CN116801869A

CN116801869A - Levodopa dosing regimen

Info

Publication number: CN116801869A
Application number: CN202180091532.9A
Authority: CN
Inventors: R•德萨扎; H•维瑟; S•古普塔
Original assignee: Anmuni Pharmaceutical Co
Current assignee: Anmuni Pharmaceutical Co
Priority date: 2020-12-22
Filing date: 2021-12-21
Publication date: 2023-09-22

Abstract

The present application provides oral dosing regimens of controlled release levodopa compositions for treating parkinson's disease patients.

Description

Levodopa dosing regimen

The application claims the benefit of U.S. Ser. No. 63/129,063 submitted at month 22 of 2020, U.S. Ser. No. 63/150,121 submitted at month 17 of 2021, U.S. Ser. No. 63/236,403 submitted at month 24 of 2020, and U.S. Ser. No. 63/247,639 submitted at month 23 of 2021, the entire contents of which are incorporated herein by reference.

Technical Field

The present application relates to an oral administration regimen of levodopa (hereinafter referred to as "LD"), in particular an oral administration regimen of a controlled release pharmaceutical composition using LD. The dosing regimen may be used to treat conditions such as neurological disorders associated with reduced or impaired dopamine levels, and is particularly useful in treating patients with parkinson's disease (hereinafter "PD").

Background

Patients with PD often have periods of mobility difficulties, which often result in immobility. Dopamine is a neurotransmitter affecting the activity and control of the skeletal muscle system, and abnormally low levels thereof are generally considered to be the primary cause of these motor symptoms in PD patients. However, the administration of dopamine is ineffective in treating motor symptoms of parkinson's disease, because dopamine cannot cross the blood brain barrier. To address this problem, PD patients are administered levodopa, which is a metabolic precursor of dopamine, but levodopa is not without problems.

Over time, patients receiving LD treatment exhibit symptoms of "pharmacodynamic off" in which single doses of levodopa no longer persist as long as the early phase of levodopa therapy (typically 5-10 years after the start of levodopa therapy). Such patients may develop motor fluctuations characterized by relapse at doses, peak dose dyskinesias, and akinesia. Advanced forms of motion fluctuations (also known as "switching" phenomena) are characterized by unpredictable fluctuations from active to inactive. Although the cause of these motor fluctuations is not completely understood, advanced patients often benefit from treatment regimens that produce stable plasma LD levels, such as by enteral infusion of LD, as this delivery method may mimic normal supplemental endogenous dopamine. However, enteral infusion of LD is limiting, invasive and cumbersome. Oral delivery of LD is preferred, but plasma concentration levels remain difficult to control by oral delivery.

Combination therapy of PD with LD and a decarboxylase inhibitor (typically carbidopa (hereinafter "CD")) is known in the pharmaceutical arts. At present, there are several formulations on the market containing combinations of LD and CD, for exampleCR、And corresponding imitations (generic products). In addition, one decarboxylase inhibitor approved for use outside the united states is benserazide, which may be administered in combination with LD.

Although many oral LD dosage forms are described in the literature, successful development of oral dosage forms for LD once or twice a day has been difficult to achieve. LD metabolism is rapid. The plasma half-life of LD was about 50 minutes when orally administered without CD, and about 1.5 hours when orally administered with CD. Because of the short plasma half-life, many efforts have been made to provide sustained release versions of LD that allow oral administration once to twice a day. While in vitro data indicate that LD can be released from oral controlled release dosage forms in a manner that allows for once and twice daily dosing, in vivo data has proven extremely difficult to obtain due in part to absorption problems of LD from the patient's gastrointestinal tract. LD is absorbed from only a very small portion of the patient's upper gastrointestinal tract. If LD is not released from the dosage form in this narrow window of absorption, the dosage form passes through the narrow window and LD is released with very low absorption in the lower gastrointestinal tract. The absorption of LD is not limited to only a small portion of the patient's upper gastrointestinal tract, but LD competes with other compounds (e.g., dietary amino acids) at the site of absorption. Even if LD is released in a patient's narrow absorption window, absorption may be prevented by other molecules that interact with the absorption site. This competition may result in the released levodopa moving through a narrow absorption window by normal gastric movement and being expelled without reaching the patient's blood flow.

There remains a need for an oral LD dosage form and regimen that provides twice or three daily dosing, provides stable LD plasma concentrations with minimal "peak-to-valley" fluctuations during daily dosing, and provides longer duration of effect than commercially available LD oral dosage forms.

There is also a need for an oral LD dosage form and dosing regimen that reduces or eliminates the amount of "Off" time or increases the amount of "On" and "Good On" time, particularly when dosing every 6, 7, 8, 9, 10, 11 or 12 hours over a 24 hour period.

There is also a need for an oral LD dosage form and dosing regimen that reduces or eliminates the amount of "off-period" time per dose, per day, and/or per wake hour (wake hour) per day, or increases the amount of "on-period" and "off-period" time, as compared to commercially available oral LD dosage forms such as immediate release CD-LD tablets, and particularly when dosed every 6, 7, 8, 9, 10, 11, or 12 hours over a 24 hour period.

There is also a need for an oral LD dosage form and regimen that can be administered prior to bedtime and provide therapeutic benefits throughout the patient's sleep and continue to provide therapeutic benefits after 7-9 hours of wakefulness after bedtime.

Disclosure of Invention

The present invention fulfills the above-described needs and others.

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

The present invention also provides a dosing regimen that will allow for twice or three times a day dosing of a newly diagnosed PD patient who has not yet begun LD treatment or who has not been treated for LD. The dosing regimen for newly diagnosed PD patients or LD untreated patients allows for dosing twice or three times a day, i.e., about every 12 hours or 8 hours a dose of oral controlled release LD formulation, wherein each dose comprises about 140 to about 700mg LD, preferably about 210mg LD to about 450mg LD, and most preferably about 280mg to about 420mg LD. One dose may be administered as a single dosage form or as multiple dosage forms about every twelve or eight hours. For example, a total daily dose of 560mg of levodopa may be administered twice daily as a single dose of 280mg of LD, i.e., every 12 hours, wherein a single 12 hour dose of 280mg of LD may be administered as two capsules per dose, wherein each capsule contains 140mg of LD, or as one capsule per dose, containing 280mg of LD. In certain embodiments, the total daily dose of the twice-a-day dosing regimen will be a dose of about 400mg to about 500mg LD or about 200mg to about 250mg every 12 hours.

The present invention also provides a dosing regimen that allows dosing every 4-12 hours, preferably every 6-12 hours, i.e. 2, 3, 4 or 5 times a day, with substantially no "off period" or zero "off period" between doses.

The present invention also 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 a day, with an increase in the "open" time or "good open" time per dose, day and/or day per awake hour as compared to an oral immediate release CD-LD dose or a total immediate release CD-LCD dose per day or awake hour.

The present invention also provides a dosing regimen that allows for administration of the controlled release dosage forms described herein prior to bedtime, thereby providing therapeutic benefit to the patient after 6 to 9 hours, preferably 7 to 8 hours of wakefulness after administration. In certain embodiments, the controlled release dosage forms useful in the present invention are administered every 6 to 7 hours or every 7 to 8 hours over a 24 hour period, and after 7 to 15 days of continuous treatment, the patient will achieve steady state minimum LD plasma levels of at least 250ng/mL, preferably at least 300ng/mL, and most preferably at least 330ng/mL between administrations and will exhibit therapeutic benefit for 7 to 8 hours before the next dose is administered.

The present invention also provides a dosing regimen that will allow dosing every 6-12 hours, i.e., 2, 3 or 4 times a day, and will reduce the number of motor fluctuations per dose, per day and/or per awake hour of day as compared to an oral immediate release CD-LD dose or a total immediate release CD-LD dose per day or awake hour.

The present invention also provides a dosing regimen that will allow for dosing every 6-12 hours, i.e., 2, 3 or 4 times a day, and will increase the emotional well-being of the patient per dose, per day and/or per awake hour of the day, as compared to the oral immediate release CD-LD dose or the total immediate release CD-LD dose per day or awake hour.

The present invention also provides a dosing regimen that will allow dosing every 6-12 hours, i.e., 2, 3 or 4 times a day, and will reduce patient perception problems and/or hallucinations per dose, per day and/or per awake 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 awake hour.

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 altered or controlled release amount of LD may be present as an altered or controlled release component, such as a bead, pill, granule or mini-tablet, comprising a LD-containing core mixed with, coated with or layered with a controlled release material and/or a mucoadhesive material, and may optionally be coated with an enteric material, preferably an enteric polymer.

The controlled release dosage forms used in the present invention may also include a decarboxylase inhibitor, such as CD. Decarboxylase inhibitors, such as CD, may be present in immediate release form, modified or controlled release form, or both.

Drawings

Figure 1 shows the in vivo levodopa plasma profile of day 1 of the formulation tested in example 8 under fasted conditions.

Figure 2 shows a day 1 dose normalized in vivo levodopa plasma profile for the formulation tested in example 8 under fasted conditions.

Figure 3 shows the in vivo carbidopa plasma profile on day 1 of the formulation tested in example 8 under fasted conditions.

Fig. 4 shows the in vivo levodopa plasma profile at day 15 of the formulation tested in example 8.

Figure 5 shows the in vivo carbidopa plasma profile of day 15 of the formulation tested in example 8.

Figure 6 shows the average MDS-UPDRS part III scores of the formulations tested in example 8 on day 1.

Figure 7 shows the time course of mean LD plasma concentration and MDS-UPDRS part III score change from mean baseline for the formulations tested in example 8 on day 1 of treatment.

Figure 8 shows the mean LD plasma concentration and the change in MDS-UPDRS part III score from the mean baseline time course of the formulation tested in example 8 on day 15 of treatment.

Fig. 9 shows in vivo levodopa plasma profiles for the formulations tested in example 9.

Figure 10 shows the in vivo carbidopa plasma profile of the formulation tested in example 9.

Figure 11 shows a summary of the investigator exercise assessment scores for the formulations tested in example 9.

Figure 12 shows the mean change in score of MDS-UPDRS part III prior to self-average dosing for the formulations tested in example 9.

Figure 13 shows the least squares mean hours for 4, 7 or 13 score increases in MDS-UPDRS part III scores for the formulations tested in example 9.

Figure 14 shows the time course of mean LD plasma concentration by treatment and the change in MDS-UPDRS part III score from the mean baseline for the formulations tested in example 9.

Fig. 15 shows in vivo levodopa plasma profiles for formulations a and E tested in example 10.

Figure 16 shows the in vivo carbidopa plasma profile of formulations a and E tested in example 10.

Fig. 17 shows the improvement in "good open time" time from baseline to end for the study described in example 11.

Figure 18 shows the improvement in time per dose "good open" for the study described in example 11 at visit 7.

Figure 19 shows the decrease in "off period" time from baseline to end for the study described in example 11.

Figure 20 shows the mean LD plasma concentrations of the administration described in example 12.

Figure 21 shows the mean CD plasma concentration for the administration described in example 12.

Detailed Description

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

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

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

As used herein, the term "immediate release" refers to a dosage form or composition that releases a specific amount of an active ingredient, such as LD and/or CD, within 30 minutes or less, 25 minutes or less, 20 minutes or less, 15 minutes or less after administration to a patient or subject or when tested in a U.S. pharmacopoeia type I or II dissolution apparatus using 500-900ml of aqueous medium. One representative example of an immediate release LD dosage form is a commercial tablet product approved by the United states Food and Drug Administration (FDA) From Merck Sharpe&Dohme Corp, or U.S. FDA "AB" rating +.>Commonly used, for example, are us 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 traditional interpretation unless the context dictates otherwise or specifically states. More specifically, the components may be elements, constituents, individual ingredients or mixtures of ingredients. For example, the immediate release component may comprise a single ingredient, such as the drug itself, or may be a combination of the drug and one or more pharmaceutically acceptable excipients, provided that the "immediate release component" will release the drug immediately upon administration.

Target patient population

The present invention is useful for all PD patients. The invention is also useful in specific target patient populations.

The first target patient population comprises (a) PD patients currently being treated with a total daily dose of 500mg or less LD, wherein the total daily dose of 500mg or less is administered in divided doses of three, four or more LD throughout a 24 hour period. In some embodiments, PD patients in the first target patient population are being administered an immediate release oral LD composition, such as an immediate release oral tablet comprising about 100mg LD and 25mg CD, three times, four times, or five times a day. In another embodiment, PD patients in the first target patient population are being administered a combination of an immediate release oral LD composition and a controlled release oral LD composition at a total daily LD dose of 500mg 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 yet begun to be treated with LD.

The second target patient population includes PD patients experiencing LD with motor fluctuations. A subset of the second target patient population includes PD patients who have received LD therapy for at least 4 years, 5 years, 6 years, 7 years, 8 years, or more and experience motor complications or motor fluctuations when receiving LD therapy, particularly immediate release oral LD therapy. This subset of the second target patient population may be referred to as advanced PD patients.

The third target patient population includes all PD patients, including those in the first and second target patient populations as well as patients with advanced PD, unless specifically stated.

Dosing regimen

The present invention allows LD to be orally administered twice a day to the first target patient population described above, thereby controlling PD symptoms in the patient. More specifically, twice-a-day dosing will control or manage motor fluctuation symptoms in the patient, and in certain embodiments, reduce the patient's total "off period" time to less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours, less than 1 hour, and less than 0.5 hours a day. Twice-a-day dosing will control or manage motor fluctuation symptoms in the patient, and in certain embodiments will also reduce the total "off period" time of the patient during each dose, day, and/or awake hours over 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 per dose, day, and/or awake hours. Twice-a-day dosing will control or manage motor fluctuation symptoms in the patient, and in certain embodiments, the total "open" time of the patient is increased to 5 hours or more, 6 hours or more, 7 hours or more, 8 hours or more, 9 hours or more, 10 hours or more, or 11 hours or more during the 12 hour dosing interval (i.e., per dose). Twice-a-day dosing will control or manage motor fluctuation symptoms in the patient, and in certain embodiments, during a 12 hour dosing interval (per dose), the patient's total "good open time" is increased to 5 hours or more, 6 hours or more, 7 hours or more, 8 hours or more, 9 hours or more, 10 hours or more, or 11 hours or more. The terms "off," "on," and "well-opened" times with respect to PD patients are well known terms to those of skill in treating PD patients, and a general description is provided in example 8 below.

The first target patient population will take or be administered a total daily dosage of LD of from about 400mg to about 1000mg LD, preferably from about 400mg to about 800mg, most preferably from about 400mg to about 600mg LD. The total daily dose of LD may be divided into about two equal or unequal doses administered every twelve hours, with a dose of about 200mg LD to about 500mg LD, preferably about 200mg to about 450mg LD, and most preferably about 200mg LD to about 400mg LD taken or administered every twelve hours. LD will be taken by or administered to PD patients 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.

In certain embodiments, the LD dose taken or administered every 12 hours for the first target patient population will comprise about 140mg LD, 210mg LD, 280mg LD, 350mg LD, 410mg LD, or 420mg LD. In certain embodiments, the LD dose taken or administered every twelve hours will comprise one or more tablets or capsules comprising: (i) about 35mg CD and about 140mg LD; (ii) about 52.5mg CD and about 210mg LD; (iii) about 70mg CD and about 280mg LD; and (iv) 87.5mg CD and about 350mg LD. The tablet or capsule may be whole grain swallowed, or alternatively, the tablet may be crushed and sprinkled on food, such as yogurt or applesauce, or the contents of the capsule may be sprinkled on food, such as yogurt or applesauce, and food that the patient swallows.

In certain embodiments of the present dosing regimen for the first target patient population, LD plasma levels of at least 300ng/mL, 325ng/mL, 350ng/mL, 375ng/mL, 400ng/mL, or 425ng/mL should be provided within 0.25 to 1 hour, preferably within 0.25 to 0.75 hours after administration based on single or multiple dose administrations. Based on single or multiple dose administration, the dosage form administered should also provide a CD plasma level 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 after administration, preferably within 0.25 to 0.75 hours after administration, and should maintain CD plasma levels above 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 to 7 or 8 hours after administration.

In certain embodiments of the dosing regimen of the invention to the first target patient population, 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 should be provided 7 to 8 hours after dosing. The dosing regimen of the invention should also achieve steady state minimum CD plasma levels of at least 40ng/mL, 45ng/mL, 50ng/mL, 55ng/mL, 60ng/mL, 65, ng/mL, 70ng/mL, or 75ng/mL after 7 to 8 hours of dosing.

The dosing regimen of the invention allows PD patients in the first target patient population to experience improved therapeutic benefit after administration and prior to the next administration compared to patient symptoms without administration of the controlled release dosage form, or compared to treatment with an immediate release CD-LD oral dosage form. The enhanced therapeutic benefit may be:

(i) Patient movement status as determined by a qualified clinician is increased or augmented by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%;

(ii) Patient movement status as determined by the patient PD diary is increased or augmented by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50%;

(iii) The subject's tremors, dyskinesias, and/or mobility measured by the Kinesia 360 sensor is increased or augmented by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%;

(iv) The unified parkinson's disease rating scale ("MDS-UPDRS") score of the dyskinesia association version decreases by 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 points or more;

(v) The total "open" time during a patient's day or wake hour is increased by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% as compared to the equivalent total immediate release CD-LD dose per day or wake hour;

(vi) The total "good open" time during a patient's day or awake hours is increased by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% as compared to the equivalent total immediate release CD-LD dose per day or awake hours;

(vii) The "open time" time during each dose, day, and/or each day of wakefulness of the patient is increased 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 the oral dose of an equivalent immediate release CD-LD dosage form or the total immediate release CD-LD dose per day or each wakefulness of the patient;

(viii) The "good open time" time during each dose, day, and/or each day of wakefulness of the patient is increased 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 the oral dose of an equivalent immediate release CD-LD dosage form or the total immediate release CD-LD dose per day or per wakefulness of the patient;

(ix) The patient's total "off period" time during each day or awake hours is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% as compared to the equivalent total immediate release CD-LD dose per day or awake hours;

(x) The "off period" time during each dose, day, and/or each day of wakefulness of the patient is reduced 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 the oral dose of an equivalent immediate release CD-LD dosage form or the total immediate release CD-LD dose per day or each wakefulness of the patient;

(xi) The patient global change impression ("PGI-C") score, clinical global change impression ("CGI-C") score, and/or 39 parkinson's disease questionnaire ("PDQ-39") score of the patient is increased by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% as compared to the oral dose of an equivalent immediate release CD-LD dosage form or the total immediate release CD-LD dosage per day or per awake hour;

(xii) The average number of daily exercise fluctuations is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% as compared to the oral dose of an equivalent immediate release CD-LD dosage form or the total immediate release CD-LD dose per day or per awake hour;

(xiii) The daily perception problem and/or hallucinations are reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% as compared to the oral dose of an equivalent immediate release CD-LD dosage form or the total immediate release CD-LD dose per day or per awake hour; or (b)

(xiv) Any combination of the above.

In certain embodiments, the improved therapeutic benefit comprises an improvement in MDS-UPDRS part III score of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

More detailed explanation of the motion state, PD diary, MDS-UPDRS, PGI-C, CGIC, and PDQ-39 are provided below in examples 8, 9, and 11 herein.

The invention also provides a dosing regimen for treating a subject having PD or primary parkinson's disease in a second or third target patient population. The dosing regimen comprises orally administering a controlled release dosage form as described herein to a patient in need of such treatment to provide an effective amount of LD to treat symptoms of PD or primary parkinson's disease for at least 6 to 9 hours, preferably 7 to 8 hours.

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 six, seven, or eight hours over a twenty-four hour period (i.e., a day) to provide an effective amount of LD to treat symptoms of PD or primary parkinson's disease. Based on single or multiple dose administration, the controlled release dosage form administered 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 within 0.25 to 0.75 hours after administration. Based on single or multiple dose administration, the administered controlled release dosage form should also provide a CD plasma level of at least 30, 40, 50, 60, 70, 75, 80, 85, 90, 95, or 100ng/mL within 0.25 to 1 hour, preferably within 0.25 to 0.75 hours after administration, and should maintain CD plasma levels above 75, 85, 95, 100, 110, 120, 125, 130, 135, 140, 145, 150ng/mL from 1 hour to 7 or 8 hours after administration.

In certain embodiments of the invention, the dosing regimen for the second or third target patient population comprises orally administering a controlled release dosage form described herein to the subject every 6 to 9 hours, preferably about every 7 to 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 250ng/mL, 275ng/mL, 285ng/mL, 290ng/mL,300ng/mL, 310ng/mL, 320ng/mL, or 330ng/mL after 6 to 9 hours, preferably about 7 to about 8 hours, and prior to the next administration. 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 achieve 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 after 6 to 9 hours, preferably about 7 to about 8 hours, and before the next administration.

The dosing regimen of the present invention to the first, second and third target patient populations may further comprise the step of orally administering a controlled release dosage form as described herein, such that at least one controlled release dosage form administration occurs within 30 minutes, 15 minutes, 10 minutes, 5 minutes, or at bedtime, and provides a therapeutic benefit in the first target patient population after 6, 7, or 8 hours of wakefulness after bedtime administration and up to about 7, 8, 9, 10, 11, or 12 hours after bedtime administration. In certain embodiments of the present method of bedtime treatment, the plasma level of awake LD, i.e., the plasma level of LD prior to the next administration, should be at least 250ng/mL, 275ng/mL, 285ng/mL, 290ng/mL,300ng/mL, 310ng/mL, 320ng/mL, or 330ng/mL, and the plasma level of awake CD should be at least 40ng/mL, 45ng/mL, 50ng/mL, 55ng/mL, 60ng/mL, 65ng/mL, 70ng/mL, or 75ng/mL after administration of the controlled release dosage forms described herein for at least 7, 8, 9, 10, 11, 12, 13, 14, or 15 days every six, seven, eight, nine, eleven, or twelve hours over a 24-hour period.

The dosing regimen of the present invention allows the second and third target patient populations to experience improved therapeutic benefit 6, 7 or 8 hours after administration and prior to the next administration, as compared to patient symptoms without administration of the controlled release dosage forms described herein, or as compared to treatment with an immediate release CD-LD oral dosage form. The enhanced therapeutic benefit may be:

(iv) MDS-UPDRS score reduction of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 points or more;

(vi) The total "good open" time during a patient's day or awake hours is increased by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% as compared to the equivalent total immediate release CD-LD dose per day or awake hours; (vii) The "open time" time during each dose, day, and/or each day of wakefulness of the patient is increased 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 the oral dose of an equivalent immediate release CD-LD dosage form or the total immediate release CD-LD dose per day or each wakefulness of the patient;

(xi) The patient's PGI-C score, CGI-C score and/or PDQ-39 score is increased by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% as compared to the oral dose of an equivalent immediate release CD-LD dosage form or the total immediate release CD-LD dosage per day or per awake hour;

(xiv) Any combination of the above.

The dosing regimen for the second and third target patient populations comprising orally administering to the patient a controlled release dosage form described herein every 6 to 9 hours, preferably about every 7 to 8 hours, will control or manage motor fluctuation symptoms in the patient, and in certain embodiments will also reduce the total "off period" time of the patient during the 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 the 24 hour period. The dosing regimen for the second and third target patient populations comprising orally administering to the subject a controlled release dosage form described herein every 6 to 9 hours, preferably about every 7 to 8 hours, will control or manage motor fluctuation symptoms in the patient, and in certain embodiments will also reduce the total "off period" time of the patient during the awake 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 the awake hours of the 24 hour period.

The dosing regimen for the second and third target patient populations comprising orally administering to the subject a controlled release dosage form described herein every 6 to 9 hours, preferably about every 7 to 8 hours, will control or manage motor fluctuation symptoms in the patient, and in certain embodiments will increase the total "open" time of the patient to more than 5 hours, more than 6 hours, more than 7 hours, or 8 hours during the dosing interval. The dosing regimen for the second and third target patient populations comprising orally administering to the subject a controlled release dosage form described herein every 6 to 9 hours, preferably about every 7 to 8 hours, will control or manage motor fluctuation symptoms in the patient, and in certain embodiments will increase the total "good open" time of the patient to more than 5 hours, more than 6 hours, more than 7 hours, or 8 hours during the dosing interval.

The dosing regimen for the second and third populations of target patients comprising orally administering to the patient a controlled release dosage form described herein every 6 to 9 hours, preferably about every 7 to 8 hours, will control or manage motor fluctuation symptoms in the patient, and in certain embodiments, increase the total "open-time" time of the patient per dose, daily and/or per day of wakefulness hours 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 as compared to oral administration of an equivalent immediate release CD-LD dose or total immediate release CD-LD dose per day or per wakefulness hour. In certain aspects of this embodiment, the controlled release dosage form is administered 3 times a day as compared to an immediate release CD-LD dose administered 4 or 5 times a day.

The dosing regimen for the second and third target patient populations comprising orally administering to the patient a controlled release dosage form described herein every 6 to 9 hours, preferably about every 7 to 8 hours, will control or manage motor fluctuation symptoms in the patient, and in certain embodiments, increase the total "good open time" time during each dose, day and/or each day of wakefulness hours of the patient 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 as compared to oral administration of an equivalent immediate release CD-LD dose or total immediate release CD-LD dose per day or each wakefulness hour. In certain aspects of this embodiment, the controlled release dosage form is administered 3 times a day as compared to an immediate release CD-LD dose administered 4 or 5 times a day.

The dosing regimen for the second and third populations of target patients comprising orally administering to the patient a controlled release dosage form described herein every 6 to 9 hours, preferably about every 7 to 8 hours, will control or manage motor fluctuation symptoms in the patient, and in certain embodiments, reduce the total "off" time during each dose, day and/or each day of wakefulness hours of the patient 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 as compared to oral administration of an equivalent immediate release CD-LD dose or total immediate release CD-LD dose per day or each wakefulness hour. In certain aspects of this embodiment, the controlled release dosage form is administered 3 times a day as compared to an immediate release CD-LD dose administered 4 or 5 times a day.

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

In certain embodiments, the increased therapeutic benefit experienced by PD patients in the first, second, and/or third target patient populations may include a total "off period" 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 PD patients in the first target group, the dosing interval was about every 12 hours. For PD patients in the second and third target groups, the dosing interval may be 6-12 hours, preferably 7-9 hours, most preferably about 8 hours.

In certain embodiments, the increased therapeutic benefit experienced by PD patients in the first, second, or third target patient populations may include a significant increase in "open" and "good" times during the wake hours, which may range from about 12 to about 16 hours in a 24 hour period. As used herein, a significant increase in "open" and "good open" times during an awake hour may mean an increase in "open" and "good open" times during an awake hour (i.e., about 12-18, 13-17, or 14-16 hours over a 24 hour period) of at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 50% as compared to treatment with an immediate release CD-LD oral dosage form.

In certain embodiments, the increased therapeutic benefit experienced by PD patients in the first, second, or third target patient populations may include a significant increase in "open" and "good open" times during the awake hours during the dosing interval (i.e., per dose) as compared to the oral administration of an equivalent immediate release CD-LD dose or the total immediate release CD-LD dose per day or awake hours, which may range from about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180 minutes, or more.

In certain embodiments, the increased therapeutic benefit experienced by PD patients in the first, second, or third target patient population may include a significant reduction in "off-period" time during the awake hours during the dosing interval (i.e., per dose) as compared to oral administration of an equivalent immediate release CD-LD dose or total immediate release CD-LD dose per day or awake hours, which may range from about 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180 minutes, or more.

In certain embodiments, the enhanced therapeutic benefit experienced by PD patients in the first, second, or third target patient populations may include the controlled release dosage forms described herein when: (i) Administered under fed conditions and when compared to administration under fasted conditions; (ii) When administered under fed conditions and compared to administration under fasted conditions, wherein the components of the controlled release dosage forms described herein are sprinkled on a food substance such as yoghurt or a fruit preparation, puree or fruit, and the sprinkled composition is administered; (iii) Administered under fasted conditions and when compared to administration under fasted conditions, wherein the components of the controlled release dosage forms described herein are sprinkled on a food substance such as yogurt or a fruit preparation, puree or preserved fruit, and the sprinkled composition is administered; or (iv) similar or improved LD pharmacokinetic parameters when combined with (i), (ii), and/or (iii). Similar or enhanced LD pharmacokinetic parameters include, but are not limited to, C _max And AUC. Similar LD pharmacokinetic parameters as used herein refer to targets obtained by administration under fed or dusted conditionsThe geometric mean ratio of the parameter values is in the range of 80-120 of the target parameter values obtained by administration under fasted conditions. By enhanced LD pharmacokinetic values is meant that the target parameter values obtained by administration under fed or spiked conditions exhibit higher or greater values than the target parameter values obtained by administration under fasted conditions. For example, PD patients in the first, second, or third target patient populations may take the controlled release dosage forms described herein with food, and LD C _max And/or the LD AUC value will be greater than the LD C obtained under fasted conditions, preferably at least 10 hours after a fasted and more preferably when the same amount of controlled release dosage form is administered after an overnight fasted period _max And/or the LD AUC values are at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% or more greater.

In certain embodiments, the enhanced therapeutic benefit experienced by PD patients in the first, second, or third target patient populations may include when the controlled release dosage forms described herein are: (i) Administered under fed conditions and when compared to administration under fasted conditions; (ii) When administered under fed conditions and compared to administration under fasted conditions, wherein the components of the controlled release dosage forms described herein are sprinkled on a food substance such as yoghurt or a fruit preparation, puree or fruit, and the sprinkled composition is administered; (iii) Administered under fasted conditions and when compared to administration under fasted conditions, wherein the components of the controlled release dosage forms described herein are sprinkled on a food substance such as yogurt or a fruit preparation, puree or preserved fruit, and the sprinkled composition is administered; or (iv) maximum LD and/or CD plasma concentration (T) is achieved when combinations of (i), (ii) and/or (iii) are used _max ) The time variation of (2) is less than 6 hours. For example, PD patients in the first, second, or third target patient populations may take the controlled release dosage forms described herein with food and obtain T under fasted conditions, preferably after at least 10 hours of fasting and more preferably after overnight fasting, after administration of the same amount of the controlled release dosage form _max The phase contrast exhibits 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 Is a variation of (c).

Dosage form

Dosage forms useful in the dosing regimen of the present invention are controlled release oral solid formulations of LD and provide relatively stable plasma or serum profiles of LD over extended periods of time, and enhanced absorption of the active agent in the gastrointestinal tract of a subject.

The dosage form may include at least two components: (i) a first component or immediate release component that provides immediate release of the LD; and (ii) a second component or controlled release component that provides controlled or sustained release of the LD. In certain embodiments, the second or controlled release component comprises a LD-containing core that is mixed with, coated with, 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 will facilitate controlled release of the LD. The rate controlling material may be part of the controlled release component. For example, the rate controlling material may be a rate controlling polymer applied to the drug-containing core and act as a subcoating comprising a coating or layer of mucoadhesive material, or the rate controlling material may be mixed with the LD to form a controlled release matrix or core of controlled release component. The second or controlled release component is critical to provide prolonged absorption and thus prolonged and stable therapeutic coverage.

Oral dosage forms useful in the present invention may also contain 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. Decarboxylase inhibitors, such as CD, may also be present in components separate and distinct from the first or immediate release LD component and/or the second or controlled release LD component. More specifically, one embodiment of the controlled release extended release absorbent oral dosage form of the present invention may comprise: (i) a first or immediate release component comprising LD; and (ii) a second or controlled release component comprising LD. Another embodiment may 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. Still 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 and CD. Another embodiment may include (i) a first or immediate release component comprising an LD; and (ii) a second or controlled release component comprising LD, (iii) a third or immediate release component comprising CD; and/or (iv) a fourth or controlled release component comprising CD.

The first, second, third, and/or fourth components may be separate and distinct components, or may be combined to form distinct portions or regions of a larger combined component. For example, the first or immediate release component may comprise a powder or granule comprising LD and/or CD and optionally one or more pharmaceutically acceptable excipients, and the powder or granule is a separate and distinct composition from the second or controlled release component, however, both may be incorporated into a capsule for administration to a patient. Alternatively, the first or immediate release component may comprise a coating or layer comprising LD and/or CD and optionally one or more pharmaceutically acceptable excipients, wherein the coating or layer is applied to or 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 different portion or component of the larger combination of components. Those skilled in the art will appreciate that the location, structure and/or placement of the first or immediate release component relative to the second or controlled release component in the final dosage form is not critical, so long as the first or immediate release component allows for immediate release of the drug, such as LD and/or CD, upon administration to a patient dosage form, and the second or controlled release component has the controlled release and/or mucoadhesive properties described herein.

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 mucoadhesive material slows or extends the release of the active agent or drug from the controlled release component, thereby further extending the release and absorption of the drug, preferably LD and optionally CD. The controlled release component should release the drug over a period of 4 to 10 hours, preferably 5 to 8 hours.

The immediate release component should provide rapid release of the drug (e.g., LD and CD) so that the drug (e.g., LD and CD) is rapidly absorbed. Rapid absorption is important for PD patients who require a rapid "open" phase. Thus, the controlled release dosage forms useful in the present invention can provide rapid increases in LD plasma levels, preferably to therapeutic levels, and for extended periods of time.

In certain embodiments, the amount of immediate release LD should be in the range of 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.

Decarboxylase inhibitors such as CD are often provided with LD formulations to inhibit decarboxylation of LD, thereby increasing bioavailability of LD. In the controlled release dosage forms useful in the present invention, the decarboxylase inhibitor may be contained 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 previously described. Preferably, the decarboxylase inhibitor is CD and is included only in immediate release form, e.g., in the immediate release component with LD or separate from LD. In alternative embodiments, the decarboxylase inhibitor, preferably CD, is included in immediate and controlled release forms as previously described, e.g., in the controlled release component with LD or in a separate controlled release component without LD. In various embodiments, the amount of immediate release decarboxylase inhibitor, preferably CD, should be 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.

In one embodiment of the 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, pills, granules or combinations thereof. The controlled release component may include a core comprising 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 will include a rate controlling material that can be mixed with the drug to form a controlled release matrix core, coated on the drug-containing core to form a subcoating beneath a coating or layer comprising a mucoadhesive material or polymer, 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.

The immediate release component may be formulated as a powder, coating, tablet, mini-tablet, bead, pill, granule, or combination thereof 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, pill, bead, or granule separate from the controlled release component. In alternative embodiments, the immediate release component may also be applied as an immediate release coating or layer over one or more of the controlled release components. In certain embodiments, the immediate release component may be applied to or around an enteric coating of the controlled release component.

In another embodiment of the 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, minitablet, bead, pill, granule, or combination thereof. The decarboxylase component may be in an immediate release form, a controlled release form, or both. The decarboxylase inhibitor may be formulated with (1) one or more controlled release components comprising LD and/or (2) one or more immediate release components comprising LD. Alternatively, the decarboxylase inhibitor may be formulated separately from one or more controlled release components comprising LD and/or one or more immediate release components comprising LD.

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

In a preferred embodiment of the present invention, the oral dosage form comprises (1) one or more controlled release ingredients comprising LD and (2) one or more immediate release ingredients comprising LD and CD. In this embodiment, the controlled release component may comprise a drug-containing core coated with a first layer comprising a rate controlling material or polymer, a second layer comprising a mucoadhesive material or polymer, and an outer or third layer comprising an enteric material or polymer. Additional coatings or layers, such as decorative coatings or nonfunctional coatings, such as water-soluble seal coatings, may also be added to separate the core, first layer, second layer, and/or third layer or to overlay the third layer. These decorative or nonfunctional coatings may also be used to separate the immediate release component from the controlled release component and to apply or adhere the immediate release component to the controlled release component. As used herein, when a composition having a non-functional or decorative coating as the outermost coating is placed in a USP dissolution apparatus (type I or type II) the non-functional or decorative coating should dissolve within 30 minutes, 25 minutes, 20 minutes, 15 minutes, 10 minutes or 5 minutes, the apparatus having 500 to 900ml of aqueous medium having a pH of 1 to 7.

According to the practice of the present invention, the components of the present invention may be obtained by any method commonly used in the art, such as blending, mixing, granulating 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 arts. The composition may also be formed using other conventional formulation techniques, such as compression and/or compaction. In addition to the drugs such as LD and CD, the controlled release component and/or immediate release component may also contain conventional pharmaceutically acceptable excipients, such as lubricants, fillers, binders, disintegrants, glidants, surfactants (sometimes referred to as wetting agents), pH adjusting agents, antioxidants, or mixtures of the foregoing.

In one embodiment of the invention, the controlled and/or immediate release component is multiparticulate encapsulated, preferably in a hard gelatin capsule. Multiparticulates may be in a form that can be sprinkled directly onto food or liquids for ingestion.

Active agents, such as CD and LD, may 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 on an inert core, such as sugar spheres, microcrystalline cellulose spheres, glass spheres, plastic spheres, or a combination thereof.

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

The mucoadhesive material used in the present invention may be a homogeneous 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 characteristics, such as hydrophilicity, hydrophobicity, cationicity, anionicity, and/or biocompatibility, and include a plurality of hydrogen bonding groups, hydrophobic surfaces, positively charged groups, and/or negatively charged groups for adhering to the mucosal surface such that the controlled release component may be retained, prolonged, or slowed at the absorption site, thereby allowing LD to be released from the controlled release component at the desired absorption site, thereby improving bioavailability. Furthermore, the mucoadhesive material or polymer may be of natural, synthetic or from biological origin. Furthermore, the mucoadhesive material or polymer may consist of a single polymer or a combination of two or more different polymers. In one embodiment, the size of the polymer may be in the range of 10,000 daltons to 1,000,000 daltons, more preferably 20,000 daltons to 200,000 daltons.

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 butyl methacrylate copolymers, amino methacrylate copolymers or aminoalkyl methacrylate copolymers, e.g(Poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1; CAS number: 24938-16-7;Evonik Industries). />Is based on a cationic copolymer of dimethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate in a ratio of 2:1:1.

Other examples of mucoadhesive polymers include, but are not limited to, glycerides, steroidal detergents, polycarbophil (CAS number 9003-97-8;lubrizol corp.), carbomer, cellulose, chitosan, diethylaminodextran, diethylaminoethyl dextran, polygalactosamine, polylysine, polyornithine, prolamin, polyimine, hyaluronic acid, sodium alginate, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethyl cellulose (CMC sodium), and alginate, or combinations thereof.

The mucoadhesive material or polymer may constitute about 1-75% by mass of the controlled release component, preferably about 2-70% by mass of the controlled release component, most preferably about 3-50% by mass of the controlled release component. Preferably, the mucoadhesive material or polymer is separate100 or in combination with at least one additional mucoadhesive material. Mass percent of the above mucoadhesive materials or polymersThe percentages are based on multiparticulates having a bead size between 0.8 and 1.2 millimeters. If the bead size is greater or less than 0.8 to 1.2mm, those skilled in the art will appreciate that the above mass percentages should be adjusted accordingly.

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 may allow the mucoadhesive material to interact with the negative charge of the intestinal wall, thereby slowing or delaying the gastrointestinal transit time of the controlled release component.

Enteric coating materials or polymers are known in the art. Generally, 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 that minimizes the release of the active agent at pH 1.0. In the controlled release formulation of the present invention, it is believed that the second, third or outer enteric coating layer provides additional advantages in preventing aggregation of the controlled release component. That is, the enteric coating layer prevents the controlled release mucoadhesive component from adhering together in the low pH environment of the stomach.

Preferred enteric materials are shellac (esters of aleurone acid), zein, cellulose Acetate Phthalate (CAP), poly (methacrylic acid-methyl methacrylate copolymer), poly (methacrylic acid-co-ethyl methacrylate), trimethyl Cellulose Acetate (CAT), poly (vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP) and hydroxypropyl methylcellulose acetate succinate. Preferred enteric polymers release at a pH greater than or equal to pH 5.5. Examples includeOr->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-mentioned percentage of enteric coated polymer is based on beads having a particle size of between 0.8 and 1.2 mmMultiparticulates of particle size. If the bead size is larger or smaller, the skilled person will understand that the above mass percentages should be adjusted accordingly.

The second, third or outer enteric coating should be designed to dissolve at a pH greater than 5.0, pH5.5 or higher, pH 6.0 or higher or pH 6.5 or higher. In certain embodiments, the second, third or outer enteric coating should be designed to dissolve at a pH in the range of 5.0 to 6.4, preferably in the range of 5.0 to 6.0.

The enteric coating polymer may comprise methacrylic acid copolymer or various types of methacrylic acid copolymers. The methacrylic acid copolymer may comprise30D-55 (poly (methacrylic acid-ethyl acrylate copolymer) 1:1;100-55 (Poly (methacrylic acid-ethyl acrylate copolymer) 1:1; ->100 (poly (methacrylic acid-methyl methacrylate copolymer), and (2)>12,5 (poly (methacrylic acid-methyl methacrylate copolymer);100 (Poly (methacrylic acid-methyl methacrylate copolymer) 1:2; ->12,5 (Poly (methacrylic acid-methyl methacrylate copolymer) 1 and +.>30D (poly (methyl acrylate-methyl methacrylate-methacrylic acid copolymer) 7:3:1, or any combination thereof.

In a preferred embodiment of the invention, the controlled release component comprises a first rate controlling coating on the drug-containing core (i.e. applied to or around the drug-containing core with or without a seal coating), a second coating comprising a mucoadhesive material applied to or around the rate controlling coating (with or without a seal coating) and a third coating comprising an enteric material applied to or around the second coating (with or without a seal coating). The first rate controlling coating may comprise a controlled release material or polymer, such as ethylcellulose, cellulose acetate, Andor mixtures thereof. Preferably, the controlled release material is insoluble in water at neutral pH. In addition, controlled release materials or polymers that may be used are described in U.S. patent 5,002,776, which is incorporated herein by reference. In certain embodiments, the controlled release material or polymer is cellulose acetate, ethylcellulose, or mixtures thereof. The first or rate controlling coating may further comprise a pore former or flux enhancer to regulate the release rate of the drug from the core. Preferably, the pore former or flux enhancer is a water soluble material, such as a salt, i.e., naCl, KCl; sugar, i.e. lactose, sucrose, mannitol, povidone, copovidone, polyethylene glycol, hydroxypropyl cellulose, hydroxypropyl methylcellulose or combinations thereof. If the pore former or flux enhancer is a water soluble polymer, it should have a low molecular weight, e.g., less than 100,000, preferably less than 50,000, and/or should dissolve rapidly in water, i.e., 2wt% of the water soluble polymer should dissolve in 100ml of water at 25 ℃ in 15 minutes or less, preferably in 10 minutes or less, most preferably in 5 minutes or less.

The controlled release component may also include a hydrophobic controlled release material in addition to or in place of the controlled release material described above. Examples of hydrophobic materials that may be used include beeswax, white wax, emulsifying wax, hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, cetyl alcohol, stearyl alcohol, free wax acids such as stearic acid, esters of cerotic acid, propylene glycol monostearate, glycerol monostearate, carnauba wax, palm wax, candela wax, montan wax, ozokerite, paraffin wax, lardacaine, chinese wax, and mixtures thereof. Other possible controlled release excipients useful in the present invention include saturated hydrocarbons having 25 to 31 carbon atoms, saturated alcohols having 25 to 31 carbon atoms, saturated monocarboxylic acids having 25 to 31 carbon atoms, esters derived from the alcohols and monocarboxylic acids, described in U.S. patent 6,923,984, incorporated herein by reference.

In an alternative embodiment, the controlled release component comprises a matrix core comprising a mixture of a controlled release material (which may be the aforementioned controlled release material and/or hydrophobic material) and a drug (i.e., CD and/or LD). The matrix core may further comprise one or more pharmaceutically acceptable excipients, such as lubricants, fillers, binders, disintegrants, glidants, surfactants (sometimes referred to as wetting agents), pH adjusting agents, antioxidants, or mixtures thereof. In this embodiment, the matrix core may be further coated with a rate controlling coating or polymer prior to coating with the mucoadhesive coating and the outer enteric coating.

In another alternative embodiment, the controlled release component may incorporate a controlled release material, which may be the aforementioned controlled release material and/or hydrophobic material, into the mucoadhesive coating. The mucoadhesive material may also function as a controlled release material or to facilitate controlled release of the drug from the controlled release component.

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.

In addition to the mucoadhesive material and the enteric material, the mucoadhesive coating or layer and the enteric coating or layer used in the present invention may further comprise one or more pharmaceutically acceptable excipients, such as plasticizers, lubricants, fillers, binders, disintegrants, glidants, surfactants (sometimes referred to as wetting agents), pH adjusters, antioxidants, or mixtures of the foregoing.

Some commonly known plasticizers include adipates, azelates, benzoates, citrates, stearates, ibutesters (isobucate), sebacates, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citrates and those described in John Wiley & Sons published Encyclopedia of Polymer Science and Technology (encyclopedia of polymer science and technology), volume 10 (1969). Preferred plasticizers are glyceryl triacetate, acetylated monoglyceride, grapeseed oil, olive oil, sesame oil, acetyltributyl citrate, acetyltriethyl citrate, glycerin sorbitol, diethyl oxalate, diethyl malate, diethyl fumarate, dibutyl succinate, diethyl malonate, dioctyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, tributyrin, and combinations thereof. Depending on the particular plasticizer, an amount of plasticizer of about 0% to about 25%, preferably about 2% to about 15%, based on the total weight of the controlled release, mucoadhesive, and/or enteric coating, may be used.

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 acids, magnesium stearate, calcium stearate, zinc stearate, sodium stearate, and, Sodium stearyl fumarate, fatty acid salts, fatty acid metal salts, glyceryl monostearate, glyceryl tribasic, glyceryl dibenkoate, and glyceryl dibenkoate>ATO, glycerol esters, sorbitol monostearate, sucrose monopalmitate, sugar esters, fatty acid esters, talc, hydrated magnesium silicate, PEG 4000, boric acid, carbowax (PEG) 4000/6000, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate, sterotex, waxes or mixtures thereof.

Examples of fillers useful in the compositions of the present invention include sugars such as lactose, sucrose, mannitol, monocalcium 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 to 50%, preferably about 2 to 45%, and most preferably about 5 to 40% by 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.

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

Examples of disintegrants that may be used in the compositions of the invention include croscarmellose sodium, starch, crospovidone, sodium starch glycolate, alginic acid, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, powdered cellulose, chitosan, guar gum, magnesium aluminum silicate, methyl cellulose, sodium alginate, and mixtures thereof. The disintegrant may constitute about 0.1 to 15%, preferably about 0.2 to 10%, and most preferably about 0.5 to 5% by mass of the immediate release component.

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

One or more surfactants may also be used in the compositions of the present invention. The surfactant can beEither nonionic or ionic. Examples of nonionic surfactants include polyethoxylated castor oil, polyoxyethylene alkyl esters, polyglycolized glycerides, sorbitol fatty acid esters, glycerol fatty acid esters, fatty acid polyglycerol esters, fatty acid alcohol polyglycol ethers, acetylene glycols, acetylenic alcohols, alkylene oxide block polymers, polyoxyethylene alkyl ethers, polyoxyethylene alkylaryl ethers, polyoxyethylene styrene aryl ethers, polyoxyethylene glycol alkyl ethers, polyoxyethylene fatty acid esters, polyoxyethylene DewateringSorbitol fatty acid ester, polyoxyethylene glycerol fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxypropylene fatty acid ester or a mixture of the above. A further list of possible nonionic surfactants can be found in Martindale, pages 1243-1249, 29 th edition of additional pharmacopoeia Extra Pharmacopoeia, which is incorporated herein by reference.

In certain embodiments, the nonionic surfactant can include fatty alkyds or amide ethoxylates, monoglyceride ethoxylates, sorbitol ester ethoxylates, alkyl polyglycosides, mixtures thereof, and the like. Some nonionic surfactants include polyoxyethylene derivatives of polyol esters, such as polysorbate 20 (TWEEN) Polysorbate 40Polysorbate 60->And polysorbate 80->

In certain embodiments, the nonionic surfactant can further comprise d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS), nonoxynol (nonoxinol), poloxamer, sorbitol monolaurate, sorbitol monooleate, sorbitol monopalmitate, sorbitol monostearate, sorbitol sesquioleate, sorbitol trioleate, tyloxapol (tyloxapol), and mixtures of the foregoing.

Any kind of ionic surfactant may also be incorporated in the compositions of the present invention. Suitable ionic surfactants include, but are not limited to, carboxylic acid esters such as soaps, acyl lactylates, acyl amides of amino acids, sulfuric esters such as alkyl sulfuric esters and ethoxylated alkyl sulfuric esters, sulfonic esters such as alkyl benzene sulfonic esters, acyl isethionates, acyl taurates and sulfosuccinates, phosphates, quaternary ammonium salts and ethoxylated amines. An example of a preferred ionic surfactant is sodium dodecyl sulfate.

The surfactant 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 or immediate release component.

Examples of pH adjusting agents useful in the compositions of the present invention include pharmaceutically acceptable acids or bases that may be present to adjust the pH of the intermediate composition that results in the final composition and to adjust the pH of the pharmaceutical environment of the final composition to the desired or optimal pH range. Representative examples of pharmaceutically acceptable acids that may be used include, but are not limited to, acetic acid, citric acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, and mixtures thereof. Representative examples of pharmaceutically acceptable bases that can be used include, but are not limited to, ammonia, ammonium carbonate, diethanolamine, potassium hydroxide, sodium bicarbonate, sodium carbonate, sodium hydroxide, triethanolamine, and mixtures thereof. In certain embodiments, the pH adjustor is an acid, preferably an organic acid, and will comprise 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 adjuster is an acid, preferably an organic acid, and is present in the controlled release component in a molar ratio of acid to levodopa of from about 1:4 to about 4:1, preferably from about 1:3 to about 3:1, most preferably from about 1:2 to about 2:1. Certain embodiments of the present invention, i.e., the immediate release component, the controlled release component, and/or the final oral dosage form, are free or substantially free of a pH adjusting acid, preferably a pH adjusting organic acid, most preferably a pH adjusting carboxylic acid, such as acetic acid, citric acid, fumaric acid, malic acid, propionic acid, tartaric acid, and mixtures thereof.

Examples of antioxidants that may be used in the compositions of the present invention include ascorbic acid, ascorbyl palmitate, butyl hydroxyanisole, butyl hydroxytoluene, hypophosphorous acid, monothioglycerol, potassium metabisulfite (potassium metabisulfate), propyl gallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfate, sodium thiosulfate, sulfur dioxide, tocopherols, and mixtures thereof.

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

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

In embodiments of the invention, the immediate release component may include 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, a controlled release component: the weight ratio of LD in the immediate release component is at least about 2:1, and most preferably 3:1. Preferably, the amount of LD in the immediate release component should provide a therapeutic dose of LD within one hour or less after administration of the dosage form, preferably within 45 minutes or less after administration, and most preferably within about 30 minutes or less after administration.

As noted above, in certain embodiments comprising 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.

In one embodiment of the invention, the controlled release component comprises one or more beads, pellets, tablets, mini-tablets or granules that pass through 12, 14 or 16 mesh in size but may remain on an 18, 20 or 25 mesh screen. In addition, the beads, pellets, tablets, mini-tablets or granules may have a size that passes 14 mesh but may remain on an 18 or 25 mesh screen. In certain embodiments, the dosage forms of the present invention include a variety of beads, pellets, tablets, minitablets, or granules that pass through 12, 14, or 16 mesh in size, but may remain on an 18, 20, or 25 mesh screen.

The controlled release component will have an in vitro dissolution profile that shows minimal release of LD at pH 1.0 and prolonged release of LD near neutral pH (e.g., at pH 7 or near pH 7). For example, using the United States Pharmacopeia (USP) I dissolution method, in simulated gastric fluid (pH 1.0, enzyme free) with a stirring speed of 75rpm for 2 hours, a minimum release may result in less than 20%, preferably less than 10%, most preferably less than 5% of LD released. Further, prolonged release may involve release beyond at least 4 hours and up to an additional 8 hours at or near pH 7 after changing to simulated intestinal fluid (pH 7.0, enzyme-free) after the first 2 hours in simulated gastric fluid (pH 1.0, enzyme-free) using USP I dissolution method with a stirring speed of 75 rpm. Further, as used herein, a pH at or near pH 7 includes a pH at or about pH 6.5, 6.6, 6.7, 6.8, 6.9, 7.1, 7.2, 7.3, 7.4, 7.5 or 7.6, or about pH 6.5, 6.6, 6.7, 6.8, 6.9, 7.1, 7.2, 7.3, 7.4, 7.5 or 7.6.

The oral controlled release dosage form useful in the present invention should include one or more immediate release components and one or more controlled release components, wherein the immediate release components should provide a therapeutic dose of LD within 1 hour or less, preferably 45 minutes or less, most preferably about 30 minutes or less, after administration of the dosage form after administration to a human patient. To achieve such therapeutic levels, the controlled release composition should exhibit the following in vitro release profile when tested using USP type I or type II apparatus at 37 ℃ at a rotational speed of 75rpms and 900ml of an aqueous medium having a pH between 6.8 and 7.4, preferably a pH of 7:

the amount of LD released 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% of the LD, preferably less than 20%, most preferably less than 15% when tested using USP type I or type II apparatus at 37 ℃ at a rotational speed of 75rpms and 900ml of aqueous medium at pH 1 for 2 hours.

In certain embodiments, oral controlled release dosage forms useful in the present invention include: (i) One or more immediate release components comprising LD and CD, and (ii) one or more controlled release components, i.e., controlled release particles, such as beads, pellets, tablets, mini-tablets, or granules, comprising: (a) a core comprising LD, optionally CD, and at least one pharmaceutically acceptable excipient, (b) a layer or coating comprising a mucoadhesive material surrounding the core, and (c) an outer coating comprising an enteric material surrounding the mucoadhesive coating (b). This embodiment may also include a controlled release material in the core or coating, including a controlled release material surrounding the core and underlying the coating, comprising a mucoadhesive material and a decorative and/or non-functional seal coating, as previously described. When this embodiment of the dosage form of the present invention is tested with 500-900mL of aqueous medium having a pH of about 1 to about 7.5 using USP type I or type II equipment, about 75% to 100% of the CD is released within 30 minutes, preferably about 85% to 100% of the CD is released within 30 minutes, and most preferably about 90% to 100% of the CD is released within 30 minutes. In addition, when this embodiment of the dosage form is tested using either a USP type I or type II device and 500-900mL of aqueous medium having a pH of about 1 to about 4.0, about 15% to 45% of the LD is released within 30 minutes, preferably about 20% to 40% of the LD is released within 30 minutes, and most preferably about 25% to 35% of the LD is released within 30 minutes. This embodiment of the dosage form when tested using USP type I apparatus at 37 ℃ ± 0.5 ℃ at 75rpms and 500-900ml simulated gastric fluid for 2 hours and after that at pH 6.8 phosphate buffer, shows the following in vitro LD curve:

Nlt=no less than.

In another embodiment, the invention comprises: a) One or more immediate release components as described previously; b) One or more controlled release components as hereinbefore described and c) one or more enteric coating components. The enteric coating component comprises a core comprising LD or an ester of LD or a salt thereof and/or a decarboxylase inhibitor and at least one pharmaceutically acceptable excipient as described previously, and an enteric coating. When tested using a USP type I or type II apparatus at 37 ℃ at a rotational speed of 75rpms and 900ml of an aqueous medium having a pH between 6.8 and 7.4, preferably a pH of 7, the enteric coating component will release 100% of the LD and/or decarboxylase inhibitor within 90 minutes, preferably within 60 minutes, most preferably within 45 minutes. The enteric coating component will also release less than 25% of the LD, preferably less than 20%, most preferably less than 15% when tested using USP type I or type II equipment at 37 ℃ at a rotational speed of 75rpms and 900ml of aqueous medium at pH 1.

LD released from the controlled release component may produce an in vivo LD plasma profile (e.g., a mean in vivo LD plasma profile) that includes peaks that do not occur about two hours before administration to a subject and that are at a maximum above peak concentration (C _max ) The 50% LD plasma concentration provides a duration of at least three hours. In another embodiment, in the plasma profile, the peak occurs after about one and one half hours after administration to the subject, and for C _max The LD plasma concentration of 50% or more of (c) exhibits a duration of at least four hours. For example, the curve may be implemented under fasted conditions.

When the formulation of the present invention includes an immediate release component and a controlled release component, the in vivo LD plasma profile after oral administration of the dosage form of the present invention to a subject may include the time of administration of the oral dosage form; corresponding to C occurring within about 6 hours or 7 hours after administration of the dosage form _max LD plasma concentration of (c); reaching 50% C within one hour of administration, more preferably within 30 minutes _max Is a mean time of (a). To 50% C _max Is less than a small timeAt the same time, and 50% C _max Hold for at least 5.0 hours. The time to maximum plasma concentration (T) _max ) For 30 minutes to 7 hours. Preferably, LD plasma level is maintained at C _max 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.

When the formulation of the present invention includes an immediate release component and a controlled release component, the in vivo LD plasma profile after oral administration of the dosage form of the present invention to a subject may include an LD fluctuation index which may range from 0.5 to 1.5, preferably from about 0.7 to about 1.3, more preferably from about 0.7 to about 1.25. The fluctuation index can be obtained by the following formula (C _max -C _min )/C _avg To determine, wherein C _max Is the maximum or peak LD concentration, 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 measured at steady state or about 10 to about 15 days after treatment with the formulations described herein, and is preferably measured during the period from the beginning of the first morning administration and 6, 7, 8, 9, 10, 11, or 12 hours after the first morning administration.

It will be appreciated by those skilled in the art that the pharmacokinetic parameters described herein may be obtained by single or multi-dose studies on healthy subjects or PD patients, unless specifically stated otherwise. It should also be appreciated that the pharmacokinetic parameters described herein may be obtained under fed or fasted conditions. It is further understood that the pharmacokinetic parameters described herein are averages obtained from single or multiple dosing studies using at least 3 or more subjects or patients unless specifically indicated.

The combination of the immediate release component and the controlled release component of the present invention provides a profile that approximates an infusion-like profile. LD C _max Is not related to clinic per se. Clinically relevant is achieving therapeutic levels of LD (e.g., 50% C _max LD level of (C), and is maintained at a therapeutic level (e.g., 50% C) _max ) Or for the above. The shorter time to reach LD therapeutic level correlates faster with the "on" time of PD patients, at or therapeutic levelThe extended period of time above then provides the desired stable "infusion-like" profile.

The present invention has the advantage of providing a sustained LD plasma concentration of greater than 5 hours in duration and a more consistent duration, wherein LD plasma concentration > 50% C _max The Coefficient of Variation (CV) of the mean duration of less than 35%, preferably less than 30%.

Preferred compositions of the present invention comprise:

a multiparticulate formulation comprising: a) One or more immediate release components comprising LD and/or CD and optionally at least one pharmaceutically acceptable excipient as described previously, and b) one or more controlled release components comprising controlled release beads, pellets, tablets, mini-tablets or granules, wherein the beads, pellets, tablets, mini-tablets or granules comprise an LD core that is free or substantially free of CD, and at least one pharmaceutically acceptable excipient as described previously, a mucoadhesive coating or layer applied to and/or surrounding the core, and an enteric coating surrounding the mucoadhesive coating, wherein the controlled release beads, pellets, tablets, mini-tablets or granules further comprise a controlled release material. The controlled release material may be: i) Mixing with LD to form a controlled release matrix core, ii) applying as a coating or layer onto a core comprising LD and at least one pharmaceutically acceptable excipient; iii) Incorporated or mixed into a mucoadhesive coating or layer, or iv) combinations of (i), (ii) and/or (iii). Decorative and/or encapsulation coatings as previously described may also be used in the immediate and controlled release components of this embodiment.

Alternative preferred compositions include:

a multiparticulate formulation comprising: a) One or more immediate release components comprising LD, CD and optionally at least one pharmaceutically acceptable excipient as described previously; b) One or more controlled release components free or substantially free of CD comprising a bead, pellet, mini-tablet or granule, wherein the bead, pellet, tablet, mini-tablet or granule comprises a core of LD and at least one pharmaceutically acceptable excipient as described previously, a mucoadhesive coating or layer applied to and/or around the core and an enteric coating around the mucoadhesive coating or layer, wherein the controlled bead, pellet, tablet, mini-tablet or granule further comprises a controlled release material, and c) an enteric coating component comprising a plurality of enteric coated beads, pellets, mini-tablets or granule comprising a core comprising a mini-LD and/or a decarboxylase inhibitor and at least one pharmaceutically acceptable excipient as described previously and an enteric coating around the core. The controlled release material used in the controlled release component may be: i) Mixing with LD and at least one pharmaceutically acceptable excipient to form a controlled release matrix core, ii) applying as a coating or layer onto the core of LD and at least one pharmaceutically acceptable excipient; iii) Incorporated or mixed into a mucoadhesive coating or layer, or iv) combinations of (i), (ii) and/or (iii).

In certain embodiments, dosage forms useful in the dosing regimen of the present invention are described in U.S. patent No. 10,292,935 and U.S. published patent application No. 2020/0009062 (U.S. serial No. 16/573,634, filed 9, 17, 2019), which are incorporated herein by reference.

Examples

Example 1

An immediate release granule having the following composition was prepared:

* Monohydrate of a salt of a compound of formula (I)

Granules were prepared using a procedure similar to that described above in example 5 of U.S. patent No. 10,292,935 (preparation component 1), example 5 being incorporated herein by reference. Typically, CD, LD and croscarmellose sodium are mixed in a high shear granulator and wet granulated with a 5 wt% aqueous povidone solution. After granulation, the wet granules were passed through a Comil with a 0.375 inch screen and dried in a fluidized bed. The dried granules were ground with a Fitzmill equipped with a 30 mesh screen and then mixed with magnesium stearate.

Example 2

Controlled release particles (beads) were prepared having the following composition:

controlled release beads were prepared by a procedure similar to that described in example 5 of U.S. patent No. 10,292,935 (preparation of component II), which is incorporated herein by reference. Typically, LD, microcrystalline cellulose, mannitol, and sodium lauryl sulfate are mixed in a high shear granulator and wet granulated with a 5 wt% aqueous povidone solution. After granulation, the wet granules were extruded using an extruder equipped with a 0.9mm aperture screen, the extrudate was collected and charged into a spheronizer equipped with a 3mm intersection disc (cross catch disc). The wet rolled beads are dried in a fluid bed dryer. The dried beads were screened through 16 commercial grade (MG) and 24MG screens and the beads that passed through the 16MG screen but remained on the 24MG screen were collected.

The collected beads were coated with a solution comprising cellulose acetate, copovidone, acetone and isopropanol using a fluid bed coating apparatus. After application of the target coating (coating) solution, the controlled release coated beads are dried in a fluidized bed. The dried controlled release beads were screened through 14MG and 24MG screens and the beads remaining on the 24MG screen were collected. The collected controlled release coated beads were coated with a mucoadhesive solution comprising Eudragit E100, talc, acetone and isopropanol in a fluidized bed. After the target mucoadhesive coating solution is applied to the controlled release coated beads, the mucoadhesive coated beads are dried in a fluidized bed. The dried mucoadhesive coated beads were coated in a fluidized bed with an enteric coating solution comprising Eudragit L100, talc-triethyl citrate, acetone and isopropanol. After the target enteric coating solution is applied to the mucoadhesive coated beads, the enteric coated beads are dried in a fluidized bed. The dried, enteric coated beads were screened through 14MG and 24MG screens and the beads remaining on the 24MG screen were collected. The collected beads were blended with talc.

Example 3

The immediate release component of example 1 and the controlled release beads of example 2 were blended to produce a mixture having 67.49wt% controlled release beads and 32.51% immediate release granule. The mixture was filled into hard gelatin capsules containing (a) 180mg LD and 45mg CD and (b) 270mg LD and 67.5mg CD. CD weight is based on anhydrous CD.

Example 4

Controlled release particles (beads) were prepared according to the procedure of example 2 having the following composition:

example 5

The immediate release component of example 1 and the controlled release beads of example 4 were blended to produce a mixture having 68.11wt% controlled release beads and 31.89% immediate release granule. The mixture was filled into hard gelatin capsules containing (a) 180mg LD and 45mg CD and (b) 270mg LD and 67.5mg CD. CD weight is based on anhydrous CD.

Example 6

example 7

The immediate release component of example 1 and the controlled release beads of example 6 were blended to produce a mixture having 67.5wt% controlled release beads and 32.5% immediate release granules. Filling the mixture to contain (a) 140mg LD and 35mg CD; (b) 210mg LD and 52.5mg CD; (c) 280mg LD and 70mg CD; and (d) in hard gelatin capsules of 350mg LD and 87.5mg CD. CD weight is based on anhydrous CD. These dosage forms contain about 25% total LD content in the immediate release component; the controlled release component contained 75% of the total LD content and the immediate release component contained 100% of the total CD content.

210mg of LD and 52.5mg of CD prepared in this example were subjected to a USP type I apparatus at 37 ℃ + -0.5 ℃ with a rotational speed of 75rpms and 900ml of simulated gastric fluid for 2 hours and then phosphate buffer pH 6.8; 280mg LD and 70mg CD;350mg LD and 87.5mg CD capsules were tested. 140mg LD and 35mg CD capsules prepared in this example were tested at 37 ℃ + -0.5 ℃ using a USP type I apparatus at a rotational speed of 75rpms and 900ml simulated gastric fluid for 2 hours and then pH 6.8 phosphate buffer. The results of the in vitro dissolution test are as follows:

Example 8

The dosage form described in example 3 was administered to 28 subjects with advanced PD in a randomized, open-label, rater blinded, multicenter, two treatments, two-cycle, multi-dose crossover study. Subjects were randomized into 1 out of 2 dosing sequences: the composition of example 3 ("IPX 203") and an immediate release CD-LD ("IR CD-LD") tablet under the trade name are receivedOr->Is commercially available from the U.S. food and drug administration class AB imitation. Subjects received 15 days of treatment with a 1 week (+ -2 days) washout period between treatment cycles.

The study consisted of four (4) clinical visits after screening. Day 1 of each treatment cycle (1 st and 3 rd visits) and day 15 of each treatment cycle (2 nd and 4 th visits). If the dosing regimen has stabilized at least 4 weeks prior to visit 1, the subject may continue to allow for non-CD-LD class PD drugs throughout the study.

To qualify for this study, subjects diagnosed with idiopathic PD at an age of > 40 years need to currently receive a stable CD-LD regimen and experience exercise complications. Motor complications are defined as subjects experiencing "pharmacodynamic off-phase" episodes each day with periods of bradykinesia and rigidity, and experiencing "off-phase" states after a majority of morning wakefulness in history.

Within 2 weeks after screening, the qualified subjects completed their PD and dosing diaries on each of the 3 days prior to visit 1 and worn the Kinesia 360 sensor on the more affected side from just after waking to bedtime. The subject is required to take his final dose of CD-LD before 10:00 a.m. before the 1 st and 3 rd visits. At the 1 st and 3 rd visits of each treatment cycle, a first morning dose of study medication was administered at the study site.

On day 1 of each treatment cycle (visit 1 and visit 3), the subject arrived at the study site and received a single dose of study medication. Subjects who received IR CD-LD at random began with a single dose of IR CD-LD dose the first morning prior to their usual study. According to the guidelines provided in table 1, subjects receiving IPX203 compositions at random began with a single dose based on their usual pre-study IR CD-LD dose in the first morning.

TABLE 1

On clinical day 1, after administration of the first study medication dose, the subject may receive rescue medication if the subject experiences an "off state for 3 hours or more after administration, or at the discretion of the researcher. A subject in need of rescue during IR CD-LD treatment receives an IR CD-LD dose corresponding to his/her typical pretreatment regimen based on the subject's dosing diary. For rescuing during IPX203 treatment, the subject will receive a dose of IPX203, as described in table 2, which he/she will typically receive after his/her morning dose.

TABLE 2

Note that: IR LD at 100mg unit dose was converted to about 270mg unit dose IPX203

After the completion of the day 1 evaluation, the subjects were discharged from the hospital and were advised to take prescribed study medication according to their initial regimen:

the initial dosing regimen for ID CD-LD was the same as the pre-stabilization regimen for the subject. If they take a single daily bedtime dose of controlled release ("CR") CD-LD, either alone or in combination with IR CD-LD, the CR CD-LD dose is stopped and replaced with a 1:1 milliequivalents IR CD-LD dose. The bedtime dose is defined as the dose of CR CD-LD taken by the subject during the normal night sleep period for 1 hour.

The initial dosing regimen for IPX203 was according to the guidelines provided in table 2, based on the pre-study IR CD-LD morning dose and daily dosing regimen for each individual. The dosing regimen for IPX203 was predicted to be 3 times a day, approximately every 7 to 8 hours.

During days 1 through 9 of each treatment cycle, the investigator can adjust each subject's study medication, if necessary, to optimize efficacy, tolerability, and safety. Dosing regimen required stability for the last 5 days (days 10-14) of each treatment cycle. In a clinical visit on day 15, subjects received the same stable medication regimen as they had taken on days 10-14.

Pharmacokinetic and efficacy/pharmacodynamics were evaluated at regular intervals at the clinic by qualified clinical staff blinded to dosing-up to 8 hours after the 1 st (1 st and 3 rd visits) of each treatment cycle and up to 10 hours on the 15 th (2 nd and 4 th visits) of each treatment cycle. These assessments were performed whether the subject received a rescue dose on day 1 or an additional dose on day 15 according to their established stable dosing regimen. In addition, the subject completed PD and dosing diaries and used a Kinesia 360 sensor on the ankle and wrist of the more affected side of the subject immediately after each day of wakefulness 3 days prior to visit 1, 2 and 4.

The main parameter is the average percentage of "off" time during the awake hours in the PD diary of the subjects collected last 3 days at the end of each treatment cycle. The secondary efficacy parameter utilizes additional data collected from the PD diary; dyskinesia, mobility, and tremor measurements obtained from the Kinesia 360 sensor; and MDS-UPDRS scores collected prior to dosing on day 15 of each treatment cycle.

Pharmacodynamics was also assessed using subject motion assessment and MDS-UPDRS part III scoring. Pharmacokinetic parameters were calculated from CD and LD plasma concentration-time curves after each treatment. Safety was assessed by reviewing reported adverse events, concomitant medications, vital signs, electrocardiogram ("ECG"), clinical laboratory tests, physical examination, columbia suicide severity rating scale (Columbia-Suicide Severity Rating Scale) ("C-SSRS") and vital signs.

Inclusion criteria:

potential subjects to be enrolled in the study must meet all of the following criteria:

1. male or female subjects diagnosed with idiopathic PD at an age of > 40 years old, who are undergoing long-term treatment with a stable CD-LD regimen, but experience motor complications. Idiopathic PD is defined by the brain diagnostic criteria of the United kingdom institute of Parkinson's disease (United Kingdom Parkinson's Disease Society Brain Bank Diagnostic Criteria). There is no known secondary cause of parkinson's disease in subjects (e.g., vascular, toxin or drug induced, metabolic or infection), nor is there another neurodegenerative disease (e.g., progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy) associated with symptoms of parkinson's disease in subjects.

2. Written informed consent can be provided and HIPAA authorization is willing to be signed before any study specific procedure is performed.

3. Female subjects with fertility potential were screened for negative urine pregnancy tests.

4. Negative urine screening and alcohol breath test screening for drugs of abuse.

Hoehn and Yahr stages 2, 3 or 4 (contained in MDS-UPDRS section III).

6. The use of a medically acceptable contraceptive method was agreed to continue throughout the study and for 6 weeks after completion of the study.

7. Montreal cognitive assessment (Montreal Cognitive Assessment) (MoCA) score > 24 at screening was in the "open-term" state.

8. For 4 weeks prior to screening, subjects experienced a "pharmacodynamic off-period" episode of daily, with bradykinesia and rigidity periods, and historically experienced a "off-period" state after most morning wakefulness.

9. In visit 1, browsing the 3-day PD diary confirms the following: the subject is able to properly complete a valid entry in the diary; and the subject has an average of at least 2.5 hours of "off period" time per day during the 3-day awake hours, wherein at least 1.5 hours of "off period" time per day. A diary that exceeded 1 day did not return, or that was missing for more than 2 hours (4 half hours) in one 24 hour diary day, indicates that the diary was not completed correctly.

10. Responsive CD-LD therapy, and is currently treated with a stabilization regimen of CD-LD for at least 4 weeks prior to visit 1, and:

a. IR CD-LD requiring 100 to 250mg LD for morning dose

b. Total daily dose of IR CD-LD requiring at least 400mg LD

c. A maximum total daily dose of 1800mg LD is administered, including ID CD-LD alone or a single daily bedtime dose combination of IR CD-LD and CR CD-LD

d. Frequency of administration of CD-LD with 4 to 9 times daily

e. ID CD-LD, usually undergoing an "open-time" response to the first dose of the day

f. Historically, the efficacy of the first morning dose of IR CD-LD persisted for less than 4 hours, usually the efficacy "off period" before the next dose; or the subject takes a second dose of PD drug 4 hours before the "off period" is avoided "

11. The CR CD-LD dose was not used except for a single daily bedtime dose for at least 4 weeks prior to the 1 st visit.

12. No dose was used 4 weeks before the 1 st visit(carbidopa and levodopa)) Sustained release capsules.

13. At the time of screening, the MDS-UPDRS part III score in the "off" state is:

a. at least 20 units

b. At least 25% or 10 units increase in the "on" state.

14. At the time of screening, the subject had a predictable "off" period defined as a 1 or 2 score for the complexity of the MDS-UPDRS part IV B (motor fluctuation) item 4.5 motor fluctuation.

15. When screened, part IV B, with MDS-UPDRS, item 4.3 (time in "off" status) scores ∈1.

16. The hemoglobin level must be above the lower limit of the laboratory normal reference range.

17. Can and is willing to follow an agreement including the completion of a diary, and availability of all scheduled study visits, data and blood sample collection times.

Selection of dosage

The initial dose of IPX203 was selected based on previous PK data obtained from an advanced PD patient using IPX203 and IR CD-LD. The IPX203 dose is intended to reach a peak LD concentration comparable (about 20%) to the subject's corresponding dose of IR CD-LD. It is estimated that an LD dose of about 270 to 360mg from IPX203 will provide a peak LD concentration comparable to the peak LD concentration of 100mg LD from IR CD-LD.

The first morning dose of IPX203 recommended on day 1 is based on the subject's pre-study IR CD-LD morning dose; the ID CD-LD of 100mg unit dose was converted to IPX203 of 360mg unit dose as described in Table 1 above. As described in table 2, the subsequent doses of IPX203 during the day are based on the subject's most frequent pre-study LD dose in the afternoon and evening (noon to bedtime), which converts the LD 100mg unit dose in IR CD-LD to LD 270mg in IPX203 in a dose-scale manner. This study allowed the evaluation of IPX203 unit doses of 270mg and 360mg as an alternative conversion to IR CD-LD for unit doses of 100 mg. The estimated IPX203 dosing regimen was 3 times a day, about every 7 to 8 hours.

The initial IR CD-LD dosing regimen was the same as the subject's pre-stabilization regimen (unless he/she took a single daily bedtime dose of CR CD-LD, either alone or in combination with IR CD-LD, in which case the CR CD-LD dose was stopped and replaced with a 1:1mg equivalent IR CD-LD dose).

The study staff can adjust the IPX203 and IR CD-LD dosage regimen for optimal efficacy, tolerability and safety during the first 9 days of each treatment cycle. The study drug regimen should remain stable from day 10 to day 15 of each treatment cycle with no dose adjustments.

At each scheduled clinical visit (day 1 and day 15 of each treatment cycle), the subject had fasted at least 8 hours when arriving and stopped taking study medication from 10 pm (day 1 and 3 visits) or at least 5 hours (2 and 4 visits) before the day. Coffee, tea, water and fruit juices are allowed to be used up to 1 hour prior to administration. All study drugs were administered using 240mL of room temperature water. The subject is instructed to swallow the study drug intact without crushing or chewing. About 1 hour after administration, a low protein breakfast was provided at the study site. Lunch was provided at least after 4 hours, and dinner was available. Snack foods are allowed to be eaten, but not within 1 hour after morning dosing.

During the home dosing phase between clinical visits, there is no restriction on the diet.

The two treatment cycles are separated by a washout period of about 1 week.

Blood samples (6 mL) were collected by direct venipuncture or IV catheter for measuring LD and CD plasma concentrations at the following nominal times:

Day 1 of each treatment cycle: pre-and post-dosing for 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 5.5, 6, 6.5, 7, 7.5 and 8 hours.

Day 15 of each treatment cycle: pre-and post-dosing for 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8 and 10 hours.

The subjects completed the PD diary on the last 3 days before returning to the clinic on the 1 st, 2 nd and 4 th visits. Each entry in the diary indicates that the subject's dominant motor state for the next 30 minutes is one of the following 5 states:

"Guanyu"

"open-term", no dyskinesia

"open-term", trouble free movement disorders

"open-term", troublesome dyskinesia

Sleep-on device

The motion state is defined as follows:

an "open period" is defined as a state in which a subject's medication provides benefits in terms of mobility, slowness, and stiffness.

"off-phase" is defined as a state in which the drug has been pharmacodynamic and no longer provides benefits in terms of mobility, slowness and stiffness.

Dyskinesia is defined as involuntary twisting and rotational movement that acts as a drug and occurs during the "open" time.

The trouble-free movement disorder does not interfere with the function or cause meaningful discomfort.

The troublesome dyskinesia interferes with function or causes meaningful discomfort.

The "good opening period" is defined as the "opening period" without movement disorder plus the "opening period" accompanied by no trouble movement disorder.

The MDS-UPDRS scale includes 4 parts: a first part (non-exercise experience of daily life); a second part (exercise history of daily life); part III (real-time exercise examination) and part fourth (exercise complications). The first, second and fourth portions are questionnaires completed by the subjects and describe their last week history. For each treatment, MDS-UPDRS fractions I, II, III and IV were administered at the time of screening (when the subject was in the "open" state) and prior to dosing on day 15. The MDS-UPDRS part III is also administered at the time of screening when the subject is in the "off" state.

The subject wears the Kinesia 360 sensor on the wrist and ankle of the subject's most affected side 3 days before returning to the 1 st, 2 nd and 4 th visits. The subject is required to wear the Kinesia 360 sensor immediately after waking up until sleeping in bed, except during a shower, bath or swimming.

The eligible treatment blindness grader (a researcher or clinical staff trained in the assessment of the state of motion) assessed the state of motion of the subject 1 hour and 0.5 hour prior to dosing, just prior to dosing, and every half hour to 8 hours on day 1 and 10 hours on day 15. The subject's state of motion is reported as one of the 5 states signed above and the "good open time" is calculated.

The MDS-UPDRS part III was administered on days 1 and 15 prior to dosing, and up to 8 hours (day 1) and 10 hours (day 15) per hour after dosing. Section III includes 18 items including speech, facial expression, stiffness, finger strokes, hand movements, supination-supination hand movements (motion-supination hand movement), toe strokes, leg mobility, lifting from a chair, gait freezing, postural stability, posture, general spontaneity of movements, hand postural tremors, hand movement tremors, resting tremor amplitude (limbs, lips/chin) and constancy of resting tremors, each score being 5 points (normal to severity); it also includes movement disorder affecting problems.

All pharmacokinetic analyses were performed according to the FDA 2003 guidelines for bioavailability and bioequivalence studies.

Non-atrioventricular method (noncompartmental method) for estimating T of LD and CD _max 、C _max 、AUC _t 、AUC _∞ Ke and t _1/2 (Phoenix WinNonlin,6.4.0 edition). By estimating AUC respectively _0-2 、AUC _2-8 And AUC _8-∞ To evaluate the extent of LD exposure between day 1 extrapolated to infinity for 0-2 hours, 2-8 hours, and 8 hours. The partial AUC (AUC) between day 15, 0 to 2 hours and 2 to 10 hours was estimated _0-2 And AUC _2-10 ). Furthermore, linear interpolation between adjacent time points was used to estimate plasma LD concentration to C for each treatment _max Time to 50% and 430ng/mL, LD plasma concentration exceeding C _max 50% and 430ng/mL duration. Bioavailability was calculated as dose normalized AUC for IPX203 and IR CD-LD _∞ Arithmetic mean ratio of values. Normalized IPX203 data were normalized to 280mg LD and 70mgCD, normalized IR CD-LD was normalized to 100mg LD and 25mg CD. Cumulative calculated AUC on day 15 _tau AUC with day 1 _tau The ratio, where the tau value on day 1 (dosing interval) is the same as the tau value on day 15. Within 10 hours of pharmacokinetic assessment on day 15, the fluctuation index was calculated as (C _max -C _min )/C _avg 。

Bioequivalence of IPX203 relative to IR CD-LD reference treatment was assessed using a mixed effect anova that included treatment, cycle and sequence as fixed effects, with subjects as random effects within the sequence.

Parkinson's disease diary data (day 12-14)

The primary efficacy parameter of this study is the average "off period" time percentage during the awake hours of the subject PD diary collected at the end of each treatment cycle. For each of the 3 days (days 12-14) that the subject recorded diary data, the total "off" time was calculated by summing the half-hour interval number of the "off" examined. The "off period" time percentage is calculated as the "off period" total time divided by the total time that it has not fallen asleep (i.e., the awake hours). The average "off period" time percentage for each subject is the average of the 3 day "off period" time percentages. The primary endpoints between treatments were compared using mixed effect ANOVA, which included treatment, cycle and sequence as fixed effects, subjects within sequence as randomized effects. Summary statistics (mean, standard deviation, median, minimum, maximum) are provided, as well as LS mean, SD and p values and 95% CI. The average "off-period" time results during the awake hours, as well as the number of subjects treated (%), are also clearly presented.

The performance of the secondary PD parameters included summary statistics, class presentation, and ANOVA treatment comparisons (LS represents differences, SD, p-values, and 95% CIS) for the following:

average total time per motion state

Normalized average total "off-period" and "good on-period" times for 16 awake hours (calculated as the ratio of hours in a particular state to awake hours multiplied by 16)

Average number of clinical (motor) fluctuations (defined as the change from "on" to "off" and vice versa)

The average duration of the "good open" state and the average duration of any "open" state.

In addition, the results of several minor parameters were explicitly summarized per treatment and compared using Fisher's exact test:

proportion of subjects in "open" or "closed" state after waking from night sleep

Subject proportion of at least 0.5, 1, 1.5, 2, 3 and 4 hours decrease in "off time" compared to baseline. The baseline "off period" time is the average "off period" time 3 days prior to visit 1.

MDS-UPDRS changes from screening to pre-dose (sections I, II, III and IV)

The mean MDS-UPDRS I, II, III, IV, II +III fractions and total fractions for each treatment were summarized at screening (when subjects were in "open" status) and prior to 15 days of dosing. The mean MDS-UPDRS part III scores were also summarized at the time of screening when the subjects were in the "off" state. Pre-dose scores for each MDS-UPDRS fractions were compared on day 15 by treatment using mixed effect ANCOVA with treatment, cycle, order as fixed effect, baseline (screening) values as covariates and subjects within order as randomized effects.

Results of individual MDS-UPDRS part IV questions were also presented using summary statistics (absolute and screening value changes) and treatment comparisons using ANCOVA-like. Also included is a categorical presentation of the subject's proportions showing each absolute or varying score.

Kinesia 360 sensor data

Kinesia 360 sensor data (tremor, dyskinesia, and mobility) were summarized by treatment using summary statistics and compared between treatments using mixed effect ANOVA, where treatment, cycle, and order are fixed effects and subjects are randomized effects within the order. The following parameters are reported:

tremor-total wear time, total tremor time, percent tremor time (percent of total wear time), number of tremor subjects (%);

dyskinesia-dyskinesia time, percent dyskinesia time, number of dyskinesia subjects (%);

mobility-rest time percentage, last activity (non-gait) time, gait time percentage, total activity time percentage, arm swing during gait percentage, wear time steps per hour.

Investigator assessment of subject exercise status (day 1 and day 15)

If the subject received rescue medication or stopped the study assessment, all subsequent motor status assessments on day 1 were assigned an "off" value for analysis.

The study investigators summarized the assessment of subject motor status on days 1 and 15, including summary statistics, class presentation, and ANOVA treatment comparisons (LS representing differences, SD, p-values, and 95% cis), as follows:

total time per motion state

Time to reach first "open" and "good" states

Furthermore, the results of several parameters were summarized explicitly according to treatment and compared using Fisher's exact test-proportion of subjects in "off" or "good on" state at time points.

MDS-UPDRS part III (sports inspection)

The MDS-UPDRS part III score is summarized in terms of treatment for each time point (1 day before dosing, 1-8 hours after dosing, 1-10 hours before dosing and 15 days after dosing). Post-dose scores were compared by treatment using a mixed effect covariance analysis (ANCOVA), where treatment, cycle, order were fixed effects, baseline (day 1 pre-dose) values were covariates, and subjects were randomized effects in order. Average MDS-UPDRS part III scores after dosing on day 1 and day 15 are also summarized and compared against treatment by using a similar ANCOVA model. Pre-dosing scores were compared by treatment using mixed effect ANOVA, where treatment, cycle and order were fixed effects and subjects were randomized effects within order.

Similarly, the mean change in MDS-UPDRS part III scores from day 1 before dosing was summarized at time points and overall (throughout the evaluation period) after dosing every hour from day 1 and day 15, and compared by treatment using the ANCOVA model, with treatment, cycle and order being fixed effects, baseline (pre-dosing day 1) values being covariates, subjects in order being randomized effects.

The results of the bradykinesia problem (questions 4 to 8 and 14) on the MDS-UPDRS part III scale were summarized as mean change from day 1 before dosing at each evaluation time and mean after dosing. For questions 4 through 8, the left and right sides were evaluated; the left and right scores are added before analysis. The results are summarized as bradykinesia score and are individually for each question. These data were compared by treatment using the mixed effect ANCOVA, where treatment, cycle and order are fixed effects, baseline (day 1 pre-dose) values are covariates, and subjects within order are randomized effects.

Day 1 and day 15 summarize the mean improvement duration of MDS-UPDRS fraction III scores from day 1 pre-dose scores of at least 4, 7, and 13 units by treatment and provide a categorical presentation of subject proportion with specific effect duration. The duration of the effect was compared in terms of treatment using a mixed effect anova, where the treatment, cycle and sequence were fixed effects and the subjects within the sequence were randomized effects.

To determine the duration of the effect, an intermediate point between two adjacent time points is used. For example, if the subject has no 4 units improvement in the MDS-UPDRS part III evaluation 1 hour after dosing, but has an improvement in the evaluation 2 hours after dosing, and lost 4 units at the evaluation 3 hours, the duration of the effect is treated as hours using the interpolated time value.

Demographics of subjects enrolled in the study were as follows:

	random (N=28)	Completer (N=27)
			Age (year)	66.4±10.1	65.9±9.8
Height (cm)	169.7±10.3	169.8±10.4
			Weight (kg)	83.0±18.7	83.4±18.9
Body mass index (kg/m) ² )	28.9±6.7	29.0±6.8
			Sex, n (%)
Male men	16(57.1％)	16(59.3％)
			Female woman	12(42.9％)	11(40.7％)
Race, n (%)
			White race	26 person (92.9%)	25(92.6％)
Others ^a	2(7.1％)	2(7.4％)

^a One subject was african americans, caucasians and asians; one subject was spanish and american indian

Baseline disease characteristics and treatment history of subjects in the study were as follows:

note that: unless otherwise indicated, the values are mean ± SD.

The pre-study distribution of daily LD doses at dosing frequency is shown in the following table:

as shown in the above table, most subjects received 4 IR CD-LD doses per day, with a total daily LD dose ranging from 400 to > 1250mg. The maximum total daily dose of LD was 1550mg. In addition, 8 subjects received a single dose of 200mg of CR CD-LD at bedtime.

On day 1, the mean LD first dose of IR CD-LD was 1593 mg, IPX203 was 573mg, and prior to day 1 administration, the median LD plasma concentration of IR CD-LD was 43ng/mL, IPX203 was 41ng/mL. The following table summarizes the pharmacokinetic values on day 1.

The main parameters of LD on day 1 are:

^a N＝26.

^b relative to IR CD-LD.

Note that: values are mean.+ -. SD, except T _max Which is the median value (min-max). The dose shown is LD; CD and LD were present in a fixed ratio of 1:4 in each treatment. All dose levels refer to the first dose on the day.

The mean levodopa plasma concentration profile on day 1 prior to rescue treatment is shown in figure 1.

The secondary parameters on day 1 of LD are:

note that: duration value is mean ± SD; the time to reach the value is the median (min-max).

Dose normalized LD parameters were:

^a n=26. Subject nos. 110-008 did not calculate AUC due to insufficient data points _∞ 。

Note that: for IR CD-LD, the values were normalized to 100 mg LD, and for IPX203, the values were normalized to 280 mg LD. The values are mean.+ -. SD.

Mean dose normalized LD plasma concentration profiles on day 1 prior to rescue treatment are shown in figure 2.

The LD portion AUC value is:

^a n=26, because the value cannot be estimated reliably in 1 subject after IR CD-LD.

^b N=25, because the values could not be estimated reliably in 1 subject after IR CD-LD and in 1 subject after IPX 203.

Note that: reported data are ratios of the test/reference ln-converted dose normalized geometric mean expressed as percentages and 90% ci. All data were normalized to 100 mg LD.

The main parameters on day 1 of CD are:

/>

^a N＝26； ^b N＝20； ^c relative to IR CD-LD; ^d N＝19； ^e N＝5； ^f N＝7； ^g N＝6

the mean CD plasma concentration profile on day 1 prior to rescue treatment is shown in figure 3.

CD dose normalization parameters were:

^a N＝26； ^b N＝20

note that: the values are mean.+ -. SD. PK parameters for IR CD-LD were normalized to 25mg CD and ipx203 was normalized to 70mg CD.

On day 15, in the clinic of the stable dosing regimen, the mean (. + -. SD) LD administered was 159.+ -. 46.1 for IR CD-LD and 560.+ -. 206.2 for IPX203 (first morning dosing), and the median time for the first re-dosing of IR CD-LD and IPX203 was 4.0 and 7.0 hours, respectively. Prior to day 15 dosing, the median LD plasma concentration of IR CD-LD was 34ng/mL and the median LD plasma concentration of IPX203 was 327ng/mL.

The mean LD plasma distribution after each treatment on day 15 throughout the 10 hour evaluation is shown in figure 4.

Pharmacokinetic values on day 15 are summarized in the table below.

The main parameters of LD on day 15 are:

Parameters (parameters)	IPX203	IR CD-LD
			(N＝27)	All doses	All doses
C _max (ng/mL)	2768±1259	2357±1179
			T _max (h)	1.5(0.5-6.0)	0.5(0.5-2.0)
AUC _tau (ng·h/mL)	11214±4887	3879±1744
			Dose level 1 (n=7)	283mg (mean)	100mg
C _max (ng/mL)	1468±383	1217±371
			T _max (h)	2.0(0.5-4.0)	1.0(0.5-1.5)
AUC _tau (ng·h/mL)	6497±1996	2362±449
			Dose level 2 (n=10)	576mg (mean)	150mg
C _max (ng/mL)	3116±1281	2489±1169
			T _max (h)	1.5(0.5-6.0)	0.5(0.5-1.5)
AUC _tau (ng·h/mL)	12016±4670	3862±1916
			Dose level 3 (n=8)	698mg (mean)	200mg
C _max (ng/mL)	3100±1005	2730±901
			T _max (h)	1.3(0.5-3.0)	0.8(0.5-2.0)
AUC _tau (ng·h/mL)	13455±4890	4662±1376
			Dose level 4 (n=2)	900mg (mean)	250mg
C _max (ng/mL)	4250±382	4195±417
			T _max (h)	2.3(2.0-2.5)	0.5(0.5-0.5)
AUC _tau (ng·h/mL)	14748±2466	6148±549

Note that: values are mean.+ -. SD, except T _max Which is the median value (min-max). The doses shown are LD; CD and LD were present in a fixed ratio of 1:4 in each treatment. Subjects were grouped into dose levels (1-4) according to their LD dose (100, 150, 200, or 250 mg) during the IR CD-LD treatment period. The mean IPX203 LD dose of the first dose is provided for each dose level.

The secondary parameters on day 15 of LD were:

/>

note that: duration values are mean ± SD. Duration values are estimated over the entire available concentration-time curve (10 hours). Subjects were grouped into dose levels (1-4) according to their LD dose (100, 150, 200, or 250 mg) of IR CD-LD during the IR CD-LD treatment period. The mean IPX203 LD dose of the first dose is provided for each dose level.

Dose normalized values on LD day 15 were:

note that: for IR CD-LD, values were normalized to 100mg LD, for IPX203, values were normalized to 280mg LD LD accumulation, fluctuation, and time invariance parameters:

^a N＝26

note that: the cumulative ratio was calculated as AUC on day 15 _tau AUC with day 1 _tau Tau on day 1 (dosing interval) was assigned the same as tau on day 15.

The fluctuation index was calculated as (C) within the 10-hour evaluation period _max -C _min )/C _avg 。

Time invariance was calculated as AUC on day 15 _tau AUC with day 1 _∞ Is a ratio of (2).

The main parameters on day 15 of CD are:

/>

note that: values are mean.+ -. SD, except T _max Which is the median value (min-max). The doses shown are LD; CD and LD were present in a fixed ratio of 1:4 in each treatment. Subjects were grouped into dose levels (1-4) according to their LD dose (100, 150, 200, or 250 mg) of IR CD-LD during the IR CD-LD treatment period. The mean IPX203 LD dose of the first dose is provided for each dose level.

The mean CD plasma profile after each treatment on day 15 throughout the 10 hour evaluation is shown in figure 5.

Dose normalized values on day 15 of CD were:

note that: for ER CD-LD, the values were normalized to 25mg CD, and for IPX203, the values were normalized to 70mg CD. CD accumulation, fluctuation and time invariance parameters were:

^a N＝26； ^b N＝20

The fluctuation index was calculated as (C) within 10 hours PK evaluation _max -C _min )/C _avg 。

Results of curative effects

The results of the main efficacy parameter "off" time as a percentage of awake hours measured from PD diary data at days 12-14 of each treatment cycle were:

the above data indicate that subjects experience significantly less "off-period" time as a percentage of awake hours, with an average of 19.3%, than 33.5% of treatment with IR CD-LD with IPX 203.

The PD diary data is summarized as follows:

note that: screening data was collected on days-3 to-1. Positive treatment data collected on days 12-14 of each treatment cycle. The mean represents the average time per day that the subject reported to be in a particular exercise state during a 3-day acquisition period.

"good open" time = "open" time without movement disorder + an "open" time with no troublesome movement disorder.

MDS-UPDRS part I-IV (day 15 before administration)

Each treatment, MDS-UPDRS fractions I, II, III and IV were administered at screening (when the subject was in "open" status) and prior to dosing on day 15. MDS-UPDRS part III is also administered at screening when the subject is in the "off" state. Sections I, II and IV contain questions asking the subject for retrospective experiences of the past week. Part III is a real-time exercise examination performed by the researcher to assess the exercise signs of PD.

When the pre-dose mean MDS-UPDRS parts I-IV were scored (LS mean difference between treatments) on day 15 according to treatment comparisons, scores for part III (-8.1 [25.3], p=0.0272), part IV (-1.6 [3.09], p=0.0109), part ii+iii (-9.0 [26.9], p= 0.0213) and MDS-UPDRS total (-11.5 [30.9], p=0.0116) were significantly lower during IPX203 treatment than during IR CD-LD treatment, indicating less PD damage. The results of parts I and II show no significant treatment differences. The mean part III score for all subjects in the "off" state was 42.6 at the time of screening; the average score on day 15 was 41.6 during IR CD-LD treatment, while the average score dropped to 33.5 during IPX203 treatment (LS mean difference-8.1 [25.0]. P=0.0025).

On day 1, the average pre-drug MDS-UPDRS part III scores for both treatments were similar (IPX 203 and IR CD-LD 42.8 and 41.4, respectively), reflecting the pre-drug "off" status, and subjects did not take PD medication since 10 pm before the day.

At the time points of 1 hour and 2 hours, during both IPX203 and IR CD-LD treatments, MDS-UPDRS part III scores were significantly reduced from pre-dose values, with no significant differences between treatments. From 3 to 8 hours post-dose, IPX203 correlated with a significantly greater decrease in MDS-UPDRS part III score compared to IR CD-LD. At the time point of 7 hours post-dose, treatment with IPX203 correlated with an average improvement of almost 10 units, versus a deterioration of 0.2 units of IR CD-LD. The mean MDS-UPDRS scores of subjects for the IPX203 and IR CD-LD treatment cycles were reduced by 19.3 points and 8.4 points, respectively, over the 8 hour period following dosing. The following is a summary of the changes in the score of MDS-UPDRS part III prior to day 1 dosing:

And (3) injection: the post rescue value on day 1 was entered as the pre-dose value.

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 units improvement). Improvements in at least 4 MDS-UPDRS part III units represent minimal changes that are clinically significant to the patient. On day 1, the total duration of the pharmacodynamic effect of the subject during IPX203 treatment was significantly longer than IR CD-LD treatment according to the minimum improvement threshold of at least 4, 7 and 13 MDS-UPDRS part III units, as shown in the summary table below:

note that: the post rescue value on day 1 was entered as the pre-dose value.

A plot of day 1 mean MDS-UPDRS, part III, is shown in FIG. 6.

Prior to day 15 dosing, mean MDS-UPDRS part III scores (33.5) were significantly lower during IPX203 treatment than during ID CD-LD treatment (41.6) when subjects were not receiving study treatment for at least 5 hours. The clinical effects of IPX203 persist until the second morning. During the 10 hour assessment period following day 15 dosing, subjects see an improvement in pre-dosing scores from day 1 with both treatments, as summarized in the following table:

^a these values reflect the change from day 1 to day 15 before dosing

And (3) injection: no values were entered after the 15 th day of re-dosing.

The minimum improvement threshold analysis of MDS-UPDRS part III scores showed that the total improvement duration for both treatment groups was similar, at least 4 and 7 units, but the total improvement duration for IPX203 was significantly longer, at least 13 units.

Figure 7 shows mean LD plasma concentrations for treatment following a single dose on day 1 and time course of change in MDS-UPDRS part III scores from mean baseline. Figure 7 shows good agreement between LD plasma concentration curves and responses assessed by changes in MDS-UPDRS part III scores. The initial decrease in MDS-UPDRS part III scores from the mean baseline (corresponding to improvement in motor symptoms) was comparable between the two treatments. However, the decrease in MDS-UPDRS part III score was sustained for a longer duration after IPX203 treatment than after IR CD-LD treatment. The time at which the maximum decline in MDS-UPDRS part III score from the mean baseline occurs lags behind the time of peak LD plasma concentration for the particular treatment.

Figure 8 shows the time course of mean LD plasma concentration and MDS-UPDRS part III score change from mean day 1 pre-dose following day 15 treatment of a subject's stable dosing regimen. Before day 15 dosing, IPX203 treatment showed a mean decrease in MDS-UPDRS part III score (-9.3) greater than IR CD-LD treatment (+0.1). Figure 8 shows good agreement between LD plasma concentration profile and MDS-UPDRS part III score change. The initial rate of improvement of motor symptoms between the two treatments was comparable. However, the improvement in MDS-UPDRS part III score persists for a longer duration after IPX203 treatment compared to IR CD-LD, which results in subjects requiring less frequent IPX203 dosing than IR CD-LD.

Among all therapeutic and pharmacodynamic measures, IPX203 treatment clearly shows advantages over IR CD-LD and its usefulness in alleviating PD symptoms. Subjects experienced significantly less "off" time as a percentage of their awake hours (19.3% mean compared to 33.5% with IR CD-LD) with IPX203 treatment. Furthermore, subjects treated with IPX203 had significantly more total "good open-time" compared to IR CD-LD, whether measured off-site by the subject with a home diary or by clinical researchers. Based on patient diary entries, the average duration of the "good onset" episodes or any "open phase" episodes with IPX203 is significantly longer compared to IR CD-LD. Treatment with IPX203 was associated with significantly less daily movement fluctuations compared to IR CD-LD. During IPX203 treatment, the subject was 73.3% less likely to receive rescue medication than during IR CD-LD treatment (day 1), 72.1% less likely to receive the second dose of treatment (day 15).

The improvement in MDS-UPDRS part III mean scores was significantly greater in subjects receiving IPX203 than in subjects receiving IR CD-LD 3 to 8 hours after dosing on day 1 and 2 to 4 hours after dosing on day 15. On day 15, when subjects did not receive study treatment for at least 5 hours, the mean pre-dose part III score was significantly reduced during the IPX203 treatment period, allowing the clinical effect of IPX203 to continue to the next morning.

According to the study's assessment of the subject's motor status, the average time to reach the first "open period" was similar during each treatment period following the first dose on day 1 and during steady state dosing following the first dose on day 15. On day 15, the average subjects became "open" about 10 minutes (0.17 hours) faster during IPX203 treatment compared to IR CD-LD treatment, and 44% of subjects during IPX203 treatment, and 26% of subjects experienced their first "open" during IR CD-LD treatment, 0.5 hours after dosing.

The assessment of the subject's motor status was performed by a rater blinded to the study treatment. The study's evaluation on day 1 is summarized below:

note that: the value is input as "off period" after the rescue on day 1 "

The proportion of subjects in the "on" or "off" state during the first 30 minutes after waking from night sleep is determined from the subject PD diary entry as follows:

/>

the p-values in the above wakefulness table are based on Fisher's exact test, analysis did not take into account the cross-properties of the study design.

The above data for the first 30 minutes after waking show that IPX203 improves the duration after waking from night sleep.

Example 9

The dosage form described in example 5 was administered to 25 subjects with advanced PD in a randomized, open-label, rater blinded, multi-center, 3-treatment, 3-cycle single dose crossover study. Subjects were randomized into 1 out of 3 dosing sequences: receive the composition of example 5 ("IPX 203"), commercially available CD-LD sustained release capsule productAnd the trade name->Is a commercially available immediate release CD-LD ("IR CD-LD") tablet. Subject at each study treatmentThree out of a single dose are reported to the study clinic with a one week washout period between visits. The subject may continue to take IR CD-LD between study visits. The subject was diagnosed in a fasted state and the last dose of IR CD-LD was taken 10 pm later than the previous day. Following administration, a subject experiencing an "off" state of ≡3 consecutive hours may receive rescue medication comprising his/her usual IR CD-LD medication dose or combination rescue comprising IR CD-LD. If the rescue medication is administered, no further pharmacokinetic or pharmacodynamic measurements are taken at the time of the visit and the subject may leave the clinic. Otherwise, the subjects remain in the clinic for final evaluation 10 hours after the study treatment dose. / >

To qualify for this study, subjects diagnosed with advanced PD with motor fluctuations are receiving IR CD-LD.

The subjects received the IPX203 randomly according to the guidelines provided in the following table, according to their usual IR CD-LD dose in the first morning prior to the study,IR CD-LD composition:

TABLE 3 Table 3

CD and LD were present in a fixed ratio of 1:4 in each intensity and treatment

The inclusion criteria were similar to those provided in example 8, except that the maximum LD total dose per day prior to the study was 1600mg, rather than 1800mg allowed in example 8.

The subjects received a single oral dose for each of the three study treatments in a randomized order based on the pre-study morning dose of IR CD-LD of the subjects as described above. IPX203 and also selectDosage to provide estimated peak LD plasma concentration at IR CD-LD dosage ± 20%Peak LD plasma concentration within the range.

All subjects were given a single oral dose of 240 ml room temperature water in a scheduled clinical trial after stopping LD and fasting for at least 8 hours at 10 pm on the previous day and instructed to swallow the study drug in its entirety in the morning without crushing or chewing. Coffee, tea, water and fruit juice are allowed at most 1 hour prior to administration. Breakfast containing about 5 grams of protein was provided about 1 hour after administration.

The pharmacokinetics was determined by the procedure outlined in example 8. Pharmacodynamics was measured by investigator assessment of subject locomotor state outlined in example 8 at 1 hour, 0.5 hour, pre-and every half hour post-dosing, and by using MDS-UPDRS part III locomotor exam outlined in example 8.

The demographics of the subjects of the study were as follows:

note that: unless otherwise indicated, the values are mean ± SD

The LD doses for subjects receiving all three treatments were ID CD-LD 168.0mg, IPX203 586.8mg and538.2mg. The mean LD plasma curve for each treatment is shown in fig. 9, with the following primary LD pharmacokinetic values:

/>

values are mean.+ -. SD, except T _max Which is the median value (min-max). The doses shown are LD; CD and LD were present in a fixed ratio of 1:4 in each treatment.

^a Calculation with respect to IR CD-LD

The secondary LD pharmacokinetic values are as follows:

duration values are mean ± SD: the time to reach the value is the median (min-max).

One subject (number 108-001) completed the study, but no plasma concentrations were obtained after any treatment.

Dose normalized LD pharmacokinetic values were as follows:

/>

the values were normalized to the lowest dose per treatment, namely 100mg LD (IR CD-LD), 360mg LD (IPX 203) and 340mg LD The values are mean.+ -. SD.

Dose normalized natural log-transformed AUC based relative to IR CD-LD _0-∞ The LD bioavailability of (C) after IPX203 (85.5%) is higher than that after IPX203After that (71.8%). The bioavailability of LD is as follows:

reported data are ratios of the test/reference ln-converted dose normalized geometric mean expressed as percentages and 90% confidence intervals.

The LD dose normalized partial AUC values are as follows:

Abbreviations: AUC (AUC) _0-2 Area under concentration-time curve of 0 to 2 hours after administration; AUC (AUC) _2-8 Area under concentration-time curve between 2 hours and S hours after dosing; AUC (AUC) _8-∞ Extrapolated from 8 hours to the area under the infinite concentration-time curve.

Mean AUC for all four dose levels _2-8 And AUC _8-∞ Examination of the values shows that LD exposure after IPX203 is higher thanThis supports higher bioavailability of IPX203 and prolonged plasma LD concentrations.

The mean CD plasma curve for each treatment is shown in fig. 10, with the following primary CD pharmacokinetic values:

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values are mean.+ -. SD, except T _max Which is the median value (min-max). AUC (AUC) _0-∞ From AUC _t And (5) value estimation.

^a Calculation of bioavailability relative to IR CD-LD。

Dose normalized CD pharmacokinetic values were as follows:

the values are mean.+ -. SD. PK parameters were normalized to the lowest dose per treatment, namely 90mg CD (IPX 203), 25mg CD (IR CD-LD) and 85mg CD

Dose normalized natural log-transformed AUC based relative to IR CD-LD _0-∞ The CD bioavailability of (C) after IPX203 (112%) is higher than that after IPX203After that (55%). The bioavailability of CD is as follows: />

The reported data is the ratio of the test/reference dose normalized ln-transformed geometric mean expressed as a percentage and 90% confidence interval.

The eligible clinical staff blinded to treatment assessed the locomotor status of each subject at 1 hour and 0.5 hour prior to dosing and at the moment of dosing and every 30 minutes after dosing by measuring periods every 10 hours. The mean total hours for each awake state of motion assessment is presented as treatment in fig. 11. The Least Squares Mean (LSM) "off period" time IPX203 in the subject's motor status assessment was 4.52 hours and IR CD-LD was 7.23 hours, indicating that IPX203 has a significant advantage of 2.7 hours (p <0.0001). And (3) withIn comparison (p=0.023), +.>The LSM "off period" time of 5.41 hours, reflecting the advantage of 0.9 hours for IPX 203. During the IPX203 treatment, with an increase in the good open time, there was an average of 2.56 hours more than IR CD-LD than +.>For 0.85 more hours (p < 0.0001 and p=0.259, respectively). Only two subjects had "open-term" troublesome dyskinesias (one human subject was in IPX203[4.5 hours]And IR CD-LD [0.5 hours ]]During treatment another subject is at +.>Treatment [3.5 hours]During which time).

The MDS-PDRS part III scores were assessed by measuring periods of time every 10 hours 1 hour and 0.5 hour prior to dosing, immediately prior to dosing, and every hour after dosing. Analysis of covariance was performed from mean changes in the third fraction of pre-dose MDS-UPDRS over a 10 hour measurement period, with the value of the third fraction of pre-dose MDS-UPDRS as a covariate.

After IPX203 treatment, in the overall change from baseline as shown in fig. 12, compared to IR CD-LD (-12.70 vs. -6.62, p)<0.0001 And also withSubjects showed significantly greater improvement (decrease) in score from MDS-UPDRS part III prior to mean dosing over 10 hours compared to (-12.75 vs.9.33, p=0.0333). When these differences were examined hour by hour, the results of administration of IPX203 and IR CD-LD at 3 to 10 hours were significantly different (p values all.ltoreq.0.029). MDS-UPDRS part III score 3 to 5 hours post-dose compared to IR CD-LDIs associated with a significantly larger variation (p values all +.0.0042). IPX203 and->The results were significantly different after 5 to 10 hours of administration (all p values +.0.0352), except 7 hours.

Based on the results of section III of MDS-UPDRS, and IR CD-LD (p < 0.0001) and(p.ltoreq. 0.0290) IPX203 has a significantly longer duration of effect as measured by the duration of improvement from 4, 7 and 13 points of the pre-dose average, as shown in FIG. 13. After IPX203 treatment, 72% of subjects had at least 20% improvement in average MDS-UPDRS part III score at 5 hours post-dose compared to pre-dose, with IR CD-LD and +.>Treatment, 12% and 52% of subjects, respectively, improved by at least 20%. IPX203, IR CD-LD and +.>The proportion of subjects who improved by 35% in 5 hours was 60%, 8% and 36%, respectively.

Figure 14 shows mean LD plasma concentrations and MDS-UPDRS part III scores as a function of time from mean baseline for treatment. Figure 14 shows good agreement between PK of LD and response assessed by variation of MDS-UPDRS part III scores. The initial rate of decline of MDS-UPDRS part III scores from the mean baseline (corresponding to improvement in motor symptoms) was comparable for all three treatments. However, with IR CD-LD or In comparison, the duration of the decrease in the III-th fraction of MDS-UPDRS after IPX203 treatment was longer. The time at which the maximum decline in MDS-UPDRS part III score from the mean baseline occurs lags behind the time of peak LD plasma concentration for the particular treatment.

Example 10

The dosage form described in example 7 was administered in a single site, open label, single dose, 5 treatments, 5 cycles single dose crossover study to 40 subjects aged between 18 and 55 years, weighing at least 55kg, body mass index between 18.5 and 30.0kg/m ² Is a healthy male and female subject. Subjects will receive the following 5 treatments with 240mL room temperature water after an overnight fast of at least 10 hours:

treatment A-single 140mg levodopa and 35mg carbidopa capsules;

treatment B-single 210mg levodopa and 52.5mg carbidopa capsules;

treatment of C-single 280mg levodopa and 70mg carbidopa capsules;

treatment of D-single 350mg levodopa and 87.5mg carbidopa capsules; and

e-single 140mg levodopa and 35mg carbidopa capsules were treated.

The capsules used in treatments a-D were produced in one of the factories of bruckhai, new york, and the capsules used in treatment E were produced in one of the factories of the south of bambusa, taiwan.

The subjects were not allowed to eat until 4 hours after dosing.

Pharmacokinetic measurements were measured by the procedure outlined in example 8, blood samples were obtained before and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12 and 24 hours after dosing.

The aim of this study was to determine the dose ratio between treatments a-D and to evaluate the bioequivalence between treatments a and E.

The results of the study determined that treatments a-D were dose-proportional and treatments a and E were bioequivalent.

The mean LD pharmacokinetic values for treatments a and E are summarized below:

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n＝40

mean LD plasma curves for treatments a and E are shown in figure 15. Treatments A and E exceeded 50% C _max The average time of (a) was 4.986 hours (SD 0.9711) and 4.945 hours (SD 0.9521), respectively.

The average CD pharmacokinetic values for treatments a and E are summarized below:

n＝40

the mean CD plasma curves for treatments a and E are shown in fig. 16.

Example 11

630 PD patients with motor fluctuations were enrolled into a randomized, double-blind, active control study to compare the dosage form described in example 7 with commercially available IR CD-LD tablets (e.g.Or->Class AB imitation approved by the united states food and drug administration). In a multicentric, randomized, double-blind, double-simulated, active-control, parallel group study, the dosage form described in example 7 was administered to about 256 PD subjects. The study consisted of using commercially available IR CD-LD tablets, e.g. +. >Or a 3-week open label IR CD-LD dose adjustment period for class AB simulated pharmaceuticals approved by the united states food and drug administration; a 4 week open label period converted to the dosage form of example 7; following a 13 week double-blind treatment period, subjects were randomized, centrally stratified, receiving the dosage form of example 7 and matched IR, CD-LD placebo or IR CD-LD and matched example 7 placebo at a ratio of about 1:1.

If the subject has a record in the pre-study regimen and the dosing regimen is stable for at least 4 weeks prior to the 1 st visit, the subject is allowed to continue taking the allowable non-CD LD class PD drug throughout the course of the study. By "stable dosing regimen" is meant that the dosage or dosing frequency is unchanged.

Within 4 weeks after the screening visit, eligible subjects completed their PD diary every day for 3 consecutive days prior to visit 1.

Following visit 1, eligible subjects entered a 3 week open label IR CD-LD treatment period, allowing for dose adjustment. The dosing regimen of IR CD-LD can be adjusted during the dose adjustment period to minimize "off period" time without causing troublesome dyskinesias. The dosages and regimens of other non-CD LD PD drugs (dopamine agonists, MAO-B inhibitors, amantadine and anticholinergic drugs) in subjects remained stable throughout the course of the study. Any adjustments to the IR CD-LD dosing regimen were made after consultation with the investigator or qualified field personnel and recorded. The IR CD-LD dosing regimen was stable for at least 5 days before returning to the 2 nd visit. Rescue with additional or modified doses of concomitant PD medication or with CD-LD products other than the study medication dispensed is not allowed and results in discontinuation of the study. The subject completed his 3-day PD diary on each of 3 consecutive days prior to visit 2.

After the end of the IR CD-LD dose adjustment period, the subjects began an open label period of 4 weeks to switch to IPX203 (example 7). The initial dosing regimen of IPX203 was based on the most frequent dose of the IR CD-LD dosing regimen by the subject at the end of the dose adjustment period (visit 2). The following table outlines the recommended transformations:

it is recommended that IPX203 should be administered approximately every 8 hours except that subjects receiving a total daily dose of less than 125-500mg IR CD-LD at the end of the dose adjustment period are initially administered every 12 hours. If the subject does not reach an acceptable duration of effect, the dosing interval is reduced to about every 8 hours. The dosing regimen of IPX203 can be adjusted during the dose transition period to achieve an optimal balance of efficacy and tolerability (minimizing "off" time without causing troublesome dyskinesia or other dopaminergic side effects). The dosages and regimens of other non-CD LD PD drugs (dopamine agonists, MAO-B inhibitors, amantadine and anticholinergic drugs) in subjects remained stable throughout the study. The subject was on a stable dosing regimen (no change in dose or dosing frequency) of IPX203 for at least 5 days before returning to visit 4. Any adjustments to the IPX203 dosing regimen are made after negotiation with the researcher or qualified field personnel and will be recorded. Rescue with additional or modified doses of concomitant PD medication or with CD-LD products other than the study medication dispensed is not allowed and results in discontinuation of the study. The subject returned to the clinic for the 3 rd visit within 2 weeks, followed by the 4 th visit after 2 weeks. The subject completed a 3-day PD diary on each of 3 consecutive days prior to the 4 th visit.

506 subjects successfully completed the IPX203 dose shift period and were randomized at about 1:1 ratio at visit 4 into one of two parallel treatment groups, either IPX203 (and matched IR CD-LD placebo) or IR CD-LD (and matched IPX203 placebo). The subjects underwent a double-blind maintenance therapy of 13 weeks, with a stable dosing regimen established for IR CD-LD at the end of week 3 (visit 2) and IPX203 at the end of week 7 (visit 4). Rescue with additional or modified doses of concomitant PD medication or with CD-LD products other than the study medication dispensed is not allowed and results in discontinuation of the study. The subject returned to the clinic for 3 visits (5 th visit [ week 10 ], 6 th visit [ week 15 ] and 7 th visit [ week 20 ]) and completed a 3-day PD diary on each of the 3 consecutive days prior to each of these visits.

Criteria for inclusion

Male or female subjects diagnosed with PD at an age of > 40 years old, who meet the brain diagnostic criteria of the uk society of parkinson's disease, and are being treated with a stable CD-LD regimen, but experience motor fluctuations.

Hoehn and Yahr stages 1, 2, 3 or 4 in "open" state (part of the unified parkinson's disease rating scale [ MDS-UPDRS ] part III of the dyskinesia association version).

Montreal cognitive assessment (MoCA) score > 24 at screening visit is in the "open" state.

Based on the medical history, subjects experienced a "pharmacodynamic off-period" episode each day during the 4 weeks prior to screening, with a combination of bradykinesia periods with at least one of resting tremors or rigidity, experienced an "off-period" state after waking in most of the morning, and reported an average of at least 2.5 accumulation hours per day during the awake hours of "off-period" time.

Can distinguish between the "open" and "closed" states, as determined by at least 75% agreement with the trained grader in the 8-graded "open/closed" grading over a training period of 4 hours. Consistency must include at least 1 "on" and 1 "off" ratings and must be achieved within two 4 hours of training sessions.

At visit 1, examination of the 3-day PD diary confirmed the following: the subject can complete the diary correctly with valid entries; the subject has an average of at least 2.5 hours of "off period" time per day during 3 days of wakefulness, wherein at least 1.5 hours of "off period" accumulate per day.

In response to CD-LD therapy, treatment with CD-LD stabilization regimen is currently continued for at least 4 weeks prior to visit 1, and:

First morning administration requires at least 100mg LD from IR CD-LD;

o requires a total daily dosage of at least 400mg LD and ingests a maximum total daily dosage of 2400mg LD from IR CD-LD alone or a single daily bedtime dose combination of IR CD-LD and CR CD-LD;

o has a frequency of administration of CD-LD of 4 to 9 times per day;

according to history, an "open-term" response is typically experienced at the first dose of IR CD-LD on the day, but the efficacy of this dose typically lasts less than 4 hours.

At the time of screening, the subject had a predictable "off period" period defined as a 1 or 2 score of MDS-UPDRS part IV, part B (motor fluctuation), item 4.5 (complexity of motor fluctuation).

At the time of screening, the MDS-UPDRS part III score in the "off" state is at least 20 units.

Exclusion criteria

Within 4 weeks prior to visit 1, any dose of Controlled Release (CR) CD-LD was used, except for a single daily bedtime dose.

Any dose used before visit 1For 4 weeks, or for therapeutic or safety reasons, is considered +.>And fail.

Neurosurgical treatment of PD was received or such surgery was planned or expected to be performed during the study period.

Allergy to any excipients in the study drug.

History of glaucoma, although properly managed, elevated intraocular pressure.

There is a history of seizures or seizures, at least 1 seizure has been experienced in the last 12 months, or no medical advice therapy or visit has been followed.

A history of myocardial infarction with residual atrial, nodular or ventricular arrhythmias, and not controlled by medical and/or surgical intervention. Recent (12 months or less) history of myocardial infarction secondary to arrhythmia is exclusive, regardless of treatment control.

Received within 4 weeks of screening or scheduled dosing during participation in the clinical study:

o any dose of CR CD-LD-any dose except for a single bedtime dose per dayAdditional CDs (e.g.)>) Or benserazide (e.g.)>) Or catechol-O-methyltransferase inhibitors (entacapone or tolcapone) or medicaments containing these inhibitors>

O non-selective monoamine oxidase inhibitors (MAOI), apomorphine or anti-dopaminergic drugs, including antiemetics.

O subjects previously enrolled in the IPX203 study.

Evaluation criteria:

two types of baselines were used in the evaluation, either a study entry baseline (study entry visit) at visit 1 or a double-blind baseline defined as the evaluation at visit 4 (random visit).

The primary secondary endpoints of the following subgroups were examined:

age: <65 years old, at study entry ≡65 years old

Gender: male and female

Race of race: white race, non-white race.

In addition, the following subgroups were also examined:

region: north America or Europe

Race: spanish, non-spanish or unknown

Concomitant drug: the following non-exclusive subgroups are defined for subjects taking the following categories of concomitant medications:

amantadine (o)

O selective MAOB inhibitors

Anticholinergic PD medicine

O dopamine agonist

O other

Weight: <75kg or more than 75kg

Body Mass Index (BMI):<25kg/m ² or not less than 25kg/m ²

PD duration at screening: less than 8 years or more than or equal to 8 years

Age of onset of PD: less than 65 years old or equal to or greater than 65 years old

Study "good open time" at entry: < 9 hours per day or more than 9 hours per day

The "off period" time at study entry: average <6 hours per day or ≡6 hours per day.

Drug effect:

the main end points are as follows: at the end of the double-blind treatment period (visit 7 or premature termination), the change in "good open" time, in hours per day, averaged over the PD diary days, compared to baseline. The "good open" time originates from a 3 day PD diary and is defined as the sum of the "open" time without movement disorder and the "open" time with trouble free movement disorder.

Key secondary endpoints:

at the end of the double-blind treatment period (visit 7 or premature termination), the change in "off" time from baseline in hours per day averaged over the PD diary days;

at the end of the double-blind treatment period (visit 7 or premature termination), the proportion of subjects with "greatly improved" or "very improved" PGI-C scores;

changes in MDS-UPDRS part III from baseline at the end of the double-blind treatment period (7 th visit or early termination); and/or

At the end of the double blind treatment period (7 th visit or early termination), the sum of parts II and III of MDS-UPDRS changed from baseline.

Additional endpoints:

the following endpoints (at visit after random grouping) were assessed by visit as changes from baseline (visit 4) and from study entry (visit 1) (as applicable):

the percentage of "off period" time during the awake hours, each successive "good open period" and the average duration of each successive "open period", derived from the 3-day PD diary;

average duration of each successive "good open period" and each successive "open period";

(1) off time (from visit 1), (2) good open time (from visit 1), (3) open time with dyskinesia, (4) open time with troublesome dyskinesia and (5) open time with trouble free dyskinesia and (6) hours of fall asleep;

The "good open" time improves the proportion of subjects at least 1, 1.5, 2, 2.5 and 3 hours;

the "off period" time was reduced by at least a subject proportion of 0.5, 1, 1.5, 2, 2.5 and 3 hours;

the proportion of subjects who "open" after waking and "well-open" after waking;

average time to reach "open" after waking;

changes from baseline in average number of daily movement fluctuations averaged over the day of PD diary. Motion fluctuations are defined as changes from an "off" to an "on" state or from an "on" to an "off" state;

MDS-UPDRS total score (sum of parts I, II, III and IV) and parts I, II and IV individually;

MDS-UPDRS part III and combined part II+III (from visit 1);

MDS-UPDRS part II problem 2.9;

total score of 39 parkinson's disease questionnaires ("PDQ-39") and individual domain (individual domain) score;

total score of non-motor symptom assessment scale (NMSS) and individual domain;

parkinsonism sleep scale 2 (PDSS-2) total score and individual domain;

combined PDSS-2 items 9, 10, 11, 12 and 13;

parkinsonism scale (PAS) total score and individual domain;

Patient overall severity impression (PGI-S);

subject proportion of "severe disease" or "extremely severe disease" based on PGI-S-severity clinical global impression (CGI-S);

subject proportion based on CGI-S suffering from "severe disease" or "most severe disease";

patient global change impression (PGI-C) score;

clinical global change impression (CGI-C) score; and

subject proportion of "substantial improvement" or "very substantial improvement" based on CGI-C.

Adverse events were monitored and recorded. Patients were subjected to a basic symptom index (GCSI) questionnaire of gastroparesis at various time points throughout the study.

Unless otherwise indicated, the evaluation followed the general procedure outlined previously in examples 8 and 9.

Wakefulness from night sleep is defined as at least one "falling asleep" state after midnight, and not falling asleep 3 hours after the onset of "falling asleep" after midnight. Those subjects that did not go to sleep for 3 hours in succession as described above were considered unclassifiable. Likewise, those without any "asleep" state after 12:00 am are considered unclassifiable.

Because the PD diary starts at 6 a.m., the "continuous 3 hours without falling asleep" consideration starts at 6 a.m., without the need for a "falling asleep" state. Thus, for diary day-3, wakefulness from night sleep is defined as not falling asleep 3 hours after 6 hours in the morning.

In the above definition, the awake hours are defined as the onset of not falling asleep for 3 consecutive hours. The number and percentage of subjects in the "open" and "good open" states within the first half hour after waking from night sleep was summarized by visit (visit 4, 5, 6 and 7 or ET) and treatment group. At least one day of unclassifiable subjects in the PD diary of a visit were excluded from the analysis of the visit.

Baseline characteristics and demographics of subjects enrolled in the study were as follows:

daily dosing frequency for IPX203 and IR CD-LD stabilization regimens used in double blind periods (visits 4-7) are shown in the following table:

frequency of daily administration	IPX203	IR CD-LD
			Mean ± SD	3.0±0.42 ^a	5.1±1.2
Median value	3	5
			Min-max	2-4	3-10

^a n=16 twice a day (BID), and n=28 four times a day (QID).

The main endpoint, the change in "good open" time (hours) from baseline, is summarized in the following table:

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the main endpoint, statistical analysis of the change in "good open" time (hours) from baseline to the 7 th visit/End of Treatment (ET) is as follows:

fig. 17 is a graph of the following data points showing improvement in time from baseline to end of study "good open time":

This data shows that treatment according to the invention (IPX 203 on average 3 doses per day) resulted in a "good open-time" of at least 0.5 hours (0.53 hours) more than IR CD-LD (on average 5 doses per day) when compared to the change from baseline (week 7) in the two study groups. The data also show that from visit 1 to visit 7, the mean LS value for the IPX203 treatment improves to 1.76 hours, while the IR CD-LD treatment improves to 1.06 hours.

Statistical analysis of the endpoints, i.e. "good open time" per dose (hours) at visit/ET 7, is as follows:

fig. 18 is a graph of the "good open time" time per dose described above.

The change in secondary endpoint "off period" time (hours) from baseline is summarized in the following table:

the secondary endpoint, statistical analysis of the change in "off" time (hours) from baseline to 7 visits/ET, is as follows:

FIG. 19 is a graph of the following data points showing the decrease in time from baseline to the end of the study "off period":

this data shows that treatment according to the invention (IPX 203 on average 3 doses per day) resulted in significantly less "off-period" time or "off-period" time of about 0.5 hours (0.48 hours) than IR CD-LD (on average 5 doses per day) when comparing the changes of the two study groups from baseline (week 7).

Analysis of the data shows that subjects receiving the present invention have a greater improvement (less increase) in the percentage of mean "off" time during the wake hours from visit 4 to visit 7 (mean 3 doses per day for IPX203 compared to IR CD-LD (mean 5 doses per day). Specifically, for the present invention, the percent mean change in "off period" time during the period from visit 4 to visit 7 was 1.75 for IR CD-LD 4.55.

Statistical analysis of the percentage of "off period" time during the awake hours from visit 4 to visit 7 was as follows:

the above analysis shows that the percentage increase in "off period" time during the awake hours of IPX203 group is less when compared to the IR CD-LD group.

Data analysis also showed a greater improvement (less reduction) in the average duration of the continuous "good open" interval and continuous "open" interval from visit 4 to visit 7 in subjects receiving the present invention (on average 3 doses per day of IPX203 compared to IR CD-LD (on average 5 doses per day). Specifically, for the present invention, the average change in the continuous "good open" interval from visit 4 to visit 7 was-0.07, while the average change for IR CD-LD was-0.98. The average change in the consecutive "open-time" interval from visit 4 to visit 7 of the present invention was-0.22, while the IR CD-LD was-0.90.

The duration of the continuous "good open" interval and the duration of the continuous "open" interval are statistically analyzed as follows:

analysis of PD diary data is shown below:

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the above PD diary data shows a greater improvement over IR CD-LD using IPX203 in the following states recorded on the PD diary:

(i) "open" time without dyskinesia: mean change from study entry baseline to 7 th visit/ET; IPX203:1.45 and IR CD-LD:1.01);

(ii) There is a "open" time for trouble free dyskinesias: mean change from study entry baseline to 7 th visit/ET; IPX203:0.36 and IR CD-LD:0.13);

(iii) "open" time with troublesome dyskinesias: mean change from study entry baseline to 7 th visit/ET; IPX203:0.04 and IR CD-LD: -0.02);

(iv) "open" time with dyskinesia: mean change from study entry baseline to 7 th visit/ET; IPX203:0.41 and IR CD-LD:0.10);

(v) Time to fall asleep: mean change from study entry baseline to 7 th visit/ET; IPX203:0.05 and IR CD-LD:0.18).

The following is a summary of the proportion of subjects who obtained from PD diary who were "open" after waking and "good open" after waking:

The above data shows that there is a significant difference in the percentage of subjects in the "open" state after at least 1 day of wakefulness in the 3 day PD diary recorded at visit 7: IPX203 treatment, 53.1% of subjects, 44.5% (p=0.0046) compared to IR CD-LD treatment. Similar differences also exist in subjects who are in a "good open" state after waking.

The following is a summary of the average time of the "open phase" after arousal obtained from the PD diary:

abbreviations: ET: early termination

^a The diary date is assessed if the subject classifies according to the awake hours and reaches an "open" state.

^b n = number of subjects given the number of days that can be evaluated. M = number of subjects with active diary.

^c The time to "open" after each subject wakes up was averaged over the available days that can be assessed. The average of the subjects was then calculated.

The above data indicate that IPX203 treatment results in a shorter average time to "open" after waking compared to IR CD-LD treatment. Specifically, the average change in IPX203 treatment from 4 th visit to 7 th visit was 0.01 hours, and the average change in IR CD-LD treatment from 4 th visit to 7 th visit was 0.09 hours. This difference was not significant (p= 0.1664).

Analysis of PD diary data showed that subjects receiving IPX203 treatment exhibited greater improvement (less increase) in average number of motor fluctuations per day during visit 4 to visit 7/ET compared to subjects receiving IR CD-LD treatment. The mean change from 4 th visit to 7 th visit/ET was 0.17 for subjects receiving IPX203 treatment and 1.47 for subjects receiving IR CD-LD treatment. The following is a statistical analysis of the average number of daily motor fluctuations obtained from the subject PD diary collected 3 days prior to the 4 th visit and prior to the 7 th visit/ET.

The secondary endpoints, MDS-UPDRS, part III total score, are summarized in the following table:

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week 0 recruitment was 29.6 for the IPX203 group and 29.7 for the ir CD-LD group.

The statistical analysis of the total score of the III part of MDS-UPDRS at the secondary endpoint, visit 7/ET, is as follows:

the secondary endpoints, MDS-UPDRS, part II and part III total scores are summarized in the following table:

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week 0 recruitment was 42.9 for the IPX203 group and 42.9 for the ir CD-LD group.

The statistical analysis of the total scores of the second endpoint, MDS-UPDRS parts II and III at visit 7/ET is as follows:

The following table provides a summary of the mean change in PDQ-39 score from visit 4 to visit 7/ET:

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as shown in the above data, no significant differences in PDQ-39 total score and other individual domain scores were observed with IPX203 treatment versus IR CD-LD treatment, except for statistically significant differences in emotional well-being scores that favor IPX203 treatment.

The following table provides a summary of the mean change in NMSS scores for the 4 th to 7 th visits/ETs:

as shown in the above data, no significant differences were observed in NMSS total score and other individual domain scores with IPX203 treatment versus IR CD-LD treatment, except for statistically significant differences in perception problems/hallucinations.

The following table shows a summary of secondary endpoints—pgi-C summary:

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at visit 7, i.e., at the end of treatment, PGI-C scores showed a 56.9% improvement (defined as minimal improvement, substantial improvement, or very improvement) in the IPX203 group (average 3 doses per day) and 46.3% in the IR CD-LD group (average 5 doses per day); 29.7% showed a large improvement or very improvement in the IPX203 group, while the IR CD-LD group was 18.8%, the difference of which was statistically significant (p=0.0015).

The following table shows a summary of CGI-C scores at visit 7/ET:

n = number of subjects with a given CGI-C score at visit. M = the number of subjects receiving CGI-C evaluation at visit.

This CGI-C data shows that 58.1% of subjects receiving IPX203 treatment reported an improvement in CGI-C score (defined as minimal improvement, substantial improvement, or very improvement) compared to 45.7% of subjects receiving IR CD-LD treatment. The response of IPX203 treatment (33.6% of subjects) was reported to be "greatly improved" or "very improved" with a statistically significant proportion of subjects (p < 0.0001) when compared to IR CD-LD treatment (19.2% of subjects).

The following table provides a summary of the primary and secondary endpoint data obtained in this study:

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the assumed p-values for equal LS mean.

^b The p-values from the Cochran-Mantel-Haenszel ("CMH") test by pooled center stratification, compare the proportion of subjects with either substantial improvement or substantial improvement between treatment groups.

^c IPX203; n=256 and IR CD-LD; n=250

^d Double blind baseline was defined as collected 3 days prior to visit 4/randomizationData obtained in the PD diary.

^e Improvement is diary collected 3 days prior to double blind baseline, i.e., visit 4/randomization. The p-values from the CMH test by pooled center stratification were compared to the ratio of each improvement level between treatment groups at visit 7/ET.

^f The decrease was in diaries collected 3 days prior to double blind baseline, i.e., visit 4/randomization. The p-values from the CMH test by pooled center stratification were compared to the ratio of each reduced level between treatment groups at visit 7/ET.

^g P-values from the "line mean score difference" CMH test stratified by pooled centers were compared to the proportion of subjects between treatment groups at visit 7/ET.

^h P-values from CMH assays by pooled center stratification are compared between treatment groups for subjects with severe or most severe disease of PGI-S and subjects with severe or most severe disease of CGI-S.

The results show that the IPX203 group had less reduction in endpoint "good open time" based on PD-diaries (LS mean = 0.5 hour "good open" time reduction) than the IR CD-LD group (least squares (LS) mean = 1.03 hour "good open" time reduction). The results also show that IPX203 group increased less endpoint "off" time based on PD diary (lsaverage = 0.38 hour "off" time increase) compared to ID CD-LD group (lsaverage = 0.86 hour "off" time increase). These results indicate that the clinical results of IPX203 group are better, statistically significant (p=0.0194 for the "good open" time and p= 0.0252 for the "closed" time).

Example 12

The dosage form described in example 7 was administered to 27 subjects between 18 and 55 years of age, having a body weight of at least 55kg, and a body weight index of 18.5 to 30.0kg/m in a single site, open label, single dose, 3 treatments, 3 cycles, crossover study ² Is a healthy male and female subject. Subjects fasted overnight for at least 10 hours, receiving a single dose of 350mg LD and 87.5CD per treatmentClearance periods of 6 to 7 days apart.

Treatment a included orally administering a capsule prepared according to example 7 containing 350mg LD and 87.5mg CD with 240mL water about 30 minutes after breakfast of high fat (about 50% of total calories on meal), high calories (about 800-1000 calories) had begun to normalize. No additional food was allowed to last for at least 4 hours after administration.

Treatment B included oral administration of a capsule prepared according to example 7 containing 350mg LD and 87.5mg CD, wherein the contents of the capsule were sprinkled on 1 tablespoon applesauce. No additional food was allowed to last for at least 4 hours after administration.

Treatment C included oral administration of a capsule prepared according to example 7 containing 350mg LD and 87.5mg CD with 240mL water. No additional food was allowed to last for at least 4 hours after administration.

For treatments a and C, the subject was instructed to swallow the capsule intact without chewing, splitting or crushing the tablet.

For treatment B, the subject was instructed to consume all applesauce without crushing or chewing the beads.

Whole blood samples were taken before dosing and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 16 and 24 hours post dosing. Plasma samples were analyzed for CD and LD concentrations by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). Evaluation of peak plasma of LD and CD (C _max ) Area under plasma concentration-time curve (AUC _t And AUC _∞ ) Time to reach maximum concentration (T _max ). The mean pharmacokinetic parameters are shown in the following table, fig. 20 and fig. 21.

All values in the table above are mean.+ -. SD, except T _max Reported as median (min-max), AUC _0-t The area under the concentration-time curve is 0 to 24 hours.

After oral administration of the capsule in the fasted state, the LD concentration rapidly increased to about 2Median hour to T _max . High fat, high caloric administration resulted in LD median T compared to fasted state administration _max Delay for about 2 hours and make LD C _max And AUC increased by about 20%. CD C in fed state compared to fasted state _max And AUC _0-t The value was reduced by about 64%. The scattering of the capsule contents onto applesauce did not substantially affect the pharmacokinetic parameters when compared to fasted state administration.

Example 13

Based on the data in the previous examples (including but not limited to examples 11 and 12), the following are oral immediate release CD-LD dosage forms (e.g.)Or->Class AB imitation of the united states food and drug administration) to a recommended starting dose for the starting dose of the capsule described in example 7). />

Alternatively, the initial daily dose of IPX203 product described in the above table may be administered in one or more dosage forms comprising 35-140mg CD-LD, 52.5-210mg CD-LD,70-280mg CD-LD or 87.5-350mg CD-LD.

From oral IR CD-LD dosage forms (e.gOr->A class AB imitation version of the U.S. food and drug administration) of less than 125-500mg CD-LD per day, one or more of the controlled release dosage forms described herein, including the controlled release formulations of examples 1-7, preferably example 7, or class AB of the U.S. food and drug administration, may be administered every 12 hoursAnd an equivalent simulated pharmaceutical. If the subject does not achieve an acceptable duration of effect, the dosing interval may be reduced to about every 8 hours.

A patient newly diagnosed with PD or LD untreated PD may take one or more of the controlled release dosage forms described herein every 12 hours, including the controlled release dosage forms of examples 1-7, preferably example 7, or an equivalent mimetic of the american food and drug administration class AB. If the subject does not achieve an acceptable duration of effect, the dosing interval may be reduced to about every 8 hours.

From oral IR CD-LD dosage forms (e.gOr->PD patients taking a total daily dose of over 125-500mg CD-LD in the United states food and drug administration class AB simulated drug version) may take one or more of the controlled release dosage forms described herein, such as the controlled release dosage forms of examples 1-7, or a simulated drug equivalent thereof in the United states food and drug administration class AB.

According to the dosing schedule of this example, a PD patient may take one or more of the controlled release dosage forms described herein every 12 hours or every 6, 7 or 8 hours, including examples 1-7 and preferred example 7, or a simulated drug equivalent thereof of class AB of the american food and drug administration, and exhibits:

(i) The total "off period" time during a 24-hour period (i.e., one day) is 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;

(ii) The total "off period" time during the awake hours is 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 the awake hours within the 24 hour period;

(iii) During the dosing interval, the total "on" time exceeds 5 hours, exceeds 6 hours, exceeds 7 hours, or 8 hours;

(iv) During the dosing interval, the total "good open" time exceeds 5 hours, exceeds 6 hours, exceeds 7 hours, or 8 hours;

(v) The "open time" time during each dose, day, and/or each day of wakefulness of the patient is increased 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 the oral dose of an equivalent immediate release CD-LD dosage form or the total immediate release CD-LD dose per day or each wakefulness of the patient;

(vi) The "good open time" time during each dose, day, and/or each day of wakefulness of the patient is increased 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 the oral dose of an equivalent immediate release CD-LD dosage form or the total immediate release CD-LD dose per day or per wakefulness of the patient;

(vii) The "off period" time during each dose, day, and/or each day of wakefulness of the patient is reduced 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 the oral dose of an equivalent immediate release CD-LD dosage form or the total immediate release CD-LD dose per day or each wakefulness of the patient; or (b)

(viii) Any combination of the above.

With respect to the foregoing increases in "open" or "good" time per dose, day, and/or day during an awake period of a patient by at least 30 to 180 minutes or more, and decreases in "off" time per dose, day, and/or day during an awake period of a patient, as compared to an equivalent oral dose of an immediate release CD-LD dosage form or total immediate release CD-LD dosage per day or awake period, it is understood that the comparison of day or awake period is based on a comparison of the total amount of LD administered via a controlled release dosage form per day or awake period to the total amount of LD administered via an immediate release formulation per day or awake period. The comparison may be a total of 2, 3 or 4 controlled release applications compared to a total of 4, 5 or 6 immediate release applications during the day (24 hour period) or 12 to 18 hour wake period.

According to the dosing schedule of this example, a PD patient may take one or more of the controlled release dosage forms described herein every 12 hours or every 6, 7 or 8 hours, including examples 1-7, preferably example 7, or an equivalent simulated drug of class AB of the american food and drug administration, and exhibit a significant reduction in total "off-period" time at the time of awakening. With immediate release CD-LD oral dosage forms (e.g Or->The total "off period" time during the awake hours (e.g., 16 hours within 24 hours) should be reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 50% as compared to the treatment of class AB imitative drug version of the united states food and drug administration.

According to the dosing schedule of this example, a PD patient may take one or more of the controlled release dosage forms described herein every 12 hours or every 6, 7, or 8 hours, including examples 1-7, preferably example 7, or a simulated drug equivalent thereof of class AB of the american food and drug administration, and exhibit 180 minutes or less, 160 minutes or less, 140 minutes or less, 120 minutes or less, 100 minutes or less during the dosing interval; a total "off period" time of 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-a-day dosing group, the dosing interval was approximately every 12 hours. For PD patients in the three-day dosing group, the dosing interval was approximately 8 hours. For PD patients in the four-day dosing group, the dosing interval was approximately 6 hours.

PD patients every 12 hours orA controlled release dosage form as described herein, including examples 1-7, preferred example 7, or a simulated drug equivalent thereof of class AB of the united states food and drug administration, is administered every 6, 7, or 8 hours and, according to the dosing schedule of this example, there is no need to increase the amount of LD administered in the morning or the first daily dose after waking. Conversely, PD patients may take the same dose at each dosing time of the day, avoiding the need for different morning, afternoon and/or evening doses, which may complicate the dosing regimen, confuse the caregivers or PD patients, and result in overdosing or underdosing. Furthermore, these PD patients administered the controlled release dosage forms as described herein and according to the dosing schedule according to the present embodiment allow for dosing at about 30 minutes or less prior to bedtime allow PD patients to experience improved night sleep and wake up in the morning in an "open" or "good open" state, thereby eliminating the need for LD rescue doses. These PD patients who administer a controlled release dosage form as described herein and according to the administration schedule of this embodiment in a time period that allows administration about 30 minutes or less before bedtime, are administered with an immediate release CD-LD oral dosage form (e.g. Or->Class AB imitation version of the united states food and drug administration) further subjects PD patients to a more rapid time to reach an "open" or "good open" state after the first morning dose of the controlled release dosage form. In combination with an immediate release CD-LD oral dosage form (e.g.)>Or->Class AB imitation version of the united states food and drug administration) can reach the "open" or "good open" state more rapidly than about 5, 6, 7, 8, 9 after the first morning dose of the controlled release dosage formA range of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 minutes.

According to the dosing schedule of this example, a PD patient can take one or more of the controlled release dosage forms described herein every 12 hours or every 6, 7 or 8 hours, including examples 1-7, preferred example 7, or a simulated pharmaceutical equivalent thereof of class AB of the United states food and drug administration, and with an immediate release CD-LD oral dosage form (e.g.Or->Class AB imitation version of the united states food and drug administration) showed a significant improvement in their PGI-C or CGI-C scores, i.e., reported a "greatly improved" or "very improved" value.

According to the dosing schedule of this example, a PD patient can take one or more of the controlled release dosage forms described herein every 12 hours or every 6, 7 or 8 hours, including examples 1-7, preferred example 7, or a simulated pharmaceutical equivalent thereof of class AB of the United states food and drug administration, and with an immediate release CD-LD oral dosage form (e.g.Or->Class AB imitation version of the united states food and drug administration) exhibit improved emotional well-being as measured by PDQ-39.

According to the dosing schedule of this example, a PD patient can take one or more of the controlled release dosage forms described herein every 12 hours or every 6, 7 or 8 hours, including examples 1-7, preferred example 7, or a simulated pharmaceutical equivalent thereof of class AB of the United states food and drug administration, and with an immediate release CD-LD oral dosage form (e.g.Or->Class AB simulated drug version of the united states food and drug administration) exhibit a reduction in perceived problems and/or hallucinations as determined by NMSS scores.

PD patients may take controlled release dosage forms as described herein, including examples 1-7, preferred example 7, or a mimic drug of the U.S. food and drug administration class AB equivalent thereto (with or without food) and, if taken with food, exhibit LD C of at least 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25% or greater when compared to administration after at least 10 hours of fasting, preferably after 10 hours of overnight fast _max And/or an increase in LD AUC value. LD C when administered with food compared to administration after fasting _max And/or increases in LD AUC may be determined using the conditions outlined in example 12 above.

The PD patient may further take a controlled release dosage form as described herein, including examples 1-7, preferred example 7, or a simulated drug equivalent thereto of class AB of the United states food and drug administration (with or without food) and, if taken with food, exhibits an LD T when compared to administration after a fasting period of at least 10 hours, preferably after an overnight fast of 10 hours _max And/or CD T _max A change (i.e., ±) 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. LD T when administered with food compared to post-fasted administration _max And/or CD T _max May be determined using the conditions outlined in example 12 above. Compared with administration after fasting, T _max Preferably, the change in (a) is such that T is reached under fed conditions _max The time increase of (a) is 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.

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

Claims

1. A method for treating a patient diagnosed with parkinson's disease, comprising orally administering a controlled release dosage form comprising levodopa and a controlled release excipient and/or a mucoadhesive excipient; administration of the controlled release dosage form occurs every 12 hours, wherein the total daily dose of levodopa provided by the controlled release dosage form is from about 400mg to about 1400mg; the dose of levodopa administered every 12 hours from the controlled release dosage form is about 200mg to about 700mg and the patient is being treated with a total daily dose of 500mg or less of levodopa administered at three, four or more doses over a 24 hour period prior to receiving the controlled release dosage form of levodopa.

2. The method of claim 1, wherein the dose of levodopa administered every 12 hours from the controlled release dosage form is about 200mg to about 500mg.

3. The method of claim 1, wherein the dose of levodopa administered every 12 hours from the controlled release dosage form is about 250mg to about 450mg.

4. The method of claim 1, wherein the controlled release dosage form further comprises carbidopa.

5. The method of claim 4, wherein the controlled release dosage form comprises one or more capsules comprising:

(a) 140mg of levodopa and 35mg of carbidopa;

(b) 210mg of levodopa and 52.5mg of carbidopa;

(c) 280mg of levodopa and 70mg of carbidopa;

(d) 350mg of levodopa and 87.5mg of carbidopa; or (b)

(e) Combinations of the above.

6. The method of claim 1, wherein the controlled release dosage form exhibits the following levodopa release profile when tested with USP apparatus I at 75rpms and 37 ° ± 0.5 ℃ with 500-900ml simulated gastric fluid for 2 hours and then phosphate buffer at pH 6.8:

20% to 60% of the levodopa is released after 2 hours;

40% to 80% of the levodopa is released after 3 hours;

60% to 100% of the levodopa is released after 4 hours; and

The release after 7 hours is not less than 80%.

7. The method of claim 1, wherein the controlled release dosage form produces a plasma level of levodopa of at least 300ng/mL within 0.25 to 1 hour after administration.

8. The method of claim 1, wherein the minimum levodopa plasma level 7 to 8 hours after administration is about 250ng/mL after at least 7 days of administration of the controlled release dosage form about every 12 hours.

9. The method of claim 4, wherein the minimum carbidopa plasma level of 7 to 8 hours after administration is about at least 40ng/mL after at least 7 days of administration of the controlled release dosage form about every 12 hours.

10. The method of claim 1, wherein the patient is newly diagnosed with parkinson's disease or is a levodopa untreated patient.

11. A method for treating a patient diagnosed with parkinson's disease, comprising orally administering a controlled release dosage form comprising levodopa and a controlled release excipient and/or a mucoadhesive excipient; administration of the controlled release dosage form occurs every 12 hours or every 7 to 8 hours and the patient exhibits: (i) The total "off period" time within the 24 hour period is less than 5 hours; (ii) The total "off period" time during the awake hours is less than 5 hours over a 24 hour period; (iii) The total open time during the dosing interval exceeds 5 hours; (iv) The total good open time during the dosing interval exceeds 5 hours; (v) The patient's daily "open-term" time is increased by at least 20 minutes as compared to the total dose of an equivalent daily oral immediate release CD-LD; (vi) The patient's daily "good open-period" time is increased by at least 20 minutes as compared to the total dose of an equivalent daily oral immediate release CD-LD; or (vii) combinations of the above.

12. The method of claim 11, wherein the controlled release dosage form comprises one or more capsules comprising:

(a) 140mg of levodopa and 35mg of carbidopa;

(b) 210mg of levodopa and 52.5mg of carbidopa;

(c) 280mg of levodopa and 70mg of carbidopa;

(d) 350mg of levodopa and 87.5mg of carbidopa; or (b)

(e) Combinations of the above.

13. A method for treating a patient diagnosed with parkinson's disease, comprising orally administering a controlled release dosage form comprising levodopa and a controlled release excipient and/or a mucoadhesive excipient; administration of the controlled release dosage form occurs every 12 hours or every 7 to 8 hours and the patient exhibits at least a 5% reduction in total "off period" time during the awake hours as compared to a patient receiving treatment with an immediate release oral dosage form of levodopa and carbidopa.

14. The method of claim 13, wherein the controlled release dosage form comprises one or more capsules comprising:

(a) 140mg of levodopa and 35mg of carbidopa;

(b) 210mg of levodopa and 52.5mg of carbidopa;

(c) 280mg of levodopa and 70mg of carbidopa;

(d) 350mg of levodopa and 87.5mg of carbidopa; or (b)

(e) Combinations of the above.

15. A method for treating a patient diagnosed with parkinson's disease, comprising orally administering a controlled release dosage form comprising levodopa and a controlled release excipient and/or a mucoadhesive excipient; administration of the controlled release dosage form occurs every 12 hours or every 7 to 8 hours and the patient exhibits a total "off period" time of 180 minutes or less during the dosing interval.

16. The method of claim 15, wherein the controlled release dosage form comprises one or more capsules comprising:

(a) 140mg of levodopa and 35mg of carbidopa;

(b) 210mg of levodopa and 52.5mg of carbidopa;

(c) 280mg of levodopa and 70mg of carbidopa;

(d) 350mg of levodopa and 87.5mg of carbidopa; or (b)

(e) Combinations of the above.

17. A method for treating a patient diagnosed with parkinson's disease, comprising orally administering a controlled release dosage form comprising levodopa and a controlled release excipient and/or a mucoadhesive excipient; administration of the controlled release dosage form occurs every 12 hours or every 7 to 8 hours, and the patient administers the controlled release dosage form about 30 minutes or less prior to bedtime and the patient wakes about 7 to about 8 in an open or well-open state.

18. The method of claim 17, wherein the controlled release dosage form comprises one or more capsules comprising:

(a) 140mg of levodopa and 35mg of carbidopa;

(b) 210mg of levodopa and 52.5mg of carbidopa;

(c) 280mg of levodopa and 70mg of carbidopa;

(d) 350mg of levodopa and 87.5mg of carbidopa; or (b)

(e) Combinations of the above.

19. A method for treating a patient diagnosed with parkinson's disease, comprising orally administering a controlled release dosage form comprising levodopa and a controlled release excipient and/or a mucoadhesive excipient; administration of the controlled release dosage form occurs every 12 hours or every 7 to 8 hours and the patient is administered the same dose at each dosing interval.

20. The method of claim 19, wherein the controlled release dosage form comprises one or more capsules comprising:

(a) 140mg of levodopa and 35mg of carbidopa;

(b) 210mg of levodopa and 52.5mg of carbidopa;

(c) 280mg of levodopa and 70mg of carbidopa;

(d) 350mg of levodopa and 87.5mg of carbidopa; or (b)

(e) Combinations of the above.

21. A method for treating a patient diagnosed with parkinson's disease, comprising orally administering a controlled release dosage form comprising levodopa and a controlled release excipient and/or a mucoadhesive excipient; administration of the controlled release dosage form occurs every 12 hours or every 7 to 8 hours and the patient administers the composition under fed or fasted conditions Controlled release dosage forms and the patient exhibits a similar or increased maximum levodopa plasma concentration (C) when the controlled release dosage form is administered under fed conditions as compared to administration under fasted conditions _max ) And/or area of levodopa (AUC) under the plasma concentration time curve.

22. The method of claim 21, wherein the controlled release dosage form comprises one or more capsules comprising:

(a) 140mg of levodopa and 35mg of carbidopa;

(b) 210mg of levodopa and 52.5mg of carbidopa;

(c) 280mg of levodopa and 70mg of carbidopa;

(d) 350mg of levodopa and 87.5mg of carbidopa; or (b)

(e) Combinations of the above.

23. The method of claim 22, wherein the time to maximum levodopa plasma concentration (T _{max levodopa} ) Or the time to reach maximum carbidopa plasma concentration (T _{max carbidopa} ) For T when the controlled release dosage form is administered under fasted conditions _{max levodopa} Or T _{max carbidopa} Is ± 5 hours.