Impulse drug delivery system for the treatment of morning akinesia

Abstract

The present invention provides a pharmaceutical composition comprising, separately or in combination, a pulsatile release component containing levodopa and a DOPA decarboxylase inhibitor for managing OFF episodes in Parkinson's disease patients.

Description

Technical Field

[0001] This invention relates to a pulsed drug delivery system that can delay the burst release of levodopa and DOPA decarboxylase inhibitors (including carbidopa) in the small intestine, thereby improving the management of morning inability to move in patients with Parkinson's disease. Background Technology

[0002] Motor disorders are often caused by impaired regulation of dopamine neurotransmission. Parkinson's disease (PD) is one example of a motor disorder associated with dysfunction in dopamine neurotransmission, resulting from the progressive degeneration of dopamine neurons. To replace lost dopamine, oral levodopa (L-DOPA, a precursor to dopamine) is currently used to treat motor symptoms of PD. Oral levodopa must empty from the stomach and be absorbed in the proximal small intestine. Levodopa is converted into dopamine in the brain and stored in neurons until the body needs to move. It remains the single most effective agent for managing Parkinson's symptoms.

[0003] Most PD patients receiving levodopa treatment experience motor fluctuations. Symptom improvement following L-DOPA administration is defined as "ON," while symptom recovery is defined as "OFF," which occurs when levodopa plasma concentrations decrease. OFF periods typically occur when the benefit of a given dose of levodopa wears off prematurely (decline OFF) or when the next L-DOPA dose produces a delayed onset (delayed ON).

[0004] Motor complications in Parkinson's disease (PD) have been reported to occur several years after levodopa treatment, in which long-duration responses are replaced by short-duration responses, resulting in an OFF period. While the OFF period can be treated with several adjunctive medications, the delayed onset of the next levodopa dose can significantly increase the duration of the OFF period.

[0005] Morning motor dysfunction, which is a delayed ON onset of the first L-DOPA daily dose, occurs in nearly 60% of patients receiving dopaminergic therapy. This is primarily a motor symptom, but has recently been considered to be associated with non-motor fluctuations.

[0006] The inability to exercise in the morning can significantly affect the quality of life of PD patients and weaken their ability to perform basic daily activities.

[0007] Due to its pharmacodynamic and pharmacokinetic aspects, as well as its short half-life, unstable gastrointestinal absorption, and competitive transport across the blood-brain barrier, standard oral levodopa treatment is insufficient for treating morning akachiness. One initial strategy attempted to address this by using long-acting, controlled-release levodopa formulations to prolong levodopa plasma levels. However, due to delayed gastric emptying, oral doses of L-DOPA may remain in the stomach for an extended period before being absorbed by the small intestine. Another approach is to administer levodopa as a liquid solution to reduce gastric transit time and improve onset of action. This approach may be beneficial for some patients with dramatic fluctuations; however, the clinical benefit of liquid levodopa compared to tablets has not been confirmed in controlled clinical trials. To manage episodes of morning akachiness and nocturnal inactivity, many patients use L-DOPA intermittently or as needed. However, the slow or unpredictable onset of action limits clinical benefit.

[0008] Alternative delivery methods for dopaminergic therapy, such as subcutaneous apomorphine, are used in OFF-state PD patients to reduce time to ON. However, morning subcutaneous self-pen injections can be problematic in disabled, advanced PD patients. Nasal, pulmonary, and sublingual formulations of levodopa are also available.

[0009] Levodopa is almost always administered in combination with a DOPA decarboxylase inhibitor such as carbidopa. Carbidopa prevents levodopa from disintegrating before it can reach the brain and exert its effects; carbidopa reduces the dosage of levodopa by a significant amount (up to 80%) and helps reduce nausea and vomiting side effects. Carbidopa / levodopa tablets are available in immediate-release (IR) and extended-release (ER) forms, as well as soluble tablets placed under the tongue. Small, portable infusion pumps deliver carbidopa and levodopa directly to the small intestine.

[0010] The combination of ER and other formulations maintains plasma levodopa concentrations for a longer period within the therapeutic window, providing patients with longer ON time and better home management and mobility; however, the improvement of movement disorders or SIP scores by ER formulations has not been established.

[0011] It has been shown that, in some cases, pretreatment with carbidopa prior to levodopa increases levodopa plasma AUC compared to concurrent administration (see, for example, Leppert et al., 1988).

[0012] Morning inability to move is one of the most common and earliest motor complications in patients with Parkinson's disease (PD), affecting almost all stages of the disease. Improving nighttime sleep patterns and morning inability to move in PD patients in a safe, non-invasive, and compliant manner remains an unmet medical need. Summary of the Invention

[0013] The inventors have developed a pharmaceutical composition that overcomes the shortcomings of existing formulations containing levodopa and DOPA decarboxylase inhibitors; it provides a composition capable of timed pulsed release of these compounds. Delayed burst release of DOPA decarboxylase inhibitors, such as carbidopa, and delayed burst release of levodopa are provided after a predetermined lag time, preferably time-separated, thereby releasing the DOPA decarboxylase inhibitor before levodopa, providing a way to manage morning dyskinesia in patients with Parkinson's disease.

[0014] Utilizing the disclosed pulsed drug delivery, patients can improve their nighttime sleep patterns and effectively recover from complete disability in the morning. Furthermore, this composition can be taken in combination with existing commercially available immediate-release and controlled-release levodopa products to provide full-day dose coverage for most patients with Parkinson's disease.

[0015] One aspect is providing a pulse-release drug composition comprising:

[0016] a. Levodopa and DOPA decarboxylase inhibitors, and

[0017] b. A pulse-release component, which provides a predetermined hysteresis time, followed by pulse release of the levodopa and the DOPA decarboxylase inhibitor.

[0018] On the other hand, a pulse-release pharmaceutical composition is provided, comprising the following components, either separately or together:

[0019] a. Contains a first pulse-release component of levodopa, the first pulse-release component providing a predetermined hysteresis time, followed by pulse-release of levodopa, and

[0020] b. A second pulse-release component comprising a DOPA decarboxylase inhibitor, the second pulse-release component providing a predetermined hysteresis time, followed by pulse release of the DOPA decarboxylase inhibitor.

[0021] In one embodiment, the hysteresis time of the first pulse-release component containing levodopa is longer than the hysteresis time of the second pulse-release component containing the DOPA decarboxylase inhibitor.

[0022] In one embodiment, the DOPA decarboxylase inhibitor is selected from carbidopa, benserazide, methyldopa, and DFMD (α-difluoromethyl-DOPA), or pharmaceutically acceptable derivatives thereof.

[0023] In one embodiment, the pharmaceutical composition is a multi-part dosage form.

[0024] In one embodiment, the pharmaceutical composition comprises one or more other active pharmaceutical ingredients, either separately or together.

[0025] In one embodiment, the pharmaceutical composition is used to treat morning movement disorder in patients with Parkinson's disease. Attached Figure Description

[0026] Figure 1 Pharmacokinetic curves of levodopa products: A) standard immediate release, B) standard controlled release, and C) the proposed delayed pulsatile product.

[0027] Figure 2 Release of model compounds: Microtablets containing 30% sodium glycolate coated with ethyl cellulose film (weight increase 20-25%): 50% release was achieved with a lag time of 3 to 5 hours using 25% coating. Data vary (see Example 1).

[0028] Figure 3: Release of model compounds: 30% sodium glycolate starch coated with ethyl cellulose membrane (weight increase 10-25%); PVA added as a pore-forming agent ( Figure 3A 10%; Figure 3B (20% PVA). For 10% PVA, a 15% coating was used to achieve a 65% release hysteresis time of 3 to 5 hours; for 20% PVA, a 20% coating was used to achieve a 70% release hysteresis time of 3 to 5 hours. The data variation was small (see Examples 2 and 3).

[0029] Figure 4: Release of model compounds: 30% sodium glycolate coated with ethyl cellulose membrane (weight increase 10-25%); HPMC added as a pore-forming agent ( Figure 4A 10%; Figure 3B (20% HPMC). For 10% HPMC, a 15% coating was used to achieve a lag time of 50% release over 3 to 5 hours; for 20% HPMC, a 20% coating was used to achieve a lag time of 75% release over 3 to 5 hours. Increased membrane weight was associated with slower release / less burst release; increased pore-forming agent was associated with higher burst release. Data showed minimal variation (see Examples 4 and 5).

[0030] Figure 5 Levodopa release: Microtablets containing 30% sodium glycolate starch coated with ethyl cellulose film (weight increase 17.5-25%); 20% HPMC added as a pore-forming agent. The release of levodopa microtablets was well controlled (see Example 9).

[0031] Figure 6Levodopa release: Microtablets containing 30% sodium glycolate starch coated with ethyl cellulose film (weight increase 10-25%); 20% HPMC added as a pore-forming agent. The release of levodopa from the microtablets was well controlled. Data on the release of model compounds were included to demonstrate a similar release pattern (see Example 8).

[0032] Figure 7 Levodopa release: Microtablets containing 10% sodium glycolate starch coated with ethyl cellulose film (weight increase 10-25%); 20% HPMC added as a pore-forming agent. The release of levodopa microtablets with low levels of superdisintegrants could not be well controlled and showed poor burst release (see Example 10).

[0033] Figure 8 Carbidopa release: Microtablets containing 40% sodium glycolate coated with ethyl cellulose film (weight increase of 17.5-25%); 20% HPMC added as a pore-forming agent. The release of carbidopa microtablets was well controlled (see Example 17). Detailed Implementation

[0034] One aspect is to provide a pharmaceutical composition that provides a timed pulsed release of levodopa and a DOPA decarboxylase inhibitor such as carbidopa in the small intestine; preferably, the release is time-separated, thereby causing the DOPA decarboxylase inhibitor such as carbidopa to be released pulsedly before levodopa. By taking this composition at bedtime, a method is provided to treat morning inability to move in patients with, for example, Parkinson's disease.

[0035] It has been recognized that gastric motility is typically slightly delayed in patients with Parkinson's disease, thus allowing for a lag time of up to 5 or 6 hours of release while the composition is still in the small intestine. The anticipated burst delivery of the full dose of levodopa in the lower small intestine is expected to improve levodopa absorption. Currently marketed levodopa products are not bioavailable in this region, therefore this novel principle offers a unique new opportunity for overnight levodopa coverage in patients with Parkinson's disease.

[0036] L-DOPA, or levodopa (L-3,4-dihydroxyphenylalanine), is synthesized from the amino acid L-tyrosine in the human body. L-DOPA is a precursor to the neurotransmitters dopamine, norepinephrine, and epinephrine, and mediates the release of neurotrophic factors from the brain and CNS. L-DOPA is marketed as a psychoactive drug under the name INN (Levodopa); brand names include Sinemet, Pharmacopa, Atamet, Stalevo, Madopar, and Prolopa. It is used in the clinical treatment of Parkinson's disease and dopamine-responsive dystonia.

[0037] L-DOPA crosses the blood-brain barrier, where it is converted to dopamine by aromatic L-amino acid decarboxylases (DOPA decarboxylases). Because L-DOPA is also converted to dopamine within the peripheral nervous system, causing excessive peripheral dopamine signaling and adverse effects, co-administration of peripheral DOPA decarboxylase inhibitors (DDCIs) is standard clinical practice. Combination therapy enhances the central effects of L-DOPA by reducing the dose-dependent effect by 4–5 times.

[0038] DOPA decarboxylase inhibitors include carbidopa, benserazide, methyldopa, and DFMD (α-difluoromethyl-DOPA).

[0039] Drugs containing carbidopa alone or in combination with L-DOPA, under the brand names Lodosyn (AtonPharma), Sinemet (Merck Sharp & Dohme Limited), Pharmacopa (Jazz Pharmaceuticals), Atamet (UCB), Stalevo (Orion Corporation), parcopa, or in combination with benserazide (the brand name of the combination drug is Madopar or Prolopa).

[0040] Drugs containing benserazide, alone or in combination with L-DOPA, are marketed under brand names such as Madopar, Prolopa, Modopar, Madopark, Neodopasol, and EC-Doparyl. Drugs containing methyldopa are marketed under brand names such as Aldomet, Aldoril, Dopamet, and Dopegyt.

[0041] Pulsed drug delivery is defined as the rapid and instantaneous release of a certain amount of molecules immediately and instantaneously within a short period of time after a predetermined off-release period, i.e., a lag time.

[0042] Pulsed drug delivery systems (PDDS) deliver a drug at the right time, the right site of action, and the right amount, with the drug being released rapidly and completely as a pulse (or burst) after a lag time. These products follow an S-shaped release profile characterized by a time interval. This release pattern is called pulsed release. These systems are advantageous for drugs with long-term pharmacological behavior that require nocturnal administration, as well as for drugs exhibiting first-pass effects. Potential disadvantages include low drug loading capacity and multiple manufacturing steps.

[0043] The lag time is defined as the time between when the dosage form is placed in an aqueous environment and the time when the active pharmaceutical ingredient begins to be released from the dosage form.

[0044] Pulse drug delivery systems can be broadly classified into three categories:

[0045] 1) Time-controlled pulse release system (delivery system with soluble coating)

[0046] a. Bulk dissolution system. Bulk dissolution means that the entry of water is faster than the rate of degradation. In this case, degradation occurs throughout the polymer sample and continues until the critical molecular weight is reached. At this point, the degradation products become small enough to dissolve and the structure begins to become significantly more porous and hydrated. Therefore, there is a time lag before drug release, corresponding to the time required to reach the critical molecular weight.

[0047] b. Surface-dissolving systems. In this type of system, the reservoir device is coated with a soluble or soluble-etchable layer that dissolves over time and releases the drug after a specified hysteresis period. When the system comes into contact with an aqueous medium, the coating emulsifies or dissolves after this hysteresis period. It is independent of gastrointestinal motility, pH, enzymes, and gastric retention. The hysteresis time and onset of action are controlled by the thickness and the viscosity grade of the polymer used. Examples include delivery systems with a ruptureable coating layer and capsule-shaped systems with a release control plug.

[0048] a. The coating can be spray-coated (e.g., rupture film coating or soluble film coating) or compression-coated.

[0049] 2) Stimulus-induced pulse release systems. Stimulus-based drug delivery systems release drugs in response to stimuli induced by the biological environment, such as temperature changes (thermoresponsive pulse release), and chemical stimuli, such as pH, enzymes, or other chemicals (chemically induced pulse release).

[0050] 3) Externally regulated pulse release systems. These include electrically responsive delivery systems (made from polyelectrolytes, thus being both pH-responsive and electroresponsive); ultrasonic stimulation; and magnetically inductive pulse release.

[0051] This invention provides a pulsed drug delivery system that provides timed pulsed release of levodopa and a DOPA decarboxylase inhibitor. In one embodiment, the pulsed drug delivery system is a pharmaceutical composition for the timed pulsed release of levodopa and a DOPA decarboxylase inhibitor.

[0052] The terms "pharmaceutical composition" and "pulsed-release pharmaceutical composition" are used interchangeably in this document.

[0053] In one aspect, a pulsed-release pharmaceutical composition is provided, comprising:

[0054] i) Levodopa and DOPA decarboxylase inhibitors, and

[0055] ii) Pulsating release of the components, providing a predetermined hysteresis time, followed by pulsed release of the levodopa and the DOPA decarboxylase inhibitor.

[0056] In one aspect, a pharmaceutical composition is provided comprising the following components, either separately or together:

[0057] i) Containing a first pulse-release component of levodopa, the first pulse-release component providing a predetermined hysteresis time, followed by pulse-release of levodopa, and

[0058] ii) A second pulse-release component comprising a DOPA decarboxylase inhibitor, the second pulse-release component providing a predetermined lag time, followed by pulse release of the DOPA decarboxylase inhibitor.

[0059] In one embodiment, the hysteresis time of the first pulse-release component containing levodopa is longer than the hysteresis time of the second pulse-release component containing the DOPA decarboxylase inhibitor.

[0060] In one aspect, a pharmaceutical composition is provided comprising the following components, either separately or together:

[0061] i) Containing a first pulse-release component of levodopa, the first pulse-release component providing a predetermined hysteresis time, followed by pulse-release of levodopa, and

[0062] ii) A second pulse-release component comprising a DOPA decarboxylase inhibitor, the second pulse-release component providing a predetermined lag time, followed by pulse release of the DOPA decarboxylase inhibitor.

[0063] The lag time of the first pulse-release component containing levodopa is longer than the lag time of the second pulse-release component containing the DOPA decarboxylase inhibitor.

[0064] In one embodiment, the DOPA decarboxylase inhibitor is selected from carbidopa, benserazide, methyldopa, and DFMD (α-difluoromethyl-DOPA), or pharmaceutically acceptable derivatives thereof.

[0065] In one implementation, the DOPA decarboxylase inhibitor is carbidopa, or a pharmaceutically acceptable derivative thereof.

[0066] In one implementation, the term levodopa also includes pharmaceutically acceptable derivatives of levodopa.

[0067] In one embodiment, the term levodopa includes a prodrug of levodopa. In one embodiment, the term levodopa includes the prodrug of levodopa, levodopa methyl ester. In one embodiment, the term levodopa includes levodopa as the prodrug XP21279.

[0068] In one embodiment, the term levodopa further includes modified levodopa. In one embodiment, the term levodopa further includes deuterated levodopa (deuterated levodopa).

[0069] In the context of this invention, the term "pharmaceutically acceptable derivative" includes pharmaceutically acceptable salts, meaning salts that are harmless to patients. These salts include pharmaceutically acceptable base or acid addition salts, as well as pharmaceutically acceptable metal salts, ammonium salts, and alkylated ammonium salts. Pharmaceutically acceptable derivatives also include esters and prodrugs, or other precursors of compounds that can be biometabolized into the active compound, or crystalline forms of the compound.

[0070] In one embodiment, the pharmaceutical composition is a time-controlled pulsed release system comprising a bulk dissolution system and a surface dissolution system.

[0071] In one embodiment, the pharmaceutical composition is a pharmaceutical dosage form.

[0072] In one implementation, the drug dosage form is a multi-particle dosage form (multi-unit dosage form).

[0073] Multiparticle or multiunit dosage forms are discrete, small, repeating units of drug particles that may have or have similar drug release patterns. They can be tailored for pulsatile drug release.

[0074] In one embodiment, the drug formulation is a multi-particle formulation comprising multiple particles, each particle providing a timed pulsed release of levodopa and / or a DOPA decarboxylase inhibitor.

[0075] In one implementation, the drug dosage form is a multi-part dosage form, which comprises two dosage forms, either separately or combined:

[0076] i) The first dosage form provides a predetermined lag time, followed by a pulsed release of levodopa, and

[0077] ii) Second dosage form, providing a predetermined lag time, followed by pulse release of the DOPA decarboxylase inhibitor.

[0078] In one implementation, the drug dosage form is a multi-part dosage form, which comprises two dosage forms, either separately or combined:

[0079] i) The first dosage form provides a predetermined lag time, followed by a pulsed release of levodopa, and

[0080] ii) The second formulation provides a predetermined lag time, followed by a pulse release of the DOPA decarboxylase inhibitor.

[0081] The lag time of the first formulation containing levodopa is longer than that of the second formulation containing a DOPA decarboxylase inhibitor.

[0082] In one embodiment, the multi-granule dosage form is packaged in capsules, sachets, sachets, or sticks. In one embodiment, a first dosage form containing levodopa and a second dosage form containing a DOPA decarboxylase inhibitor are packaged in capsules, sachets, sachets, or sticks. In one embodiment, the capsules are hard-shell capsules, such as hard gelatin capsules.

[0083] In one implementation scheme, the multi-particle dosage form

[0084] i) Including 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 16 to 17, 17 to 18, 18 to 19, 19 to 20, 20 to 21, 21 to 22, 22 to 23, 23 to 24, 24 to 25, 25 to 26, 26 to 27, 27 to 28, 28 to 29, 29 to 30, 30 to 35, 35 to 4 0, 40 to 45, 45 to 50, 50 to 55, 55 to 60, 60 to 65, 65 to 70, 70 to 75, 75 to 80, 80 to 85, 85 to 90, 90 to 95, 95 to 100, 100 to 110, 110 to 120, 120 to 130, 130 to 140, 140 to 150, 150 to 160, 160 to 170, 170 to 180, 180 to 190, 190 to 200 first dosage forms containing levodopa; and

[0085] ii) Including 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 16 to 17, 17 to 18, 18 to 19, 19 to 20, 20 to 21, 21 to 22, 22 to 23, 23 to 24, 24 to 25, 25 to 26, 26 to 27, 27 to 28, 28 to 29, 29 to 30, 30 to 35, 35 to 40. 40 to 45, 45 to 50, 50 to 55, 55 to 60, 60 to 65, 65 to 70, 70 to 75, 75 to 80, 80 to 85, 85 to 90, 90 to 95, 95 to 100, 100 to 110, 110 to 120, 120 to 130, 130 to 140, 140 to 150, 150 to 160, 160 to 170, 170 to 180, 180 to 190, 190 to 200 second dosage forms containing DOPA decarboxylase inhibitors.

[0086] The number of dosage forms in a multi-particle dosage form is determined by factors such as the dosage of the active pharmaceutical ingredient and the size of the dosage form.

[0087] In one embodiment, the drug dosage form, such as the first and second dosage forms, is an oral solid dosage form. In one embodiment, the oral solid dosage form is selected from tablets, mini-tablets, micro-tablets, balls, micro-pellets, granules, and capsules.

[0088] In one embodiment, the oral solid dosage form includes a coating. In one embodiment, the oral solid dosage form includes a core and a coating. In one embodiment, the core contains an active pharmaceutical ingredient. In one embodiment, the coating does not contain an active pharmaceutical ingredient.

[0089] In one embodiment, the oral solid dosage form is selected from coated tablets, coated microtablets, coated microtablets, coated spheres, coated micropellets, coated granules, and coated capsules.

[0090] In one embodiment, the oral solid dosage form comprises a swellable and soluble core.

[0091] In one implementation, the coating is a film coating.

[0092] In one embodiment, the coating is a semi-permeable coating, such as a semi-permeable insoluble membrane coating. After the core swells, the active pharmaceutical ingredient is released through the semi-permeable membrane coating.

[0093] In one implementation, the coating is an insoluble coating.

[0094] In one implementation, the coating is a ruptureable coating.

[0095] In one embodiment, the coating is a ruptureable, insoluble coating. After the core component swells, the outer coating ruptures and releases the contents.

[0096] In one implementation, the coating is a soluble or etchable coating.

[0097] In one embodiment, the oral solid dosage form comprises a soluble core coated with an insoluble membrane, such as an insoluble semipermeable membrane.

[0098] In one embodiment, the pharmaceutical dosage form is a coated microtablet. In another embodiment, the pharmaceutical dosage form is a tablet, such as a coated tablet. In yet another embodiment, the pharmaceutical dosage form is a tablet comprising a coated microtablet compressed into a tablet.

[0099] In one embodiment, the coating is spray coating. In another embodiment, the coating is compression coating.

[0100] In one embodiment, the coating comprises a film-forming polymer. In one embodiment, the coating comprises a water-insoluble polymer. In one embodiment, the coating further comprises a pore-forming agent, such as a hydrophilic pore-forming agent.

[0101] Microtablets are tablets with a diameter of ≤3mm and represent a new trend in solid dosage form design. They overcome some therapeutic barriers such as impaired swallowing and polydrug therapy, and also provide some therapeutic benefits such as dosage flexibility and co-release modes.

[0102] In one embodiment, the microtablet is a tablet with a diameter less than or equal to (≤) 3 mm, such as ≤2.5 mm, for example ≤2 mm, such as ≤1.5 mm, for example ≤1 mm. In one embodiment, the microtablet is a tablet with a diameter of 1 to 1.5 mm, such as 1.5 to 2 mm, for example 2 to 2.5 mm, such as 2.5 to 3 mm. In one embodiment, the microtablet is a tablet with a diameter of about 2 mm.

[0103] In one embodiment, the pharmaceutical composition provides an S-shaped release profile of levodopa and a DOPA decarboxylase inhibitor, preferably varied in time, wherein the lag time of the first pulse release of levodopa is longer than the lag time of the second pulse release of the DOPA decarboxylase inhibitor.

[0104] The hysteresis time of the pulse release components is adjusted to release the levodopa and the DOPA decarboxylase inhibitor in the small intestine (e.g., the lower part of the small intestine).

[0105] In one embodiment, the lag time of the pulse-release component comprising levodopa and a DOPA decarboxylase inhibitor is 2 to 8 hours; such as 2 to 3 hours, such as 3 to 4 hours, such as 4 to 5 hours, such as 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours.

[0106] Preferably, the hysteresis time of the first pulse-release component containing levodopa and the second pulse-release component containing a DOPA decarboxylase inhibitor is adjusted to release the active pharmaceutical ingredient in the small intestine (e.g., the lower part of the small intestine). Preferably, the DOPA decarboxylase inhibitor is released before levodopa is released in the small intestine (e.g., the lower part of the small intestine).

[0107] In one embodiment, the hysteresis time of the first pulse-release component containing levodopa is 2 to 8 hours; such as 2 to 3 hours, such as 3 to 4 hours, such as 4 to 5 hours, such as 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours.

[0108] In one implementation, the hysteresis time of the first pulse-release component containing levodopa is 3 to 6 hours, such as 4 to 6 hours, such as 3 to 5 hours.

[0109] In one embodiment, the hysteresis time of the first pulse release component containing levodopa is at least 2 hours, such as at least 3 hours, such as at least 4 hours.

[0110] In one embodiment, the lag time of the second pulse-release component containing the DOPA decarboxylase inhibitor is 2 to 8 hours; such as 2 to 3 hours, such as 3 to 4 hours, such as 4 to 5 hours, such as 5 to 6 hours, such as 6 to 7 hours, such as 7 to 8 hours.

[0111] In one embodiment, the lag time of the second pulse-release component containing the DOPA decarboxylase inhibitor is 3 to 6 hours, such as 4 to 6 hours, or 3 to 5 hours.

[0112] In one embodiment, the lag time of the second pulse-release component containing the DOPA decarboxylase inhibitor is at least 2 hours, such as at least 3 hours, such as at least 4 hours.

[0113] In one implementation, the lag times of the first formulation containing levodopa and the second formulation containing a DOPA decarboxylase inhibitor are altered over time, with the first formulation containing levodopa having the longest lag time.

[0114] In one implementation, the lag time of the first formulation containing levodopa is longer than that of the second formulation containing the DOPA decarboxylase inhibitor, such that the DOPA decarboxylase inhibitor is released before the levodopa is released.

[0115] In one implementation, the lag time of the first dosage form containing levodopa is 5 to 90 minutes longer than that of the second dosage form containing a DOPA decarboxylase inhibitor; for example, 5 to 10 minutes longer than the second dosage form containing a DOPA decarboxylase inhibitor, such as 10 to 15 minutes, 15 to 20 minutes, 20 to 25 minutes, 25 to 30 minutes, 30 to 35 minutes, 35 to 40 minutes, 40 to 45 minutes, 45 to 50 minutes, 50 to 55 minutes, 55 to 60 minutes, 60 to 65 minutes, 65 to 70 minutes, 70 to 75 minutes, 75 to 80 minutes, 80 to 85 minutes, for example, 85 to 90 minutes.

[0116] In one embodiment, the lag time of the first dosage form containing levodopa is 90 to 240 minutes longer than that of the second dosage form containing a DOPA decarboxylase inhibitor; for example, 90 to 100 minutes, 100 to 110 minutes, 110 to 120 minutes, 120 to 130 minutes, 130 to 140 minutes, 140 to 150 minutes, 150 to 160 minutes, 160 to 170 minutes, 170 to 180 minutes, 180 to 200 minutes, 200 to 220 minutes, or 220 to 240 minutes longer than that of the second dosage form containing a DOPA decarboxylase inhibitor.

[0117] In one embodiment, the lag time of the first dosage form containing levodopa is at least 5 minutes longer than the lag time of the second dosage form containing a DOPA decarboxylase inhibitor, such as at least 10 minutes longer, such as at least 15 minutes longer, such as at least 20 minutes longer, such as at least 25 minutes longer, such as at least 30 minutes longer, such as at least 35 minutes longer, such as at least 40 minutes longer, such as at least 45 minutes longer, such as at least 50 minutes longer, such as at least 55 minutes longer, or such as at least 60 minutes longer.

[0118] In one implementation, the lag time of the first dosage form containing levodopa is approximately 10 minutes longer than that of the second dosage form containing a DOPA decarboxylase inhibitor, such as approximately 15 minutes, approximately 20 minutes, approximately 25 minutes, approximately 30 minutes, approximately 35 minutes, approximately 40 minutes, approximately 45 minutes, approximately 50 minutes, approximately 55 minutes, or approximately 60 minutes.

[0119] After a lag time, the active pharmaceutical ingredient is released from the pharmaceutical composition or dosage form.

[0120] In one implementation, a first dosage form containing levodopa is released before a second dosage form containing a DOPA decarboxylase inhibitor.

[0121] In one embodiment, the first dosage form containing levodopa is released 5 to 10 minutes, such as 10 to 15 minutes, such as 15 to 20 minutes, such as 20 to 25 minutes, such as 25 to 30 minutes, such as 30 to 35 minutes, such as 35 to 40 minutes, such as 40 to 45 minutes, such as 45 to 50 minutes, such as 50 to 55 minutes, such as 55 to 60 minutes, such as 60 to 65 minutes, such as 65 to 70 minutes, such as 70 to 75 minutes, such as 75 to 80 minutes, such as 80 to 85 minutes, such as 85 to 90 minutes before the release of the second dosage form containing the DOPA decarboxylase inhibitor.

[0122] In one embodiment, the release of 70 to 100% of the drug loading from the pharmaceutical composition is measured 2 to 5 hours after the hysteresis period, i.e., the release of 70 to 100% of levodopa and / or DOPA decarboxylase inhibitor is measured 2 to 5 hours later.

[0123] In one embodiment, the release of 70 to 100% of the drug loading from the pharmaceutical composition is measured over 2 to 5 hours, such as 70 to 75%, 75 to 80%, 80 to 85%, 85 to 90%, 90 to 95%, or 95 to 100% of the drug loading over 2 to 5 hours.

[0124] In one embodiment, the pharmaceutical composition releases up to 100% of the drug loading within 2 hours after the hysteresis period. In one embodiment, the pharmaceutical composition releases 70%, such as 80%, such as 90%, such as 100% of the drug loading within 2 hours after the hysteresis period. In one embodiment, the pharmaceutical composition releases 70%, such as 80%, such as 90%, such as 100% of the drug loading within 2 to 5 hours after the hysteresis period, such as within 2 hours, such as within 3 hours, such as within 4 hours, such as within 5 hours.

[0125] Coated tablets

[0126] In one embodiment, the pharmaceutical dosage form comprises one or more coated tablets containing levodopa and a DOPA decarboxylase inhibitor, which provides a predetermined lag time followed by a pulsed release of the levodopa and the DOPA decarboxylase inhibitor.

[0127] In one embodiment, the drug dosage form is a multi-part dosage form that comprises the following components, either separately or together:

[0128] i) Coated tablets that provide a predetermined lag time, followed by a pulsed release of levodopa, and

[0129] ii) Coated tablets that provide a predetermined lag time followed by pulsed release of the DOPA decarboxylase inhibitor.

[0130] In one embodiment, the hysteresis time of the coated tablet containing levodopa is longer than that of the coated tablet containing a DOPA decarboxylase inhibitor.

[0131] In one embodiment, the coated tablet comprises a tablet core containing the active pharmaceutical ingredient and an outer coating.

[0132] Coated tablets include coated tablets and coated microtablets. In one embodiment, the coated tablet is a coated tablet. In another embodiment, the coated tablet is a coated microtablet.

[0133] In one embodiment, the coated tablet comprises a swellable and soluble micro-tablet core.

[0134] In one embodiment, the coated tablet comprises a semi-permeable membrane coating. After core swelling, the active pharmaceutical ingredient is released through the semi-permeable membrane.

[0135] In one embodiment, the coated tablet is a coated microtablet containing a semi-permeable membrane coating. After the microtablet core swells, the active pharmaceutical ingredient is released through the semi-permeable membrane.

[0136] In one embodiment, the coated tablet comprises a ruptureable, insoluble coating. After the core component swells, the outer coating ruptures and bursts the contents.

[0137] In one embodiment, a coated microtablet containing levodopa includes a swellable and soluble microtablet core containing levodopa and an outer semi-permeable membrane coating.

[0138] In one embodiment, a coated microtablet containing a DOPA decarboxylase inhibitor comprises a swellable and soluble microtablet core containing a DOPA decarboxylase inhibitor and an outer semi-permeable membrane coating.

[0139] In one embodiment, a coated tablet containing levodopa includes a swellable and soluble tablet core containing levodopa and a ruptureable insoluble coating.

[0140] In one embodiment, a coated tablet containing a DOPA decarboxylase inhibitor comprises a swellable and soluble tablet core containing a DOPA decarboxylase inhibitor and a ruptureable insoluble coating.

[0141] In one embodiment, the tablet core containing levodopa comprises or is composed of the following components:

[0142] -L-DOPA,

[0143] -Super disintegrant

[0144] - One or more excipients, and

[0145] -Optional, anti-adhesion agent.

[0146] In one embodiment, the tablet core contains 25 to 75% w / w of levodopa, such as 25 to 30%, 30 to 35%, 35 to 40%, 40 to 45%, 45 to 50%, 50 to 55%, 60 to 65%, 65 to 70%, or 70 to 75% w / w of levodopa.

[0147] In one embodiment, the microcapsule contains 1 to 5 mg of levodopa, such as 1 to 1.25 mg, 1.25 to 1.5 mg, 1.5 to 1.75 mg, 1.75 to 2 mg, 2 to 2.25 mg, 2.25 to 2.5 mg, 2.5 to 2.75 mg, 2.75 to 3 mg, 3 to 3.25 mg, 3.25 to 3.5 mg, 3.5 to 3.75 mg, 3.75 to 4 mg, 4 to 4.25 mg, 4.25 to 4.5 mg, 4.5 to 4.75 mg, or 4.75 to 5 mg of levodopa. In one embodiment, the microcapsule contains 2.5 to 3.5 mg of levodopa. In one embodiment, the microcapsule contains at least 2 mg, such as at least 2.5 mg of levodopa.

[0148] In one embodiment, the tablet core containing the DOPA decarboxylase inhibitor comprises or is composed of the following components:

[0149] -DOPA decarboxylase inhibitor

[0150] -Super disintegrant

[0151] - One or more excipients, and

[0152] -Optional, anti-adhesion agent.

[0153] In one embodiment, the tablet core contains 25 to 75% w / w of DOPA decarboxylase inhibitor, such as 25 to 30%, 30 to 35%, 35 to 40%, 40 to 45%, 45 to 50%, 50 to 55%, 60 to 65%, 65 to 70%, or 70 to 75% w / w of DOPA decarboxylase inhibitor.

[0154] Superdisintegrants are substances used in tablet pharmaceutical formulations that cause the tablets to disintegrate and release their drug substances upon contact with water.

[0155] In one embodiment, the tablet core contains 15 to 50% w / w of a superdisintegrant, such as 15 to 20%, 20 to 25%, 25 to 30%, 30 to 35%, 35 to 40%, 40 to 45%, or 45 to 50% w / w. In one embodiment, the tablet core contains at least 20% w / w of a superdisintegrant, such as at least 25% or at least 30% w / w. In one embodiment, the tablet core contains about 30% w / w of a superdisintegrant.

[0156] In one embodiment, the superdisintegrant is selected from cross-linked starch, cross-linked cellulose, cross-linked PVP (polyvinylpyrrolidone), cross-linked alginate, soybean polysaccharide, calcium silicate, gellan gum, and xanthan gum.

[0157] In one embodiment, the tablet core comprises one or more superdisintegrants selected from: sodium glycolate starch (sodium carboxymethyl starch), croscarmellose sodium, cross-linked carboxymethyl cellulose, crosspovidone, crosspovidone XL, crosspovidone CL, and low-substituted hydroxypropyl cellulose (L-HPC). In one embodiment, the superdisintegrant is sodium glycolate starch.

[0158] Excipients are pharmacologically (or chemically) inactive substances formulated together with the active pharmaceutical ingredient of a drug. Excipients are commonly used to increase the composition of formulations containing the active pharmaceutical ingredient (and are therefore often called "bulking agents," "fillers," or "diluents") to allow for convenient and accurate dispensing of the drug substance during the production of the dosage form.

[0159] In one embodiment, the core contains 10 to 50% w / w of excipients, such as 10 to 15%, 15 to 20%, 20 to 25%, 25 to 30%, 30 to 35%, 35 to 40%, 40 to 45%, or 45 to 50% w / w of excipients.

[0160] In one embodiment, the excipient acts as a binder, filler, solid carrier, diluent, flavoring agent, solubilizer, lubricant, flow aid, suspending agent, preservative, anti-adhesion agent, wetting agent, disintegrant, or adsorbent, or a combination thereof.

[0161] In one embodiment, the core comprises one or more fillers, such as those selected from calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, glucose dextrorate, dextrin, glucose, ethyl cellulose, fructose, isomaltitol, lactitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, microcrystalline cellulose (MCC), polydextrin, sodium alginate, sorbitol, talc, and xylitol.

[0162] In one embodiment, the core comprises one or more adhesives, such as those selected from gum arabic, alginate, carbomer, sodium carboxymethyl cellulose, carrageenan, cellulose acetate phthalate, chitosan, copovidone, glucose binder, dextrin, glucose, ethyl cellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, hydroxypropyl methyl cellulose (HPMC or hydroxypropyl methyl cellulose), methyl cellulose, microcrystalline cellulose (MCC), poloxamer, polydextrose, polyethylene oxide, povidone, sodium alginate, sucrose, starch, pregelatinized starch, and maltodextrin.

[0163] In one embodiment, the core comprises one or more wet adhesives. In another embodiment, the microcore comprises one or more wet adhesives selected from pregelatinized starch, HPMC, methylcellulose, and gelatin.

[0164] In one embodiment, the core contains 5 to 25% w / w of adhesive, such as 5 to 7.5%, 7.5 to 10%, 10 to 12.5%, 12.5 to 15%, 15 to 17.5%, 17.5 to 20%, 20 to 22.5%, or 22.5 to 25% w / w of adhesive.

[0165] In one embodiment, the core comprises 1 to 20% w / w of wet adhesive, such as 1 to 2.5%, 2.5 to 5%, 5 to 7.5%, 7.5 to 10%, 10 to 12.5%, 12.5 to 15%, 15 to 17.5%, or 17.5 to 20% w / w of wet adhesive.

[0166] In one embodiment, the microchip core comprises microcrystalline cellulose (MCC) and pregelatinized starch.

[0167] In one embodiment, the core comprises 5 to 25% w / w microcrystalline cellulose, such as 5 to 7.5%, 7.5 to 10%, 10 to 12.5%, 12.5 to 15%, 15 to 17.5%, 17.5 to 20%, 20 to 22.5%, or 22.5 to 25% w / w microcrystalline cellulose. In another embodiment, the microcore comprises 10 to 20% w / w microcrystalline cellulose.

[0168] In one embodiment, the core contains 1 to 20% w / w of pregelatinized starch, such as 1 to 2.5%, 2.5 to 5%, 5 to 7.5%, 7.5 to 10%, 10 to 12.5%, 12.5 to 15%, 15 to 17.5%, or 17.5 to 20% w / w of pregelatinized starch. In one embodiment, the micro-core contains 5 to 15% w / w, such as 5 to 10% w / w of pregelatinized starch.

[0169] In one embodiment, the core comprises an anti-adhesion agent, such as an anti-adhesion agent comprising 0.25 to 0.50% w / w, such as 0.50 to 0.75%, such as 0.75 to 1.0%, such as 1.0 to 1.25%, such as 1.25 to 1.50%, such as 1.50 to 1.75%, such as 1.75 to 2.0% w / w.

[0170] In one embodiment, the anti-adhesion agent is selected from magnesium stearate, calcium stearate, zinc stearate, glyceryl monostearate, hydrogenated castor oil, hydrogenated vegetable oil, medium-chain triglycerides, palmitic acid, poloxamer, polyethylene glycol, stearic acid, and talc. In one embodiment, the anti-adhesion agent is magnesium stearate.

[0171] In one embodiment, the tablet core containing levodopa comprises or is composed of the following components:

[0172] -25 to 75% w / w levodopa; such as 25 to 30%, 30 to 35%, 35 to 40%, 40 to 45%, 45 to 50%, 50 to 55%, 60 to 65%, 65 to 70%, 70 to 75% w / w levodopa,

[0173] -15 to 50% w / w superdisintegrant; such as 15 to 20%, such as 20 to 25%, such as 25 to 30%, such as 30 to 35%, such as 35 to 40%, such as 40 to 45%, such as 45 to 50% w / w superdisintegrant.

[0174] -10 to 50% w / w excipients; such as 10 to 15%, such as 15 to 20%, such as 20 to 25%, such as 25 to 30%, such as 30 to 35%, such as 35 to 40%, such as 40 to 45%, such as 45 to 50% w / w excipients, and

[0175] -0 to 2% w / w anti-adhesion agent; such as 0.25 to 0.50% w / w anti-adhesion agent, such as 0.50 to 0.75%, such as 0.75 to 1.0%, such as 1.0 to 1.25%, such as 1.25 to 1.50%, such as 1.50 to 1.75%, such as 1.75 to 2.0% w / w anti-adhesion agent.

[0176] In one embodiment, the tablet core containing levodopa comprises or is composed of the following components:

[0177] -40 to 60% w / w of levodopa,

[0178] -20 to 40% w / w super disintegrant

[0179] -10 to 30% w / w excipients, and

[0180] -0.5 to 1.5% w / w of anti-adhesion agent.

[0181] In one embodiment, the tablet core containing levodopa comprises or is composed of the following components:

[0182] -40 to 60% w / w, such as 45 to 55% w / w levodopa

[0183] -20 to 40% w / w, such as 25 to 35% w / w sodium glycolate starch.

[0184] -5 to 25% w / w, such as 10 to 20% w / w microcrystalline cellulose.

[0185] -1 to 20% w / w, such as 5 to 10% w / w pregelatinized starch, and

[0186] -0.5 to 1.5% w / w, such as 1% w / w magnesium stearate.

[0187] In one embodiment, the tablet core containing the DOPA decarboxylase inhibitor comprises or is composed of the following components:

[0188] - 25 to 75% w / w DOPA decarboxylase inhibitors; such as 25 to 30%, 30 to 35%, 35 to 40%, 40 to 45%, 45 to 50%, 50 to 55%, 60 to 65%, 65 to 70%, 70 to 75% w / w DOPA decarboxylase inhibitors.

[0189] -15 to 50% w / w superdisintegrant; such as 15 to 20%, such as 20 to 25%, such as 25 to 30%, such as 30 to 35%, such as 35 to 40%, such as 40 to 45%, such as 45 to 50% w / w superdisintegrant.

[0190] -10 to 50% w / w excipients; such as 10 to 15%, such as 15 to 20%, such as 20 to 25%, such as 25 to 30%, such as 30 to 35%, such as 35 to 40%, such as 40 to 45%, such as 45 to 50% w / w excipients, and

[0191] -0 to 2% w / w anti-adhesion agent; such as 0.25 to 0.50% w / w anti-adhesion agent, such as 0.50 to 0.75%, such as 0.75 to 1.0%, such as 1.0 to 1.25%, such as 1.25 to 1.50%, such as 1.50 to 1.75%, such as 1.75 to 2.0% w / w anti-adhesion agent.

[0192] In one implementation, the chip core contains carbidopa.

[0193] In one embodiment, the coated tablets are produced by granulation, compression, and subsequent film coating.

[0194] In one embodiment, the coated microtablets are compressed to form tablets.

[0195] In one embodiment, the coated microtablets are packaged in capsules, sachets, pouches, or sticks.

[0196] Coating

[0197] Imagine applying an outer coating to increase the weight of the tablet to some extent, thereby delaying the release of the substance. As defined herein, weight increase or bulking is an increase relative to the weight of the tablet core.

[0198] In one embodiment, an outer coating is applied to increase the weight of the microchip by 10 to 40% w / w, such as 10 to 12.5%, 12.5 to 15%, 15 to 17.5%, 17.5 to 20%, 20 to 22.5%, 22.5 to 25%, 25 to 27.5%, 27.5 to 30%, 30 to 32.5%, 32.5 to 35%, 35 to 37.5%, or 37.5 to 40% w / w. In one embodiment, this applies to microchips containing levodopa and microchips containing a DOPA decarboxylase inhibitor.

[0199] In one embodiment, an outer coating is applied to increase the weight of the microchip by 17.5% to 25% w / w, such as 20 to 25% w / w.

[0200] In one embodiment, an outer coating is applied to increase the weight of the microchip by at least 15% w / w, such as at least 17.5%, at least 20%, at least 22.5%, or at least 25% w / w.

[0201] In one embodiment, an outer coating is applied to increase the weight of the microchip by about 15% w / w, such as about 17.5%, about 20%, about 22.5%, about 25%, about 27.5%, or about 30% w / w.

[0202] In one embodiment, an outer coating is applied to increase the weight of the tablet core (non-microtablet) by 1 to 20% w / w, such as 1 to 2.5%, 2.5 to 5%, 5 to 7.5%, 7.5 to 10%, 10 to 12.5%, 12.5 to 15%, 15 to 17.5%, or 17.5 to 20% w / w. In one embodiment, this applies to tablet cores containing levodopa and tablet cores containing DOPA decarboxylase inhibitors.

[0203] In one implementation, an outer coating is applied to a tablet core containing levodopa to achieve the desired hysteresis time as defined elsewhere herein.

[0204] In one embodiment, an outer coating is applied to a tablet core containing a DOPA decarboxylase inhibitor to achieve the desired hysteresis time as defined elsewhere herein.

[0205] In one embodiment, the weight of the coating of a tablet core containing levodopa is increased and the weight of the coating of a tablet core containing a DOPA decarboxylase inhibitor is increased to release levodopa prior to the DOPA decarboxylase inhibitor as specified herein.

[0206] In one embodiment, the weight increase of the coating of a tablet core containing levodopa is higher than the weight increase of the coating of a tablet core containing a DOPA decarboxylase inhibitor.

[0207] In one implementation, the weight increase of the coating of a tablet core containing levodopa is 1 to 25 percentage points higher than that of a tablet core containing a DOPA decarboxylase inhibitor, such as 1 to 2 percentage points higher, such as 2 to 3 percentage points higher, such as 3 to 4 percentage points higher, such as 4 to 5 percentage points higher, such as 5 to 6 percentage points higher, such as 6 to 7 percentage points higher, such as 7 to 8 percentage points higher, such as 8 to 9 percentage points higher, such as 9 to 10 percentage points higher, such as 10 to 11 percentage points higher, such as 11 to 12 percentage points higher, such as 12 to 13 percentage points higher, such as 13 to 14 percentage points higher, such as 14 to 15 percentage points higher, such as 15 to 16 percentage points higher, such as 16 to 17 percentage points higher, such as 17 to 18 percentage points higher, such as 18 to 19 percentage points higher, such as 19 to 20 percentage points higher, such as 20 to 21 percentage points higher, such as 21 to 22 percentage points higher, such as 22 to 23 percentage points higher, such as 23 to 24 percentage points higher, such as 24 to 25 percentage points higher.

[0208] In one embodiment, the coating is an insoluble and ruptureable film.

[0209] In one implementation, the coating is an insoluble semipermeable membrane.

[0210] In one implementation, the coating is a semi-permeable membrane.

[0211] In one embodiment, the coating comprises a film-forming polymer.

[0212] In one embodiment, the coating comprises a water-insoluble polymer.

[0213] In one embodiment, the coating comprises one or more of ethyl cellulose, hydroxypropyl cellulose, cellulose acetate, acrylic polymer, enteric polymer, hydroxypropyl methyl cellulose succinate, shellac, VAX, and ethyl cellulose dispersion.

[0214] In one embodiment, the coating comprises ethyl cellulose.

[0215] In one embodiment, the coating further comprises a pore-forming agent, such as a hydrophilic pore-forming agent. In one embodiment, the pore-forming agent is selected from polyvinyl alcohol (PVA), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone (PVP), and polyethylene glycol (PEG).

[0216] In one embodiment, the coating comprises a water-insoluble polymer and a hydrophilic pore-forming agent.

[0217] In one embodiment, the coating comprises ethyl cellulose and a pore-forming agent, such as a pore-forming agent selected from PVA, HPMC, PVP, and PEG. In one embodiment, the outer coating comprises ethyl cellulose and PVA. In one embodiment, the outer coating comprises ethyl cellulose and HPMC.

[0218] In one embodiment, the coating comprises 5 to 40% w / w of a pore-forming agent, such as 5 to 10% w / w, 10 to 15% w / w, 15 to 20% w / w, 20 to 25% w / w, 25 to 30% w / w, 30 to 35% w / w, or 35 to 40% w / w. In one embodiment, the outer coating comprises 10 to 30%, such as 15 to 25% w / w, of a pore-forming agent.

[0219] In one embodiment, the ratio of film-forming polymer (or water-insoluble polymer) to hydrophilic pore-forming agent in the coating is about 10 / 90, 15 / 85, 20 / 80, 25 / 75, or 30 / 70.

[0220] In one embodiment, the coating comprises about 80% w / w ethyl cellulose and about 20% w / w HPMC. In another embodiment, the outer coating comprises about 80% w / w ethyl cellulose and about 20% w / w PVA.

[0221] Application and dosage

[0222] The pharmaceutical compositions disclosed herein are preferably administered to individuals in need of treatment at pharmaceutically effective doses. A therapeutically effective dose of a compound or active pharmaceutical ingredient is an amount sufficient to cure, prevent, or reduce the risk of a given disease or movement disorder and its complications, or to alleviate or partially prevent its clinical manifestations. The effective dose for a specific therapeutic purpose will depend on the severity and type of the movement disorder, as well as the subject's weight and general condition.

[0223] The pharmaceutical composition according to this disclosure can be administered once or several times a day, such as 1 to 4 times a day, such as 1 to 3 times a day, such as 1 to 2 times a day, such as 2 to 4 times a day, such as 2 to 3 times a day. In one specific embodiment, the composition is administered once a day, such as twice a day, for example, 3 times a day, such as 4 times a day.

[0224] Application can last for a limited time, or it can be long-term, such as from the start of diagnosis, or throughout an individual's lifespan, or as long as the individual will benefit from it, i.e., when the movement disorder is present or when there is an increased risk of developing the movement disorder.

[0225] In one implementation, the pharmaceutical composition is administered whenever a movement disorder exists or whenever there is an increased risk of developing a movement disorder.

[0226] The concentrations of each active pharmaceutical ingredient (i.e., levodopa and ii) DOPA decarboxylase inhibitor in the pharmaceutical composition of the present invention are optimized to obtain an appropriate dose of each active pharmaceutical ingredient.

[0227] In one embodiment, the pharmaceutical composition comprises an amount of levodopa from 1 mg to 1000 mg per dose; such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 100, 150, 200, 250, 300, 400, 500, 600, 700, 800, 900, or 1000 mg of levodopa per dose, wherein said dose may be composed of one or more dosage forms containing said amount of levodopa.

[0228] Similarly, the pharmaceutical composition in one embodiment further comprises an amount of DOPA decarboxylase inhibitor of 1 to 250 mg per dose; such as about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 50, 75, 100, 125, 150, 175, 200 or 250 mg of DOPA decarboxylase inhibitor per dose, wherein said dose may be composed of one or more dosage forms containing said amount of DOPA decarboxylase inhibitor.

[0229] In one specific embodiment, the amount of levodopa in the pharmaceutical composition is about 100 mg, and the amount of a DOPA decarboxylase inhibitor such as carbidopa is about 25 mg.

[0230] In one embodiment, the pharmaceutical composition is a multi-particulate dosage form comprising the following:

[0231] i) The first dosage form, which contains approximately 100 mg of levodopa in 10 to 50 microtablets, such as 20 to 40 microtablets, such as about 33 microtablets, and

[0232] ii) Second dosage form, which contains about 25 mg of DOPA decarboxylase inhibitor such as carbidopa in 5-15 microtablets, such as about 10 microtablets.

[0233] Treatment for morning exercise inability

[0234] Oral levodopa typically provides robust and reliable symptom relief when first started. However, after several months or years of medication, most patients with Parkinson's disease begin to experience fluctuating responses to levodopa.

[0235] The fluctuating response is divided into "ON" times, during which the medication works well and controls Parkinson's symptoms, and "OFF" times, during which medication fails or is delayed in taking effect and Parkinson's symptoms are poorly controlled. Morning ataxia is a form of "OFF" episode. Symptoms of morning ataxia include tremor, bradykinesia, muscle rigidity, stiffness, and falls, as well as difficulty moving and walking in the morning.

[0236] One aspect of the present invention is to provide a pulsed-release pharmaceutical composition as defined herein for the treatment of morning dyskinesia in patients with Parkinson's disease.

[0237] One aspect of the present invention is to provide a pulsed-release pharmaceutical composition comprising...

[0238] i) Levodopa and DOPA decarboxylase inhibitors, and

[0239] ii) A pulsed release component, which provides a predetermined hysteresis time, followed by a pulsed release of the levodopa and the DOPA decarboxylase inhibitor.

[0240] Morning exercise is not recommended for patients with Parkinson's disease.

[0241] One aspect of the present invention is to provide a pharmaceutical composition comprising, separately or together, the following components:

[0242] i) Containing a first pulse-release component of levodopa, the first pulse-release component providing a predetermined hysteresis time, followed by pulse-release of levodopa, and

[0243] ii) A second pulse-release component comprising a DOPA decarboxylase inhibitor, the second pulse-release component providing a predetermined lag time, followed by pulse release of the DOPA decarboxylase inhibitor.

[0244] Optionally, the hysteresis time of the first pulse-release component containing levodopa is longer than the hysteresis time of the second pulse-release component containing the DOPA decarboxylase inhibitor.

[0245] It is used to treat patients with Parkinson's disease who cannot exercise in the morning.

[0246] One aspect of the present invention is to provide the use of a pharmaceutical composition for the production of a medicament for treating morning dyskinesia in patients with Parkinson's disease, said pharmaceutical composition comprising the following components, separately or together:

[0247] i) Containing a first pulse-release component of levodopa, the first pulse-release component providing a predetermined hysteresis time, followed by pulse-release of levodopa, and

[0248] ii) A second pulse-release component comprising a DOPA decarboxylase inhibitor, the second pulse-release component providing a predetermined lag time, followed by pulse release of the DOPA decarboxylase inhibitor.

[0249] Optionally, the hysteresis time of the first pulse-release component containing levodopa is longer than the hysteresis time of the second pulse-release component containing the DOPA decarboxylase inhibitor.

[0250] In one aspect, a method is provided for treating morning inability to move in a patient with Parkinson's disease, the method comprising administering a pharmaceutical composition comprising the following components, either separately or together:

[0251] i) Containing a first pulse-release component of levodopa, the first pulse-release component providing a predetermined hysteresis time, followed by pulse-release of levodopa, and

[0252] ii) A second pulse-release component comprising a DOPA decarboxylase inhibitor, the second pulse-release component providing a predetermined lag time, followed by pulse release of the DOPA decarboxylase inhibitor.

[0253] Optionally, the hysteresis time of the first pulse-release component containing levodopa is longer than the hysteresis time of the second pulse-release component containing the DOPA decarboxylase inhibitor.

[0254] Also provided are pharmaceutical compositions as defined herein for use in the following ways: a) improving nighttime sleep patterns in patients with Parkinson's disease; b) reducing sleep disturbances involved in triggering morning OFF periods; c) providing overnight levodopa coverage in patients with Parkinson's disease; d) reducing OFF time in patients with Parkinson's disease; e) reducing nocturnal dopaminergic decline; and / or f) increasing ON time in patients with Parkinson's disease.

[0255] Also provided are pharmaceutical compositions as defined herein, and methods for alleviating motor and non-motor symptoms associated with morning inability to move in patients with Parkinson's disease.

[0256] The main nonmotor symptoms associated with morning inability to exercise are urinary urgency, anxiety, drooling, pain, low mood, paresthesia of the limbs, and dizziness.

[0257] Other recent symptoms not associated with morning exercise include postprandial bloating, abdominal discomfort, early satiety, nausea, vomiting, weight loss, and malnutrition.

[0258] As used herein, the term "treatment" refers to the management and care of a patient in order to combat a condition, disease, or symptom. This term is intended to encompass comprehensive treatment of a patient with a given condition, such as the administration of a composition for the purpose of: relieving or reducing symptoms or complications; and / or preventing the condition, disease, or symptom, where "prevention" is understood to mean the management and care of the patient to prevent the development of the condition, disease, or symptom, and includes the administration of a composition to prevent or reduce the risk of the onset of symptoms or complications. Patients to be treated are preferably mammals, particularly humans.

[0259] The terms “Parkinson’s disease”, “PD”, and “Parkinson’s syndrome” refer to a neurological syndrome characterized by dopamine deficiency, caused by degenerative, vascular, or inflammatory changes in the substantia nigra-basal ganglia. The term also refers to syndromes similar to Parkinson’s disease, but these may or may not be caused by Parkinson’s disease, such as Parkinson’s-like side effects caused by certain antipsychotic medications.

[0260] In one embodiment, the composition is administered in a therapeutically effective amount. As used herein, a therapeutically effective amount means an amount sufficient to cure, alleviate, prevent, or reduce a given disease or condition and its complications (particularly the inability to move in the morning in patients with Parkinson's disease), decrease its risk, or partially prevent its clinical manifestations.

[0261] In one embodiment, the pharmaceutical composition is administered before bedtime.

[0262] In one embodiment, the pharmaceutical composition is administered once daily before bedtime.

[0263] In one embodiment, the pharmaceutical composition is administered before bedtime.

[0264] In one embodiment, the pharmaceutical composition is administered once daily before bedtime.

[0265] In one embodiment, the pharmaceutical composition is administered 4 to 0 hours before bedtime, such as 4 to 3 hours before bedtime. 1 / 2 hours, such as 3 1 / 2 to 3 hours, such as 3 hours to 2 1 / 2 hours, such as 2 1 / 2 hours to 2 hours, such as 2 hours to 1 1 / 2 hours, such as 1 1 / 2 hours to 1 hour, such as 1 hour to 45 minutes, such as 45 minutes to 30 minutes, such as 30 minutes to 20 minutes, such as 20 minutes to 15 minutes, such as 15 minutes to 10 minutes, such as 10 minutes to 5 minutes, such as 5 minutes to 1 minute, such as 1 minute to 0 minutes.

[0266] In one embodiment, the pharmaceutical composition is administered 4 to 0 hours before bedtime, such as 4 to 3 hours before bedtime. 1 / 2 hours, such as 3 1 / 2 to 3 hours, such as 3 hours to 2 1 / 2 hours, such as 2 1 / 2 hours to 2 hours, such as 2 hours to 1 1 / 2 hours, such as 1 1 / 2 hours to 1 hour, such as 1 hour to 45 minutes, such as 45 minutes to 30 minutes, such as 30 minutes to 20 minutes, such as 20 minutes to 15 minutes, such as 15 minutes to 10 minutes, such as 10 minutes to 5 minutes, such as 5 minutes to 1 minute, such as 1 minute to 0 minutes.

[0267] In one embodiment, the pharmaceutical composition is administered in combination with an immediate-release levodopa product and / or a controlled-release levodopa product.

[0268] Other active pharmaceutical ingredients

[0269] In one embodiment, the pharmaceutical composition further comprises one or more other active pharmaceutical ingredients, either separately or together. Such other active pharmaceutical ingredients may be present in a first dosage form containing levodopa, a second dosage form containing a DOPA decarboxylase inhibitor, or a third dosage form.

[0270] In one embodiment, other active pharmaceutical ingredients are selected from dopamine; dopamine receptor agonists such as bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine, ergotamine and their derivatives; catechol-O-methyltransferase (COMT) inhibitors, such as tocapone and entacapone; apomorphine, such as apomorphine injection; NMDA antagonists such as amatidine (Symmetrel); MAO-B inhibitors such as selegiline and rasagiline; serotonin receptor modulators; κ opioid receptor agonists such as TRK-820 ((E)-N-[17-cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl]-3-(furan-3-yl)-N-methylpropyl-2-enamide monohydrochloride); GABA modulators; neuronal potassium channel modulators such as flupirtine and retigabine; and glutamate receptor modulators.

[0271] In one embodiment, the pharmaceutical composition is administered in combination with other levodopa-containing pharmaceutical compositions having immediate-release and controlled-release properties to achieve pharmacologically active levels of levodopa for a prolonged period, such as approximately 1-8 hours. This would significantly reduce the dosing frequency for most Parkinson's disease patients compared to currently used products.

[0272] In one embodiment, the pharmaceutical composition is administered in combination with an immediate-release product containing levodopa, and / or in combination with a controlled-release product containing levodopa.

[0273] In one embodiment, the pharmaceutical composition is administered in combination with one or more products selected from Sinemet, Pharmacopa, Atamet, Stalevo, Madopar, Prolopa, Parcopa, Lodosyn, Modopar, Madopark, Neodopasol, EC-Doparyl, Aldomet, Aldoril, Dopamet, and Dopegyt.

[0274] In one embodiment, the pharmaceutical composition as disclosed herein and other active pharmaceutical ingredients are administered simultaneously, separately, or sequentially.

[0275] Reagent test kit

[0276] This disclosure also provides a kit for treating morning exercise insufficiency as described herein.

[0277] The kit according to this disclosure includes a pharmaceutical composition as defined herein for the treatment, prevention, or relief of morning motor insufficiency. The kit allows for the simultaneous, sequential, or separate administration of the pharmaceutical composition and one or more other active pharmaceutical ingredients as described herein.

[0278] Example

[0279] Example 1

[0280] Lactose, microcrystalline cellulose, sodium glycolate starch, and the model compound (nicotinamide) were mixed in a drum mixer for 5 minutes. Magnesium stearate was then added and mixed for 30 seconds. The mixture was compressed into tablets, each weighing 6.6 mg, measuring 2 mm, and containing 0.28 mg of the model compound. The tablet thickness was approximately 1.7 mm.

[0281] lactose 183.20 microcrystalline cellulose 76.00 Sodium glycolate starch 120.00 Model compounds 16.80 magnesium stearate 4.00 total 400.00

[0282] Microtablets of the model compound were membrane-coated in a fluidized bed using an ethyl cellulose-based semi-permeable membrane. The membrane composition is given in the table below. For a 325g chip, 1000g of membrane solution was produced to achieve the desired tablet weight gain of up to 25.0%, including a 10% production loss excess. Spray conditions were controlled with an outlet air temperature of 28–30°C. To achieve the desired weight gains of 20%, 23%, and 25%, 682.0g, 784.9g, and 853.1g of membrane solution were applied, respectively.

[0283] Ethyl cellulose 7cps 100.0 96% ethanol 900.0 total 1000.0

[0284] The dissolution of 44 microtablets was tested using a USP2 paddle apparatus (USP paddle dissolution test method). Each container contained 600 ml of isotonic sodium chloride solution and was rotated at 75 rpm. The re-extracted samples were quantified at 260 nm using a spectrophotometer. Results were obtained in... Figure 2 As shown in the image.

[0285] Example 2

[0286] The microtablets of Example 1 were membrane-coated in a fluidized bed using an ethyl cellulose-based semi-permeable membrane. The membrane composition is given in the table below. For a 325g chip, 1000g of membrane solution was produced to achieve the desired tablet weight increase of up to 25.0%, including a 10% production loss excess. Spray conditions were controlled with an outlet air temperature of 28-29°C. To achieve the desired weight gains of 10%, 15%, 20%, and 25%, 341.3g, 511.9g, 682.5g, and 853.1g of membrane solution were applied, respectively.

[0287] Ethyl cellulose 7cps 90.0 96% ethanol 675.0 Polyvinyl alcohol 10.0 Purified water 225.0 total 1000.0

[0288] Dissolution of 44 microtablets was tested using a USP2 paddle apparatus. Each container contained 600 ml of isotonic sodium chloride solution and was rotated at 75 rpm. The re-extracted samples were quantified at 260 nm using a spectrophotometer. Results were obtained in... Figure 3A As shown in the image.

[0289] Example 3

[0290] As described in Example 2, the microtablets of Example 1 were coated with the following film composition:

[0291] Ethyl cellulose 7cps 76.0 96% ethanol 678.7 Polyvinyl alcohol 19.01 Purified water 226.2 total 1000.0

[0292] As described in Example 2, the microtablets were tested, and the results were... Figure 3B The information is provided in the text.

[0293] Example 4

[0294] As described in Example 2, the microtablets of Example 1 were coated with the following film composition:

[0295] Ethyl cellulose 7cps 90.0 96% ethanol 675.75 Hydroxypropyl methylcellulose 3 9.0 Purified water 225.25 total 1000.0

[0296] As described in Example 2, the microtablets were tested, and the results were... Figure 4A The information is provided in the text.

[0297] Example 5

[0298] As described in Example 2, the microtablets of Example 1 were coated with the following film composition:

[0299] Ethyl cellulose 7cps 80.0 96% ethanol 675.0 Hydroxypropyl methylcellulose 3 20.0 Purified water 225.0 total 1000.0

[0300] As described in Example 2, the microtablets were tested, and the results were... Figure 4B The information is provided in the text.

[0301] Example 6

[0302] L-DOPA was mixed with microcrystalline cellulose, sodium glycolate starch, and pregelatinized starch in a 1L high-shear mixer for 2 minutes. Purified water was slowly added over 3–4 minutes while mixing until the appropriate moisture content was achieved, then granulated for 2 minutes. The resulting granules were dried overnight at 40°C and sieved through a 0.6 mm sieve.

[0303] Levodopa 180.00 microcrystalline cellulose 60.00 Sodium glycolate starch 30.00 Pregelatinized starch 30.00 Purified water qs (≈160g) total 300.0

[0304] The produced levodopa granules are mixed with sodium glycolate starch and magnesium stearate.

[0305] L-DOPA granules 277.0 Sodium glycolate starch 80.91 magnesium stearate 3.62 total 361.53

[0306] The mixture was compressed into tablets, each weighing 6.15 mg, measuring 2 mm in size, and containing 2.8 mg of levodopa. The tablets were approximately 1.7 mm thick.

[0307] composition ％ mg / tablet Levodopa 46.0％ 2.83 microcrystalline cellulose 15.3％ 0.94 Sodium glycolate starch 30.0％ 1.85 Pregelatinized starch 7.7％ 0.47 magnesium stearate 1.0％ 0.06 total 6.15

[0308] Levodopa microtablets were membrane-coated in a fluidized bed using an ethyl cellulose-based semi-permeable membrane. The membrane composition is given in the table below. For 320g chips, 900g of membrane solution was produced to achieve the desired tablet weight gain of up to 25.0%, including a 10% production loss excess. Spray conditions were controlled with an outlet air temperature of 27–29°C. To achieve the desired weight gains of 10%, 15%, 20%, and 25%, 336.0g, 504.0g, 672.0g, and 840.0g of membrane solution were applied, respectively.

[0309] Ethyl cellulose 7cps 72.0 96% ethanol 607.5 Hydroxypropyl methylcellulose 3cps 18.0 Purified water 202.5 total 900.0

[0310] 100mg of levodopa corresponds to approximately 35 microtablets.

[0311] Example 7

[0312] L-DOPA was mixed with microcrystalline cellulose, sodium glycolate starch, and pregelatinized starch in a 1L high-shear mixer for 2 min. Purified water was slowly added over 3–4 min while mixing until the appropriate moisture content was achieved, followed by granulation for 2 min. The resulting granules were dried overnight at 40°C and sieved through a 0.6 mm sieve.

[0313] Levodopa 195.00 microcrystalline cellulose 60.00 Sodium glycolate starch 15.00 Pregelatinized starch 30.00 Purified water qs (≈160g) total 300.0

[0314] The produced levodopa granules were mixed with sodium glycolate starch and magnesium stearate. The mixture was compressed into tablets, each weighing 6.4 mg, measuring 2 mm, and containing 3.0 mg of levodopa. The tablet thickness was approximately 1.7 mm.

[0315] L-DOPA granules 254.03 Sodium glycolate starch 92.47 magnesium stearate 3.50 total 350.0

[0316] Levodopa microtablets were membrane-coated in a fluidized bed using an ethyl cellulose-based semi-permeable membrane. The membrane composition is given in the table below. For 300g chips, 900g of membrane solution was produced to achieve the desired tablet weight gain of up to 25.0%, including a 10% production loss excess. Spray conditions were controlled with an outlet air temperature of 27–29°C. To achieve the desired weight gains of 17.5%, 20%, 22.5%, and 25%, 551.3g, 630.0g, 708.8g, and 787.5g of membrane solution were applied, respectively.

[0317] Ethyl cellulose 7cps 72.0 96% ethanol 607.5 Hydroxypropyl methylcellulose 3cps 18.0 Purified water 202.5 total 900.0

[0318] 100mg of levodopa corresponds to approximately 33 microtablets.

[0319] Example 8

[0320] The dissolution of the microtablets of Example 6 was tested using a USP2 paddle apparatus. Microtablets corresponding to 100 mg levodopa were tested in each container using 600 ml of isotonic sodium chloride solution and 75 rpm. The re-extracted samples were quantified at 284 nm using a spectrophotometer. Results were shown... Figure 6 The results shown in (solid line) and Example 5 (dashed line) demonstrate that levodopa has similar release compared to the model compound.

[0321] Example 9

[0322] The dissolution of the microtablets of Example 7 was tested using a USP2 paddle apparatus. Microtablets corresponding to 100 mg levodopa were tested in each container using 600 ml of isotonic sodium chloride solution and 75 rpm. The re-extracted samples were quantified at 284 nm using a spectrophotometer. Results were shown... Figure 5 middle.

[0323] Example 10

[0324] L-DOPA was mixed with microcrystalline cellulose, sodium glycolate starch, and pregelatinized starch in a 1L high-shear mixer for 2 min. Purified water was slowly added over 3–4 min while mixing until the appropriate moisture content was achieved, followed by granulation for 2 min. The resulting granules were dried overnight at 40°C and sieved through a 0.6 mm sieve.

[0325]

[0326]

[0327] The produced levodopa granules were mixed with sodium glycolate starch and magnesium stearate. The mixture was compressed into tablets, each weighing 5.75 mg, measuring 2 mm, and containing 4.0 mg of levodopa. The tablet thickness was approximately 1.6 mm.

[0328] L-DOPA granules 292.22 Sodium glycolate starch 16.66 magnesium stearate 3.12 total 312.0

[0329] As described in Example 6, levodopa microtablets were membrane-coated in a fluidized bed using a semi-permeable membrane. 100 mg of levodopa corresponds to approximately 44 microtablets.

[0330] The dissolution rate of the microtablets was tested as described in Example 8, and the results were as follows: Figure 7 The results show that using low levels of superdisintegrants results in poor control and poor burst release.

[0331] Example 11

[0332] Carbidopa was mixed with microcrystalline cellulose, sodium glycolate starch, and pregelatinized starch in a 1L high-shear mixer for 2 min. Purified water was slowly added over 3–4 min while mixing until the appropriate moisture content was achieved, followed by granulation for 2 min. The resulting granules were dried overnight at 40°C and sieved through a 0.6 mm sieve.

[0333] Carbidopa 100.00 microcrystalline cellulose 70.00 Sodium glycolate starch 10.00 Pregelatinized starch 20.00 Purified water qs (≈70g) total 200.0

[0334] The produced carbidopa granules were mixed with sodium glycolate starch and magnesium stearate. The mixture was compressed into tablets, each weighing 6.90 mg, measuring 2 mm, and containing 2.5 mg of carbidopa. The tablet thickness was approximately 1.9 mm.

[0335] Carbidopa Granules 217.74 Sodium glycolate starch 79.26 magnesium stearate 3.00 total 300.0

[0336] Carbidopa microtablets were membrane-coated in a fluidized bed using an ethyl cellulose-based semi-permeable membrane. The membrane composition is given in the table below. For 300g chips, 900g of membrane solution was produced to achieve the desired tablet weight gain of up to 25.0%, including a 10% production loss excess. Spray conditions were controlled with an outlet air temperature of 27–29°C. To achieve the desired weight gains of 10%, 15%, 20%, and 25%, 336.0g, 504.0g, 672.0g, and 840.0g of membrane solution were applied, respectively.

[0337] Ethyl cellulose 7cps 72.0 96% ethanol 607.5 Hydroxypropyl methylcellulose 3cps 18.0 Purified water 202.5 total 900.0

[0338] 25mg of carbidopa corresponds to approximately 10 microtablets.

[0339] Example 12

[0340] The dissolution of the microtablets of Example 11 was tested using a USP2 paddle apparatus. Microtablets corresponding to 25 mg carbidopa were tested in each container using 600 ml of isotonic sodium chloride solution and 75 rpm. The re-extracted samples were quantified at 284 nm using a spectrophotometer.

[0341] Example 13

[0342] Thirty-three levodopa microtablets coated to a 25% weight gain from Example 7 and ten film-coated carbidopa microtablets from Example 11 were mixed and filled into hard-shell gelatin capsules of capsule type 0. Each capsule contained a dose of 100 mg levodopa + 25 mg carbidopa, with the active ingredient released after a lag time; carbidopa was released, followed by levodopa.

[0343] Example 14

[0344] Morning exercise is not possible, Phase I PK study

[0345] A randomized, open-label, crossover study in healthy subjects to evaluate the pharmacokinetic characteristics and relative bioavailability of a single dose of several selected prototype formulations containing carbidopa and L-DOPA.

[0346] The primary endpoint was to evaluate the pharmacokinetic (PK) characteristics and relative bioavailability of a single dose of a variety of selected prototype pulse-release formulations containing carbidopa and L-DOPA.

[0347] The following evaluation will be conducted:

[0348] • Use concentration-time data from plasma to calculate applicable PK parameters for L-DOPA and carbidopa, including maximum plasma levels (Cmax and Tmax).

[0349] Example 15

[0350] Morning exercise is not recommended, Phase Ib, efficacy / safety and pharmacokinetics studies.

[0351] A randomized, double-blind, placebo-controlled, crossover study in Parkinson's disease patients with morning inability to move, evaluating the short-term efficacy and safety, as well as pharmacokinetic characteristics, of a single dose of several selected prototype formulations containing carbidopa and L-DOPA.

[0352] The primary endpoint was to evaluate the efficacy (short-term) of a single dose of a variety of selected prototype pulse-release formulations containing carbidopa and L-DOPA.

[0353] The following evaluation will be conducted:

[0354] • After treatment with a selected prototype formulation containing carbidopa and L-DOPA, assess Parkinson's disease symptoms in the morning when morning exercise is not frequent (using the UPDRS scale).

[0355] Example 10

[0356] Carbidopa was mixed with microcrystalline cellulose, sodium glycolate starch, and pregelatinized starch in a 1L high-shear mixer for 2 min. A solution of pregelatinized starch in purified water was slowly added over 2–3 min, mixing until the appropriate moisture content was achieved, followed by granulation for 1 min. The resulting granules were dried in a STREAM fluidized bed at approximately 60°C until the water activity was below 20%, and then sieved through a 1.4 mm sieve.

[0357] Carbidopa 75.00 microcrystalline cellulose 31.95 Sodium glycolate starch 28.05 Pregelatinized starch 10.00 Purified water 121 Pregelatinized starch 5.00 total 150.0

[0358] The produced carbidopa granules were mixed with sodium glycolate starch and magnesium stearate. The mixture was compressed into tablets, each weighing approximately 7.20 mg, measuring 2 mm in size, and containing 2.6 mg of carbidopa. The tablet thickness was approximately 1.8 mm.

[0359] Carbidopa Granules 254.10 Sodium glycolate starch 92.49 magnesium stearate 3.50 total 350.0

[0360] Carbidopa microtablets were membrane-coated in a fluidized bed using an ethyl cellulose-based semi-permeable membrane. The membrane composition is given in the table below. For 300g chips, 900g of membrane solution was produced to achieve the desired tablet weight gain of up to 25.0%, including a 5% production loss excess. Spray conditions were controlled with an outlet air temperature of 27–29°C. To achieve the desired weight gains of 15%, 17.5%, 20%, 22.5%, and 25%, 441.0g, 514.5g, 588.0g, 661.5g, and 735.0g of membrane solution were applied, respectively.

[0361]

[0362]

[0363] 25mg of carbidopa corresponds to approximately 10 microtablets.

[0364] Example 11

[0365] The dissolution of the microtablets of Example 16 was tested using a USP2 paddle apparatus. Microtablets corresponding to 25 mg carbidopa were tested in each container using 600 ml of isotonic sodium chloride solution and 75 rpm. The re-extracted samples were quantified at 284 nm using a spectrophotometer. Results were shown... Figure 8 middle.

Claims

1. A pulse-release multi-particle oral solid dosage form, comprising the following components: i) A first pulse-release component comprising levodopa, the first pulse-release component providing a lag time of 2 to 8 hours, followed by pulse-release of levodopa, wherein 70 to 100% of the levodopa is measured to be released 2 to 5 hours after the lag time, wherein the first pulse-release component is a coated microtablet, the coated microtablet comprising a core containing i. 35 to 50% w / w of levodopa, ii. 30 to 40% w / w sodium glycolate starch, iii. 10 to 20% w / w microcrystalline cellulose and 5%-10% w / w pregelatinized starch, iv. 0.5% to 2% w / w magnesium stearate, The microtablets comprise a semi-permeable membrane coating containing 4:1 ethyl cellulose and hydroxypropyl methylcellulose, and ii) A second pulse-release component comprising carbidopa, the second pulse-release component providing a lag time of 2 to 8 hours, followed by pulse release of the carbidopa, wherein 70 to 100% of the carbidopa is measured to be released 2 to 5 hours after the lag time, wherein the second pulse-release component is a coated microtablet, the coated microtablet comprising a core containing i. 30 to 40% w / w carbidopa, ii. 30 to 40% w / w sodium glycolate starch, iii. 15 to 25% w / w microcrystalline cellulose and 5%-10% w / w pregelatinized starch, and iv. 0.5% to 2% w / w magnesium stearate, The microtablets comprise a semi-permeable membrane coating containing ethyl cellulose and hydroxypropyl methylcellulose in a 4:1 ratio. The coating of the microtablets increases the weight of the microtablet core by 20-40% w / w.

2. The multi-particle oral solid dosage form according to claim 1, wherein the levodopa is selected from levodopa, pharmaceutically acceptable derivatives of levodopa, levodopa prodrugs, levodopa methyl ester, XP21279, modified levodopa, and deuterated levodopa.

3. The multi-particle oral solid dosage form according to claim 1, wherein the multi-particle dosage form is packaged in capsules, sachets, sachets or strips.

4. The multi-particle oral solid dosage form according to claim 1, wherein the first pulse-release component contains levodopa, and its lag time is longer than that of the second pulse-release component containing carbidopa, that is, by adjusting the increase of the coating weight of the micro-tablet core containing levodopa and the increase of the coating weight of the micro-tablet core containing carbidopa, carbidopa is released first, followed by levodopa.

5. The multi-particle oral solid dosage form according to claim 1, wherein the lag time of the first pulse-release component containing levodopa is 5 to 90 minutes longer than the lag time of the second pulse-release component containing carbidopa; for example, 5 to 10 minutes longer, 10 to 15 minutes longer, 15 to 20 minutes longer, 20 to 25 minutes longer, 25 to 30 minutes longer, 30 to 35 minutes longer, 35 to 40 minutes longer, 40 to 45 minutes longer, 45 to 50 minutes longer, 50 to 55 minutes longer, 55 to 60 minutes longer, 60 to 65 minutes longer, 65 to 70 minutes longer, 70 to 75 minutes longer, 75 to 80 minutes longer, 80 to 85 minutes longer, or 85 to 90 minutes longer.

6. The multi-particle oral solid dosage form according to claim 1, wherein the lag time of the first pulse-release component containing levodopa is at least 5 minutes longer than the lag time of the second pulse-release component containing carbidopa, such as at least 10 minutes, at least 15 minutes, at least 20 minutes, at least 25 minutes, at least 30 minutes, at least 35 minutes, at least 40 minutes, at least 45 minutes, at least 50 minutes, at least 55 minutes, or at least 60 minutes.

7. The multi-particle oral solid dosage form according to claim 1, wherein the coated microtablets are compressed into tablets.

8. The multi-particle oral solid dosage form according to claim 1, wherein the microcapsule core of the first pulse-release component comprises 1 to 5 mg of levodopa, such as 1 to 1.25 mg, such as 1.25 to 1.5 mg, such as 1.5 to 1.75 mg, such as 1.75 to 2 mg, such as 2 to 2.25 mg, such as 2.25 to 2.5 mg, such as 2.5 to 2.75 mg, such as 2.75 to 3 mg, such as 3 to 3.25 mg, such as 3.25 to 3.5 mg, such as 3.5 to 3.75 mg, such as 3.75 to 4 mg, such as 4 to 4.25 mg, such as 4.25 to 4.5 mg, such as 4.5 to 4.75 mg, such as 4.75 to 5 mg of levodopa.

9. The multi-particle oral solid dosage form according to claim 1, wherein the coating is applied to increase the weight of the microparticle core by 20 to 30% w / w.

10. The multi-particle oral solid dosage form of claim 1, wherein the coating is applied to increase the weight of the microparticle core by 20 to 25% w / w.

11. Use of the multi-particle oral solid dosage form according to any one of claims 1-10 in the preparation of a medicament for treating morning motor insufficiency in patients with Parkinson's disease.

12. Use of the multiparticle oral solid dosage form according to any one of claims 1-10 in the preparation of a medicament for treating morning motor insufficiency in patients with Parkinson's disease, wherein the medicament is administered before bedtime.

13. Use of the multi-particle oral solid dosage form according to any one of claims 1-10 in the preparation of a medicament for treating morning dyskinesia in patients with Parkinson's disease, wherein the medicament is administered in combination with an immediate-release levodopa product and / or a sustained-release levodopa product.

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