hour per day compared to a comparable oral dose of an immediate release CD-LD dosage form, or a total immediate release CD-LD dose per day or per awake hour; (ix) at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% reduction in the patient's total "off" time per day or per waking hour compared to an equivalent total immediate release CD-LD dose per day or per waking hour; (x) a reduction in patient “off” time 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 more per dose, per day, and / or per awake hour per day compared to a comparable oral dose of an immediate release CD-LD dosage form, or a total immediate release CD-LD dose per day or per awake hour; (xi) at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% increase in the patient's PGI-C score, CGI-C score, and / or PDQ-39 score compared to a comparable oral dose of an immediate release CD-LD dosage form, or the total immediate release CD-LD dose per day or per waking hour; (xii) at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% reduction in the average number of motor fluctuations per day compared to an equivalent oral dose of an immediate release CD-LD dosage form, or the total immediate release CD-LD dose per day or per waking hour; (xiii) at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% reduction in perceptual problems and / or hallucinations per day compared to an equivalent oral dose of an immediate release CD-LD dosage form, or a total immediate release CD-LD dose per day or per waking hour; or (xiv) any combination of the foregoing.

[0044] In certain embodiments, the improved therapeutic benefit comprises at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% improvement in MDS-UPDRS Part III score.

[0045] Dosing regimens for the second and third target patient populations comprising orally administering to a patient a controlled release dosage form described herein every 6-9 hours, preferably about every 7-8 hours, control or manage the patient's motor fluctuation symptoms, and in certain embodiments also reduce the patient's total "off" time during a 24 hour period 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 a 24 hour period. Dosing regimens for the second and third target patient populations comprising orally administering to a subject a controlled release dosage form described herein every 6-9 hours, preferably about every 7-8 hours, control or manage the patient's motor fluctuation symptoms, and in certain embodiments 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 during a 24 hour period.

[0046] A dosing regimen for a second or third target patient population comprising orally administering to a subject a controlled release dosage form described herein every 6-9 hours, preferably about every 7-8 hours, controls or manages the patient's motor fluctuation symptoms, and in certain embodiments increases the patient's total "on" time to more than 5 hours, more than 6 hours, more than 7 hours, or 8 hours during a dosing time interval. A dosing regimen for a second or third target patient population comprising orally administering to a subject a controlled release dosage form described herein every 6-9 hours, preferably about every 7-8 hours, controls or manages the patient's motor fluctuation symptoms, and in certain embodiments also increases the patient's total "good on" time to more than 5 hours, more than 6 hours, more than 7 hours, or 8 hours during a dosing time interval.

[0047] A dosing regimen for a second or third target patient population comprising orally administering to a patient a controlled release dosage form described herein every 6-9 hours, preferably about every 7-8 hours, controls or manages the patient's motor fluctuation symptoms, and in certain embodiments increases the patient's total "on" time per dose, per day, and / or per waking hour 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 more compared to a comparable oral administration of an immediate release CD-LD dose or a total immediate release CD-LD dose per day or per waking hour. In certain aspects of this embodiment, the controlled release dosage form is administered three times daily compared to an immediate release CD-LD dosage administered four or five times daily.

[0048] A dosing regimen for a second or third target patient population comprising orally administering to a patient a controlled release dosage form described herein every 6-9 hours, preferably about every 7-8 hours, controls or manages the patient's motor fluctuation symptoms, and in certain embodiments also increases the patient's total "good on" time per dose, per day, and / or per waking hour 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 more compared to a comparable oral administration of an immediate release CD-LD dose or a total immediate release CD-LD dose per day or per waking hour. In certain aspects of this embodiment, the controlled release dosage form is administered three times daily compared to an immediate release CD-LD dosage administered four or five times daily.

[0049] A dosing regimen for a second or third target patient population comprising orally administering to a patient a controlled release dosage form described herein every 6-9 hours, preferably about every 7-8 hours, controls or manages the patient's motor fluctuation symptoms, and in certain embodiments also reduces the patient's total "off" time per dose, per day, and / or per waking hour 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 more compared to a comparable oral administration of an immediate release CD-LD dose or a total immediate release CD-LD dose per day or per waking hour. In certain aspects of this embodiment, the controlled release dosage form is administered three times daily compared to an immediate release CD-LD dosage administered four or five times daily.

[0050] In certain embodiments, the improved therapeutic benefit experienced by PD patients in the first, second and / or third target patient populations can include a substantial reduction in the total "off" time during waking hours, which can range from about 12 to about 16 hours in a 24 hour period. As used herein, a substantial reduction in the total "off" time during waking hours can mean at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% or 50% reduction in the total "off" time during waking hours, about 12 to 18, 13 to 17 or 14 to 16 hours in a 24 hour period, compared to treatment with an immediate release CD-LD oral dosage form.

[0051] In certain embodiments, the improved therapeutic benefit experienced by the PD patients of the first, second and / or third target patient populations may include a total "off" time during the dosing interval of 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, or 0 minutes. For the PD patients of the first target group, the dosing interval is about every 12 hours. For the PD patients of the second and third target groups, the dosing interval may be 6 to 12 hours, preferably 7 to 9 hours, and most preferably about 8 hours.

[0052] In certain embodiments, the improved therapeutic benefit experienced by PD patients of the first, second, or third target patient populations can include a substantial increase in "on" and "good on" time during waking hours, which can range from about 12 to about 18 hours or about 14 to about 16 hours in a 24 hour period. As used herein, a substantial increase in the total "on" and "good on" time during waking hours can 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 to 18, 13 to 17, or 14 to 16 hours in a 24 hour period) compared to treatment with an immediate release CD-LD oral dosage form.

[0053] In certain embodiments, the improved therapeutic benefit experienced by PD patients in the first, second, or third target patient populations can include a substantial increase in "on" and "good on" time during waking hours, which can be in the range of 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 more during the dosing interval (i.e., per dose) compared to a comparable oral administration of an immediate release CD-LD dose or a total immediate release CD-LD dose per day or per waking hour.

[0054] In certain embodiments, the improved therapeutic benefit experienced by PD patients in the first, second, or third target patient populations can include a substantial reduction in "off" time during waking hours, which can be in the range of 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 more during the dosing interval (i.e., per dose) compared to a comparable oral administration of an immediate release CD-LD dose or a total immediate release CD-LD dose per day or per waking hour.

[0055] In certain embodiments, the improved therapeutic benefit experienced by PD patients of the first, second, or third target patient populations may include similar or improved LD pharmacokinetic parameters when the controlled release dosage form described herein is (i) administered under fed conditions and compared to administration under fasted conditions; (ii) administered under fed conditions and compared to administration under fasted conditions where the ingredients of the controlled release dosage form described herein are sprinkled on a food substance, such as yogurt or a fruit preparation, puree, or compote, and the sprinkled composition is administered; (iii) administered under fasted conditions and compared to administration under fasted conditions where the ingredients of the controlled release dosage form described herein are sprinkled on 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). Similar or improved LD pharmacokinetic parameters include, but are not limited to, C max The LD pharmacokinetic parameters include, but are not limited to, AUC and AUC. Similar LD pharmacokinetic parameters, as used herein, mean that the geometric mean ratio of the target parameter values ​​obtained from administration under fed or sprinkled conditions is within 80-120 of the target parameter values ​​obtained from administration under fasting conditions. Improved LD pharmacokinetic values ​​mean that the target parameter values ​​obtained from administration under fed or sprinkled conditions exhibit higher or greater values ​​compared to the target parameter values ​​obtained from administration under fasting conditions. For example, PD patients in the first, second or third target patient populations may take the controlled release dosage form described herein with food and achieve an LD C. max and / or LD AUC value is the LD C value obtained when the same amount of the controlled release dosage form is administered under fasting conditions, preferably after at least 10 hours of fasting, more preferably after an overnight fast. max and / or may be at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25% or more than the LD AUC value.

[0056] In certain embodiments, the improved therapeutic benefit experienced by PD patients in the first, second, or third target patient populations is a maximum LD and / or CD plasma concentration (T) of less than 6 hours when the controlled release dosage form described herein is (i) administered under fed conditions and compared to administration under fasted conditions; (ii) administered under fed conditions and compared to administration under fasted conditions where the ingredients of the controlled release dosage form described herein are sprinkled on a food substance, such as yogurt or a fruit preparation, puree, or compote, and the sprinkled composition is administered; (iii) administered under fasted conditions and compared to administration under fasted conditions where the ingredients of the controlled release dosage form described herein are sprinkled on 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). max For example, PD patients in the first, second, or third target patient populations may take a controlled release dosage form described herein with food and may have a T obtained after administering the same amount of the controlled release dosage form under fasting conditions, preferably after at least a 10 hour fast, more preferably after an overnight fast. max compared to an LD T of less than 5 hours, less than 4.5 hours, less than 4.0 hours, less than 3.5 hours, less than 3.0 hours, less than 2.5 hours, less than 2.0 hours, less than 1.5 hours, less than 1.0 hours, or less than 0.5 hours max and / or CD T max may show changes in

[0057] Dosage form Dosage forms useful in the dosing regimens of the present invention are controlled release oral solid formulations of LD that provide a relatively stable LD plasma or serum concentration profile over an extended period of time and enhance absorption of the active agent in the subject's gastrointestinal tract.

[0058] The dosage form may include at least two components: (i) a first or immediate release component that provides an immediate release of LD; and (ii) a second or controlled release component that provides a controlled or sustained release of LD. In certain embodiments, the second or controlled release component includes a core containing LD mixed with, coated or layered with a mucoadhesive material, preferably a mucoadhesive polymer, and externally coated with an enteric material, preferably an enteric polymer. The second or controlled release component may also contain a rate-controlling material that contributes to the controlled release of 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 drug-containing core as a subcoat to a coating or layer containing a mucoadhesive material, or the rate-controlling material may be mixed with the LD to form a controlled release matrix or core of the controlled release component. The second or controlled release component is essential to provide sustained absorption, thereby providing long-term and stable therapeutic coverage.

[0059] The oral dosage form useful in the present invention may also include 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 both the first or immediate release LD component and the second or controlled release LD component. The decarboxylase inhibitor such as CD may also be present in a different component separate 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 sustained absorption oral dosage form of the present invention may include (i) a first or immediate release component comprising LD; and (ii) a second or controlled release component comprising LD. Another embodiment may include (i) a first or immediate release component comprising LD and CD; and (ii) a second or controlled release component comprising LD. Further embodiments may include (i) a first or immediate release component comprising LD; and (ii) a second or controlled release component comprising LD and CD. Further embodiments may include (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 include (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.

[0060] The first, second, third and / or fourth components may be separate and distinct components or may be combined to form different portions or regions of a larger combined component. For example, the first or immediate release component may comprise a powder or granules comprising LD and / or CD and optionally one or more pharma- ceutically acceptable excipients, which are separate and distinct compositions from the second or controlled release component, but both may be incorporated into a capsule for administration to a patient. Alternatively, the first or immediate release component may comprise a coating or layer comprising LD and / or CD and optionally one or more pharma- ceutically acceptable excipients, which coating or layer is applied to or is 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 separate portion or component of a larger combined component. It will be understood by those skilled in the art that the location, structure and / or arrangement of the first or immediate release component relative to the second or controlled release component in the final dosage form is not important, so long as the first or immediate release component allows for immediate release of a 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 mucoadhesive properties described herein.

[0061] In some embodiments, the controlled release component includes a rate-controlling material, which may be the same as or different from the mucoadhesive material. The rate-controlling material and / or the mucoadhesive material slows or prolongs the release of the active agent or drug from the controlled release component, thereby further prolonging the release and absorption of the drug, preferably the LD and optionally the CD. The controlled release component should release the drug, such as the LD or CD, over a period of 4-10 hours, preferably 5-8 hours.

[0062] The immediate release component should provide rapid release of drugs such as LD and CD, thereby providing rapid absorption of drugs such as LD and CD. Rapid absorption is important for PD patients who require a fast "on". As a result, the controlled release dosage forms useful in the present invention can provide LD plasma levels that rise quickly, preferably to therapeutic levels, and are sustained for an extended period of time.

[0063] In certain embodiments, the amount of immediate release LD should range from about 10% to about 40%, preferably about 15% to 35%, and most preferably about 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30% based on the total amount of LD in the oral dosage form.

[0064] Decarboxylase inhibitors such as CDs are often provided in LD formulations to inhibit the decarboxylation of LDs, thereby increasing LD bioavailability. In controlled release dosage forms useful in the present invention, the decarboxylase inhibitor may be included in the immediate release component, the controlled release component, both the immediate release component and the controlled release component, or in separate immediate release and / or controlled release components as described above. Preferably, the decarboxylase inhibitor is a CD and is included only in the immediate release form, such as an immediate release component with LD or an immediate release component separate from LD. In an alternative embodiment, the decarboxylase inhibitor, preferably a CD, is included in both the immediate release form described above and in a controlled release form, such as a controlled release component with LD or a separate controlled release component without LD. In various embodiments, the amount of immediate release decarboxylase inhibitor, preferably CD, should be in the range of about 75% to about 100%, 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% based on the total amount of decarboxylase inhibitor in the oral dosage form.

[0065] In one embodiment of the present invention, the oral dosage form comprises (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 tablets, mini-tablets, beads, pellets, granules, or combinations thereof. The controlled release component may comprise a core containing LD coated with a layer comprising a mucoadhesive 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 comprises a rate-controlling material, which may be mixed with the drug to form a controlled release matrix core, may be coated on the drug-containing core to form a subcoat under a coating or layer comprising a mucoadhesive material, may be incorporated into a coating or layer comprising a mucoadhesive material or polymer, or a combination thereof. In some embodiments, the controlled release material and the mucoadhesive material may be mixed together with the LD to form a controlled release / mucoadhesive core.

[0066] The immediate release component may be formulated as a powder, coating, tablet, mini-tablet, 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 on 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.

[0067] In another embodiment of the present invention, the oral dosage form comprises (1) one or more controlled release components comprising 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 a combination thereof. The decarboxylase component may be in immediate release form, controlled release form, or immediate release and controlled release form. The decarboxylase inhibitor may be co-formulated with (1) one or more of the controlled release components comprising LD, and / or (2) one or more of the immediate release components comprising LD. Alternatively, the decarboxylase inhibitor may be formulated separately from one or more of the controlled release components comprising LD, and / or one or more of the immediate release components comprising LD.

[0068] The controlled release component may comprise a drug-containing core containing both LD and a decarboxylase inhibitor such as CD, or the LD may be a separate controlled release component that contains the decarboxylase inhibitor. In one embodiment of the present invention, the controlled release component comprises a LD-containing core that is free or substantially free of a decarboxylase inhibitor such as CD. In this embodiment, substantially free means that 15% or less, 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 total amount of the decarboxylase inhibitor in the dosage form is in the controlled release component. 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.

[0069] In a preferred embodiment of the present invention, the oral dosage form comprises (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 components may comprise a drug-containing core coated with a first layer comprising a rate-controlling material or polymer, a second layer comprising a mucoadhesive material or polymer, and an outer or third layer comprising an enteric material or polymer. Additional coatings or layers, such as cosmetic or non-functional coatings, e.g., water-soluble seal coatings, may also be added to separate the core, the first, second and / or third layers, or to overcoat the third layer. These cosmetic or non-functional coatings may also be used to separate the immediate release components from the controlled release components, and to apply or adhere the immediate release components to the controlled release components. 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 a composition having the non-functional or cosmetic coating as its outermost coating is placed in either a Type I or II USP dissolution apparatus having 500-900 ml of aqueous medium having a pH of 1-7.

[0070] According to the practice of the present invention, the components of the present invention can be obtained by any method 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 is well known in the pharmaceutical art. The compositions may also be formed using other conventional formulation techniques, such as compression and / or slugging. In addition to the drugs, such as LD and CD, the controlled release component and / or immediate release component may further contain conventional pharma-ceutically acceptable excipients, such as lubricants, fillers, binders, disintegrants, glidants, surfactants (sometimes called wetting agents), pH adjusters, antioxidants, or mixtures thereof.

[0071] In one embodiment of the present invention, the controlled release and / or immediate release components are multiparticulates, preferably encapsulated in a hard gelatin capsule. The multiparticulates may be in a form that can be sprinkled directly onto food or liquids for easy ingestion.

[0072] Active agents such as CD and LD can be combined and dispersed throughout the drug-containing core. In another embodiment, the active agent may be present in the center of the drug-containing core or layered / coated onto an inert core such as sugar spheres, microcrystalline cellulose spheres, glass spheres, plastic spheres or combinations thereof.

[0073] In one embodiment of the invention, the oral dosage form may contain two or more controlled release components that release a drug, such as CD and LD, at different rates. In this embodiment, the oral dosage form contains at least two controlled release components that differ in type, number, thickness and / or composition of a first coating comprising a rate-controlling material, a second coating comprising a mucoadhesive material, and / or a third coating comprising an enteric material.

[0074] The mucoadhesive material used in the present invention may be a homogenous mucoadhesive material, i.e., a single type of mucoadhesive material or polymer, or may comprise multiple types of mucoadhesive materials and / or polymers. The mucoadhesive material or polymer may have certain properties, such as being hydrophilic, hydrophobic, cationic, anionic and / or biocompatible, and may comprise multiple hydrogen bonding groups, hydrophobic surfaces, positively charged groups and / or negatively charged groups for adhering to mucosal surfaces, thus retaining, prolonging or slowing down the controlled release component at the absorption site, thereby allowing the release of LD from the controlled release component at the desired absorption site, thereby enhancing bioavailability. Furthermore, the mucoadhesive material or polymer may be derived from natural, synthetic or biological sources. Furthermore, the mucoadhesive material or polymer may be composed of a single polymer or a combination of two or more different polymers. In one embodiment, the polymer may range in size from 10,000 Daltons to 1,000,000 Daltons, more preferably from 20,000 Daltons to 200,000 Daltons.

[0075] Examples of mucoadhesive polymers include, but are not limited to, basic methacrylate copolymers, such as amino methacrylate copolymers.Preferred examples of methacrylate copolymers are basic butylated methacrylate copolymers, amino methacrylate copolymers, or amino alkyl methacrylate copolymers, 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 based on dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate in a ratio of 2:1:1.

[0076] Other examples of mucoadhesive materials or polymers include, but are not limited to, glycerides, steroidal surfactants, polycarbophil (CAS No. 9003-97-8; Noveon® AA-1; Lubrizol Corp.), carbomer, cellulose, chitosan, diethylaminodextran, diethylaminoethyldextran, polygalactosamine, polylysine, polyomitin, prolamines, polyimines, hyaluronic acid, sodium alginate, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (sodium CMC), and alginates or combinations thereof.

[0077] The mucoadhesive material or polymer may constitute about 1-75% of the mass of the controlled release component, preferably about 2-70% of the mass of the controlled release component, most preferably about 3-50% of the mass of the controlled release component. Preferably, the mucoadhesive material or polymer is Eudragit® E100 alone or in combination with at least one further mucoadhesive material. The above mass percentages of mucoadhesive material or polymer are based on multiparticulates having a bead size between 0.8 and 1.2 mm. If the bead size is larger or smaller than 0.8 mm to 1.2 mm, one skilled in the art will understand that the above mass percentages should be adjusted accordingly.

[0078] Alternatively, the mucoadhesive material or polymer is a material capable of forming a positive ionic charge at the pH present in the human gastrointestinal tract. It is believed that the positive charge allows the mucoadhesive material to interact with the negative charges of the intestinal wall, thereby slowing or retarding the gastrointestinal transit time of the controlled release component.

[0079] Enteric coating materials or polymers are known in the art. In general, enteric coating polymers are designed to prevent drug release from oral solid dosage forms in the low pH environment of the stomach, thereby delaying drug release until the dosage form reaches the small intestine. Thus, the controlled release component of the present invention has an in vitro release profile with minimal release of active agent at pH 1.0. In the controlled release formulation of the present invention, the second, third or outer enteric coating layer is believed to provide an additional advantage in preventing aggregation of the controlled release component. That is, the enteric coat layer prevents the controlled release mucoadhesive components from sticking together in the low pH environment of the stomach.

[0080] Preferred enteric materials are shellac (ester of aryl acids), 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 succinate. Preferred enteric polymers release at a pH of 5.5 or higher. Examples include Eudragit® L100 or Eudragit® L100-55. The enteric polymer may comprise about 1-40%, preferably about 1.5-30%, and most preferably about 1.5-25% of the mass of the controlled release component. The above percentages of enteric coating polymer are based on a multiparticulate bead size of 0.8-1.2 mm. If the bead size is smaller or larger, one skilled in the art will understand that the above weight percentages should be adjusted accordingly.

[0081] The second, third or outer enteric coating should be designed to dissolve at a pH above 5.0, a pH of 5.5 or greater, a pH of 6.0 or greater, or a pH of 6.5 or greater. 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.

[0082] The enteric coating polymer may include a methacrylic acid copolymer or multiple types of methacrylic acid copolymers. The methacrylic copolymer may include 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 any combination thereof.

[0083] In a preferred embodiment of the present invention, the controlled release component comprises a first rate-controlling coating on the drug-containing core (i.e., applied to or surrounding the drug-containing core with or without a seal coating), a second coating (with or without a seal coating) comprising a mucoadhesive material applied to or surrounding the rate-controlling coating, and a third coating (with or without a seal coating) comprising an enteric material applied to or surrounding the second coating. The first rate-controlling coating may comprise a controlled release material or polymer, such as ethyl cellulose, cellulose acetate, Eudragit® E, Eudragit® RS, Eudragit® RL, and Eudragit® NE, or mixtures thereof. Preferably, the controlled release material is not soluble in water at neutral pH. Additional controlled release materials or polymers that may be used are described in U.S. Patent No. 5,002,776, which is incorporated herein by reference. In certain embodiments, the controlled release material or polymer is cellulose acetate, ethyl cellulose, or mixtures 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, KCl, a sugar, i.e., lactose, sucrose, mannitol, povidone, copovidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose, or a combination thereof.If the pore-forming agent or flux enhancer is a water-soluble polymer, it should have a low molecular weight, such as less than 100,000, preferably less than 50,000, and / or should be rapidly soluble in water, i.e., 2% by weight of the water-soluble polymer should dissolve in 100 ml of water at 25°C within 15 minutes, preferably within 10 minutes, most preferably within 5 minutes.

[0084] The controlled release component may also contain hydrophobic controlled release materials in addition to or instead of the above controlled release materials. Examples of hydrophobic materials that can be used include beeswax, white wax, emulsifying wax, hydrogenated vegetable oils, 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 25-31 carbon atoms, saturated alcohols having 25-31 carbon atoms, saturated monocarboxylic acids having 25-31 carbon atoms, and esters obtained from said alcohols and monocarboxylic acids, as described in U.S. Patent No. 6,923,984, which is incorporated herein by reference.

[0085] In an alternative embodiment, the controlled release component comprises a matrix core comprising a mixture of a controlled release material, which may be the above-mentioned controlled release material and / or a hydrophobic material, and a drug, i.e., CD and / or LD. The matrix core may further contain one or more pharma- ceutically acceptable excipients, such as lubricants, fillers, binders, disintegrants, glidants, surfactants (sometimes called wetting agents), pH adjusters, antioxidants, or mixtures thereof. In this embodiment, the matrix core may be further coated with a rate-controlling coating or polymer before being coated with the mucoadhesive coating and the outer enteric coating.

[0086] In another alternative embodiment, the controlled release component may incorporate a controlled release material, which may be the controlled release materials described above and / or a hydrophobic material, in the mucoadhesive coating. The mucoadhesive material may also function as a controlled release material or contribute to the controlled release of the drug from the controlled release component.

[0087] The controlled release material may comprise about 1-35%, preferably about 2-30%, and most preferably about 3-25% of the mass of the controlled release component.

[0088] The mucoadhesive and enteric coatings or layers used in the present invention may further comprise, in addition to the mucoadhesive and enteric materials, one or more pharma- ceutically acceptable excipients such as plasticizers, lubricants, fillers, binders, disintegrants, glidants, surfactants (sometimes called wetting agents), pH adjusters, antioxidants, or mixtures of the foregoing.

[0089] Some commonly known plasticizers include adipate, azelate, benzoate, citrate, stearate, isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citric acid esters, and those listed in Encyclopedia of Polymer Science and Technology, Vol. 10 (1969) published by John Wiley & Sons. Preferred plasticizers are triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyl tributyl citrate, acetyl triethyl citrate, glycerol sorbitol, diethyl oxalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, glycerol tributyrate, and combinations thereof. Depending on the particular plasticizer, an amount of plasticizer ranging from about 0% to about 25%, preferably from about 2% to about 15%, based on the total weight of the controlled release, mucoadhesive and / or enteric coating can be used.

[0090] Lubricants useful in pharmaceutical formulations are known in the art. Examples of suitable lubricants 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, salts of fatty acids, metal salts of fatty acids, glyceryl monostearate, glyceryl tribehenate, glyceryl dibehenate, Compritol® 888 ATO, glyceride esters, sorbitan monostearate, sucrose monopalmitate, sugar esters, fatty acid esters, talc, hydrated magnesium silicate, PEG4000, boric acid, Carbowax (PEG) 4000 / 6000, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate, Sterotex, wax, or mixtures thereof.

[0091] Examples of fillers that may be used in the compositions 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 comprise about 1-50%, preferably about 2-45%, and most preferably about 5-40% of the mass of the controlled release component. Similarly, the filler may comprise about 1-50%, preferably about 2-45%, and most preferably about 5-40% of the mass of the immediate release component.

[0092] Examples of binders that may be used in the compositions of the present invention include acacia, povidone, hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, polyethylene oxide, polymethacrylates, methylcellulose, ethylcellulose, pregelatinized starch, gelatin, tragacanth, zein, or mixtures thereof. Preferably, the binder is selected from povidone, hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, polymethacrylates, methylcellulose, gelatin, and ethylcellulose, or mixtures thereof. Particularly preferred binders include water-soluble binders such as povidone, hypromellose, hydroxypropylcellulose, gelatin, and mixtures thereof. The binder may comprise about 0.1-15%, preferably about 0.2-10%, and most preferably about 0.5-5% of the mass of the controlled release component. The binder may comprise about 0.1-15%, preferably about 0.2-10%, and most preferably about 0.5-5% of the mass of the immediate release component.

[0093] Examples of disintegrants that may be used in the compositions of the present invention include croscarmellose sodium, starch, crospovidone, sodium starch glycolate, alginic acid, calcium carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, powdered cellulose, chitosan, guar gum, magnesium aluminum silicate, methylcellulose, sodium alginate, and mixtures thereof. The disintegrant may comprise about 0.1-15%, preferably about 0.2-10%, and most preferably about 0.5-5% of the mass of the immediate release component.

[0094] Examples of glidants that may be used in the compositions of the present invention include colloidal silicon dioxide, corn starch, talc or mixtures thereof.

[0095] One or more surfactants may also be used in the compositions of the present invention. The surfactant may be a non-ionic surfactant or an ionic surfactant. Examples of non-ionic surfactants include polyethoxylated castor oil, polyoxyethylene alkyl esters, polyglycolized glycerides, sorbitan fatty acid esters, glycerin fatty acid esters, fatty acid polyglycerides, fatty acid alcohol polyglycol ethers, acetylene glycols, acetylene alcohols, oxyalkylene block polymers, polyoxyethylene alkyl ethers, polyoxyethylene alkylaryl ethers, polyoxyethylene styrylaryl ethers, polyoxyethylene glycol alkyl ethers, polyoxyethylene fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene glycerin fatty acid esters, polyoxyethylene hydrogenated castor oil, polyoxypropylene fatty acid esters, or mixtures thereof. A further list of possible non-ionic surfactants can be found in Martindale, The Extra Pharmacopoeia 29, incorporated herein by reference. th ed., pages 1243-1249.

[0096] In certain embodiments, nonionic surfactants may include fatty alcohol acid or amide ethoxylates, monoglyceride ethoxylates, sorbitan ester ethoxylates, alkyl polyglycosides, mixtures thereof, etc. Certain nonionic 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®).

[0097] In certain embodiments, nonionic surfactants may also include d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS), nonoxynol, poloxamer, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan sesquioleate, sorbitan trioleate, tyloxapol, and mixtures of the foregoing.

[0098] Any of various ionic surfactants can also be incorporated into the composition 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, acyltaurates and sulfosuccinates, phosphates, quaternary ammonium salts, and ethoxylated amines.An example of a preferred ionic surfactant is sodium lauryl sulfate.

[0099] The surfactant may comprise about 0.1 to 15%, preferably about 0.2 to 10%, and most preferably about 0.5 to 5% by weight of the controlled release or immediate release component.

[0100] Examples of pH adjusting agents that may be used in the compositions of the present invention include pharma- ceutically acceptable acids or bases that may be present to adjust the pH of intermediate compositions leading to the final composition and to adjust the pH of the drug environment of the final composition to a desired or optimal pH range. Representative examples of pharma-ceutically 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 pharma-ceutically 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 comprises about 0.5-20%, preferably about 0.75-15%, and most preferably about 1-10% of the mass of the controlled release component. Alternatively, the pH adjusting agent is an acid, preferably an organic acid, and is 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.Certain embodiments of the present invention, the immediate release component, the controlled release component and / or the final oral dosage form are free or substantially free of pH adjusting acids, preferably pH adjusting organic acids, most preferably pH adjusting carboxylic acids, such as acetic acid, citric acid, fumaric acid, malic acid, propionic acid, tartaric acid, and mixtures thereof.

[0101] Examples of antioxidants that may be used 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.

[0102] In one embodiment of the invention, the CD and LD are present in the dosage forms 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. One particular embodiment comprises a ratio of about 1:4 CD and LD, with all or substantially all of the CD being in the immediate release component.

[0103] Examples of useful amounts of LD-CD include (a) about 140 mg LD and about 35 mg CD; (b) about 210 mg LD and about 52.5 mg CD; (c) about 280 mg LD and about 70 mg CD; and (d) about 350 mg LD and about 87.5 mg CD. The above values ​​are based on the weight of anhydrous CD. If the monohydrate form of CD is used, the amounts will be slightly higher. For example, 35 mg anhydrous CD is equivalent to 37.79 mg CD monohydrate, and similarly, 70 mg anhydrous CD is equivalent to 75.58 mg CD monohydrate.

[0104] In one embodiment of the present invention, the immediate release component may comprise less than the controlled release component. For example, the ratio of LD in the immediate release component to LD in the controlled release component may be in the range of 0.15 to 0.49. For example, the weight ratio of LD in the controlled release component to LD in the 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 after administration of the dosage form, preferably within 45 minutes after administration, and most preferably within about 30 minutes after administration.

[0105] As noted above, in certain embodiments including a decarboxylase inhibitor such as CD, all or substantially all of the decarboxylase inhibitor should be in the immediate release component. The amount of immediate release decarboxylase inhibitor, preferably CD, in the immediate release component should be in the range of about 75% to about 100%, preferably about 80% to 100%, most preferably about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99 or 100% based on the total amount of decarboxylase inhibitor in the oral dosage form.

[0106] 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 can be retained on an 18, 20, or 25 mesh sieve. Additionally, the beads, pellets, tablets, mini-tablets or granules can have a size that passes through 14 mesh but can be retained on an 18 or 25 mesh sieve. In certain embodiments, the dosage form of the present invention comprises a plurality of beads, pellets, tablets, mini-tablets or granules having a size that passes through 12, 14, or 16 mesh but can be retained on an 18, 20, or 25 mesh sieve.

[0107] The controlled release component has an in vitro dissolution profile that shows a minimum release of LD at pH 1.0 and a sustained release of LD near neutral, for example at or near pH 7. For example, the minimum release may involve a release of less than 20%, preferably less than 10%, and most preferably less than 5% of LD using the United States Pharmacopeia (USP) I dissolution method in simulated gastric fluid (pH 1.0, no enzymes) at an agitation speed of 75 rpm for 2 hours. Furthermore, the sustained release may include release at or near pH 7 for at least over 4 hours and up to 8 hours when changed to simulated intestinal fluid (pH 7.0, no enzymes) after the first 2 hours in simulated gastric fluid (pH 1.0, no enzymes) using the USPI dissolution method at an agitation speed of 75 rpm. Furthermore, as used herein, at or near pH 7 includes pH 6.5, 6.6, 6.7, 6.8, 6.9, 7.1, 7.2, 7.3, 7.4, 7.5, or 7.6, or a pH approximation thereof.

[0108] Oral controlled release dosage forms useful in the present invention should include one or more immediate release components and one or more controlled release components, and upon administration to a human patient, the immediate release component should provide a therapeutic dose of LD within 1 hour, preferably within 45 minutes, and most preferably within about 30 minutes after administration of the dosage form. To achieve this therapeutic level, the controlled release component should exhibit the following in vitro release profile when tested using USP Type I or II apparatus at 37° C., a rotation speed of 75 rpm, and 900 ml of aqueous medium at a pH between 6.8 and 7.4, preferably pH 7:

[0109]

number

[0110] The LD release amount in the above table is based on the total amount of LD present in the controlled release component. In certain embodiments, the controlled release component should also release less than 25%, preferably less than 20%, and most preferably less than 15% of the LD when tested using USP Type I or II apparatus at 37° C., 75 rpm rotation speed, and 900 ml of pH 1 aqueous medium for 2 hours. In certain embodiments, oral controlled release dosage forms useful in the present invention comprise (i) one or more immediate release components comprising a LD and a 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 a LD, optionally a CD, and at least one pharma- ceutically acceptable excipient, (b) a layer or coating surrounding the core comprising a mucoadhesive material, and (c) an outer coating comprising an enteric material surrounding the mucoadhesive 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 a mucoadhesive material beneath the coating, as well as a cosmetic and / or non-functional seal coating as described above. When this embodiment of the dosage form of the present invention is tested using USP Type I or Type II apparatus with 500-900 mL of aqueous medium having a pH of about 1 to about 7.5, about 75%-100% of the CD is released within 30 minutes, preferably about 85%-100% of the CD is released within 30 minutes, and most preferably about 90%-100% of the CD is released within 30 minutes. Furthermore, when this embodiment of the dosage form is tested using USP Type I or Type II apparatus and 500-900 mL of aqueous medium having a pH of about 1 to about 4.0, about 15%-45% of the LD is released within 30 minutes, preferably about 20%-40% of the LD is released within 30 minutes, and most preferably about 25%-35% of the LD is released within 30 minutes. This embodiment of the dosage form, when tested using a USP Type I apparatus at 37°C ± 0.5°C, a rotation speed of 75 rpm and 500-900 ml of simulated gastric fluid for 2 hours followed by pH 6.8 phosphate buffer, exhibits the following LD in vitro profile:

[0111]

number

[0112] In a further embodiment, the present invention comprises a) one or more immediate release components as described above, b) one or more controlled release components as described above, and c) one or more enteric coated components. The enteric coated components comprise a core comprising LD or an ester of LD or a salt thereof and / or a decarboxylase inhibitor, at least one pharma- ceutically acceptable excipient as described above, and an enteric coating. The enteric coated components release 100% of the LD and / or decarboxylase inhibitor within 90 minutes, preferably within 60 minutes, and most preferably within 45 minutes, when tested using a USP Type I or Type II apparatus at 37° C., a rotation speed of 75 rpm, and 900 ml of aqueous medium at pH 6.8-7.4, preferably pH 7. The enteric coated components should also release less than 25%, preferably less than 20%, and most preferably less than 15% of the LD when tested using a USP Type I or II apparatus at 37° C., a rotation speed of 75 rpm, and 900 ml of aqueous medium at pH 1.

[0113] The LD released from the controlled release component may result in an in vivo LD plasma profile (e.g., a mean in vivo LD plasma profile) that includes a peak that occurs at about 2 hours or more after administration to a subject, and has a maximum peak concentration (C max In another embodiment, the plasma profile provides a peak at about 1.5 hours after administration to a subject and a C max The profile exhibits a duration of at least 4 hours for a LD plasma concentration that is 50% or greater of the LD2 concentration. By way of example, the profile may be achieved under fasting conditions.

[0114] When the formulations of the present invention include 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 is determined based on the time of administration of the oral dosage form; the C max LD plasma concentration corresponding to the C within 1 hour, more preferably within 30 minutes of administration. max C max The time to 50% of C is less than 1 hour. max50% of the maximum plasma concentration is maintained for at least 5.0 hours. max ) is between 30 minutes and 7 hours. Preferably, the LD plasma level is at least 5.5 hours, more preferably at least 6.0 hours, even more preferably at least 6.5 hours, and most preferably at least 7.0 hours, C max will be maintained at more than 50% of the

[0115] When the formulations of the invention comprise an immediate release component and a controlled release component, the in vivo LD plasma profile following oral administration of the dosage form of the invention to a subject may comprise an LD fluctuation index which may range from 0.5 to 1.5, preferably from about 0.7 to about 1.3, and more preferably from about 0.7 to about 1.25. The fluctuation index is calculated according to the following formula (C max -C min ) / C avg where C max is the maximum or peak LD concentration, and C min is the minimum LD concentration, and C avg is the average LD concentration over the entire measurement interval. In certain embodiments, the fluctuation index is determined at steady state or after about 10 to about 15 days of treatment with the formulations described herein, preferably during the period beginning with the first morning dose and 6, 7, 8, 9, 10, 11, or 12 hours after the first morning dose.

[0116] It is understood by those skilled in the art that the pharmacokinetic parameters listed herein can be obtained by single or multiple dose studies on healthy subjects or PD patients, unless otherwise specified. It is also understood that the pharmacokinetic parameters listed herein can be obtained under fed or fasting conditions. It is further understood that the pharmacokinetic parameters listed herein are average values ​​obtained from single or multiple dose studies using at least three or more subjects or patients, unless otherwise specified.

[0117] The combination of immediate release and controlled release components of the present invention provides an almost injection-like profile. maxThe time to reach a therapeutic level of LD (e.g., 50% C max LD level) and above therapeutic level (e.g. 50% C max ) is the time that the LD level is maintained at 0.5 mg / kg / day. A shorter time to reach therapeutic LD levels is associated with a faster "on" time for PD patients, while a longer period above therapeutic levels provides the desired stable "infusion-like" profile.

[0118] The advantages of the present invention are that it provides sustained LD plasma concentrations over a sustained period of more than 5 hours and max The objective of the present invention is to provide a more consistent duration in which the percent coefficient of variation (CV) of the mean duration of LD plasma concentrations above 35% is less than 35%, preferably less than 30%.

[0119] A preferred composition of the present invention comprises: 1. A multiparticulate formulation comprising: a) one or more immediate release components comprising LD and / or CD and optionally at least one pharma- ceutically acceptable excipient as described above; and b) one or more controlled release components comprising controlled release beads, pellets, tablets, minitablets or granules, wherein the beads, pellets, tablets, minitablets or granules comprise a core of LD that is free or substantially free of CD, at least one pharma- ceutically acceptable excipient as described above, a mucoadhesive coating or layer applied to and / or surrounding the core, and an enteric coating surrounding the mucoadhesive coating or layer, wherein the controlled release beads, pellets, tablets, minitablets or granules also comprise a controlled release material. The controlled release material may i) be mixed with the LD to form a controlled release matrix core, ii) be applied as a coating or layer onto a core comprising the LD and at least one pharma- ceutically acceptable excipient, iii) be incorporated into or mixed with a mucoadhesive coating or layer, or iv) be a combination of (i), (ii) and / or (iii). The cosmetic and / or seal coatings described above may also be used for the immediate and controlled release components of this embodiment.

[0120] An alternative preferred composition comprises: a) one or more immediate release components comprising LD, CD and optionally at least one pharmaceutically acceptable excipient as described above; b) one or more controlled release components 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 free or substantially free of CD, at least one pharmaceutically acceptable excipient as described above, a mucoadhesive coating or layer applied to and / or surrounding the core, and an enteric coating surrounding the mucoadhesive coating or layer, wherein the controlled release beads, pellets, tablets, mini-tablets or granules also comprise 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 described above, and an enteric coating surrounding the core. The controlled release material used in the controlled release component may i) be mixed with the LD and at least one pharma- ceutically acceptable excipient to form a controlled release matrix core, ii) be applied as a coating or layer onto a core of LD and at least one pharma-ceutically acceptable excipient, iii) be incorporated into or mixed with a mucoadhesive coating or layer, or iv) be a combination of (i), (ii) and / or (iii).

[0121] In certain embodiments, dosage forms useful in the dosing regimens of the present invention are described in U.S. Pat. No. 10,292,935 and U.S. Patent Application Publication No. 2020 / 0009062 (U.S. Patent Application No. 16 / 573,634, filed Sep. 17, 2019), which are incorporated herein by reference. EXAMPLES

[0122] Example 1 An immediate release granule was prepared having the following composition:

number

[0123] The granules were prepared by blending using a procedure similar to that described above in Example 5, component 1 preparation of U.S. Patent No. 10,292,935, which is incorporated herein by reference. In general, CD, LD and croscarmellose sodium were blended in a high shear granulator and wet granulated with a 5% by weight solution of povidone in water. After granulation, the wet granules were passed through a Comil equipped with a 0.375 inch screen and dried in a fluid bed. The dried granules were milled in a Fitzmill equipped with a 30 mesh screen and then blended with magnesium stearate.

[0124] Example 2 Controlled release particles (beads) were prepared having the following composition:

number

[0125] The controlled release beads were prepared by a process similar to that described in Example 5, Component II Preparation of U.S. Patent No. 10,292,935, which is incorporated herein by reference. In general, LD, microcrystalline cellulose, mannitol and sodium lauryl sulfate were mixed in a high shear granulator and wet granulated with a 5% by weight aqueous solution of povidone. After granulation, the wet granules were extruded using an extruder equipped with a 0.9 mm hole size screen, the extrudate was collected and charged into a spheronizer equipped with a 3 mm crosshatch disk. The wet spheronized beads were dried in a fluidized bed dryer. The dried beads were sieved through a 16 market grade (MG) and a 24 MG mesh screen, and the beads that passed through the 16 MG screen but remained on the 24 MG screen were collected.

[0126] Using a fluid bed coating apparatus, the collected beads were coated with a solution containing cellulose acetate, copovidone, acetone, and isopropyl alcohol. After the target coating solution was applied, the controlled release coated beads were dried in the fluid bed. The dried controlled release beads were sieved through 14MG and 24MG mesh screens, and the beads remaining on the 24MG screen were collected. The collected controlled release coated beads were coated with a mucoadhesive solution containing Eudragit E100, talc, acetone, and isopropyl alcohol in the fluid bed. After the target mucoadhesive coating solution was applied to the controlled release coated beads, the mucoadhesive coated beads were dried in the fluid bed. The dried mucoadhesive coated beads were coated with an enteric coating solution containing Eudragit L 100, triethyl citrate, acetone, and isopropyl alcohol in the fluid bed. After the target enteric coating solution was applied to the mucoadhesive coated beads, the enteric coated beads were dried in the fluid bed. The dried enteric coated beads were sieved through a 14MG and 24MG mesh screen and the beads retained on the 24MG screen were collected. The collected beads were blended with talc.

[0127] Example 3 The immediate release component of Example 1 and the controlled release beads of Example 2 were blended to make a mixture of 67.49% by weight of the controlled release beads and 32.51% of the immediate release granules. The mixture was filled into hard gelatin capsules containing (a) 180 mg of LD and 45 mg of CD, and (b) 270 mg of LD and 67.5 mg of CD. The CD weight is based on anhydrous CD.

[0128] Example 4 Following the procedure of Example 2, controlled release particles (beads) were prepared having the following composition:

number

[0129] Example 5 The immediate release component of Example 1 and the controlled release beads of Example 4 were blended to make a mixture with 68.11% by weight of controlled release beads and 31.89% of 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 anhydrous CD.

[0130] Example 6 Following the procedure of Example 2, controlled release particles (beads) were prepared having the following composition:

number

[0131] Example 7 The immediate release component of Example 1 and the controlled release beads of Example 6 were blended to make a mixture with 67.5% by weight of the controlled release beads and 32.5% of the 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 weights are based on anhydrous CD. 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. 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, a rotation speed of 75 rpm, and 900 ml of simulated gastric fluid for 2 hours, followed by a pH 6.8 phosphate buffer. The 140 mg LD and 35 mg CD capsules prepared in this example were tested using a USP Type I apparatus at 37°C ± 0.5°C, a rotation speed of 75 rpm, and 900 ml of simulated gastric fluid for 2 hours, followed by a pH 6.8 phosphate buffer. The results of the in vitro dissolution test were as follows:

[0132]

number

[0133] Example 8 Twenty-eight subjects with advanced PD were administered the dosage form described in Example 3 in a randomized, open-label, assessor-blinded, multicenter, two-treatment, two-period, multiple-dose crossover study. Subjects were randomized to one of two dosing sequences receiving the composition of Example 3 ("IPX203") and immediate release CD-LD ("IR CD-LD") tablets marketed under the trade name SINEMET®, or the US FDA AB grade generic product of SINEMET®. Subjects received treatment for 15 days with a one-week (± 2 days) washout period between treatment periods.

[0134] The study consisted of four clinical visits after screening: on Day 1 of each treatment period (Visits 1 and 3) and on Day 15 of each treatment period (Visits 2 and 4). If the dosing regimen was stable for at least 4 weeks prior to Visit 1, subjects were allowed to continue their non-CD-LD based PD medication throughout the study.

[0135] To be eligible for the study, subjects had to be 40 years of age or older, diagnosed with idiopathic PD, currently receiving a stable regimen of CD-LD, and experiencing motor complications, defined as subjects experiencing daily "wearing off" episodes with periods of bradykinesia and rigidity, and experiencing an "off" state upon awakening most mornings by medical history.

[0136] Within 2 weeks after screening, on each of the 3 days prior to Visit 1, eligible subjects completed a PD and medication diary and wore a Kinesia 360 sensor on the more affected side from immediately after awakening until bedtime. Subjects were instructed to take their last dose of CD-LD by 10:00 PM the evening before Visits 1 and 3. The first morning dose of study medication was administered at the test site at Visits 1 and 3 of each treatment period.

[0137] On Day 1 of each treatment period (Visit 1 and Visit 3), subjects arrived at the study site and received a single dose of study medication. Subjects randomized to receive IR CD-LD began with a single dose of the first morning IR CD-LD dose before the usual study. Subjects randomized to receive IPX203 compositions began with a single dose based on the first morning IR CD-LD dose before the usual study, according to the guidelines provided in Table 1. [Table 1]

[0138] On Day 1 at the clinic, after taking the first dose of study drug, if the subject experienced an "off" state for 3 or more consecutive hours after dosing, or otherwise at the investigator's discretion, the subject could receive rescue medication. Subjects requiring rescue during IR CD-LD treatment received a dose of IR CD-LD corresponding to their typical pretreatment regimen based on the subject's medication diary. For rescue during IPX 203 treatment, subjects were to receive the dose of IPX203 that they would typically receive after the morning dose as described in Table 2. [Table 2]

[0139] After completing the Day 1 assessments, subjects were discharged and encouraged to take prescribed study medication according to the initial regimen as follows:

[0140] The initial dosing regimen of ID CD-LD was the same as the subject's stable pre-study regimen. If they were taking a once-daily bedtime dose of controlled-release ("CR") CD-LD, either alone or in combination with IR CD-LD, the CR CD-LD dose was discontinued and replaced with a 1:1 milligram equivalent IR CD-LD dose. A bedtime dose was defined as a dose of CR CD-LD taken within 1 hour of the subject's usual nighttime sleep period.

[0141] The initial dosing regimen for IPX203 followed the guidance provided in Table 2, which was based on each individual's pre-study morning dose of IR CD-LD and daily dosing regimen. The dosing regimen for IPX203 was estimated to be three times daily, approximately every 7-8 hours.

[0142] During Days 1-9 of each treatment period, the investigator could adjust each subject's study medication as necessary to optimize efficacy, tolerability, and safety. The dosing regimen was required to be stable for the final 5 days (Days 10-14) of each treatment period. At the Day 15 clinic visit, subjects received the same stable drug regimen they had taken on Days 10-14.

[0143] Pharmacokinetics and efficacy / pharmacodynamics were assessed periodically in the clinic by qualified clinical staff blinded to dosing up to 8 hours after dosing on Day 1 of each treatment period (Visits 1 and 3) and up to 10 hours on Day 15 of each treatment period (Visits 2 and 4). These assessments were performed regardless of whether subjects received a rescue dose on Day 1 or a booster dose on Day 15 according to an established stable dosing regimen. In addition, subjects completed a PD and medication diary and used Kinesia 360 sensors on the ankle and wrist of the more affected side immediately after awakening on each of the 3 days prior to Visits 1, 2, and 4.

[0144] The primary parameter was the mean percent "off" time during waking hours based on the subject's PD diary for the last 3 days collected at the end of each treatment period. Secondary efficacy parameters utilized additional data collected from the PD diary; dyskinesia, motility, and tremor measurements obtained from the Kinesia 360 sensor; and MDS-UPDRS scores collected pre-dose on day 15 of each treatment period.

[0145] Pharmacodynamics were also assessed using subjective motor assessment and MDS-UPDRS part III scores. Pharmacokinetic parameters were calculated from CD and LD plasma concentration-time profiles after each treatment. Safety was assessed by reviewing reported adverse events, concomitant medications, vital signs, electrocardiograms ("ECG"), laboratory tests, physical examinations, Columbia-Suicide Severity Rating Scale ("C-SSRS"), and vital signs.

[0146] Inclusion Criteria: Potential subjects had to meet all of the following criteria to be enrolled in the study: 1. Male or female subjects aged 40 years or older diagnosed with idiopathic PD who are chronically treated with a stable regimen of CD-LD but experience motor complications. Idiopathic PD is defined by the UK Parkinson's Disease Society Brain Bank diagnostic criteria. The subject has no known secondary causes of parkinsonism (e.g., vascular, toxin or drug-induced, metabolic, or infectious), and the subject does not have another neurodegenerative disorder with parkinsonism symptoms (e.g., progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy). 2. Able to provide written informed consent and willing to sign a HIPAA authorization prior to conducting any study-specific procedures. 3. A negative urine pregnancy test in female subjects of childbearing potential at screening. 4. Negative urine screen for drugs of abuse and negative alcohol breath test screen. 5. Hoehn and Yahr stage 2, 3 or 4 (included in MDS-UPDRS part III). 6. Agree to use a medically acceptable method of contraception throughout the study and for 6 weeks following completion of the study. 7. Montreal Cognitive Assessment (MoCA) score ≥ 24 at screening in the "on" state. 8. During the 4 weeks prior to screening, subject experiences daily "wearing off" episodes with periods of bradykinesia and rigidity, and has a medical history of experiencing "off" states upon awakening most mornings. 9. At Visit 1, review of the 3-day PD diary will verify: the subject is able to properly complete the diary with valid entries; and that the subject has an average of at least 2.5 hours of "off" time per day during waking hours over the 3 days, with at least 1.5 hours of "off" time on each day. Failure to return the diary for more than one day, or missing more than 2 hours (four 30 minute periods) of one 24 hour diary day, indicates an inability to properly complete the diary. 10. Responsive to CD-LD therapy and currently being treated with a stable regimen with CD-LD for at least 4 weeks prior to Visit 1, a. Morning dose requires 100-250 mg LD IR CD-LD b. Requires a total daily dose of IR CD-LD of at least 400 mg LD c. Take a maximum one total dose of 1800 mg LD, including ID CD-LD alone or IR CD-LD in combination with a once daily bedtime dose of CR CD-LD d. CD-LD has a dosing frequency of 4 to 9 times a day e. Typically experiences an "on" response with the first dose of ID CD-LD of the day f. Medical history indicates that the effectiveness of the first morning dose of IR CD-LD lasts less than 4 hours, typically resulting in a wearing "off" before the next dose; or subject takes a second dose of PD medication 4 hours prior to avoiding the "off". 11. Have not used any dose of CR CD-LD apart from the once daily bedtime dose for at least 4 weeks prior to Visit 1. 12. Have not used any dose of RYTARY® (carbidopa and levodopa) extended-release capsules during the past 4 weeks prior to Visit 1. 13. At screening, have an MDS-UPDRS part III total score in the "OFF" state: a. At least 20 credits b. At least 25% or 10 units greater in the "on" state. 14. At screening, subject has predictable "off" periods defined by a score of 1 or 2 on item #4.5, MDS-UPDRS part IV B Motor Fluctuations Complex (Motor Fluctuations). 15. Score ≥ 1 on item #4.3 (time spent in "off" state) of MDS-UPDRS Part IV B at Screening. 16. Hemoglobin levels must be above the lower limit of the normal laboratory reference range. 17. Able and willing to comply with the protocol, including completing the diary and availability for all scheduled study visits, and data and blood sample collection times.

[0147] Dose Selection The initial dose of IPX203 was selected based on previous PK data obtained with IPX203 and IR CD-LD in patients with advanced PD. The IPX203 dose was intended to achieve peak LD concentrations equivalent (approximately 20%) to the corresponding dose of IR CD-LD in the subjects. A dose of approximately 270-360 mg LD from IPX203 was estimated to provide peak LD concentrations equivalent to those of a 100 mg LD from IR CD-LD.

[0148] The recommended initial morning dose of IPX203 on Day 1 was based on the subject's pre-study morning dose of IR CD-LD. 100 mg unit doses of ID CD-LD were converted to 360 mg unit doses of IPX203 as described in Table 1 above. Subsequent doses of IPX203 during the day were based on the subject's most frequent pre-study LD doses in the afternoon and evening (noon to bedtime) with the LD 100 mg unit dose in IR CD-LD dose proportionally converted to LD 270 mg in IPX203 as described in Table 2 above. This study allowed for the evaluation of 270 mg and 360 mg IPX203 unit doses as alternative conversions to the 100 mg unit dose of IR CD-LD. The estimated IPX203 dosing regimen was three times daily, dosed approximately every 7-8 hours.

[0149] The initial IR CD-LD dosing regimen was the same as the subject's stable pre-study regimen (unless they were taking a once-daily bedtime dose of CR CD-LD, alone or in combination with IR CD-LD, in which case the CR CD-LD dose was discontinued and replaced with a 1:1 mg equivalent IR CD-LD dose).

[0150] During the first 9 days of each treatment period, investigators were able to adjust the IPX203 and IR CD-LD dose regimens for optimal efficacy, tolerability, and safety. On days 10-15 of each treatment period, the study drug regimen remained stable without dose adjustments.

[0151] At each scheduled clinic visit (Days 1 and 15 of each treatment period), subjects were fasted for at least 8 hours upon arrival and had abstained from study medication since 10 PM (Visits 1 and 3) or at least 5 hours (Visits 2 and 4) the previous evening. Coffee, tea, water, and juice were permitted up to 1 hour prior to dosing. All study medication was administered with 240 mL of room temperature water. Subjects were instructed to swallow the study medication whole, without crushing or chewing. A low protein breakfast was provided at the study site approximately 1 hour after dosing. Lunch was provided at least 4 hours later, and dinner could be provided. Snacks were permitted except within ± 1 hour of the morning dose.

[0152] There were no dietary restrictions during the home dosing phase between clinic visits.

[0153] The two treatment periods were separated by a washout period of approximately 1 week.

[0154] Blood samples (6 mL) were collected by direct venipuncture or IV catheter for measurement of LD and CD plasma concentrations at the following nominal times: Day 1 of each treatment period: pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5 and 8 hours after administration. On day 15 of each treatment period: pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8 and 10 hours after administration.

[0155] Subjects completed a PD diary for the final 3 days before returning to the clinic at Visits 1, 2, and 4.

[0156] Each diary entry indicated the subject's predominant motor state over the following 30 minutes as one of the following five states: ·"off" "On" without dyskinesia "On" with non-problematic dyskinesias "On" with problematic dyskinesias ·Sleeping.

[0157] The kinetic states were defined as follows: "On" is defined as the state when the drug of interest is providing benefits in terms of motility, slowness and rigidity. "Off" is defined as the state when the drug has worn off and is no longer providing benefit in terms of motility, slowness, and rigidity.

[0158] Dyskinesia is an effect of the drug and is defined as involuntary twisting, rotating movements that occur during "on" times.

[0159] Benign dyskinesias do not interfere with function and do not cause significant discomfort.

[0160] Problematic dyskinesias interfere with function and cause significant discomfort.

[0161] "Good on" is defined as "on" without dyskinesias and "on" with non-problematic dyskinesias.

[0162] The MDS-UPDRS scale includes four parts: Part I (non-motor experiences of daily life); Part II (motor experiences of daily life); Part III (real-time motor examination) and Part IV (motor complications). Parts I, II and IV are questionnaires completed by the subject describing their respective experiences during the past week. MDS-UPDRS Parts I, II, III and IV were administered at screening (while the subject was in the "on" state) and before dosing on day 15 for each treatment. MDS-UPDRS Part III was also administered at screening while the subject was in the "off" state.

[0163] Subjects wore the Kinesia 360 sensors on the wrist and ankle of their most affected side for the last 3 days before returning for Visits 1, 2, and 4. Subjects were instructed to wear the Kinesia 360 sensors immediately upon waking until going to bed, except while showering, bathing, or swimming.

[0164] Qualified treatment-blinded assessors (investigators or clinical staff trained in assessing motor status) performed investigator assessments of the subject's motor status at clinic visits 1 and 0.5 hours pre-dose, immediately prior to dosing, and every 30 minutes post-dose, up to 8 hours on day 1, and up to 10 hours on day 15. Subjects' motor status was reported as one of the five states identified above and calculated as "good on."

[0165] The MDS-UPDRS Part III was administered pre-dose and hourly for up to 8 hours (Day 1) and 10 hours (Day 15) post-dose on Days 1 and 15. Part III includes 18 items including speech, facial expression, rigidity, finger tapping, hand movement, pronation-supination hand movement, toe tapping, leg agility, chair rise, gait, freezing of gait, postural stability, posture, overall movement spontaneity, postural tremor of the hand, kinetic tremor of the hand, rest tremor amplitude (limb, lip / chin), and rest tremor constancy, each scored on a 5-point normal to severe scale, and also includes a question regarding the impact of dyskinesias.

[0166] All pharmacokinetic analyses were performed in accordance with the FDA 2003 Guidance for Bioavailability and Bioequivalence Studies.

[0167] Using non-compartmental methods, T for LD and CD max , C max , AUC t , AUC∞, ke and t 1 / 2 were estimated (Phoenix WinNonlin, version 6.4.0). The extent of LD exposure on day 1 between 0-2 h, 2-8 h, and 8 h, extrapolated to infinity, was assessed by estimating AUC0-2, AUC2-8, and AUC8-∞, respectively. The partial AUCs between 0-2 h and 2-10 h on day 15 (AUC0-2 and AUC2-∞) were estimated (Phoenix WinNonlin, version 6.4.0). 10 ) was estimated. Furthermore, the plasma LD concentration was C max Time to reach 50% and 430 ng / mL, and C max Duration of LD plasma concentrations >50% and >430 ng / mL was estimated for each treatment using linear interpolation between adjacent time points. Bioavailability was calculated as the arithmetic mean ratio of dose-normalized AUC∞ values ​​for IPX203 and IR CD-LD. Normalized IPX203 data is shown normalized to 280 mg LD and 70 mg CD, and normalized IR CD-LD is shown normalized to 100 mg LD and 25 mg CD. Accumulation was calculated based on AUC on Day 1. tau AUC on day 15 tau The tau (dosing interval) on day 1 was assigned the same value as the tau on day 15. The pharmacokinetic index over 10 hours on day 15 was calculated as (C max -C min ) / C avg It was calculated as:

[0168] The bioequivalence of IPX203 was assessed compared to the IR CD-LD reference treatment using a mixed-effects analysis of variance with treatment, period, and sequence as fixed effects and subject within sequence as a random effect.

[0169] Parkinson's disease diary data (days 12-14) The primary efficacy parameter for this study was the mean percent "off" time during awake hours based on subject PD diaries collected at the end of each treatment period. Total "off" time was calculated by summing the number of 30-minute intervals in which subjects checked "off" for each of the three days (Days 12-14) for which subjects recorded diary data. Percent "off" time was calculated as the total "off" time divided by the total non-sleep time (i.e., awake time). The mean percent "off" time for each subject was the average of the percent "off" time across the three days. Primary endpoints were compared between treatments using a mixed-effects ANOVA with treatment, period, and sequence as fixed effects and subjects within sequence as a random effect. Summary statistics (mean, SD, median, min, max) are presented along with LS mean difference, SD, p-values, and 95% CI. Results for mean "off" time during awake hours were also presented categorically with the number (%) of subjects by treatment.

[0170] Presentation of secondary PD parameters included summary statistics, categorical presentations, and ANOVA treatment comparisons (LS mean difference, SD, p-values, and 95% CIS) for the following: -Average total time for each exercise state Average total "off" time and "good on" time normalized to 16 hours of awake time (calculated as the percentage of time in a particular state relative to awake time multiplied by 16) The mean number of clinical (motor) fluctuations (defined as changes from "on" to "off" or vice versa) · Average duration of a "good on" state and average duration of any "on" state.

[0171] In addition, results for several secondary parameters were summarized categorically by treatment and compared using Fisher's exact test: Percentage of subjects in the "on" or "off" state upon awakening from nighttime sleep Proportion of subjects with a reduction in "OFF" time from baseline of at least 0.5, 1, 1.5, 2, 3, and 4 hours. Baseline "OFF" time was the average "OFF" time from the 3 days prior to Visit 1.

[0172] Changes from Screening to Premedication on the MDS-UPDRS (Parts I, II, III, and IV) Mean MDS-UPDRS Part I, II, III, IV, II+III and total scores were summarized at screening (while subjects were in the "on" state) and pre-dose on day 15 of each treatment. Mean MDS-UPDRS Part III scores were also summarized at screening while subjects were in the "off" state. Day 15 pre-dose scores for each MDS-UPDRS part were compared by treatment using a mixed-effects ANCOVA with treatment, period, sequence as fixed effects, baseline (screening) value as a covariate, and subject within sequence as a random effect.

[0173] Results for individual MDS-UPDRS Part IV questions were also presented using similar ANCOVAs, with summary statistics (absolute scores and change from screening) and treatment comparisons. Categorical displays showing the percentage of subjects with each absolute or change score are also included.

[0174] Kinesia 360 Sensor Data Kinesia 360 sensor data (tremor, dyskinesia, and mobility) were summarized by treatment using summary statistics and compared between treatments using a mixed-effects ANOVA with treatment, period, and sequence as fixed effects, and subjects within sequence as a random effect. The following parameters were reported: Tremor - total wear time, total tremor time, percentage of tremor time (percentage of total wear time), number of subjects with tremor (%); Dyskinesia - time spent in dyskinesia, percentage of time spent in dyskinesia, number of subjects with dyskinesia (%); Mobility - Percent resting time, Recent active (non-walking) time, Percent walking time, Percent total active time, Percent arm swing while walking, Steps during wearing time, Steps per hour of wearing time.

[0175] Investigator assessment of subject's motor status (Days 1 and 15) If a subject received rescue medication or discontinued study assessments, all subsequent locomotor assessments on Day 1 were assigned a value of "off" for analysis.

[0176] Investigator assessments of subject motor status were summarized on days 1 and 15 and summary statistics, categorical displays and ANOVA treatment comparisons (LS means difference, SD, p-values ​​and 95% CIS) were provided for the following: -Total time for each exercise state Time to first "on" (any "on" state) and "good on" state

[0177] In addition, results for several parameters were summarized categorically by treatment and compared using Fisher's exact test-proportion of subjects in "off" or "good on" state by time point.

[0178] MDS-UPDRS Part III (Motor Examination) MDS-UPDRS part III scores were summarized by treatment at each time point (pre-dose, hourly from 1-8 hours post-dose on day 1, and hourly from 1-10 hours post-dose on day 15). Post-dose scores were compared by treatment using a mixed-effects analysis of variance (ANCOVA) with treatment, period, and sequence as fixed effects, baseline (pre-dose day 1) values ​​as covariates, and subject within sequence as a random effect. Post-dose mean MDS-UPDRS part III scores on days 1 and 15 were also summarized and compared by treatment using a similar ANCOVA model. Pre-dose scores were compared by treatment using a mixed-effects ANOVA with treatment, period, and sequence as fixed effects and subject within sequence as a random effect.

[0179] Similarly, mean changes from pre-dose on Day 1 in MDS-UPDRS Part III scores on Days 1 and 15 were summarized for each post-dose time point and overall (overall assessment period) and compared by treatment using an ANCOVA model with treatment, period, and sequence as fixed effects, baseline (pre-dose on Day 1) values ​​as covariates, and subject within sequence as a random effect.

[0180] Results for the MDS-UPDRS Part III scale bradykinesia questions (questions 4-8 and 14) were summarized by treatment as the mean change from predose on Day 1 and the postdose mean at each assessment time point. For questions 4-8, assessments were performed on both the left and right side, and left and right scores were summed before analysis. Results were summarized separately for each question as a total bradykinesia score. These data were compared by treatment using a mixed-effects ANCOVA with treatment, period, and order as fixed effects, baseline (predose Day 1) values ​​as covariates, and subjects within sequences as random effects.

[0181] Mean duration of improvement in MDS-UPDRS Part III scores of at least 4, 7, and 13 units from pre-dose scores on Day 1 was summarized by treatment on Days 1 and 15 to provide a categorical representation of the proportion of subjects with a particular duration of effect. Duration of effect was compared by treatment using a mixed-effects ANOVA with treatment, period, and sequence as fixed effects and subject within sequence as a random effect.

[0182] The midpoint between two adjacent time points was used to determine duration of effect. For example, if a subject did not have a 4-unit improvement from the pre-dose MDS-UPDRS Part III assessment at the 1-hour post-dose assessment, but had an improvement at the 2-hour post-dose assessment, and lost 4 units of improvement at the 3-hour assessment, the duration of effect was considered in hours using the interpolated time value.

[0183] The demographics of subjects enrolled in the study were as follows:

number

[0184] The baseline disease characteristics and treatment history of the subjects in the study are as follows:

number

[0185] The pre-study distribution of daily LD doses by dosing frequency is shown in the table below:

number

[0186] As shown in the table above, most of the subjects received four IR CD-LD doses per day, with a total daily LD dose range of 400 mg to over 1250 mg. The maximum total daily dose of LD was 1550 mg. Additionally, eight subjects received a single dose of CR CD-LD 200 mg at bedtime.

[0187] On Day 1, the mean LD loading dose was 159 mg for IR CD-LD and 573 mg for IPX203, and the median LD plasma concentrations were 43 ng / mL for IR CD-LD and 41 ng / mL for IPX203 pre-dose on Day 1. Pharmacokinetic values ​​on Day 1 are summarized in the table below.

[0188] The main parameters on the first day of LD were as follows:

number

[0189] The mean levodopa plasma concentration profiles on day 1 before rescue treatment are shown in FIG.

[0190] Secondary parameters on day 1 of LD were as follows:

number

[0191] The dose-normalized LD parameters were as follows:

number

[0192] The mean dose-normalized LD plasma concentration profiles on day 1 before rescue treatment are shown in FIG.

[0193] The LD partial AUC values ​​were as follows:

number

[0194] The main parameters on day 1 of CD were as follows:

[0195]

number

[0196] The mean CD plasma concentration profile on day 1 before rescue treatment is shown in FIG.

[0197] The CD dose normalization parameters were as follows:

number

[0198] On day 15, the mean (±SD) LD administered in clinic on stable dosing regimens was 159±46.1 for IR CD-LD and 560±206.2 for IPX203 (first morning dose), with median times to first re-dosing of 4.0 and 7.0 hours for IR CD-LD and IPX203, respectively. Prior to dosing on day 15, median LD plasma concentrations were 34 ng / mL for IR CD-LD and 327 ng / mL for IPX203.

[0199] The mean LD plasma profiles after each treatment on day 15 across all 10-hour evaluations are shown in FIG.

[0200] Pharmacokinetic values ​​on day 15 are summarized in the table below.

[0201] The main parameters on the 15th day of LD were as follows:

number

[0202] Secondary parameters on day 15 of LD were as follows:

number

[0203] The dose-normalized values ​​for LD on day 15 were as follows:

number

[0204] The LD accumulation, fluctuation and time invariance parameters were as follows:

number

[0205] The main parameters on day 15 of CD were as follows:

number

[0206] The mean CD plasma profiles after each treatment on day 15 across all 10-hour evaluations are shown in FIG.

[0207] Dose-normalized values ​​on day 15 of CD were as follows:

number

[0208] The CD accumulation, fluctuation and time invariance parameters were as follows:

number

[0209] Efficacy Results Results for the primary efficacy parameter, "off" time as a percentage of awake time, measured from PD diary data on days 12 to 14 of each treatment period were as follows:

number

[0210] The data above show that with IPX203 treatment, subjects experienced significantly less "off" time as a percentage of awake time, averaging 19.3% compared to 33.5% with IR CD-LD.

[0211] PD diary data are summarized as follows:

number

[0212] MDS-UPDRS Parts I to IV (15 days before administration) MDS-UPDRS parts I, II, III and IV were administered at screening (while subjects were in the "on" state) and pre-dose on day 15 for each treatment. MDS-UPDRS part III was also administered at screening while subjects were in the "off" state. Parts I, II and IV contain questions asking about the subject's retrospective experiences over the past week. Part III is a real-time motor test administered by the investigator to assess motor signs of PD.

[0213] When pre-dose mean MDS-UPDRS Parts I-IV scores were compared by treatment at day 15 (LS mean difference between treatments), Parts III (-8.1 [25.3], p=0.0272), IV (-1.6 [3.09], p=0.0109), II+III (-9.0 [26.9], p=0.0213) and MDS-UPDRS total scores (-11.5 [30.9], p=0.0116) were significantly lower during IPX203 treatment than during IR CD-LD treatment, indicating less PD disability. Parts I and II results did not show significant treatment differences. At screening, the mean Part III score for all subjects in the "off" state was 42.6; at day 15 the mean score was 41.6 during IR CD-LD treatment, decreasing to 33.5 during IPX203 treatment (LS mean difference -8.1 [25.0]; p=0.0255).

[0214] On Day 1, mean pre-dose MDS-UPDRS part III scores were similar for both treatments (42.8 and 41.4 for IPX203 and IR CD-LD, respectively), reflecting a pre-dose "off" state in which subjects had not taken PD medication since 10 PM the previous evening.

[0215] At 1 and 2 hours, there was a significant reduction in MDS-UPDRS part III scores from pre-dose values ​​during both IPX203 and IR CD-LD treatment, with no significant differences between treatments. From 3 to 8 hours post-dose, IPX203 reduced MDS-UPDRS part III scores significantly more than IR CD-LD. At 7 hours post-dose, treatment with IPX203 was associated with a mean improvement of nearly 10 units versus a worsening of 0.2 units in IR CD-LD. Over the 8-hour post-dose period, the mean MDS-UPDRS scores were reduced by 19.3 and 8.4 points for subjects in the IPX203 and IR CD-LD treatment periods, respectively. Below is a summary of the changes from pre-dose MDS-UPDRS part III scores on Day 1:

[0216]

number

[0217] To further characterize the duration of effect of each treatment, MDS-UPDRS part III data were analyzed using minimum improvement thresholds (4, 7, and 13 unit improvement). A combined improvement of at least 4 MDS-UPDRS part III units represents the minimum clinically meaningful change for patients. On Day 1, subjects experienced a significantly longer total duration of pharmacodynamic effect during IPX 203 treatment than IR CD-LD treatment, based on minimum improvement thresholds of at least 4, 7, and 13 MDS-UPDRS part III units, as shown by the summary table below.

[0218]

number

[0219] A graph of the mean MDS-UPDRS part III on day 1 is shown in FIG.

[0220] On pre-dose Day 15, when subjects had not received study treatment for at least 5 hours, mean MDS-UPDRS part III scores were significantly lower during IPX203 treatment (33.5) than during ID CD-LD treatment (41.6). The clinical effect of IPX203 carried over to the next morning. During the 10-hour post-dose evaluation period on Day 15, subjects saw improvements from their pre-dose scores on Day 1 with both treatments, as summarized in the table below.

[0221]

number

[0222] Analysis of minimal improvement thresholds for MDS-UPDRS Part III scores shows similar total duration of improvement of at least 4 and 7 units for both treatment groups, but a significantly longer total duration of improvement for IPX203 of at least 13 units.

[0223] Figure 7 shows the time course of mean LD plasma concentrations by treatment and the change from mean baseline in MDS-UPDRS part III scores after a single dose on day 1. Figure 7 shows good agreement between LD plasma concentration profiles and response as assessed by change in MDS-UPDRS part III scores. The initial reduction in MDS-UPDRS part III scores from mean baseline (corresponding to improvement in motor symptoms) was comparable between the two treatments. However, the reduction in MDS-UPDRS part III scores was sustained for a longer period after IPX203 treatment than after IR CD-LD treatment. The maximum reduction in MDS-UPDRS part III scores from mean baseline occurred at a time later than the time of peak plasma concentration of LD for a particular treatment.

[0224] FIG. 8 shows the mean LD plasma concentration over time by treatment and the mean day 1 pre-dose change in MDS-UPDRS part III score on day 15 of subjects' stable dosing regimens. At day 15 pre-dose, treatment with IPX203 showed a greater mean decrease in MDS-UPDRS part III score (-9.3) than treatment with IR CD-LD (+0.1). FIG. 8 shows good agreement between LD plasma concentration profiles and change in MDS-UPDRS part III score. The initial improvement rate of motor symptoms was comparable between the two treatments. However, the improvement in MDS-UPDRS part III score was sustained for a longer period after IPX203 treatment than IR CD-LD, and as a result, subjects required less frequent dosing of IPX203 than IR CD-LD.

[0225] Across all efficacy and pharmacodynamic measures, IPX203 treatment clearly demonstrated its advantage over IR CD-LD and its usefulness in alleviating PD symptoms. With IPX203 treatment, subjects experienced significantly less "off" time as a percentage of awake time (mean 19.3% compared to 33.5% with IR CD-LD). Furthermore, subjects had significantly more total "good on" time with IPX203 treatment compared to IR CD-LD, whether measured outside the clinic by subjects with home diaries or by the investigator in the clinic. The mean duration of "good on" episodes or any "on" episodes based on patient diary entries was significantly longer with IPX203 compared to IR CD-LD. Treatment with IPX203 was also associated with significantly less daily motor fluctuations than IR CD-LD. During IPX203 treatment, subjects were 73.3% less likely to receive rescue medication (day 1) and 72.1% less likely to receive a second dose (day 15) than during IR CD-LD treatment.

[0226] Improvements in MDS-UPDRS part III mean scores were significantly greater in subjects receiving IPX203 than in IR CD-LD at 3-8 hours post-dose on day 1 and 2-4 hours post-dose on day 15. On day 15, when subjects had not received study treatment for at least 5 hours, mean pre-dose part III scores were significantly lower during IPX203 treatment, allowing for carryover of the clinical effect of IPX203 into the next morning.

[0227] Based on the investigator's assessment of the subject's motor status, the mean time to first "on" was similar during each treatment after the first dose on day 1 and during steady-state dosing after the first dose on day 15. On average, subjects became "on" approximately 10 minutes (0.17 hours) faster during IPX203 treatment compared to IR CD-LD treatment on day 15, and by 0.5 hours post-dose, 44% of subjects experienced their first "on" during IPX203 treatment versus 26% of subjects during IR CD-LD treatment.

[0228] Investigator assessments of subject motor status were performed by assessors blinded to study treatment. Investigator assessments on Day 1 are summarized as follows:

number

[0229] The percentage of subjects in the "on" or "off" state during the first 30 minutes after awakening from nocturnal sleep was determined based on the subjects' PD diary entries as follows:

number

[0230] The p-values ​​in the above awakening table are based on Fisher's exact test, and the analysis does not take into account crossover of study designs.

[0231] The above data for the first 30 minutes after awakening show that IPX203 improves on-time after awakening from a night's sleep.

[0232] Example 9 Twenty-five subjects with advanced PD were administered the dosage form described in Example 5 in a randomized, open-label, assessor-blinded, multicenter, three-treatment, three-period single-dose crossover study. Subjects were randomized to one of three dosing sequences to receive the composition of Example 5 ("IPX203"), the commercially available CD-LD extended release capsule product RYTARY®, and immediate release CD-LD ("IR CD-LD") tablets marketed under the trade name SINEMET®. Subjects reported to the study clinic three times for a single dose of each study treatment, with a one-week washout period between visits. Subjects were allowed to continue taking IR CD-LD between study visits. Subjects arrived at the clinic in a fasted state, having taken their last dose of IR CD-LD by 10 PM the previous day. Subjects who experienced an "off" state for three or more consecutive hours after dosing were allowed to receive rescue medication containing their regular IR CD-LD drug dose or combination rescue containing IR CD-LD. If rescue medication was administered, no further pharmacokinetic or pharmacodynamic measurements were performed at that visit and the subject was allowed to leave the clinic, otherwise subjects remained in the clinic until the final evaluation 10 hours after the study treatment dose.

[0233] To be eligible for the study, subjects diagnosed with advanced PD with motor fluctuations were undergoing IR CD-LD.

[0234] Subjects were randomized to receive a composition of IPX203, RYTARY®, IR CD-LD based on their first regular pre-study morning IR CD-LD dose according to the guidelines provided in the table below. [Table 3]

[0235] Inclusion criteria were similar to those provided in Example 8, except that the pre-study total maximum daily LD dose for this study was 1600 mg rather than the 1800 mg allowed in Example 8.

[0236] Subjects received a single oral dose of each of the three study treatments in a randomized order based on the subject's IR CD-LD dose the morning before the study, as outlined above. The IPX203 and RYTARY® doses were also selected to provide peak LD plasma concentrations that were estimated to be within ±20% of the peak LD plasma concentration of the IR CD-LD dose.

[0237] After abstaining from LD from 10 PM the evening before and fasting for at least 8 hours, all subjects were given a single oral dose with 240 mL of room temperature water and instructed to swallow the study drug whole without crushing or chewing in the morning at the scheduled clinical. Coffee, tea, water, and juice were allowed up to 1 hour before dosing. A breakfast containing approximately 5 grams of protein was given approximately 1 hour after dosing.

[0238] Pharmacokinetics were determined by procedures outlined in Example 8. Pharmacodynamics were measured by investigator assessment of the subject's motor status at 1 hour pre-dose, 0.5 hour, immediately prior to dosing, and every 30 minutes post-dose, as outlined in Example 8, and by use of the MDS-UPDRS Part III Motor Test, as outlined in Example 8.

[0239] The demographics for this study were as follows:

number

[0240] The LD doses in subjects receiving all three treatments were 168.0 mg for ID CD-LD, 586.8 mg for IPX203, and 538.2 mg for RYTARY®. The mean LD plasma profiles for each treatment are shown in Figure 9, and the primary LD pharmacokinetic values ​​were as follows:

number

[0241] The secondary LD pharmacokinetic values ​​were as follows:

number

[0242] One subject (number 108-001) completed the study, but no post-treatment plasma concentrations were available.

[0243] Dose-normalized LD pharmacokinetic values ​​were as follows:

number

[0244] Dose-normalized natural log-transformed AUC 0- Bioavailability of LD based on ∞ was higher after IPX203 (85.5%) than after RYTARY® (71.8%) compared to IR CD-LD. Bioavailability of LD was as follows:

number

[0245] The LD dose-normalized partial AUC values ​​were as follows:

number

[0246] The mean CD plasma profiles for each treatment are shown in FIG. 10 and the primary CD pharmacokinetic values ​​were as follows:

number

[0247] Dose-normalized CD pharmacokinetic values ​​were as follows:

number

[0248] Dose-normalized natural log-transformed AUC 0-Bioavailability of CD based on ∞ was higher after IPX203 (112%) than after RYTARY® (55%) compared to IR CD-LD. Bioavailability of CD was as follows:

number

[0249] Qualified clinical staff blinded to treatment assessed each subject's motor status 1 hour and 0.5 hours prior to dosing, as well as prior to dosing and every 30 minutes after dosing throughout each 10 hour measurement period. The mean total time for each awake motor status assessment is shown by treatment in FIG. 11. The least squares mean (LSM) "off" time for subjects' motor status assessments was 4.52 hours for IPX203 and 7.23 hours for IR CD-LD, demonstrating a significant 2.7 hour advantage for IPX203 (p<0.0001). The LSM "off" time for RYTARY® was 5.41 hours, reflecting a 0.9 hour advantage for IPX203 compared to RYTARY® (p=0.023). During IPX203 treatment, this was accompanied by increased good on-time, an average of 2.56 hours longer than IR CD-LD and 0.85 hours longer than RYTARY® (p<0.0001 and p=0.259, respectively). Only two subjects had "on" times with problematic dyskinesias (one subject during IPX203 [4.5 hours] and IR CD-LD [0.5 hours] treatment and another subject during RYTARY® treatment [3.5 hours]).

[0250] MDS-PDRS part III scores were assessed 1 and 0.5 hours prior to dosing, pre-dose, and every hour post-dose throughout each 10-hour measurement period. Analysis of covariance was performed on the mean change from the mean pre-dose MDS-UPDRS part III over the 10-hour measurement period, with pre-dose MDS-UPDRS part III values ​​as the covariate.

[0251] Following IPX203 treatment, subjects demonstrated significantly greater improvement (reduction) from the mean pre-dose MDS-UPDRS part III score over 10 hours compared to IR CD-LD (-12.70 vs. -6.62, p<0.0001) and compared to RYTARY® (-12.70 vs. 9.33, p=0.0333) in overall change from baseline, as shown in Figure 12. When these differences were examined over time, the results for IPX203 vs. IR CD-LD were significantly different from 3 to 10 hours of dosing (all p-values ​​≦0.029). RYTARY® was also associated with significantly greater change in MDS-UPDRS part III score compared to IR CD-LD from 3 to 5 hours post-dose (all p-values ​​≦0.0042). IPX203 vs. RYTARY® results were significantly different from 5 to 10 hours post-dose, except for 7 hours (all p-values ​​≦0.0352).

[0252] Based on the MDS-UPDRS Part III results, IPX203 had a significantly longer duration of effect compared to IR CD-LD (p<0.0001) and compared to RYTARY® (p≦0.0290) as measured by duration of 4, 7, and 13 point improvement from the mean pre-dose value, as shown in Figure 13. Following IPX203 treatment, 72% of subjects had at least a 20% improvement from the mean pre-dose MDS-UPDRS Part III score at 5 hours post-dose, compared to 12% and 52% of subjects treated with IR CD-LD and RYTARY®, respectively. The percentage of subjects with a 35% improvement at 5 hours was 60%, 8%, and 36% for IPX203, IR CD-LD, and RYTARY®, respectively.

[0253] FIG. 14 shows the time course of mean LD plasma concentrations and change from baseline in mean MDS-UPDRS part III scores by treatment. FIG. 14 shows good agreement between the PK of LD and response as assessed by change in MDS-UPDRS part III scores. The initial rate of decrease in MDS-UPDRS part III scores from mean baseline (corresponding to improvement in motor symptoms) was similar for all three treatments. However, the decrease in MDS-UPDRS part III scores was sustained for a longer period following IPX203 treatment than following IR CD-LD or RYTARY®. The maximum decrease in MDS-UPDRS part III scores from mean baseline occurred at a time later than the time of peak plasma concentration of LD for the particular treatment.

[0254] Example 10 The dosage form described in Example 7 was administered to 40 healthy male and female subjects between the ages of 18-55 years, weighing at least 55 kg and with a body mass index between 18.5 and 30.0 kg / m2, in a single-site, open-label, single-dose, five-treatment, five-period, single-dose crossover study. Subjects received the following five treatments with 240 mL of room temperature water after an overnight fast of at least 10 hours: Treatment A - a single 140 mg levodopa and 35 mg carbidopa capsule; Treatment B - a single capsule of 210 mg levodopa and 52.5 mg carbidopa; Treatment C - a single 280 mg levodopa and 70 mg carbidopa capsule; Treatment D - a single 350 mg levodopa and 87.5 mg carbidopa capsule; and Treatment E - A single 140 mg levodopa and 35 mg carbidopa capsule.

[0255] The capsules used in treatments A-D were manufactured at the Brookhaven, New York facility, and the capsules used in treatment E were manufactured at the Zhunan, Taiwan facility.

[0256] Subjects were fasted until 4 hours after dosing.

[0257] Pharmacokinetics were determined by procedures outlined in Example 8 by obtaining blood samples pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours after dosing.

[0258] The objectives of the study were to determine dose proportionality between treatments AD and to assess bioequivalence between treatments A and E.

[0259] The results of the study determined that treatments AD were dose proportional and that treatments A and E were bioequivalent.

[0260] The mean LD pharmacokinetic values ​​for Treatments A and E are summarized below.

number

[0261] The mean LD plasma profiles for treatments A and E are shown in Figure 15. max The mean time above 0.986 hours (SD 0.9711) and 4.945 (SD 0.9521), respectively.

[0262] The mean CD pharmacokinetic values ​​for Treatments A and E are summarized below.

number

[0263] The mean CD plasma profiles for treatments A and E are shown in FIG.

[0264] Example 11: Six hundred and thirty PD patients with motor fluctuations were enrolled in a randomized, double-blind, active-controlled study to compare the safety and efficacy of the dosage form described in Example 7 with a commercially available IR CD-LD tablet such as SINEMET® or a US FDA approved AB grade generic of SINEMET®. The dosage form described in Example 7 was administered to approximately 256 subjects with PD in a multi-center, randomized, double-blind, double-dummy, active-controlled, parallel-group study. The study consisted of a 3-week open-label IR CD-LD titration period using a commercially available IR CD-LD tablet such as SINEMET® or a US FDA approved AB grade generic; a 4-week open-label period for conversion to the dosage form of Example 7; followed by a 13-week double-blind treatment period with subjects randomized in an approximately 1:1 ratio stratified by center to receive either the matching IR, Example 7 with CD-LD placebo or the IR CD-LD with matching Example 7 placebo dosage form.

[0265] Throughout the study, subjects could continue taking permitted non-CD-LD based PD medications if documented in the pre-study regimen and if the dosing regimen was stable for at least 4 weeks prior to Visit 1. "Stable dosing regimen" means no change in dose or dosing frequency.

[0266] Within 4 weeks after the screening visit, eligible subjects completed a PD diary for each of the 3 consecutive days immediately preceding Visit 1.

[0267] After Visit 1, eligible subjects entered a 3-week open-label IR CD-LD treatment period to allow for dose adjustments. The IR CD-LD dosing regimen could be adjusted during the dose adjustment period to minimize "off" time without causing problematic dyskinesias. The doses and regimens of the subjects' other non-CD-LD PD medications (dopamine agonists, MAO-B inhibitors, amantadine, and anticholinergics) remained stable throughout the study. Adjustments to the IR CD-LD dosing regimen were made and recorded in consultation with the investigator or qualified site personnel. The IR CD-LD dosing regimen was stable for at least 5 days before returning for Visit 2. Rescue with additional or modified doses of concomitant PD medications or use of CD-LD products other than the dispensed study drug was not permitted and would induce discontinuation from the study. Subjects completed a 3-day PD diary on each of the 3 consecutive days immediately preceding Visit 2.

[0268] After completing the IR CD-LD titration period, subjects began a 4-week open-label period for conversion to IPX203 (Example 7). The initial dosing regimen of IPX203 was based on the most frequent dose of the subject's IR CD-LD dosing regimen at the end of the titration period (Visit 2). The following table summarizes the recommended conversions.

number

[0269] It was recommended that IPX203 should be administered approximately every 8 hours, except for subjects who were receiving a total daily dose of IR CD-LD between 125 and <500 mg at the end of the dose titration period, who were initially administered every 12 hours. If the subject did not achieve an acceptable duration of effect, the dosing interval was reduced to approximately every 8 hours. The dosing regimen of IPX203 could be adjusted during the dose conversion period to achieve an optimal balance between efficacy and tolerability (minimizing "off" time without causing problematic dyskinesias or other dopaminergic side effects). The doses and regimens of the subjects' other non-CD-LD PD medications (dopamine agonists, MAO-B inhibitors, amantadine, and anticholinergics) remained stable throughout the study. Subjects were on a stable dosing regimen of IPX203 (no changes in dose or dosing frequency) for at least 5 days before returning for Visit 4. Adjustments to the IPX203 dosing regimen were made in consultation with the investigator or qualified site personnel and would be recorded. Rescue with additional or modified doses of concomitant PD medication or use of CD-LD products other than the dispensed study drug was not permitted and would induce discontinuation from the study. Subjects returned to the clinic 2 weeks later at Visit 3, followed by Visit 4 2 weeks later. Subjects completed a 3-day PD diary on each of the 3 consecutive days immediately preceding Visit 4.

[0270] Five hundred and six subjects successfully completed the IPX203 dose conversion period and were randomized in an approximate 1:1 ratio to one of two parallel treatment arms, IPX203 (with matching IR CD-LD placebo) or IR CD-LD (with matching IPX203 placebo) at Visit 4. Subjects received 13 weeks of double-blind maintenance therapy, with a stable dosing regimen established at the end of week 3 (Visit 2) for IR CD-LD and at the end of week 7 (Visit 4) for IPX203. Rescue with additional or modified doses of concomitant PD medication or use of CD-LD products other than the dispensed study drug was not permitted and would induce discontinuation from the study. Subjects returned to the clinic for three visits (Visit 5 [Week 10], Visit 6 [Week 15], Visit 7 [Week 20]) and completed a 3-day PD diary on each of the three consecutive days immediately preceding each of these visits.

[0271] Inclusion criteria Male or female subjects aged 40 years or older, diagnosed with PD matching the UK Parkinson's Disease Society Brain Bank criteria, who are being treated with a stable regimen of CD-LD but experiencing motor fluctuations. · Hoehn and Yahr stages 1, 2, 3, or 4 in the "on" state (part of the Movement Disorder Society version of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS] Part III). Montreal Cognitive Assessment (MoCA) score ≥ 24 at the screening visit in the "on" state. Medical history indicates that during the 4 weeks prior to screening, the subject experienced daily "wearing off" episodes with periods of bradykinesia combined with at least one of resting tremor or rigidity, experienced the "off" state upon most morning awakenings, and reported an average of at least 2.5 cumulative hours of "off" time per day during waking hours. Able to distinguish the "on" state from the "off" state as judged by at least 75% agreement with trained raters in "on / off" ratings for eight ratings over a four-hour training period. Agreement must include at least one "on" and one "off" rating and must be achieved within two four-hour training sessions. At Visit 1, review of the 3-day PD diary confirmed that: the subject was able to properly complete the diary with valid entries; and that the subject had an average of at least 2.5 hours of "off" time per day during waking hours over the 3 days, with a cumulative "off" time of at least 1.5 hours each day. Responding to CD-LD therapy and currently being treated with a stable regimen of CD-LD at least 4 weeks prior to Visit 1; The first morning dose requires at least 100 mg LD from the IR CD-LD; requiring a total daily dose of at least 400 mg LD, with a maximum total daily dose of 2400 mg LD from IR CD-LD alone or IR CD-LD in combination with a once-daily bedtime dose of CR CD-LD; have a dosing frequency of CD-LD 4–9 times per day; By medical history, an "on" response was typically experienced with the first dose of IR CD-LD of the day, with the effectiveness of this dose typically lasting less than 4 hours. At Screening, subjects have predictable "off" periods as defined by a score of 1 or 2 on item #4.5 (complexity of motor fluctuations) of MDS-UPDRS part IV B (Motor Fluctuations). -Had an MDS-UPDRS part III total score of at least 20 units in the "OFF" state at screening. Exclusion criteria Use of any dose of controlled-release (CR) CD-LD apart from the once-daily bedtime dose within the 4 weeks prior to Visit 1. Have used any dose of RYTARY® in the past 4 weeks prior to Visit 1 or have had a considered failure of RYTARY® for efficacy or safety reasons. had undergone a previous neurosurgical procedure for PD or such a procedure was planned or anticipated during the study period. Allergies to any of the excipients in the study drug. · History of glaucoma with elevated intraocular pressure despite adequate medical management. · History of seizures or epilepsy and having experienced at least one seizure in the past 12 months, or failure to comply with medically recommended treatment or visits. History of myocardial infarction with residual atrial, nodal, or ventricular arrhythmias that were not controlled with medical and / or surgical intervention. Recent (within 12 months) history of myocardial infarction with secondary arrhythmias was excluded, regardless of treatment control. -Having had any of the following within 4 weeks of screening or planning for participation in a clinical trial: CR CD-LD at any dose except the once daily bedtime dose, RYTARY at any dose, additional CD (e.g., LODOSYN) or benserazide (e.g., SERAZIDE), or a catechol-O-methyltransferase inhibitor (entacapone or tolcapone), or a drug containing these inhibitors (STALEVO); Nonselective monoamine oxidase inhibitors (MAOIs), apomorphine, or antidopaminergic drugs, including antiemetics. -Subjects who have previously participated in the IPX203 study.

[0272] Evaluation criteria: There were two types of baselines used in the assessment: they could be either the study entry baseline (study entry visit) conducted at Visit 1 or the double-blind baseline (randomization visit) defined as the assessment conducted at Visit 4.

[0273] Key secondary endpoints were examined in the following subgroups: Age: Under 65 years old at the time of study entry, 65 years old or older ·Gender: Male, Female · Race: Caucasian, Non-Caucasian. In addition, the following subgroups were examined: Region: North America or Europe Ethnicity: Hispanic, Non-Hispanic, or Unknown Concomitant medications: The following non-exclusive subgroups were defined for subjects taking concomitant medications in the following categories: Amantadine Selective MAOB inhibitors Anticholinergic PD drugs Dopamine agonists others Weight: Under 75kg or over 75kg Body Mass Index (BMI): 25kg / m 2 Less than or 25kg / m 2 End Duration of PD at screening: <8 years or >8 years Age at onset of PD: <65 years or >65 years "Good on" time at time of study entry: < 9 hours per day or > 9 hours per day "Off" time at time of study entry: an average of less than 6 hours per day or more than 6 hours per day.

[0274] Efficacy: Primary endpoint: Change from baseline ('good on' time (hours / day), averaged across PD diary days at the end of the double-blind treatment period (Visit 7 or early termination)). 'Good on' time is derived from a 3-day PD diary and is defined as the sum of 'on' time without dyskinesias and 'on' time with problematic dyskinesias.

[0275] Key secondary endpoints: · Change from baseline ("off" time (hours / day), average across PD diary days at the end of the double-blind treatment period (Visit 7 or early termination); The proportion of subjects with either "much improved" or "very much improved" PGI-C scores at the end of the double-blind treatment period (Visit 7 or early termination); Change from baseline in MDS-UPDRS Part III at the end of the double-blind treatment period (Visit 7 or early termination); and / or Change from baseline in MDS-UPDRS Part II and III combined scores at the end of the double-blind treatment period (Visit 7 or early termination).

[0276] Additional assessment items: The following endpoints were assessed by visit (at post-randomization visits) as change from baseline (Visit 4) and, where applicable, change from study entry (Visit 1). · Percentage of “off” time during waking hours derived from the 3-day PD diary – average duration of each consecutive “good on” and each consecutive “on”; · the average duration of each successive "good on" and each successive "on"; · (1) duration of “off” time (from Visit 1), (2) “good on” time (from Visit 1), (3) “on” time with dyskinesias, (4) “on” time with problematic dyskinesias, and (5) “on” time with non-problematic dyskinesias, and (6) duration of sleep time derived from the 3-day PD diary; Proportion of subjects with improvement in "good on" time of at least 1, 1.5, 2, 2.5, and 3 hours; Percentage of subjects with reduction in "off" time of at least 0.5, 1, 1.5, 2, 2.5, and 3 hours; Proportion of subjects who are "on" after waking and "good on" after waking; ·Average time to "on" after waking; Change from baseline in the mean number of motor fluctuations per day averaged across PD diary days. Motor fluctuations are defined as changes from an "off" state to an "on" state or from an "on" state to an "off" state. · MDS-UPDRS total score (sum of parts I, II, III, and IV) and parts I, II, and IV separately; ·MDS-UPDRS Part III and Part II+III combined (from Visit 1); ·MDS-UPDRS Part II Question 2.9; · 39-item Parkinson's Disease Questionnaire ("PDQ-39") total score and individual domain scores; · Non-Motor Symptom Scale (NMSS) total score and individual domains; · Parkinson's Disease Sleep Scale-2 (PDSS-2) total score and individual domains; Combined PDSS-2 items 9, 10, 11, 12, and 13; · Parkinson Anxiety Scale (PAS) total score and individual domains; · Patient Global Impression of Severity (PGI-S); · Proportion of subjects with either "severe" or "very severe" on the Clinical Global Impression of Severity (CGI-S); · Proportion of subjects with either "severe" or "most severe" CGI-S; · Patient Global Impression of Change (PGI-C) score; Clinical Global Impression of Change (CGI-C) score; and Proportion of subjects with either "much improved" or "very much improved" on the CGI-C.

[0277] Adverse events were monitored and recorded. Patients completed the Gastroparesis Core Symptom Index (GCSI) questionnaire at various time points throughout the study.

[0278] Unless otherwise stated, evaluations followed the general procedures outlined above in Examples 8 and 9. Awakening from nighttime sleep was defined as having at least one "sleep" state after midnight and 3 consecutive hours of non-sleep following a "sleep" episode after midnight. Subjects who did not meet the above 3 consecutive hours of non-sleep were considered unclassifiable. Similarly, those who did not have any "sleep" state after 12:00AM were considered unclassifiable.

[0279] Because the PD diary began at 6:00 AM, consideration of "3 consecutive hours of non-sleep" began at 6:00 AM and did not require having a "sleep" state. Thus, for diary day -3, awakenings from nighttime sleep were defined as having 3 consecutive hours of non-sleep after 6:00 AM.

[0280] Time of awakening was defined as the onset of 3 consecutive hours of non-sleep as defined above. The number and percentage of subjects on days 0, 1, 2, and 3 in the "on" and "good on" states during the first half-hour interval after awakening from nighttime sleep were summarized by visit (Visits 4, 5, 6, and 7 or ET) and treatment group. Subjects who were unclassifiable on at least one day of the PD diary for a visit were excluded from the analysis for that visit. Baseline characteristics and demographics of subjects enrolled in the study are as follows:

number

[0281] The daily dosing frequency for the IPX203 and IR CD-LD stable regimens used during the double-blind period (Visits 4-7) is shown in the following table:

number

[0282] A summary of the change from baseline in the primary endpoint, "good on" time (hours), is shown in the table below.

number

[0283] Statistical analysis of the primary endpoint, change in "good on" time (hours) from baseline to Visit 7 / End of Treatment (ET), is as follows:

number

[0284] FIG. 17 is a graph of the following data points showing improvement in "good on" time from baseline to end of study.

number

[0285] The data show that treatment according to the invention (IPX203 dosed an average of 3 times per day) resulted in at least 0.5 hours (0.53 hours) more "good on" time than IR CD-LD (dosed an average of 5 times per day) when comparing the change from baseline (week 7) in both study groups. The data also showed a LS mean improvement from Visit 1 to Visit 7 of 1.76 hours for IPX203 treatment and 1.06 hours for IR CD-LD treatment.

[0286] Statistical analysis of the endpoint, "good on" time (hours) per dose at Visit 7 / ET, is as follows:

number

[0287] FIG. 18 is a graph of the "good on" time per dose.

[0288] A summary of the change from baseline in the secondary endpoint, "off" time (hours), is shown in the table below.

number

[0289] Statistical analysis of the secondary endpoint, change in "off" time (hours) from baseline to Visit 7 / ET is as follows:

number

[0290] FIG. 19 is a graph of the following data points showing the reduction in "off" time from baseline to the end of the study.

number

[0291] This data shows that when comparing changes from baseline (week 7) in both study arms, treatment according to the invention (IPX203 dosed an average of 3 times per day) resulted in significantly less "off" time or approximately 0.5 hours (0.48 hours) of "off" time compared to IR CD-LD (dose an average of 5 times per day).

[0292] Analysis of the data showed a greater improvement (less increase) in the mean percent "off" time during waking hours from Visit 4 to Visit 7 for subjects receiving the present invention (IPX203 was dosed an average of 3 times per day compared to IR CD-LD (dosed an average of 5 times per day). Specifically, the mean change in the percent "off" time during waking hours from Visit 4 to Visit 7 for the present invention was 1.75 and for IR CD-LD was 4.55.

[0293] Statistical analysis of percent "off" time during waking hours from Visit 4 to Visit 7 is shown below:

number

[0294] The above analysis shows that there was less increase in percent "off" time during waking hours in the IPX203 group when compared to the IR CD-LD group.

[0295] Analysis of the data also showed greater improvements (less decreases) in consecutive "good on" intervals and mean duration of consecutive "on" intervals from Visit 4 to Visit 7 for subjects receiving the present invention (IPX203 was dosed an average of 3 times per day compared to IR CD-LD (dosed an average of 5 times per day). Specifically, the mean change in consecutive "good on" intervals from Visit 4 to Visit 7 of the present invention is -0.07 and the mean change in IR CD-LD is -0.98. The mean change in consecutive "on" intervals from Visit 4 to Visit 7 of the present invention is -0.22 and the mean change in IR CD-LD is -0.90.

[0296] The statistical analysis of the duration of consecutive "good on" intervals and the duration of consecutive "on" intervals is as follows.

number

[0297] Analysis of PD diary data showed:

number

[0298] The PD diary data above showed greater improvement with IPX203 than with IR CD-LD in the following conditions recorded in the PD diary: (i) "On" time without dyskinesia: mean change from study entry baseline to Visit 7 / ET; IPX203: 1.45 and IR CD-LD: 1.01); (ii) “On” time with non-troublesome dyskinesias: mean change from study entry baseline to visit 7 / ET; IPX203: 0.36 and IR CD-LD: 0.13); (iii) “On” time with problematic dyskinesias: mean change from study entry baseline to visit 7 / ET; IPX203: 0.04 and IR CD-LD: −0.02); (iv) "on" time with dyskinesia: mean change from study entry baseline to visit 7 / ET; IPX203: 0.41 and IR CD-LD: 0.10); (v) "Sleep" time: mean change from study entry baseline to Visit 7 / ET; IPX203: 0.05 and IR CD-LD: 0.18).

[0299] Below is a summary of the percentage of subjects who were "on" after awakening and "good on" after awakening taken from the PD diary.

number

[0300] The data above show that at Visit 7, there was a significant difference in the percentage of subjects who were in an "on" state after awakening for at least one of the three PD diary days recorded: IPX203-treated, 53.1% of subjects vs. IR CD-LD-treated, 44.5% (p=0.0046). A similar difference was observed in subjects who were in a "good on" state after awakening.

[0301] A summary of the mean time to "on" after awakening taken from the PD diary is shown below.

number

[0302] The data above show that IPX203 treatment resulted in a shorter mean time to "on" after awakening compared to IR CD-LD treatment. Specifically, the mean change from Visit 4 to Visit 7 for IPX203 treatment was 0.01 hours, and the mean change from Visit 4 to Visit 7 for IR CD-LD treatment was 0.09. This difference was not significant (p=0.1664).

[0303] Analysis of the PD diary data showed that subjects receiving IPX203 treatment showed greater improvement (less increase) in the average number of motor fluctuations per day from Visit 4 to Visit 7 / ET when compared to subjects receiving IR CD-LD treatment. The average change from Visit 4 to Visit 7 / ET for subjects receiving IPX203 treatment was 0.17 and the average change from Visit 4 to Visit 7 / ET for subjects receiving IR CD-LD was 1.47. Below is a statistical analysis of the average number of motor fluctuations per day obtained from subject PD diaries collected over the 3 days prior to Visit 4 and prior to Visit 7 / ET.

number

[0304] A summary of the secondary outcome measures, MDS-UPDRS part III total score, is shown in the table below.

number

[0305] The week 0 enrollment values ​​were 29.6 for the IPX203 group and 29.7 for the IR CD-LD group.

[0306] Statistical analysis of the secondary outcome, MDS-UPDRS Part III total score at Visit 7 / ET, is as follows:

number

[0307] A summary of the secondary outcomes, MDS-UPDRS Part II and III total scores, is shown in the table below.

number

[0308] The week 0 enrollment score was 42.9 for the IPX203 group and 42.9 for the IR CD-LD group.

[0309] Statistical analysis of the secondary endpoints, MDS-UPDRS Part II and III total scores at Visit 7 / ET, is as follows:

number

[0310] A summary of the mean change in PDQ-39 scores from Visit 4 to Visit 7 / ET is provided in the table below.

number

[0311] As shown by the data above, except for a statistically significant difference in favor of IPX203 treatment for emotional well-being scores, no notable differences were observed between IPX203 treatment versus IR CD-LD treatment in the PDQ-39 total score and other individual domain scores.

[0312] A summary of the mean change in NMSS scores from Visit 4 to Visit 7 / ET is provided in the table below.

number

[0313] As shown by the data above, with the exception of a statistically significant difference in perceptual problems / hallucinations, no notable differences were observed in the NMSS total score or other individual domain scores between IPX203 treatment and IR CD-LD treatment.

[0314] A summary of secondary endpoints and a summary of PGI-C are shown in the table below.

number

[0315] At the end of treatment, Visit 7, PGI-C scores showed improvement (defined as minimally improved, much improved, or very much improved) in 56.9% of the IPX203 group (average of 3 doses per day) versus 46.3% of the IR CD-LD group (average of 5 doses per day); 29.7% showed much or very improved in the IPX203 group versus 18.8% of the IR CD-LD group, the latter difference being statistically significant (p=0.0015).

[0316] A summary of the CGI-C scores at Visit 7 / ET is shown in the table below:

number

[0317] The CGI-C data show that 58.1% of subjects receiving IPX203 treatment reported improvement in CGI-C score (defined as minimally improved, much improved, or very much improved) compared to 45.7% of subjects receiving IR CD-LD treatment. A statistically significant proportion of subjects (p<0.0001) (33.6% of subjects) reported a "much improved" or "very much improved" response to IPX203 treatment when compared to IR CD-LD treatment (19.2% of subjects).

[0318] The following table provides a summary of the primary and secondary endpoint data obtained in this study.

number

[0319] The results show that the PD diary-based endpoint, "good on" time, decreased less in the IPX203 group (LS mean = 0.5 hour decrease in "good on" time) compared to the IR CD-LD group (LS mean = 1.03 hour decrease in "good on" time). The results also show that the PD diary-based endpoint, "off" time, increased less in the IPX203 group (LS mean = 0.38 hour increase in "off" time) compared to the ID CD-LD group (LS mean = 0.86 hour increase in "off" time). These results demonstrate better clinical outcomes in the IPX203 group with statistical significance (p = 0.0194 for "good on" time and p = 0.0252 for "off" time).

[0320] Example 12 The dosage form described in Example 7 was administered to subjects with a body weight of at least 55 kg and 18.5 to 30.0 kg / m in a single-site, open-label, single-dose, 3-treatment, 3-period crossover study. 2 The study was administered to 27 healthy male and female subjects between the ages of 18 and 55 years with a body mass index of 0.5 to 1.0. Subjects fasted overnight for at least 10 hours and received a single dose of 350 mg LD and 87.5 CD for each treatment separated by a washout period of 6 to 7 days.

[0321] Treatment A involved one capsule containing 350 mg LD and 87.5 mg CD, prepared according to Example 7, administered orally with 240 mL of water approximately 30 minutes after the start of a standardized high-fat (approximately 50% of the total caloric content of the diet), high-calorie (approximately 800-1000 calories) breakfast. No further food was allowed for at least 4 hours after administration.

[0322] Treatment B involved oral administration of one capsule prepared according to Example 7 containing 350 mg LD and 87.5 mg CD, the contents of the capsule sprinkled onto 1 tablespoon of applesauce. No further food was allowed for at least 4 hours after dosing.

[0323] Treatment C involved one capsule containing 350 mg LD and 87.5 mg CD prepared according to Example 7 administered orally with 240 mL of water. No food was allowed for at least 4 hours after dosing.

[0324] For Treatments A and C, subjects were instructed to swallow the capsule whole and not to chew, split, or crush the tablet.

[0325] For Treatment B, subjects were instructed to consume all of the applesauce without crushing or chewing the beads.

[0326] Whole blood samples were collected pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 16, and 24 hours post-dose. Plasma samples were analyzed for concentrations of CD and LD by a validated liquid chromatography-tandem mass spectrometry (LC-MS / MS) method. Peak plasma (C max ), area under the plasma concentration-time curve (AUC t and AUC∞), and time to maximum concentration (T max ) were evaluated. The mean pharmacokinetic parameters are shown in the table below and in Figures 20 and 21.

number

[0327] All values ​​in the above table are reported as median (min-max). max The mean ± SD is used except for AUC 0-t is the area under the concentration-time curve from 0 to 24 hours.

[0328] After oral administration of the capsule in the fasting state, LD concentrations increased rapidly, reaching a median T of approximately 2 h. max The high-fat, high-calorie treatment, compared with the fasted-state treatment, achieved a median LD of T max Delay for about 2 hours, LD C max and AUC increased by approximately 20%. max and AUC0-t Values ​​were approximately 64% lower in the fed vs. fasted state. Sprinkling the capsule contents onto applesauce did not substantially affect pharmacokinetic parameters when compared to administration in the fasted state.

[0329] Example 13 Based on the data from the preceding examples, including but not limited to Examples 11 and 12, the following is a recommended starting dose for converting PD patients taking an oral immediate release CD-LD dosage form, such as SINEMET® or the US FDA AB grade generic of SINEMET®, to the starting dose of capsules described in Example 7:

number

[0330] Alternatively, the starting daily dose of an IPX203 product as set forth in the table above may be administered in one or more dosage forms containing 35-140 mg CD-LD, 52.5-210 mg CD-LD, 70-280 mg CD-LD, or 87.5-350 mg CD-LD.

[0331] PD patients receiving less than 125-500 mg total daily dose of CD-LD from an oral IR CD-LD dosage form, such as SINEMET® or a US FDA AB rated generic version of SINEMET®, can receive one or more of the controlled release dosage forms described herein, including those of Examples 1-7, preferably those of Example 7, or their US FDA AB rated generic equivalents, every 12 hours. If the subject does not achieve an acceptable sustained effect, the dosing interval can be reduced to approximately every 8 hours.

[0332] PD patients who are newly diagnosed with PD or LD-naive can take one or more of the controlled release dosage forms described herein, including those of Examples 1-7, preferably those of Example 7 or their US FDA AB grade generic equivalents, every 12 hours. If the subject does not achieve an acceptable sustained effect, the dosing interval can be reduced to approximately every 8 hours.

[0333] PD patients taking a total daily dose of 125-500 mg or more of CD-LD from an oral IR CD-LD dosage form, such as SINEMET® or a US FDA AB rated generic version of SINEMET®, can take one or more of the controlled release dosage forms described herein, such as those in Examples 1-7, or their FDA AB rated generic equivalents, every 8 hours.

[0334] A PD patient may take one or more of the controlled release dosage forms described herein, including Examples 1-7 and preferably Example 7, or its U.S. FDA AB grade generic equivalents, every 12 hours or every 6, 7 or 8 hours according to the dosing schedule of this example, and may: (i) A total "off" time during a 24-hour period, i.e., day, of 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 that 24-hour period; (ii) total "off" time during waking hours of 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; (iii) a total "on" time of more than 5 hours, more than 6 hours, more than 7 hours, or more than 8 hours during the dosing interval; (iv) total "good on" time greater than 5 hours, greater than 6 hours, greater than 7 hours, or up to 8 hours during the dosing interval; (v) an increase in patient "on" time 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 more per dose, per day, and / or per awake hour per day compared to a comparable oral dose of an immediate release CD-LD dosage form, or a total immediate release CD-LD dose per day or per awake hour; (vi) an increase in the patient's "good on" time 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 more per dose, per day, and / or per awake hour per day compared to a comparable oral dose of an immediate release CD-LD dosage form, or a total immediate release CD-LD dose per day or per awake hour; (vii) a reduction in patient “off” time 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 more per dose, per day, and / or per awake hour per day compared to a comparable oral dose of an immediate release CD-LD dosage form, or a total immediate release CD-LD dose per day or per awake hour; or (viii) Any combination of the above.

[0335] With respect to the above increases in patient "on" or "good on" time of at least 30 to 180 minutes or more, and the reduction in patient "off" time per dose, per day and / or during waking hours per day, compared to a comparable oral dose of an immediate release CD-LD dosage form or the total immediate release CD-LD dose per day or per waking hour, it is understood that the comparison per day or per waking hour is based on the total amount of LD administered via the controlled release dosage form per day or per waking hour period, compared to the total amount of LD administered via the immediate release formulation per day or per waking hour. This comparison may be a total including 2, 3 or 4 controlled release administrations compared to a total of 4, 5 or 6 immediate release administrations during a day (24 hour period) or a 12 to 18 hour waking period.

[0336] A PD patient may take one or more of the controlled release dosage forms described herein, including Examples 1-7, preferably Example 7, or equivalent US FDA AB rated generics, every 12 hours or every 6, 7, or 8 hours according to the dosage schedule of this example and show a substantial reduction in the total "off" time during waking hours. The reduction in the total "off" time should be at least a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% or 50% reduction in the total "off" time during waking hours, such as 16 hours in a 24 hour period, compared to treatment with an immediate release CD-LD oral dosage form, such as SINEMET® or a US FDA AB rated generic version of SINEMET®.

[0337] PD patients may take one or more of the controlled release dosage forms described herein, including Examples 1-7, preferably Example 7, or equivalent US FDA AB grade generics, every 12 hours or every 6, 7, or 8 hours according to the dosage schedule of this example, and may exhibit a total "off" time between dosing intervals of 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, or 0 minutes. For PD patients in the twice-daily dosing group, the dosing interval is about every 12 hours. For PD patients in the three times-daily dosing group, the dosing interval is about 8 hours. For PD patients in the four times-daily dosing group, the dosing interval is about 6 hours.

[0338] PD patients who receive a controlled release dosage form as described herein, including Examples 1-7, preferably Example 7, or equivalent US FDA AB grade generics, every 12 hours or every 6, 7, or 8 hours according to the dosage schedule of this example, do not require an increase in the amount of LD administered in the morning or the first daily dose after awakening. Rather, PD patients can receive the same dose at each dosing time throughout the day, thereby avoiding the need for different morning, afternoon, and / or evening doses, which can complicate the dosing regimen, confuse the caregiver or the PD patient, and result in over- or under-dosing. Furthermore, these PD patients are administered a controlled release dosage form as described herein and according to the dosage schedule of this example on a schedule that allows for dosing within about 30 minutes before going to bed, allowing the PD patient to experience improved nighttime sleep and awaken in the morning in an "on" or "good on" state, thereby eliminating the need for a rescue dose of LD. These PD patients are administered the controlled release dosage form as described herein and according to the dosage chart of this example on a schedule that allows for dosing within about 30 minutes before bedtime, and further allows the PD patients to experience a faster time to "on" or "good on" state after the first morning dose of the controlled release dosage form compared to treatment with an immediate release CD-LD oral dosage form such as SINEMET® or a US FDA AB rated generic version of SINEMET®. The faster time to "on" or "good on" state after the first morning dose of the controlled release dosage form can be in the range of about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 minutes faster compared to treatment with an immediate release CD-LD oral dosage form such as SINEMET® or a US FDA AB rated generic version of SINEMET®.

[0339] PD patients taking one or more of the controlled release dosage forms described herein, including Examples 1-7, preferably Example 7, or equivalent US FDA AB rated generics, every 12 hours or every 6, 7 or 8 hours, according to the dosing schedule of this example, may show substantial improvement in their PGI-C or CGI-C scores, i.e., report values ​​of "much improved" or "very much improved" compared to treatment with an immediate release CD-LD oral dosage form, such as SINEMET® or a US FDA AB rated generic version of SINEMET®.

[0340] PD patients taking one or more of the controlled release dosage forms described herein, including Examples 1-7, preferably Example 7, or equivalent U.S. FDA AB rated generics, every 12 hours or every 6, 7 or 8 hours, according to the dosage schedule of this example, may show improved emotional well-being as determined by PDQ-39, as compared to treatment with an immediate release CD-LD oral dosage form, such as SINEMET® or a U.S. FDA AB rated generic version of SINEMET®.

[0341] PD patients taking one or more of the controlled release dosage forms described herein, including Examples 1-7, preferably Example 7, or equivalent U.S. FDA AB rated generics, every 12 hours or every 6, 7 or 8 hours, according to the dosing schedule of this example, may show a reduction in sensory problems and / or hallucinations as determined by NMSS scores, compared to treatment with an immediate release CD-LD oral dosage form, such as SINEMET® or a U.S. FDA AB rated generic version of SINEMET®.

[0342] PD patients may take the controlled release dosage forms described herein, including Examples 1-7, preferably Example 7, or their U.S. FDA AB graded generic equivalents, with or without food, and when taken with food, may experience a LD C increase compared to administration after at least a 10 hour fast, preferably after an overnight fast of 10 hours. maxand / or an increase in LD AUC value of at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25% or more. max And / or the increase in LD AUC may be determined using the conditions outlined in Example 12 above.

[0343] PD patients may further administer a controlled release dosage form as described herein, including Examples 1-7, preferably Example 7, or a U.S. FDA AB graded generic equivalent thereof, with or without food, which, when administered with food, provides an LD T of less than 5 hours, less than 4.5 hours, less than 4.0 hours, less than 3.5 hours, less than 3.0 hours, less than 2.5 hours, less than 2.0 hours, less than 1.5 hours, less than 1.0 hours, or less than 0.5 hours compared to administration after at least a 10 hour fast, preferably after an overnight fast of 10 hours. max and / or CD T max The change in LD T when administered with food compared to administration after fasting is shown (i.e. ±). max and / or CD T max The change in T can be determined using the conditions outlined in Example 12 above. max The change in T under fed conditions compared to administration after fasting was less than 5 hours, less than 4.5 hours, less than 4.0 hours, less than 3.5 hours, less than 3.0 hours, less than 2.5 hours, less than 2.0 hours, less than 1.5 hours, less than 1.0 hours, or less than 0.5 hours. max It is preferable that the time is increased to

[0344] The present invention illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations not specifically disclosed herein. Thus, for example, in each example 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 used are used as terms of description and not of limitation, and in the use of such terms and expressions, there is no intention to exclude the features shown and described or equivalents of some thereof, but it is recognized that various modifications are possible within the scope of the invention as claimed. Thus, although the present invention has been specifically disclosed by preferred embodiments and optional features, it should be understood that modifications and variations of the concepts disclosed herein may be made by those skilled in the art, and such modifications and variations are considered to be within the scope of the invention as defined by the appended claims.

Claims

1. 1. A controlled release dosage form for use in a method of treating a patient diagnosed with Parkinson's disease, comprising levodopa and a controlled release excipient and / or a mucoadhesive excipient; The method comprises orally administering the controlled release dosage form; The controlled release dosage form is administered every 12 hours or every 6 to 8 hours; (ii) a total "off" time during awake periods of less than 5 hours in a 24 hour period; (iii) a total on time during the dosing interval of more than 5 hours; (iv) a total good on time during the dosing interval of more than 5 hours; (v) an increase in the patient's "on" time per day of at least 20 minutes compared to a total equivalent oral immediate release carbidopa (CD)-levodopa (LD) dose per day; (vi) an increase in the patient's "good on" time per day of at least 20 minutes compared to a total equivalent oral immediate release CD-LD dose per day; or (vii) a combination of the above.

2. 1. A controlled release dosage form for use in a method of treating a patient diagnosed with Parkinson's disease, comprising levodopa and a controlled release excipient and / or a mucoadhesive excipient; The method includes orally administering the controlled release dosage form; The controlled release dosage form is administered every 12 hours or every 6-8 hours, and the patient exhibits at least a 5% reduction in total "off" time during waking hours compared to a patient receiving treatment with an immediate release levodopa and carbidopa oral dosage form.

3. 1. A controlled release dosage form for use in a method of treating a patient diagnosed with Parkinson's disease, comprising levodopa and a controlled release excipient and / or a mucoadhesive excipient; The method includes orally administering the controlled release dosage form; A controlled release dosage form, wherein administration of said controlled release dosage form occurs every 12 hours or every 6-8 hours, and said patient exhibits a total "off" time during the dosing interval of less than or equal to 180 minutes.

4. 1. A controlled release dosage form for use in a method of treating a patient diagnosed with Parkinson's disease, comprising levodopa and a controlled release excipient and / or a mucoadhesive excipient; The method includes orally administering the controlled release dosage form; The controlled release dosage form, wherein administration of the controlled release dosage form occurs every 12 hours or every 6-8 hours, and the patient is administered the controlled release dosage form within about 30 minutes before going to sleep, and the Parkinson's disease patient awakens in an on or good on state in about 7 to about 8 hours.

5. 1. A controlled release dosage form for use in a method of treating a patient diagnosed with Parkinson's disease, comprising levodopa and a controlled release excipient and / or a mucoadhesive excipient; The method includes orally administering the controlled release dosage form; A controlled release dosage form, wherein administration of the controlled release dosage form occurs every 12 hours or every 6-8 hours, and the patient receives the same dose at each dosing interval.

6. 1. A controlled release dosage form for use in a method of treating a patient diagnosed with Parkinson's disease comprising levodopa and a controlled release excipient and / or a mucoadhesive excipient, The method includes orally administering the controlled release dosage form; The controlled release dosage form is administered every 12 hours or every 6 to 8 hours; the patient is administered the controlled release dosage form under fed or fasted conditions; The patient experienced similar or increased maximum plasma concentrations of levodopa (C) when the controlled release dosage form was administered under fed conditions compared to administration under fasted conditions. ｍａｘ ) and / or levodopa area under the plasma concentration time curve (AUC).

7. 1. A controlled release dosage form for use in a method of treating a patient diagnosed with Parkinson's disease, comprising levodopa and a controlled release excipient and / or a mucoadhesive excipient; The method includes orally administering the controlled release dosage form; administration of said controlled release dosage form occurs every 12 hours and the total daily dose is from about 280 mg to about 1,400 mg of levodopa provided by said controlled release dosage form; A controlled release dosage form, wherein the dose of levodopa administered from said controlled release dosage form every 12 hours is from about 140 mg to about 700 mg, and wherein prior to receiving said controlled release dosage form of levodopa, said patient was being treated with a total daily dose of levodopa of 500 mg or less administered in three, four or more doses in a 24 hour period.

8. 8. The controlled release dosage form of claim 7, wherein the dose of levodopa administered every 12 hours from said controlled release dosage form is from about 140 mg to about 350 mg.

9. 8. The controlled release dosage form of claim 7, wherein the controlled release dosage form further comprises carbidopa.

10. The controlled release dosage form comprises: (a) 140 mg levodopa and 35 mg carbidopa; (b) 210 mg levodopa and 52.5 mg carbidopa; (c) 280 mg levodopa and 70 mg carbidopa; (d) 350 mg levodopa and 87.5 mg carbidopa; or (e) A combination of the above 10. The controlled release dosage form of any one of claims 1 to 6 and 9, comprising one or more capsules comprising:

11. When tested using USP Apparatus I at 75 rpm and 37±0.5° C. with 500 ml to 900 ml of simulated gastric fluid for 2 hours and then with phosphate buffer at pH 6.8, the controlled release dosage form: 20% to 60% of levodopa is released after 2 hours; After 3 hours, 40% to 80% of levodopa is released; 60% to 100% of levodopa is released after 4 hours; and More than 80% is released after 7 hours 8. The controlled release dosage form of claim 7, which exhibits a levodopa release profile of:

12. Upon administration, the controlled release dosage form provides a levodopa plasma level of at least 300 ng / mL within 0.25 to 1 hour after administration; and / or 8. The controlled release dosage form of claim 7, wherein after administration of said controlled release dosage form about every 12 hours for at least 7 days, the minimum levodopa plasma level is about 250 ng / mL 7-8 hours after dosing.

13. 10. The controlled release dosage form of claim 9, wherein after administration of said controlled release dosage form about every 12 hours for at least 7 days, the minimum carbidopa plasma level is at least about 40 ng / mL 7-8 hours after dosing.

14. 8. The controlled release dosage form of claim 7, wherein the patient is a newly diagnosed Parkinson's disease patient or a levodopa naive patient.

15. The controlled release dosage form comprises: (g) 140 mg levodopa and 35 mg carbidopa; (h) 210 mg levodopa and 52.5 mg carbidopa; (i) 280 mg levodopa and 70 mg carbidopa; (d) 350 mg levodopa and 87.5 mg carbidopa; or (e) A combination of the above and one or more capsules comprising 7. The controlled release dosage form of claim 6, wherein the time to maximum levodopa plasma concentration (Tmax levodopa) or time to maximum carbidopa plasma concentration (Tmax carbidopa) when the controlled release dosage form is administered under fed conditions is ±5 hours of the Tmax levodopa or Tmax carbidopa when the controlled release dosage form is administered under fasting conditions.

16. The controlled release dosage form of any one of claims 1 to 6 and 10, wherein the controlled release dosage form is administered every 7 to 8 hours.

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