Multi-compartment composition for use in the treatment of parkinson's disease

Abstract

The present invention relates to a solid composition comprising at least two compartments, a first active pharmaceutical ingredient (API) and a second API, and its use in the treatment of Parkinson's disease, preferably for increasing the intake of the second API, thereby optimizing its use in the treatment of Parkinson's disease, in particular increasing its clinical activity and reducing its side effects associated with the treatment of Parkinson's disease.

Description

Technical Field

[0001] This invention relates to a solid composition and its use in the treatment of Parkinson's disease, the solid composition comprising at least two compartments, namely a first active pharmaceutical ingredient (API) and a second API, preferably for increasing the intake of the second API, thereby optimizing its use in the treatment of Parkinson's disease, particularly improving its clinical activity and reducing its side effects associated with the treatment of Parkinson's disease. Background Technology

[0002] Parkinson's disease (PD) is a chronic, progressive neurodegenerative disease that affects motor control. PD is characterized by the gradual loss of dopamine-producing cells, a neurotransmitter crucial for coordinating controlled muscle movement. The main symptoms of PD include tremor, bradykinesia (slowness of movement), rigidity, and postural instability. While these motor symptoms are the most prominent, individuals with Parkinson's disease may also experience a range of non-motor symptoms, such as cognitive impairment, mood disorders, sleep disturbances, and autonomic dysfunction.

[0003] While there is currently no cure for Parkinson's disease (PD), various treatment options, including medication, physical therapy, and in some cases surgical intervention, can help manage an individual's symptoms and improve their quality of life. A common medical treatment for PD is levodopa (L-DOPA or L-dopa). Levodopa is converted into dopamine in the brain, compensating for dopamine deficiency in PD patients, and is a key medication in managing PD. It is often combined with other medications to enhance the efficacy of those other drugs and address various aspects of the condition. Some common medications that contain or work in combination with levodopa include carbidopa / levodopa (Sinemet). This is one of the most widely used medications for PD. Carbidopa helps prevent levodopa from breaking down in the blood, allowing more levodopa to reach the brain, where it can be converted into dopamine. Sinemet is available in different formulations, including immediate-release and delayed-release versions. To date, only a few other levodopa / carbidopa formulations exist, such as delayed-release formulations, gel formulations, or orally disintegrating tablets.

[0004] Another approach to treating PD is a combination of levodopa with a so-called catechol-O-methyltransferase (COMT) inhibitor. For example, Stalevo is a drug that combines levodopa with carbidopa and entacapone. Entacapone is a COMT inhibitor, and it works by preventing the breakdown of levodopa in peripheral tissues, thereby prolonging the efficacy of levodopa.

[0005] In this context, several documents describe existing technologies. For example, WO 2019 / 136306 A1 relates to "off-phase ( off The method of administering an effective dose of a dry pharmaceutical composition containing levodopa, wherein the dose is administered via an intranasal delivery device. Further, WO 2023 / 059716 relates to a method comprising intranasal administration of a nanoparticle formulation containing a pharmaceutically effective amount of levodopa or a pharmaceutically acceptable salt thereof. WO 2022 / 107125 relates to a method for treating a neurological or motor disorder in an individual in need by parenteral administration of levodopa and a dopa decarboxylase inhibitor (DDCI) (such as carbidopa, benserazide, or any combination thereof), while simultaneously administering levodopa, DDCI (such as carbidopa, benserazide, or any combination thereof) orally.

[0006] As Parkinson's disease (PD) progresses, the remaining cells may become less responsive to levodopa, requiring higher doses to achieve the same level of symptom control. Furthermore, as the duration of levodopa treatment increases, higher doses may be needed to maintain efficacy. Higher doses of levodopa are also associated with an increased risk of side effects and complications. Long-term use of levodopa is associated with the development of motor fluctuations, including wearing-off periods and on / off fluctuations. Wearing-off or end-of-dose wearing-off. This refers to a weakening of levodopa's efficacy before the next dose is taken, leading to a relapse of symptoms. Specifically, in this situation, patients often experience what is known as gait freeze. Therefore, a common drawback of existing levodopa treatments for Parkinson's disease is that higher doses are inevitably required as the disease progresses. Long-term use of levodopa may cause patients to experience… End-of-dose "During the final stages of a dosing interval, the drug's effect diminishes before the next dose is taken, leading to a relapse of symptoms. Specifically, towards the end of each dosing interval, patients may experience a decline in the effectiveness of levodopa. This is known as '...'" The efficacy of the medicine diminishes at the end of the dose. This can manifest as a recurrence of PD symptoms (such as frozen gait) before the next dose is taken. Additionally, some patients may experience an 'on-off' fluctuation, characterized by improvements in mobility ("on-off" fluctuations). Open state ) and worsening of symptoms (" Guan Zhuang state Unpredictable fluctuations between these and other conditions. Another common drawback is their limited effect on non-motor symptoms such as cognitive impairment, depression, and autonomic dysfunction.

[0007] Levodopa increases dopamine levels in the brain, thereby alleviating motor symptoms such as bradykinesia and rigidity. However, it also has some significant limitations and complexities. Within 5 years of levodopa treatment, 40% to 50% of patients experience motor dysfunction and fluctuations (including off-phase symptoms), rising to 70% to 80% after 10 years (Rizek P et al. CMAJ(2016), 188: 1157-65). It is generally believed that pulsatile levodopa blood concentrations induced by conventional LD ​​formulations are associated with fluctuations and the development of motor complications. Therefore, there is a need for levodopa formulations that can provide continuous levodopa delivery to continuously generate dopamine in the brain.

[0008] Therefore, the fundamental problem of the present invention is to provide an improved PD treatment method in order to at least partially overcome the above-mentioned defects of the prior art. Summary of the Invention

[0009] Solutions are provided based on the subject matter of each independent claim.

[0010] The aforementioned problems are solved by various aspects of the present invention. The above-mentioned objectives are achieved, at least in part, by the subject matter of the independent claims. Preferred embodiments are the subject matter of the dependent claims, and other suitable aspects of the invention are described in the general disclosure of this application.

[0011] The headings provided in this disclosure are included only for ease of reading and to maintain an overview. These headings are not intended to limit the scope of this disclosure, nor do they exclude combinations of features derived from corresponding embodiments.

[0012] Although several compositions and their uses in treating diseases are described below, it should be noted that the subject matter described should be understood as equivalent expressions of methods of treatment, treatment methods, treatment modalities, or any alternative wording.

[0013] Composition for use The aforementioned problems are addressed at least in part by a solid composition for treating symptoms associated with Parkinson's disease, the composition comprising: at least two compartments separately arranged in the solid composition; a first active pharmaceutical ingredient (API) disposed in the first compartment of the at least two compartments, wherein the first API is selected from the group consisting of DOPA decarboxylase inhibitors or catechol-O-methyltransferase (COMT-) inhibitors; and a second API disposed in the second compartment of the at least two compartments, wherein the second API is an amino acid.

[0014] In the aforementioned prior art, PD treatment is based on orally administered formulations, which typically require continuous increases in individual dosage throughout the course of the disease. To reduce individual symptoms, the frequency of daily doses of the medical formulation is usually increased. This inevitably leads to increased side effects and a "dose-end-of-dose" phenomenon, particularly... Early morning closing period (morning off state, EMO) Symptoms such as gait freeze may occur. Patients may experience a recurrence of Parkinson's disease symptoms in the morning, which usually happens just before the next scheduled dose.

[0015] This invention is based on a different approach. The beneficial effects are particularly significant in altering the pharmacokinetic properties of the solid composition. Furthermore, the bioavailability of the API in the solid composition is enhanced compared to conventional compositions in the art. Specifically, the solid composition allows for the sequential release of the API, which may be desirable when administering one or more individual APIs. In this manner, the solid composition allows for convenient and efficient administration. In particular, the inventors have found that when using the solid composition according to this disclosure, the solid composition according to this disclosure exhibits a 50% to 120% increase in the bioavailability of the second API as assessed by the area under the curve (AUC). Furthermore, when using the solid composition according to this disclosure, the total number of API intakes during the course of disease is reduced. This is based on a longer duration of action, which is directly associated with the increased bioavailability. The resulting continuous blood profile of the second API may lead to another positive effect: the solid composition can significantly prolong the time patients live without experiencing motor complications (including fluctuations such as off-phase and dyskinesia) associated with pulsatile blood concentrations of the second API in conventional formulations. Furthermore, when using the solid composition according to this disclosure, the side effects associated with the second API are reduced or even eliminated. This is because, in fact, using API1 (e.g., carbidopa) first more comprehensively blocks API2 activity in the periphery compared to using API1 (e.g., carbidopa) and API2 (e.g., levodopa) simultaneously, thereby blocking API2-related side effects (i.e., immediate benefit).

[0016] Furthermore, the inventors have discovered that the solid composition allows for a reduction in the total dose required to achieve therapeutic benefits, for example, compared to commonly used compositions in the art. Additionally, when treating patients with PD, for example, using the solid composition according to this disclosure, the number of daily doses required is reduced compared to commonly used compositions known in the art. This results in a reduction in side effects for patients when treated according to the method of this disclosure. Furthermore, the solid composition reduces… The efficacy of the medicine decreases at the end of the dose. retreat"Phenomena, particularly EMO, such as gait freezing. Therefore, when patients are treated, for example, with the solid composition according to this disclosure, they do not suffer from relapse of PD symptoms, especially in the morning. The inventors have discovered that by using the solid composition according to this disclosure to treat PD patients, the bioavailability of the second API in the patient's body is increased and simultaneously enhanced. In this way, the inevitable increase in the dose of the API during the course of the disease is delayed or even reduced. The inventors can demonstrate that, due to this delay and dose reduction, the total daily dose is further reduced compared to the total daily dose required when using conventional compositions. Therefore, when using the solid composition of this disclosure, undesirable side effects associated with treatment by a specific API are successfully reduced, and in addition, disease-specific symptoms are alleviated."

[0017] “ Using the solid composition " The solid composition in use "and / or " The solid combination for drug delivery thing "or" The solid composition when administered "This should be understood as, but not limited to, the individual's intake and / or absorption of the solid composition. Furthermore, " Using the solid composition " The solid composition in use "and / or " The solid drug Composition "or" The solid composition when administered "This should be understood as, but is not limited to, the process of dissolving the solid composition. In some embodiments, the use may be for the prevention and / or treatment of Parkinson's disease."

[0018] The group of DOPA-decarboxylase inhibitors according to this disclosure includes one or more of the following: benserazide, carbidopa, methyldopa, α-difluoromethyl-DOPA (DFMD), 3',4',5,7-tetrahydroxy-8-methoxyisoflavone, epigallocatechin gallate (EGCG), or epigallocatechin (EGC). The group of catechol-O-methyltransferase (COMT) inhibitors according to this disclosure includes one or more of the following: entacapone, niticocapone, opipiccapone, or tocapone. The amino acids according to this disclosure may be preferably aromatic amino acids, non-protein amino acids, and / or α-amino acids. The amino acid according to this disclosure may be preferably levodopa.

[0019] In some implementations, the first and / or second API may be selected from the group consisting of dopamine agonists, anticholinergic drugs, and / or MAO inhibitors.

[0020] The compartments are preferably configured such that they dissolve during use. For example, when the composition is administered orally, the compartments dissolve in bodily fluids. The compartments may also be soluble in water. Therefore, the compartments may include basic components soluble in bodily fluids and / or water. Therefore, the composition itself may also be soluble in bodily fluids and / or water.

[0021] In some embodiments, the first and second compartments are arranged adjacent to each other. The inventors have discovered that this arrangement of compartments positively influences and improves the bioavailability of the API, particularly its AUC. Furthermore, the adjacent arrangement of the compartments allows for precise design of the composition to provide customized and desired API release characteristics. The API can be uniformly arranged within its respective compartment.

[0022] According to this disclosure, Adjacent "This should be understood as, but not limited to, being arranged adjacent to each other, in direct contact, or separated by, for example, another layer or compartment. For example, the first compartment may be arranged on top of the second compartment, or the first compartment may be arranged below the second compartment. The first compartment may be in direct contact with the second compartment. The first compartment and the second compartment may be separated from each other by an additional layer located between the compartments. This additional layer may be, for example, a coating."

[0023] In some embodiments, the first compartment may surround the second compartment. For example, the first compartment may completely cover the second compartment, such that the second compartment forms the core of the composition, while the first compartment forms a shell around the second compartment. In this way, when the solid composition is used and / or administered, the first compartment may dissolve before the second compartment.

[0024] In some embodiments, the composition may have a plate-like structure, wherein the length of the structure may be greater than the height of the structure. This allows for convenient arrangement of compartments, for example, convenient arrangement of compartments adjacent to each other. Specifically, the release and dissolution characteristics of the plate-like structure can be easily modified in this manner. Plate-like structure "This should be understood as, but is not limited to, a flat structure, meaning a structure whose planar dimensions are greater than its height. For example, a plate-like structure can be rectangular, square, or elliptical."

[0025] In some embodiments, the compartments can be arranged adjacent to each other along the height of the plate-like structure of the composition. For example, the compartments can also be plate-like and stacked on top of each other to form the composition. This allows the solid composition to be specifically designed according to the compartments of the solid composition. For example, identical or different compartments can be arranged adjacent to each other. In this way, individual compositions can be achieved, thereby allowing for efficient and personalized use by the patient (e.g., treatment). Furthermore, the manufacturing process is simplified because the compartments can be manufactured using similar manufacturing processes. It is also conceivable that the composition can be manufactured using a single manufacturing step.

[0026] In some embodiments, the second compartment may provide up to 20%, preferably up to 15%, and more preferably up to 10% of the total surface area of ​​the solid composition. The total surface area of ​​the solid composition affects pharmacokinetics, particularly the bioavailability of the API. Specifically, in this way, the release characteristics of the second API are improved. Specifically, it has been found that the pharmacokinetic properties of the solid composition are improved. Solid compositions containing, for example, up to 20%, preferably up to 15%, and more preferably up to 10% of the second compartment allow for increased overall bioavailability of the second API.

[0027] In some embodiments, the first API may be further disposed in a third compartment of the at least two compartments. Therefore, the composition may comprise at least three separate compartments. In this manner, the bioavailability of the second API is further improved compared to the bioavailability associated with API release in conventional formulations. Providing the first API in the third compartment allows for better tailoring of the first API's release profile.

[0028] In some embodiments, the first and third compartments may have the same dimensions and API release characteristics. For example, the first and third compartments may have the same structural dimensions (length, width, height, form) and may be composed of the same components. This allows for simple manufacturing of the composition and simple design of its release characteristics.

[0029] In some embodiments, the first and third compartments may occupy at least 80%, preferably at least 85%, and more preferably at least 90% of the total surface area of ​​the solid composition. The inventors have discovered that the total surface area of ​​the solid composition affects its pharmacokinetics. Furthermore, in this manner, the bioavailability and release characteristics of different APIs are improved. Specifically, it has been found that this method improves the pharmacokinetic properties of the solid composition. The solid composition comprising, for example, at least 80%, preferably at least 85%, and more preferably at least 90% of the first and third compartments allows for increased overall bioavailability of both APIs.

[0030] In some embodiments, the second compartment may be located between the first and third compartments. For example, the second compartment may be arranged as a layer between the first and third compartments, resulting in a sandwich-like structure. In this context, the first and third compartments may also be arranged in layers. It is also conceivable that the second compartment is encapsulated within the first and third compartments. The inventors have found that this thus increases the bioavailability of the second API and significantly enhances the therapeutic benefit.

[0031] In some embodiments, the second compartment may have the same width and length as the first compartment. This has a positive impact on both dissolution and release properties. Therefore, these properties are beneficial for the therapeutic use of the solid composition.

[0032] In some embodiments, the first compartment does not contain the second API, and the second compartment does not contain the first API. This ensures improved bioavailability of the second API.

[0033] In some embodiments, the composition for use can be administered orally. For example, the solid composition can be administered orally by an individual, which may be a patient. Oral administration represents the most convenient and safest route of drug delivery. In this way, convenient, non-invasive, and patient-compliant administration can be achieved. Furthermore, patient independence is maintained during treatment. In addition, it has been found that the oral bioavailability of APIs is improved compared to the bioavailability of individual APIs.

[0034] In some embodiments, the first compartment may be characterized by a first dissolution rate. In some embodiments, the second compartment may be characterized by a second dissolution rate different from the first dissolution rate. The dissolution of the solid composition may be individualized for the patient. This allows for better compliance and a potentially beneficial process during use (i.e., treatment of the disease).

[0035] In some implementations, the first API and the second API can be released simultaneously or sequentially. According to the "..." of this disclosure Sequential release " Sequential release "or" Released in a sequential manner"This should be understood as, but not limited to, sequential and / or ordered release. For example, the first API may be released first and / or before the second API. However, the second API may also be released simultaneously with the first API. This sequential release allows for more effective dosing regimens during treatment. For example, sequential release allows patients to achieve the same therapeutic effect, for instance, without increasing the dose of the API during the course of the disease. Therefore, higher doses are not necessarily required as the disease progresses. Furthermore, the inventors have found that sequential release shortens the 'end-of-dose' period. Therefore, the decline in the therapeutic effect of the API toward the end of each dosing interval is reduced and / or even prevented. For example, gait freezing symptoms, especially before taking the first dose in the morning, are relieved."

[0036] In some implementations, the release of the first API may have a first peak value as a percentage of API release over time, while the release of the second API may have a different second peak value as a percentage of API release over time. In this way, the individual peak values ​​of API release as a percentage appear sequentially. This sequential release allows for more effective dosing regimens during treatment.

[0037] In some implementations, the second peak value may occur after the first peak value. A particular advantage of this is that the first API is released at a higher concentration than the second API and can exert its pharmacological effect at a higher concentration. This is because the second peak value of the second API's release, expressed as a percentage of the first API's release, is delayed compared to the first peak value of the first API's release.

[0038] In some embodiments, the treatment is characterized by a reduction in side effects associated with Parkinson's disease. These side effects may be related to API 1 and / or API 2. Furthermore, the side effects may be long-term and / or short-term. Therefore, the side effects associated with Parkinson's disease are reduced. This has the advantage of improved treatment and clinical benefit for patients when treated with the solid composition according to the invention.

[0039] In some implementations, the side effects associated with Parkinson's disease can be selected from motor symptoms and / or non-motor symptoms. The treatment specifically reduces motor symptoms and / or non-motor symptoms. These symptoms typically occur during the disease course and negatively impact treatment benefits. Therefore, by reducing motor symptoms and / or non-motor symptoms, treatment benefits can be improved.

[0040] In some implementations, the motor symptoms and / or the non-motor symptoms may be selected from one or more of the following: bradykinesia, impaired mobility, tremor, rigidity, dysphagia, or freezing of gait (FOG), preferably bradykinesia, impaired mobility, tremor, or FOG, more preferably FOG. Specifically, by reducing one or more of these symptoms, adherence and overall treatment benefits are improved.

[0041] In some implementations, the purpose may be the prevention and / or treatment of Parkinson's disease. In particular, the prevention and / or treatment of Parkinson's disease is desired, which can lead to an improvement in quality of life.

[0042] In some embodiments, the total dose of the first API may be between 5 mg and 50 mg, preferably between 10 mg and 40 mg, and more preferably between 15 mg and 35 mg. Specifically, it has been shown that these doses affect pharmacokinetics and, in addition, allow for improved API bioavailability. Furthermore, this allows for improved treatment outcomes.

[0043] In some embodiments, the total dose of the second API may be between 50 mg and 500 mg, preferably between 80 mg and 250 mg, more preferably between 90 mg and 150 mg; or preferably between 120 mg and 450 mg, more preferably between 150 mg and 400 mg. The inventors have demonstrated that these doses of the second API improve the pharmacokinetics of the API and the solid composition, and particularly enhance the bioavailability of the API.

[0044] In some embodiments, the first API may be carbidopa, and the second API may be levodopa. The inventors have discovered that when the first and second APIs are carbidopa and levodopa, the therapeutic benefit is enhanced compared to conventional compositions.

[0045] In some embodiments, the solid composition according to this disclosure can be administered daily, wherein the total daily dose of carbidopa can be between 30 mg and 300 mg, preferably between 50 mg and 250 mg, and more preferably between 80 mg and 200 mg. This allows for a reduction in side effects compared to a conventional total daily dose. Furthermore, this results in a reduction in the intake of the solid composition during the day. For example, the solid composition can be administered 5 times during the day, preferably 4 times, and more preferably 3 times.

[0046] In some embodiments, the solid composition according to this disclosure may be administered daily, wherein the total daily dose of levodopa may be between 150 mg and 2000 mg, preferably between 250 mg and 1200 mg, and more preferably between 300 mg and 1000 mg. In this manner, the side effects associated with levodopa are reduced while maintaining the same or even enhanced therapeutic effect. Furthermore, it has been shown that gait freezing symptoms can be significantly reduced in patients during treatment.

[0047] In some embodiments, when used, the first API is immediately released upon application of the composition. This enhances the bioavailability of the API and leads to improved PD treatment.

[0048] In some embodiments, when using a solid composition, the first API is released within less than 3 hours, preferably within 2 hours, and more preferably within 1 hour. In this manner, the immediate release of the first API occurs. This has been shown to result in enhanced bioavailability of the second API and enhanced overall bioavailability of the solid composition.

[0049] In some embodiments, when the solid composition is used, the second API is released within approximately less than 5 hours, preferably within 4 hours, more preferably within 3 hours, most preferably less than 1.5 hours, and / or approximately more than 0.5 hours, preferably more than 1 hour. Therefore, the delayed release of the second API allows for enhanced API bioavailability.

[0050] In some embodiments, the solid composition may further comprise one or more of the following: a pharmaceutically acceptable coating, a pharmaceutically acceptable carrier, or a pharmaceutically acceptable substituent. In this way, the solid composition can be provided in a pharmaceutically acceptable form. This allows the solid composition to be used for improved pharmaceutical applications.

[0051] In some embodiments, the composition may be a tablet. This provides a user-friendly and convenient administration method. In particular, this embodiment can be manufactured in a time-saving and cost-effective manner.

[0052] In some embodiments, the tablets may have a ring-shaped, elliptical, and / or rectangular shape. The inventors have discovered that shape can affect the pharmacokinetics of the solid composition. In this way, therapeutic treatments can be designed and tailored to the individual needs of the patient.

[0053] We emphasize that all aspects, features, and options discussed and disclosed in the context of the first aspect above are applicable to or in combination with the discussion and disclosure of the second aspect below, and vice versa, unless physically or technically excluded, even if not all possible combinations or sub-combinations of features are explicitly listed below. Therefore, the technical advantages of such options and functions already discussed above will not be repeated, at least not in such detail, and for the sake of brevity, please refer to the corresponding explanations above.

[0054] Composition In a second aspect, the present invention relates to a solid composition comprising: at least two compartments disposed separately in the composition; a first active pharmaceutical ingredient (API) disposed in the first compartment of the at least two compartments, wherein the first API is selected from the group consisting of DOPA decarboxylase inhibitors and / or catechol-O-methyltransferase (COMT-) inhibitors; and a second API disposed in the second compartment of the at least two compartments, wherein the second API is an amino acid.

[0055] Enhanced bioavailability of the second API is achieved by using the solid composition of the present invention. Furthermore, the solid composition allows for sequential release of the first and second APIs, which further improves the bioavailability of the second API. Specifically, by using the solid composition of the present invention, a bioavailability increase of up to approximately 120% is achieved compared to conventional compositions. In addition, the duration of effective plasma concentration of the second API is prolonged. The plasma concentration of the second API induced by the solid composition of the present invention lasts for at least 120 minutes longer than that induced by conventional compositions. Furthermore, a uniform plasma concentration of the API is achieved. A uniform plasma concentration is associated with better efficacy of the API. A reduction in the dose of the second API is achieved by using the solid composition of the present invention. Sequential release achieves a higher and more consistent plasma concentration of the second API compared to conventional dosage forms. Therefore, the conventional daily dose associated with treatment complications can be reduced. Accordingly, the solid composition of the present invention significantly alters the side effect profile of conventional dosage forms. Furthermore, the solid composition of the present invention allows for a reduction in the dose of the first API. The sequential release of the API also results in a higher plasma concentration of the first API. Accordingly, a lower dose is sufficient to achieve an increased plasma concentration comparable to that of conventional formulations and adequate to exert the effects of the solid composition of the present invention. The reduction of side effects mediated by the intake of the first API was achieved as a positive side effect.

[0056] The first compartment may be arranged adjacent to the second compartment. The solid composition may have a plate-like structure, wherein the length of the structure may be greater than the height of the structure. The compartments may be arranged adjacent to each other along the height of the plate-like structure of the solid composition.

[0057] This arrangement allows for improved bioavailability of the second API driven by geometry. For example, the solid composition can have a two-layer design. In this way, the release characteristics of the API may be affected by the shape of the composition.

[0058] The height of the first compartment may be at least 0.3 cm. Preferably, the height of the first compartment may be at least 0.5 cm. More preferably, the height of the first compartment may be at least 0.7 cm. Alternatively, the height of the first compartment may be at most 1.4 cm. Preferably, the height of the first compartment may be at most 1.2 cm. More preferably, the height of the first compartment may be at most 1.0 cm.

[0059] The height of the second compartment may be at least 1.8 cm. Preferably, the height of the second compartment may be at least 2.2 cm. More preferably, the height of the second compartment may be at least 2.4 cm. Alternatively, the height of the second compartment may be at most 3.8 cm. Preferably, the height of the second compartment may be at most 3.6 cm. More preferably, the height of the second compartment may be at most 2.8 cm.

[0060] These specific heights allow for improved bioavailability of both the first and second APIs. Specifically, the thickness of each layer (compartment) can be adjusted using different heights and lengths. To obtain a thicker coating, the height can be increased. This may affect the dissolution and / or bioavailability of the API.

[0061] The ratio of the height of the first compartment to the height of the second compartment can be at least 0.1:1. Preferably, the ratio can be at least 0.2:1. More preferably, the ratio can be at least 0.3:1. The ratio of the surface area of ​​the first compartment to the surface area of ​​the second compartment can be at least 0.1:1. Preferably, the ratio can be at least 0.2:1. More preferably, the ratio can be at least 0.3:1.

[0062] Alternatively, the height ratio of the first compartment to the second compartment may be at most 0.8 to 1. Preferably, the height ratio of the first compartment to the second compartment may be at most 0.6 to 1. More preferably, the height ratio of the first compartment to the second compartment may be at most 0.5 to 1.

[0063] Alternatively, the surface area ratio of the first compartment to the second compartment may be at most 0.8:1. Preferably, the surface area ratio of the first compartment to the second compartment may be at most 0.6:1. More preferably, the surface area ratio of the first compartment to the second compartment may be at most 0.5:1.

[0064] A specific ratio of the height and / or surface area of ​​the first and / or second compartments provides for improved bioavailability of the first and / or second API. For example, the solid composition may have a third compartment, such as a three-layer design. In this way, the release characteristics of the API may be affected by the surface area of ​​the three compartments.

[0065] The first compartment may contain an immediate-release formulation. The immediate-release formulation is characterized in that, at pH 1.2, the first API can be released in an amount substantially 50% by weight relative to the total weight of the first and / or third compartments within less than 30 minutes. Preferably, the immediate-release formulation is characterized in that, at pH 1.2, the first API can be released in an amount substantially 50% by weight relative to the total weight of the first and / or third compartments within less than 25 minutes. More preferably, the immediate-release formulation is characterized in that, at pH 1.2, the first API can be released in an amount substantially 50% by weight relative to the total weight of the first and / or third compartments within less than 20 minutes. Most preferably, the immediate-release formulation is characterized in that, at pH 1.2, the first API can be released in an amount substantially 50% by weight relative to the total weight of the first and / or third compartments within less than 15 minutes.

[0066] The second compartment may contain a delayed-release formulation. The delayed-release formulation is characterized in that the second API is released at pH 1.2 within less than 380 min, preferably 240 min, and / or at pH 6.8 after 120 min, in an amount substantially 50% by weight relative to the total weight of the second compartment. Preferably, the delayed-release formulation is characterized in that the second API is released at pH 1.2 within less than 200 min, and / or at pH 6.8 after 120 min, in an amount substantially 50% by weight relative to the total weight of the second compartment. More preferably, the delayed-release formulation is characterized in that the second API is released at pH 1.2 within less than 180 min, and / or at pH 6.8 after 120 min, in an amount substantially 50% by weight relative to the total weight of the second compartment. Most preferably, the delayed-release formulation is characterized in that the second API can be released in an amount substantially 50% by weight relative to the total weight of the second compartment within less than 160 min at pH 1.2 and / or after 120 min at pH 6.8.

[0067] This sequential release of APIs (sequential arrangement of peak values) allows for improved bioavailability due to the optimized interval between the release of the first and second APIs from the first compartment (and the third compartment (if present)) and the second compartment.

[0068] The first and / or second compartments may contain polymers and / or polymer mixtures, wherein the polymers and / or polymer mixtures are short-chain polymers, long-chain polymers, or any combination thereof. The third compartment may contain polymers and / or polymer mixtures, wherein the polymers and / or polymer mixtures are short-chain polymers, long-chain polymers, or any combination thereof. Long-chain polymers include hydroxypropyl methylcellulose (HPMC), polyethylene glycol (PEG), sodium carboxymethylcellulose (NaCMC), hydrophobic polymers (e.g., ethyl cellulose, Eudragit), matrix forming agents (e.g., carbomer, xanthan gum), coating agents (e.g., cellulose derivatives, shellac), plasticizers (e.g., glycerol, propylene glycol), disintegrants (e.g., croscarmellose sodium carboxymethylcellulose, crospovidone), pH adjusters (e.g., citric acid, sodium bicarbonate), release regulators (e.g., lecithin), and / or surfactants. Short-chain polymers include polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), and / or polyethylene glycol (PEG).

[0069] The polymer may comprise hydroxypropyl methylcellulose (HPMC), ethyl cellulose (EC), cellulose acetate phthalate (CAP), carboxymethyl cellulose (CMC), or polyvinyl acetate phthalate (PVAP) or any combination thereof. Additionally, methacrylic acid copolymers, such as Eudragit® L, S, RS, and / or RL, are also considered.

[0070] Long-chain polymers can control the release of APIs. In particular, long-chain polymers allow for delayed release of APIs. Short-chain polymers can control the release of APIs. In particular, short-chain polymers allow for rapid release of APIs.

[0071] The ratio of short-chain polymer to long-chain polymer can be up to 1:9, preferably up to 1:7, and more preferably up to 1:6.

[0072] In this way, formulation-driven bioavailability enhancement was achieved. Furthermore, the release interval between the first and second APIs was optimized to provide improved bioavailability. Together with geometry-driven bioavailability enhancement, this synergistically improves overall bioavailability.

[0073] The solid composition may be coated. The coating may be pH-dependent. The solid composition may be pH-dependent. The solid composition and / or coating may comprise cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), and methacrylic acid copolymer (i.e., Eudragit).

[0074] The second compartment may occupy up to 70% of the total surface area of ​​the solid composition. Preferably, the second compartment may occupy up to 65% of the total surface area of ​​the solid composition. More preferably, the second compartment may occupy up to 60% of the total surface area of ​​the solid composition. Most preferably, the second compartment may occupy up to 50% of the total surface area of ​​the solid composition.

[0075] Specifically, the second compartment (12) may occupy 0% of the total surface area of ​​the solid composition, and the first compartment (11) may occupy 100% of the total surface area of ​​the tablet (10). In this way, when the tablet is used, the first API is completely released before the second API is released. Accordingly, the intake of the first API occurs before the intake of the second API. In this way, the bioavailability of the second API is enhanced.

[0076] This specific surface area value provides improved bioavailability of the API. Furthermore, in this manner, the release interval between the first and second APIs is optimized to provide further enhanced bioavailability.

[0077] The first API may be further arranged in a third compartment of the at least two compartments. The first and third compartments may have the same API and / or API release characteristics. This arrangement is beneficial for shape-induced enhancement of API bioavailability. For example, the three-layer solid composition can guide API release and subsequent ingestion due to its geometry. It is further conceivable that the third compartment has the same dimensions as the first compartment.

[0078] The third compartment may contain a polymer and / or a polymer mixture, wherein the polymer and / or polymer mixture is a short-chain polymer, a long-chain polymer, or any combination thereof. The first and third compartments may have the same and / or different polymer and / or polymer mixtures, preferably the same polymer and / or polymer mixture.

[0079] The first and third compartments may contain an immediate-release formulation. The immediate-release formulation is characterized in that, at pH 1.2, the first API can be released in an amount substantially 50% by weight relative to the total weight of the first and third compartments within less than 30 minutes. Preferably, the immediate-release formulation is characterized in that, at pH 1.2, the first API can be released in an amount substantially 50% by weight relative to the total weight of the first and third compartments within less than 25 minutes. More preferably, the immediate-release formulation is characterized in that, at pH 1.2, the first API can be released in an amount substantially 50% by weight relative to the total weight of the first and third compartments within less than 20 minutes. Most preferably, the immediate-release formulation is characterized in that, at pH 1.2, the first API can be released in an amount substantially 50% by weight relative to the total weight of the first and third compartments within less than 15 minutes.

[0080] The second compartment may contain a delayed-release formulation. The delayed-release formulation is characterized in that the second API is released in an amount substantially 50% by weight relative to the total weight of the second compartment within less than 280 minutes at pH 1.2 and / or after 120 minutes at pH 6.8. The second compartment may contain a delayed-release formulation. The delayed-release formulation is characterized in that the second API is released in an amount substantially 50% by weight relative to the total weight of the second compartment within less than 240 minutes at pH 1.2 and / or after 120 minutes at pH 6.8. Specifically, the delayed-release formulation is characterized in that the second API is released in an amount substantially 50% by weight relative to the total weight of the second compartment within less than 200 minutes at pH 1.2 and / or after 120 minutes at pH 6.8. Preferably, the delayed-release formulation is characterized in that the second API is released in an amount substantially 50% by weight relative to the total weight of the second compartment within less than 180 minutes at pH 1.2 and / or after 120 minutes at pH 6.8. More preferably, the delayed-release formulation is characterized in that the second API is released in an amount substantially 50% by weight relative to the total weight of the second compartment within less than 150 minutes at pH 1.2 and / or after 120 minutes at pH 6.8. Most preferably, the delayed-release formulation is characterized in that the second API is released in an amount substantially 50% by weight relative to the total weight of the second compartment within less than 130 minutes at pH 1.2 and / or after 120 minutes at pH 6.8.

[0081] In some embodiments, the delayed-release formulation is characterized in that the second API is released in an amount substantially 50% by weight relative to the total weight of the second compartment within less than 280 minutes at pH 1.2 and / or after 120 minutes at pH 6.8. Preferably, the delayed-release formulation is characterized in that the second API is released in an amount substantially 50% by weight relative to the total weight of the second compartment within less than 240 minutes at pH 1.2 and / or after 120 minutes at pH 6.8.

[0082] The first and third compartments may occupy at least 80% of the total surface area of ​​the solid composition. Preferably, the first and third compartments may occupy at least 85% of the total surface area of ​​the solid composition. More preferably, the first and third compartments may occupy at least 90% of the total surface area of ​​the solid composition.

[0083] The second compartment can be located between the first and third compartments.

[0084] The second compartment may have the same width and length as the first compartment. The first compartment may not contain the second API, and the second compartment may not contain the first API. The first compartment may have a first dissolution rate. The second compartment may have a second dissolution rate. The second dissolution rate may be different from the first dissolution rate. The first API and the second API may be released simultaneously or sequentially.

[0085] In some embodiments, when using the solid composition, the release of the first API may have a first peak value as a percentage of API release over time, while the release of the second API may have a different second peak value as a percentage of API release over time. The second peak value may be after the first peak value.

[0086] Compared to conventional compositions, the sequential arrangement of the peak values ​​of the API (sequential release) provides improved bioavailability.

[0087] The amount of the first API can be between 5 mg and 50 mg. Preferably, the amount of the first API can be between 10 mg and 40 mg. More preferably, the amount of the first API can be between 15 mg and 35 mg. The amount of the second API can be between 50 mg and 500 mg. Preferably, the amount of the second API can be between 80 mg and 250 mg. More preferably, the amount of the second API can be between 90 mg and 150 mg.

[0088] Alternatively or concurrently, preferably, the amount of the second API may be between 120 mg and 450 mg. More preferably, the amount of the second API may be between 150 mg and 400 mg. The first API may be carbidopa, and the second API may be levodopa.

[0089] It has been demonstrated that these specific doses of the first and / or second API allow for optimal release kinetic intervals, which enhances the bioavailability of the API.

[0090] In some embodiments, when the solid composition is used, the first API is released immediately upon use. In some embodiments, the first API is released in less than 3 hours when the solid composition is used. Preferably, the first API is released in less than 2 hours when the solid composition is used. More preferably, the first API is released in less than 1 hour when the solid composition is used. In some embodiments, the second API is released in approximately less than 5 hours when the solid composition is used. Preferably, the second API is released in less than 4 hours when the solid composition is used. More preferably, the second API is released in less than 3 hours when the solid composition is used. Most preferably, the second API is released in less than 1.5 hours when the solid composition is used. Preferably, the second API is released in approximately longer than 0.5 hours when the solid composition is used. Preferably, the second API is released in approximately longer than 1.0 hour when the solid composition is used.

[0091] These specific release characteristics allow for optimized intervals, which enhances the bioavailability of the API.

[0092] The solid composition may further comprise one or more of the following: a pharmaceutically acceptable coating, a pharmaceutically acceptable carrier, or a pharmaceutically acceptable substituent. The solid composition may be a tablet. The tablet may have a ring shape. The tablet may have an elliptical shape.

[0093] The tablet may have a rectangular shape. The composition may be a solid composition. The composition for use may be a solid composition for use. The solid composition may be a pharmaceutical composition. The solid composition for use may be a pharmaceutical composition for use.

[0094] The solid composition is used to treat symptoms associated with Parkinson's disease. In some embodiments, the solid composition for use is characterized in that the use may be for treating Parkinson's disease and / or preventing the progression of Parkinson's disease.

[0095] We emphasize that all aspects, features, and options discussed and disclosed in the context of the first aspect above are applicable to or in combination with the discussion and disclosure of the second aspect below, and vice versa, unless physically or technically excluded, even if not all possible combinations or sub-combinations of features are explicitly listed below. Therefore, the technical advantages of such options and functions already discussed above will not be repeated, at least not in such detail, and for the sake of brevity, please refer to the corresponding explanations above. Attached Figure Description

[0096] Possible embodiments of the invention are further described in the following detailed description with reference to the accompanying drawings, in which: Figure 1 The diagram schematically illustrates a solid composition according to an embodiment of the present disclosure.

[0097] Figure 2a and Figure 2b The diagram illustrates the release characteristics and bioavailability of solid compositions according to embodiments of the present disclosure, and also illustrates the improvement in bioavailability of solid compositions according to embodiments of the present disclosure.

[0098] Figure 3 The dissolution profiles (immediate and delayed release) of the solid composition are shown compared to those of conventional release-enhanced compositions.

[0099] Figure 4a and Figure 4b The illustration depicts a multi-compartment composition according to an embodiment of the present disclosure.

[0100] Figure 5 The dissolution profiles and AUCs of compositions comprising levodopa and carbidopa according to embodiments of the present disclosure are illustrated compared to conventional release-enhancing compositions.

[0101] Figure 6 The diagram illustrates the dissolution profiles of molded tablets comprising different compartments according to embodiments of the present disclosure.

[0102] Figure 7 The diagram illustrates the dissolution profiles of molded tablets comprising different compartments according to embodiments of the present disclosure.

[0103] Figures 8a to 8c Dissolution and pharmacokinetic profiles of a three-compartment molded tablet according to an embodiment of the present disclosure are illustrated in a comparative manner.

[0104] Figures 9a to 9c Dissolution and pharmacokinetic profiles of formed tablets with different formulations comprising two compartments, according to embodiments of the present disclosure, are illustrated in a comparative manner.

[0105] Figure 10 The effect of the interval between the release of the first API and the release of the second API on the bioavailability and duration of plasma concentration of the second API is shown for the formed tablets of Figures 9A to 9C. Detailed Implementation

[0106] The following describes only some possible embodiments of the present invention in detail. However, the present invention is not limited to these, and many other embodiments are applicable without departing from the scope of the present invention. The proposed embodiments can be modified in various ways and combined with each other where compatible, and certain seemingly dispensable features can be omitted. Specifically, the disclosed embodiments can be modified by combining certain features of one embodiment with one or more features of another embodiment.

[0107] It should be understood that, in order to achieve the technical advantages provided by this disclosure, it is not necessary to present all the features of the described aspects / implementations, as defined by the subject matter of the claims. The disclosed aspects / implementations can be modified by combining certain features of one aspect / implementation with one or more features of another aspect / implementation. Specifically, those skilled in the art will understand that features and / or functional elements of one aspect / implementation of this disclosure can be combined with technically compatible features and / or functional elements of any other aspect / implementation of this disclosure, provided that the resulting combination falls within the definition of this disclosure.

[0108] Although the following embodiments are described primarily with reference to the compositions used, those skilled in the art will understand that the disclosure of the present invention can also be applied to a number of different technical fields and / or use cases.

[0109] Throughout the accompanying drawings and description, the same reference numerals refer to the same elements. For clarity and brevity, certain features, parts, elements, aspects, components, and / or steps of certain embodiments are presented without excessive detail, wherein such details would be obvious to those skilled in the art based on the teachings herein, or wherein such details would obscure the understanding of more relevant aspects of the embodiments.

[0110] As those skilled in the art should understand, and / or to avoid redundancy, reference should also be made to the explanations in the preceding sections, which also apply to the following detailed description. Furthermore, for the sake of brevity and clarity, not all features, parts, elements, aspects, components, and / or steps are explicitly designated with reference numerals. This is particularly relevant where those skilled in the art recognize that such features, parts, elements, aspects, components, and / or steps exist in multiple forms.

[0111] exist Figure 1 In the middle, tablets (10) as a solid composition Figure 1 The left side of the image shows a conventional composition in the art ( Figure 1 (Next to the right side of the middle). Specifically, Figure 1A tablet (10) for treating symptoms associated with Parkinson's disease is illustrated. The tablet contains three compartments (11, 12, 13), which are individually arranged within the tablet (10).

[0112] The first API is disposed in the first compartment (11), wherein the first API is carbidopa, which is a DOPA-decarboxylase inhibitor. Figure 1 In the illustrated embodiment, carbidopa is further disposed in a third compartment (13). The second API is disposed in a second compartment (12) of the tablet (10), wherein the second API is levodopa. Accordingly, in Figure 1 In this implementation, the first API is carbidopa, which is disposed in the first compartment (11) and the third compartment (13); and the second API is levodopa, which is disposed in the second compartment (12). The compartments are arranged adjacent to each other, such that the second compartment (12) is disposed between the first compartment (11) and the third compartment (13). The compartments are in direct contact with each other and have the same structure.

[0113] like Figure 1 The tablet (10) shown comprises a sheet-like structure and has an elliptical shape. Specifically, the length of the sheet-like structure is greater than the height of the structure. The three compartments (11, 12, 13) are also sheet-like and arranged such that they are stacked on top of each other. The three compartments (11, 12, 13) are arranged adjacent to each other along the height of the sheet-like structure, i.e., they are stacked on top of each other. As can be seen, the first compartment (11) and the third compartment (13) have the same structural dimensions. In particular, the first compartment (11) and the third compartment (13) have the same length, width, and height. The second compartment (12) has the same planar characteristics as the first compartment (11) and the third compartment (13), i.e., the same length and width, but a different height. The second compartment (12) occupies 20% of the total surface area of ​​the tablet (10), i.e., at the edge of the tablet (10). The first compartment (11) and the third compartment (13) together provide 80% of the total surface area of ​​the tablet (10).

[0114] The top and bottom surfaces of the tablet (10) are defined by a first compartment (11) and a third compartment (13), respectively. The main surface of the second compartment (12) is completely covered by the first compartment (11) and the third compartment (13). The sides of the tablet (10) are defined by all three compartments. At the sides of the tablet, the second compartment (12) is not covered by the other two compartments (11, 13).

[0115] The compartments are configured to dissolve upon use (e.g., during oral administration). Therefore, when the tablet (10) is used, the tablet dissolves. As those skilled in the art will understand, when the compartments dissolve, the corresponding APIs are released. The initial dissolution phase is characterized by the release of carbidopa disposed in the outer compartments of the tablet (10). A small amount of levodopa is also released at the edge of the tablet (10) during the initial dissolution phase. Subsequent dissolution phases are characterized by a strong release of levodopa once the first and third compartments are completely dissolved.

[0116] exist Figure 1 In the illustrated embodiment, the first compartment (11) and the third compartment (13) have the same dimensions and API release characteristics. They differ from the second compartment (12) in size and API release characteristics. Figure 2a It is specially illustrated in the middle. Figure 2a The API release and dissolution data are plotted.

[0117] Return to Figure 1 The second compartment (12) of the tablet (10) has the same length as the first compartment (11), but a different width. The first compartment (11) does not contain the second API, and the second compartment (12) does not contain carbidopa. Also, the third compartment (13) does not contain levodopa. However, it is conceivable that in some embodiments, the third compartment (13) may also contain levodopa.

[0118] The following table illustrates the preferred characteristics of the tablets according to this disclosure (diameter d, height h, width b, surface area SA, hardness in N, mass in g, and dissolution rate in %): Comparative dissolution study Figure 2b Conventional solid compositions are shown in a comparative manner. Figure 2b (top of) and the solid composition disclosed herein ( Figure 2b The AUC curves are compared to those at the bottom of the image. Specifically, it can be seen that the AUC curves of carbidopa (API 1) and levodopa (API 2) in the solid composition are arranged in a sequential manner (“sequential release”). Figure 2b (bottom right corner). In particular, compared with conventional in vivo compositions (C max Compared to API, it can achieve a higher maximum concentration (C). max ) increase. In addition, Figure 2b The results show that the use of the solid composition not only leads to an increase in levodopa concentration after use, but also to an increase in the total AUC of the API. These results indicate that the solid composition disclosed in this invention can effectively improve the bioavailability of levodopa in vivo.

[0119] The duration of additional plasma drug concentration of the solid composition's API due to "sequential release" is illustrated by arrows (in...). Figure 2b (In the middle, between the dotted lines).

[0120] exist Figure 3 The dissolution profiles of the solid composition were compared with those of conventional compositions known in the art. In particular, the dissolution profiles of tablets are shown. The released substances (shown as average API content in %) of tablets containing two conventional components, carbidopa (API 1) and levodopa (API 2), were measured in vitro over 300 minutes. Figure 3 The conventional compositions shown are 1) immediate-release formulations and 2) sustained-release formulations. (As in...) Figure 3 As can be seen, the release characteristics of the two compartments in the tablet are comparable to those of immediate-release and delayed-release formulations. Specifically, carbidopa in the tablet is released rapidly, similar to conventional immediate-release compositions. This rapid release is evident from the steep rise in the first graph. On the other hand, levodopa (API 2) is released more slowly compared to carbidopa (API 1). Levodopa is similar to release-enhancing compositions, such as sustained-release formulations. Therefore, the tablet combines the release characteristics of two different formulations. In another embodiment, the tablet combines more than two release characteristics.

[0121] Multi-compartment composition exist Figure 4a and Figure 4b Several preferred embodiments are shown. In particular, tablets (10) are shown as comprising two or three compartments. These compartments contain the same or different APIs and release properties. In particular, tablets (10) in the form of multi-compartment tablets are shown. These multi-compartment tablets are produced using a common printing method. The printing method includes screen printing, 3D printing, or 3D screen printing. As can be seen, the compartments of the tablet (10) are adjacent to each other along the plate-like structure (in Figure 4a and Figure 4b (in the middle, right side), or arranged by coating (in) Figure 4a and Figure 4b (Middle, left side).

[0122] exist Figure 4aOn the left, a tablet (10) is shown, in which a first compartment (11) surrounds a second compartment (12). The first compartment (11) contains a first API, and the second compartment (12) contains a second API. The first compartment (11) does not contain the second API, and the second compartment (12) does not contain the first API. In this particular embodiment, the first compartment (11) and the second compartment (12) have different dimensions and API release characteristics. Specifically, the compartments have different heights, widths, and lengths. Specifically, the second compartment (12) occupies 0% of the total surface area of ​​the solid composition, and the first compartment (11) occupies 100% of the total surface area of ​​the tablet (10). In this way, when the tablet is used, the first API is completely released before the second API is released. Accordingly, the intake of the first API occurs before the intake of the second API. In this way, the bioavailability of the second API is enhanced.

[0123] exist Figure 4a On the right side, a tablet (10) is shown, in which a first compartment (11) is adjacent to a second compartment (12) along a plate-like structure. In this particular embodiment, the first compartment (11) has a different height than the second compartment (12). The height of the first compartment (11) is greater than the height of the second compartment (12). As can be seen, the second compartment (12) is disposed on top of the first compartment (11). The compartments are in direct contact with each other. The first compartment (11) contains a first API, and the second compartment (12) contains a second API. The first compartment (11) does not contain the second API, and the second compartment (12) does not contain the first API. In this particular embodiment, the compartments have different API release characteristics.

[0124] Another implementation may include a third compartment (13), the third compartment being in Figure 4b Shown in the middle.

[0125] Specifically, Figure 4b The left side shows a tablet (10) for use according to this disclosure, particularly an orally administered tablet (10). The tablet comprises three compartments (11, 12, 13). The third compartment (13), of the at least two compartments, is surrounded by the second compartment (12), which in turn is surrounded by the first compartment (11). In this way, the first compartment (11) occupies 100% of the total surface area of ​​the tablet (10). On the other hand, the second compartment (12) and the third compartment (13) occupy 0% of the total surface area of ​​the tablet (10). In particular, the compartments have different heights, widths, and lengths. Figure 4bThe tablet (10) shown contains a first API disposed in a first compartment (11) and a third compartment (13). These compartments do not contain a second API, which is disposed in the intermediate second compartment (12). In this way, the total amount of the first API is not released before the second API. In this particular embodiment, the second API is released only after the first API has been completely released from the first compartment (11). After the second API has been completely released, the first API is further released from the third compartment (13). It is conceivable that the third compartment (13) contains a third API, which is different from the first and second APIs.

[0126] In such Figure 4b In this particular embodiment shown on the left, the compartments are arranged in a centrally symmetrical manner. It is conceivable that if the compartments were arranged differently, this would alter the release characteristics.

[0127] exist Figure 4b On the right side, a tablet (10) is shown, which comprises three compartments. The first compartment (11), the second compartment (12), and the third compartment (13) are arranged overlapping each other and, in particular, adjacent to each other along the plate-like structure of the tablet (10). These compartments (11, 12, 13) are in direct contact with each other. The first compartment (11) and the third compartment (13) have the same size and API release characteristics. The second compartment (12) has different sizes and API release characteristics. Specifically, the first compartment (11) and the third compartment (13) occupy at least 80% of the total surface area of ​​the tablet (10). In this particular embodiment, when the tablet is used, both APIs are released simultaneously. However, a larger amount of the first API is released because it occupies a larger portion of the total surface area. During this phase, a small amount of the second API is released. After the first API has been completely released from the first compartment (11) and the third compartment (13), a larger amount of the second API (“…”) is released. Sequential In this way, the peak values ​​of the AUC curves of the first API and the second API appear sequentially, that is, the peak value of the first API appears before the peak value of the second API.

[0128] Improve bioavailability and reduce dosage In vitro dissolution test Dissolution tests were performed according to the "Acetaminophen Tablets" section of the USP monograph in the United States Pharmacopeia. The dissolution tests were conducted using a Vankel® VK 7000 dissolution apparatus equipped with a VK750D heater. Dissolution was performed using 900 mL of phosphate buffer at pH 5.8, at 37.0 ± 0.5 °C, with stirring at 50 rpm. Wire clamps were used to hold the tablets to the bottom of the container during the test.

[0129] Analysis was performed using a Thermo® Evolution 300 UV / Vis spectrophotometer equipped with flow-through cuvettes and powered by an Ismatec® IPS multichannel peristaltic pump (n=6). Absorbance at λ=243 nm was measured continuously over 8 hours using Thermo Vision Pro software. Calibration curves were constructed for the range of 2–150 mg acetaminophen, with a correlation coefficient R = 0.9999.

[0130] In vivo testing Tablet administration: Measurement of drug intake after direct administration of tablets into the stomach of pigs using gastroscopy. The concentration of the active ingredient in the blood was measured after application and continued until 24 hours after application.

[0131] Measurement points: 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 240 minutes, 360 minutes, 480 minutes, and 24 hours. Analysis method: According to César et al.; Development and validation of a high-performance liquid chromatography-electrospray ionization MS / MS method for the simultaneous quantitation of levodopa and carbidopa in human plasma J. Mass. Spectrom. 2011, (46), 943-948, prepared plasma samples by precipitating proteins with perchlorate and adding methyldopa as an internal standard; centrifuging at 2000 rpm and 5°C for 15 minutes.

[0132] Samples were analyzed using ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry (UHPLC) with a THERMO (Bremen, Germany) UltiMate HPG-3400 RS binary pump and a WPS-3000 autosampler, set at 10°C and equipped with a 25 µL syringe and a 100 µL sample loop. The column was stored in a TCC-3200 column chamber at 25°C. A THERMO Accucore® C-18 RP (100 × 2.1 mm; 2.6 µm) column was used at a constant flow rate of 0.4 mL / min using the gradients in Table 2. Eluent A was water containing 2% acetonitrile and 0.1% formic acid. Eluent B was pure acetonitrile.

[0133] Mass spectra were recorded using a THERMOTHERMO QExactive plus Orbitrap mass spectrometer connected to a heated electrospray source (HESI).

[0134] In vitro release characteristics and in vivo bioavailability of the solid compositions of this disclosure have been studied. Tablets (10) have been used and administered for both in vitro and in vivo studies. The following doses were used and administered: tablets with a total carbidopa dose between 10 mg and 15 mg and a total levodopa dose between 90 mg and 150 mg were used in in vitro studies, and the tablets were administered in in vivo studies. The content of carbidopa as the first API (“carbidopa”) was measured in vitro over 200 min. API 1 in solid compositions ) and levodopa as the second API (" API 1 in solid compositions The average API content of the tablets, expressed as a percentage, compared with two conventional compositions (“ API 1 General / API 2 General "and" In solid compositions API 1 / API 2 in solid compositions The comparison was performed using triangles (represented by points). Figure 5 The left side of the graph depicts the corresponding dissolution profiles for these conventional formulations. As can be seen, the carbidopa (“…”) of the tablets… API 1 in solid compositions The release characteristics of ) are similar to those of carbidopa immediate-release formulations (" Regular API 1 The dissolution curves of the tablets were quite similar to those of the tablets containing levodopa (""). API 1 in solid compositions The release characteristics of ) and levodopa delayed-release formulations (" API in solid compositions 2The dissolution profiles of the tablets (represented by triangular dots) are comparable. In particular, it has been shown that the tablets release carbidopa immediately after use. The dissolution profile of this immediate-release carbidopa formulation after use is similar to that of conventional immediate-release compositions. On the other hand, levodopa releases more slowly in tablets compared to carbidopa, particularly similar to release-enhancing compositions such as sustained-release formulations. In solid compositions (represented by a triangular point). Specifically, as in... Figure 5 As can be seen on the left side, the average API release of carbidopa in the tablet is 100% by weight in less than 1 hour, preferably 2 hours, more preferably 1 hour. The levodopa in the tablet is characterized by an average API release of 100% by weight in less than 2 hours.

[0135] For in vivo studies, the tablets were administered orally. API levels were measured within 24 hours (1600 minutes) after administration. Figure 5 On the right side, it is shown as if in Figure 5 The tablets discussed on the left (indicated as " LD sandwich Agent The in vivo data for "" were obtained. Based on these measured data, bioavailability has been calculated by plotting an AUC curve, which can be viewed... Figure 5 See the right side. Specifically, when compared to conventional immediate-release compositions (AUC 40) (e.g., Sinemet), the tablets achieve 89 (AUC 89), which represents a 100% increase in the bioavailability of levodopa. Compared to release-enhancing compositions, the tablets according to this disclosure, when compared to sustained-release compositions (“…”),… In solid compositions The AUC of the tablets (represented by a triangle) represents a 50% increase in levodopa bioavailability compared to (e.g., Dopadura Retard) when it achieves an AUC of 60. Therefore, the AUC of these tablets differs significantly from the individual AUCs of conventional formulations (e.g., [missing information]). Figure 5 The upper right side indicates " LD Dopadura retard "and" LD Sinemet (”).

[0136] Specifically, the AUC of levodopa is increased when administered in tablet form compared to conventional compositions. Correspondingly, the bioavailability of levodopa when administered in tablet form differs significantly in vivo from the bioavailability of individual APIs in conventional formulations. In this way, when using the tablets of this disclosure, the treatment of patients requiring, for example, six conventional doses daily is significantly reduced to only three doses daily by using the solid composition of this disclosure. Simultaneously, the prolonged bioavailability alleviates gait freezing symptoms when taking the first dose of the day in the morning.

[0137] In summary, in vitro and in vivo data indicate enhanced pharmacokinetics and increased bioavailability compared to conventional compositions. These results further demonstrate the potential effectiveness of the tablets in the treatment of PD. Specifically, the solid composition is used in the prevention and treatment of PD. This is due to the achievement of higher bioavailability (in... Figure 5 (on the right side), thus reducing the dose required to achieve therapeutic benefits. In this way, treatment with reduced PD-related side effects can be achieved. Specifically, side effects such as motor symptoms and / or non-motor symptoms are therefore alleviated. In this way, the phenomenon of "end-of-dose lethargy," such as frozen gait (FOG), is reduced because bioavailability is even prolonged compared to conventional compositions (see [link to original text]). Figure 5 The right side and Figure 2b ).

[0138] Shape and composition exist Figure 6 The image shows dissolution profiles for three preferred embodiments, namely tablets with rectangular, ring-shaped, and elliptical shapes. As can be seen, the different shaped tablets contain one or more compartments with different API release characteristics. Specifically, and compared to known dissolution profiles of immediate-release and delayed-release formulations, the dissolution profiles of the rectangular compositions are similar to those of the immediate-release formulations. On the other hand, the dissolution profiles of the elliptical compositions are similar to those of the delayed-release formulations. The ring-shaped compositions are… Hybrid The dissolution curve it showed resembled an immediate-release curve in the first 20 minutes, and then resembled a delayed-release curve thereafter.

[0139] exist Figure 7 The dissolution profiles of the ring-shaped tablets according to this disclosure are shown. Specifically, the results indicate that the ring-shaped tablets contain one API in two different compartments having two different API release characteristics (immediate release and delayed release). Specifically, embodiments with the following ratios were used: 100% immediate release; 75% immediate release and 25% delayed release; 50% immediate release and 50% delayed release; 25% immediate release and 75% delayed release; and 100% delayed release. Different dissolution profiles were achieved by varying the ratio between the two compartments within the ring-shaped tablet.

[0140] In vitro and in vivo testing of tablets with three compartments Figures 8a to 8c Dissolution and pharmacokinetic profiles of a three-compartment formed tablet according to embodiments of the present disclosure are illustrated. Two embodiments of the invention are shown in comparison to conventional levodopa (“LD”) / carbidopa (“CD”) formulations. The formulations are in tablet form.

[0141] for Figures 8a to 8cThe dissolution and bioavailability studies shown have been conducted on two formulations (formulation 1 and formulation 2) prepared according to the present invention: Formulation 1: Table 1: Composition of Levodopa Tablets 044 Table 2: Composition of Carbidopa Layer Tablets 044 Formulation 2: Table 3: Composition of Levodopa Layer Tablets 273 Table 4: Composition of Carbidopa Layer Tablets 273 The tested formulation contained the following amounts of LD and CD: Regular tablets: LD50 100 mg; CD50 25 mg; Formulation 1 (immediate release): 100 mg LD; 25 mg CD; wherein the ratio of HPC to HPMCAS is 1:7.

[0142] Formulation 2 (Sustained Release): 100 mg LD; 25 mg CD; wherein the ratio of HPC to HPMCAS is 1:7.

[0143] Figures 8a to 8cThe solid composition used in the study shown comprises: at least two compartments, the at least two compartments being separately arranged in the solid composition; a first active pharmaceutical ingredient (API), the first API being disposed in a first compartment (11) of the at least two compartments, wherein the first API is selected from the group consisting of DOPA decarboxylase inhibitors and / or catechol-O-methyltransferase (COMT-) inhibitors; and a second API, the second API being disposed in a second compartment (12) of the at least two compartments, wherein the second API is an amino acid. The first compartment (11) is arranged adjacent to the second compartment. The solid composition has a plate-like structure, wherein the length of the structure is greater than the height of the structure. In particular, the compartments are arranged adjacent to each other along the height of the plate-like structure of the solid composition. In particular, the height of the first compartment is at least 0.3 cm, preferably 0.5 cm, more preferably 0.7 cm. Alternatively or additionally, the height of the first compartment (11) is at most 1.4 cm, preferably 1.2 cm, more preferably 1.0 cm. Specifically, the height of the second compartment (13) is at least 1.8 cm, preferably 2.2 cm, more preferably 2.4 cm. Alternatively, the height of the second compartment is at most 3.8 cm, preferably 3.6 cm, more preferably 2.8 cm. The ratio of the height of the first compartment (11) to the height of the second compartment (12) is at least 0.1:1, preferably 0.2:1, more preferably 0.3:1; and / or wherein the ratio of the height of the first compartment (11) to the height of the second compartment (12) is at most 0.8:1, preferably 0.6:1, more preferably 0.5:1. Specifically, the first compartment (11) contains an immediate-release formulation. The immediate-release formulation is characterized in that, at pH 1.2, the first API is released in an amount substantially 50% by weight relative to the total weight of the first compartment (11) within a period of less than 30 min, preferably 25 min, more preferably 20 min, and most preferably 15 min.

[0144] Furthermore, the second compartment contains a delayed-release formulation. The delayed-release formulation is characterized in that the second API is released at pH 1.2 within less than 380 min, preferably 240 min, more preferably 160 min, even more preferably 120 min, most preferably 90 min, and / or at pH 6.8 after 120 min, in an amount substantially 50% by weight relative to the total weight of the second compartment (12).

[0145] Specifically, the first and / or second compartments (11, 12) contain polymers and / or polymer mixtures, wherein the polymers and / or polymer mixtures are short-chain polymers, long-chain polymers, or any combination thereof. The ratio of short-chain polymers to long-chain polymers is at most 1:9, preferably at most 1:7, more preferably at most 1:6. The second compartment (12) occupies at most 70% of the total surface area of ​​the solid composition, preferably at most 65%, more preferably at most 60%, and most preferably at most 50%.

[0146] The first API is further disposed in the third compartment. In the solid composition according to the preceding claims, the first and third compartments (11, 13) have APIs and / or API release characteristics of the same size. Specifically, the first and third compartments (11, 13) contain an immediate-release formulation. Specifically, the immediate-release formulation is characterized in that, at pH 1.2, the first API is released in an amount substantially 50% by weight relative to the total weight of the first and / or third compartments (11, 13) within less than 30 min, preferably 25 min, more preferably 20 min, and most preferably 15 min. The first and third compartments (11, 13) occupy at least 80%, preferably at least 85%, more preferably at least 90% of the total surface area of ​​the solid composition. Specifically, the second compartment (12) is disposed between the first compartment (11) and the third compartment (13). The second compartment (12) has the same width and length as the first compartment (11) and preferably the same occupies the same area. The first and third compartments (11, 13) do not contain a second API, and the second compartment (12) does not contain a first API. The first and third compartments (11, 13) are characterized by a first dissolution rate, and the second compartment (12) is characterized by a second dissolution rate different from the first dissolution rate. Specifically, the release of the first API has a first peak value as a percentage of API release over time, and the release of the second API has a different second peak value as a percentage of API release over time, and / or the second peak value is after the first peak value. Specifically, the amount of the first API is between 5 mg and 50 mg, preferably between 10 mg and 40 mg, more preferably between 15 mg and 35 mg. The amount of the second API is between 50 mg and 500 mg, preferably between 80 mg and 250 mg, more preferably between 90 mg and 150 mg; or preferably between 120 mg and 450 mg, more preferably between 150 mg and 400 mg. Specifically, the first API is carbidopa, and the second API is levodopa.

[0147] Upon use of the solid composition, the first API is released immediately. The first API is released within less than 3 hours, preferably 2 hours, more preferably 1 hour. The second API is released within approximately less than 5 hours, preferably 4 hours, more preferably 3 hours, most preferably less than 1.5 hours and approximately longer than 0.5 hours, preferably longer than 1 hour.

[0148] The solid composition further comprises: a pharmaceutically acceptable coating, a pharmaceutically acceptable carrier, or a pharmaceutically acceptable substituent. The solid composition is a tablet (10). The tablet (10) has an oval shape. The tablet (10) may have a ring-shaped and / or rectangular shape.

[0149] The solid composition is used to treat symptoms associated with Parkinson's disease. Specifically, the solid composition is administered orally. Specifically, the treatment is characterized by a reduction in Parkinson's disease-related side effects. Parkinson's disease-related side effects are selected from motor symptoms and / or non-motor symptoms. The motor symptoms and / or the non-motor symptoms are selected from one or more of the following: bradykinesia, impaired mobility, tremor, rigidity, dysphagia, or frozen gait (FOG), preferably bradykinesia, impaired mobility, tremor, or FOG, more preferably FOG. The solid composition for use is characterized in that the use is for treating Parkinson's disease and preventing the progression of Parkinson's disease. Specifically, the solid composition is administered daily. Specifically, the first API is carbidopa, and the second API is levodopa. Specifically, the total daily dose of levodopa is between 150 mg and 2000 mg, preferably between 250 mg and 1200 mg, and more preferably between 300 mg and 1000 mg. The total daily dose of carbidopa is between 30 mg and 300 mg, preferably between 50 mg and 250 mg, and more preferably between 80 mg and 200 mg. Specifically, the solid composition is a pharmaceutical solid composition.

[0150] Dissolution studies were performed in 750 mL of 0.1 M HCl solution at 100 rpm and 37 °C. After 2 h, the pH was adjusted to 6.88 by adding 250 mL of 0.2 M sodium tribasic phosphate solution. Samples were analyzed by high-performance liquid chromatography (HPLC) (NaHPO4 buffer, pH 2.7 + 5% acetonitrile (ACN) on a C18 column (Agilent Zorbax Eclipse Plus C18 RR 150 × 4.6 mm, 3.5 µm), with UV detection at 280 nm, column temperature at 40 °C, injection volume at 5 µL, and run time at 9 min).

[0151] Bioavailability studies were performed in animal models (pigs) with group sizes of 4 to 8 pigs per group. Pigs were fasted for 24 hours before tablet administration, followed by direct gastric administration of the tablets under complete anesthesia. After 20–30 minutes, the pigs were fed (hay), and blood samples were immediately collected for processing. The plasma was then refrigerated and analyzed. Samples were measured using HPLC-MS / MS to determine levodopa / carbidopa in plasma: a C18 column (50 × 4.6 mm, 5 µm) with a mobile phase of 0.2% formic acid and acetonitrile (90:10). A high-resolution mass spectrometer equipped with an electrospray ionization source in positive ion mode was set up in selective reaction monitoring mode to detect the ion transitions of levodopa, carbidopa, and methyldopa (as an internal standard): m / z 198.1 -> m / z 107.0, m / z 227.2 -> m / z 181.0, m / z 212.1 -> m / z 139.2. Plasma samples were prepared by protein precipitation using perchlorate. Centrifugation was performed at 2000 rpm for 15 min at 5 °C.

[0152] exist Figure 8a The table shows the average API content (in percent) over time for formulations 1, 2, and the conventional formulation (shown as "LD / CD 1" for formulation 1; "LD / CD 2" for formulation 2; and "LD / CD Conventional" for the conventional formulation). (See table below for reference.) Figure 8a It can be seen that the LD and CD from the conventional formulation are completely released in less than 1 / 2 hour (data points overlap, see reference). Figure 8aThe release of API, LD, and CD in formulations 1 and 2 was significantly slower. Specifically, the release of LD was slower in both formulations 1 and 2, while CD showed a faster release, e.g., immediate release. In particular, formulation 1 showed complete release of CD within approximately 1 hour. Complete release of LD occurred within approximately 3 hours. Formulation 2 showed a slower release kinetics than formulation 1. Complete release of CD in formulation 2 occurred within approximately 1.5 hours, and complete release of LD in formulation 2 was achieved within approximately 5 hours.

[0153] Now go to Figure 8b The bioavailability of the LD of formulation 1, formulation 2, and conventional tablets is shown (e.g., in...). Figure 8a (As discussed in the context). In particular, the LD plasma concentrations of the respective formulations over time have been measured, and the corresponding AUCs for the LDs have been determined to be 7.54 µg*h / mL for formulation 1, 4.82 µg*h / mL for formulation 2, and 3.01 µg*h / mL for the conventional formulation.

[0154] As from Figure 8b It can be seen that the AUC values ​​of the LD of formulations 1 and 2 increased compared to the conventional formulations. Specifically, the AUC value of the LD of formulation 1 was the highest (7.54 µg*h / mL) compared to both formulation 2 and the conventional formulation. Specifically, the AUC of the LD from formulation 1 increased by 2.5 compared to the conventional formulation. Correspondingly, the bioavailability of levodopa increased by 2.5 times. Figure 8b This is especially due to the sequential release of carbidopa and levodopa from formulation 1. Figure 8a For formulation 2, the AUC of LD (4.82 µg*h / mL) increased by more than 1.5 times compared to the conventional formulation (3.01 µg*h / mL).

[0155] Similarly, such as Figure 8c As shown, the AUC values ​​of CD for formulations 1 and 2 increased compared to the CD values ​​of conventional formulations. In particular, formulation 1 had the highest AUC value of CD compared to both formulation 2 and conventional formulations.

[0156] Figures 8a to 8c The study demonstrated that the bioavailability of the LD of the three-compartment composition was increased by 2.5-fold, with the two outer compartments exhibiting immediate release of CD (IR, with a fast-release short-chain polymer), while the inner second compartment with LD exhibited a sandwich geometry (3 layers) for either rapid or prolonged release formulation. The release of the two active ingredients was determined by the geometry and formulation. Figure 8a This indicates that the sequential release of two active ingredients can be achieved solely through geometric design. As a result, a greater amount of LD is absorbed due to the faster release of CD. Figure 8b The results shown indicate that LD plasma concentrations remained consistently higher over a longer period compared to conventional LD / CD formulations. Furthermore, these data suggest that geometry-induced levodopa plasma concentrations lasted approximately 2 hours longer than those of commercially available standard products.

[0157] pH-dependent tablets with two compartments for in vitro and in vivo testing Dissolution studies were performed in 900 mL of 0.1 M HCl solution at 100 rpm and 37 °C. Samples were analyzed by high-performance liquid chromatography (HPLC) using NaHPO4 buffer (pH 2.7 + 5% ACN) on a C18 column (Agilent Zorbax EclipsePlus C18 RR 150 × 4.6 mm, 3.5 µm), with UV detection at 280 nm, column temperature at 40 °C, injection volume at 5 µL, and run time at 9 min.

[0158] Bioavailability studies were performed in animal models (pigs) with group sizes of 4 to 8 pigs per group. Pigs were fasted for 24 hours before tablet administration, followed by direct gastric administration of the tablets under complete anesthesia. After 20–30 minutes, the pigs were fed (hay), and blood samples were immediately collected for processing. The plasma was then refrigerated and analyzed. Samples were measured using HPLC-MS / MS to determine levodopa / carbidopa in plasma: a C18 column (50 × 4.6 mm, 5 µm) with a mobile phase of 0.2% formic acid and acetonitrile (90:10). A high-resolution mass spectrometer equipped with an electrospray ionization source in positive ion mode was set up in selective reaction monitoring mode to detect the ion transitions of levodopa, carbidopa, and methyldopa (as an internal standard): m / z 198.1 -> m / z 107.0, m / z 227.2 -> m / z 181.0, m / z 212.1 -> m / z 139.2. Plasma samples were prepared by protein precipitation with perchlorate and centrifuged at 2000 rpm for 15 min at 5 °C.

[0159] Now go to Figures 9a to 9c The document presents, in a comparative manner, dissolution and pharmacokinetic profiles of formed tablets comprising two compartments constituting the composition with different formulations, according to embodiments of the present disclosure. Figure 9a and Figure 9c The dosage form used in the dissolution test combined two-compartment geometries with fast (carbidopa: a short-chain polymer with rapid CD release) and slow (levodopa: a long-chain polymer with prolonged LD release) CD and LD formulations, respectively.

[0160] Contrary to the embodiments discussed in the context of Figures 8A to 8C, the following embodiments, i.e., embodiments according to this disclosure, have a two-layer tablet having two compartments constituting the composition, for use in... Figure 9a The dissolution and bioavailability tests are shown. The advantage of this two-layer geometry is fewer screen changes and therefore faster overall production. The release of both APIs is primarily controlled by the formulation. In particular, the release of levodopa is especially controlled by the ambient pH (e.g., the pH of the solution). Specifically, these formulations release LD at alkaline pH (e.g., in the alkaline environment of the small intestine). Figure 9c The results shown have already demonstrated this, and we will discuss this in more detail below.

[0161] For dissolution and bioavailability studies, three formulations (“Formulation A”, “Formulation B”, and “Formulation C”) according to the present invention have been prepared: Formulation A is prepared according to the following: Table 5: Composition of Levodopa Layer Tablets 044 Table 6: Composition of Carbidopa Layer Tablets 044 Formulation B is prepared according to the following: Table 7: Composition of Levodopa Layer Tablets 273 Table 8: Composition of Carbidopa Layer Tablets 273 Formulation C is prepared according to the following: Levodopa: Table 9: Composition of the Levodopa Layer Carbidopa (as formulation 2): Table 10: Composition of the Levodopa Layer The tested formulation contained the following amounts of LD and CD as API: Regular tablets (extended release): LD50 250 mg; CD50 25 mg; Formulation A (immediate release): LD50 of 100 mg; CD50 of 25 mg; Formulation B (Sustained Release): LD50 of 100 mg; CD50 of 25 mg; Formulation C (Sustained Release): LD 100 mg; CD 25 mg.

[0162] Formulations A, B, and C are embodiments of the present invention. (See below for details.) Figure 9a It can be seen that, among all three formulations, CD was completely released in less than approximately 1 hour. Formulation A showed a 50% release in less than approximately 60 minutes and a complete release of LD in approximately 2 hours. In particular, LD (and CD) was released at acidic pH (pH 1.2), such as in gastric media. Compared to formulation A, formulation B showed a slower LD release. Specifically, at pH 1.2, formulation B reached approximately 30% LD release in approximately 2 hours.

[0163] As from Figure 9a It can be seen that further LD release occurs in an alkaline environment at pH 6.8, such as in the small intestinal medium, where 100% release of LD is achieved in less than 240 min. Specifically, the LD release curve rises significantly at pH 6.8. Compared to formulations A and B, formulation C shows the slowest LD release, releasing less than 40% of the LD in approximately 2 hours at pH 1.2. At pH 6.8, as from... Figure 9a As can be seen, the release curve rises significantly, indicating faster dissolution in alkaline media. Formulation C released 100% of its LD in approximately 4 hours.

[0164] The alkaline pH may be at least 5.8. Preferably, the alkaline pH may be at least 6.2. More preferably, the alkaline pH may be at least 6.8. Most preferably, the alkaline pH may be at least 7.2. Even more preferably, the alkaline pH may be at least 7.8.

[0165] The dissolution characteristics of all three embodiments differ. Therefore, formulation A exhibits faster LD release compared to formulations B and C. Consequently, formulations B and C exhibit slower LD release compared to formulation A. Specifically, the LD release of formulations B and C is pH-dependent. In particular, the amount of LD released in formulations B and C increases with increasing pH (e.g., alkaline pH). Formulation C exhibits the slowest LD release.

[0166] The bioavailability of the tested formulations (conventional formulation, formulation A, formulation B, and formulation C) has been tested, and the results are in... Figure 9b and Figure 9c As shown in the image.

[0167] Figure 9b Bioavailability of the conventional extended-release formulation containing 250 mg LD and 25 mg CD is shown. Plasma concentrations of CD and LD over time were measured, and the corresponding AUC for LD was determined to be 431.5 µg*min / mL. Figure 9c The bioavailability of formulation B, containing 100 mg LD and 25 mg CD, is shown in the figure. Plasma concentrations of CD and LD over time were measured, and the corresponding AUC for LD was determined to be 542 µg*min / mL.

[0168] Figure 9b and Figure 9c The data shown demonstrate that the bioavailability of LD in Formulation B is significantly improved compared to conventional formulations containing higher amounts of LD. In other words, the compositions of the present invention achieve higher bioavailability with significantly less LD in the formulation. In this way, therapeutic effects are enhanced while reducing side effects associated with LD intake.

[0169] This data further demonstrates that, under the protection of carbidopa, a greater amount of levodopa is absorbed, and the blood concentration of levodopa remains consistently high over a longer period of time.

[0170] In summary, by using the compositions of the present invention, the following advantages are achieved compared to conventional formulations: 1) Enhanced bioavailability—The sequential release of the first and second APIs, namely carbidopa and levodopa (Figure 9B), improves the bioavailability of the second API, levodopa. The AUC achieved by the composition of the present invention at a 100 mg LD is approximately 20% higher than that achieved by conventional 250 mg LD extended-release tablets.

[0171] 2) Duration of effective blood concentration — The blood concentration of the second API, namely levodopa, induced by the composition of the present invention lasts for at least 120 minutes longer than that induced by conventional compositions.

[0172] 3) Uniform blood drug concentration—The compositions of the present invention achieve uniform blood drug concentrations of the second API, namely levodopa. For example, uniform LD blood drug concentrations from a duodenal pump result in better efficacy in the patient's therapeutic treatment.

[0173] 4) Reduced API dosage—Due to sequential release, higher and more consistent plasma concentrations are achieved compared to conventional formulations, particularly for the second API. The conventional daily dose of the second API, levodopa, is associated with side effects and / or treatment complications such as movement disorders. Therefore, the compositions of this invention significantly alter the side effect profile of the second API, levodopa, compared to conventional formulations.

[0174] 5) Reducing the total dose—the sequential release of the first API, i.e., LD and CD, also leads to a higher plasma concentration of the first API. Therefore, a similar increase in the plasma concentration of the second API can be achieved by using a lower dose of the first API. This results in a reduction of side effects mediated by the first API.

[0175] Interval-mediated increase in bioavailability Figure 10 The plasma concentrations and bioavailability of LD after administration of three formulations (formulations B, C, and D) according to the invention and a conventional formulation are shown. The only difference between formulations B, C, and D is the interval between CD release and LD release.

[0176] Formulation D is prepared according to the following: Levodopa: Table 11: Composition of the Levodopa Layer Carbidopa (as formulation 2) Table 12: Composition of the Levodopa Layer As from Figure 10 It can be seen that the bioavailability (n=4) of the conventional formulation is 35.48 µg*min / mL*kg. Formulation B shows the highest AUC (n=4) of LD at 61.32 µg*min / mL*kg. Formulation C shows an AUC (n=4) of LD at 28.21 µg*min / mL*kg. Formulation D shows an AUC (n=4) of LD at 15.49 µg*min / mL*kg.

[0177] Formulation B is characterized by the complete release of LD within approximately 160 minutes after the complete release of CD. Figure 9a (The dashed line in the text). Formulation C has a 20-30 min interval (180-190 min); Figure 9a (The dashed line in the diagram). Formulation D showed a 30–40 min extension in the interval (190–200 min); Figure 9a (Not shown in the image).

[0178] The bioavailability of LD is controlled by the duration of the interval between CD release and LD release, particularly for formulations B and C. These data suggest that, based on selected conditions (160 min, 180–190 min, or 190–200 min), an interval of 160 min between CD and LD release is optimal for enhancing bioavailability and increasing the duration of effective LD plasma concentration.

[0179] It should be noted that the above-described features of the system apply to the corresponding method steps, and vice versa. In other words, any features disclosed in the context of the composition for use in this invention should also be disclosed for the composition itself. It should further be noted that the above embodiments and / or examples can be combined with other aspects as described herein, and details of the embodiments and / or examples may be omitted, as will be understood by those skilled in the art. The scope of protection is defined by the claims and is not limited to the embodiments and / or examples disclosed in the above drawings.

Claims

1. A solid composition comprising: At least two compartments, wherein the at least two compartments are separately arranged in the solid composition; A first active pharmaceutical ingredient (API) is disposed in a first compartment (11) of the at least two compartments, wherein the first API is selected from the group consisting of: DOPA decarboxylase inhibitors and / or catechol-O-methyltransferase (COMT-) inhibitors; and The second API is disposed in the second compartment (12) of the at least two compartments, wherein the second API is an amino acid.

2. The solid composition according to claim 1, wherein the first compartment (11) is arranged adjacent to the second compartment (12).

3. The solid composition according to any one of the preceding claims, wherein the solid composition has a plate-like structure, wherein the length of the structure is greater than the height of the structure.

4. The solid composition according to the preceding claims, wherein the compartments are arranged adjacent to each other along the height of the plate-like structure of the solid composition.

5. The solid composition according to any one of the preceding claims, wherein the height of the first compartment (11) is at least 0.3 cm, preferably 0.5 cm, more preferably 0.7 cm; And / or wherein the height of the first compartment (11) is at most 1.4 cm, preferably 1.2 cm, more preferably 1.0 cm.

6. The solid composition according to the preceding claims, wherein the height of the second compartment (13) is at least 1.8 cm, preferably 2.2 cm, more preferably 2.4 cm; and / or among them, The height of the second compartment (13) is at most 3.8 cm, preferably 3.6 cm, and more preferably 2.8 cm.

7. The solid composition according to the preceding claims, wherein the ratio of the height of the first compartment (11) to the height of the second compartment (12) is at least 0.1 to 1, preferably 0.2 to 1, and more preferably 0.3 to 1; And / or the ratio of the height of the first compartment (11) to the height of the second compartment (12) is at most 0.8 to 1, preferably 0.6 to 1, and more preferably 0.5 to 1.

8. The solid composition according to any one of the preceding claims, wherein the first compartment (11) comprises an immediate-release formulation.

9. The solid composition according to the preceding claims, wherein the immediate-release formulation is characterized in that, at pH 1.2, the first API is released in an amount substantially 50% by weight relative to the total weight of the first compartment (11) within less than 30 min, preferably within 25 min, more preferably within 20 min, and most preferably within 15 min.

10. The solid composition according to any one of the preceding claims, wherein the second compartment comprises a delayed-release formulation.

11. The solid composition according to the preceding claims, wherein the delayed-release formulation is characterized in that the second API is released at pH 1.2 within less than 380 min, preferably within 240 min, more preferably within 160 min, even more preferably within 120 min, most preferably within 90 min and / or at pH 6.8 after 120 min, in an amount substantially 50% by weight relative to the total weight of the second compartment (12).

12. The solid composition according to the preceding claims, wherein the first and / or second compartments (11, 12) comprise polymers and / or polymer mixtures, wherein the polymers and / or polymer mixtures are short-chain polymers, long-chain polymers, or any combination thereof.

13. The solid composition according to the preceding claims, wherein the ratio of the short-chain polymer to the long-chain polymer is at most 1:9, preferably at most 1:7, and more preferably at most 1:

6.

14. The solid composition according to any one of the preceding claims, wherein the second compartment (12) occupies up to 70% of the total surface area of ​​the solid composition, preferably up to 65%, more preferably up to 60%, and most preferably up to 50%.

15. The solid composition according to any one of the preceding claims, wherein the first API is further disposed in a third compartment (13) of the at least two compartments.

16. The solid composition according to the preceding claims, wherein the first compartment and the third compartment (11, 13) have the same API and / or API release characteristics.

17. The solid composition according to any one of claims 15 or 16, wherein the first compartment and the third compartment (11, 13) comprise an immediate-release formulation.

18. The solid composition according to the preceding claims, wherein the immediate-release formulation is characterized in that, at pH 1.2, the first API is released in an amount substantially 50% by weight relative to the total weight of the first and / or third compartments (11, 13) within less than 30 min, preferably within 25 min, more preferably within 20 min, and most preferably within 15 min.

19. The solid composition according to any one of claims 15 to 18, wherein the first and / or third compartments (11, 13) occupy at least 80% of the total surface area of ​​the solid composition, preferably at least 85%, more preferably at least 90%.

20. The solid composition according to any one of claims 15 to 19, wherein the second compartment (12) is disposed between the first compartment (11) and the third compartment (13).

21. The solid composition according to any one of the preceding claims, wherein the second compartment (12) has the same width and length as the first compartment (11), and preferably the second compartment (12) has the same area occupied as the first compartment (11).

22. The solid composition according to any one of the preceding claims, wherein the first and / or third compartments (11, 13), if present, are free of the second API, and wherein the second compartment (12) is free of the first API.

23. The solid composition according to any one of the preceding claims, wherein the first and / or third compartments (11, 13), if present, are characterized by a first dissolution rate; and wherein the second compartment (12) is characterized by a second dissolution rate, the second dissolution rate being different from the first dissolution rate.

24. The solid composition according to the preceding claim, wherein, When the first API is used, the release of the first API has a first peak value of API release as a percentage over time, and the release of the second API has a different second peak value of API release as a percentage over time. The second peak value is after the first peak value.

25. The solid composition according to any one of the preceding claims, wherein the amount of the first API is between 5 mg and 50 mg, preferably between 10 mg and 40 mg, and more preferably between 15 mg and 35 mg.

26. The solid composition according to any one of the preceding claims, wherein the amount of the second API is between 50 mg and 500 mg, preferably between 80 mg and 250 mg, more preferably between 90 mg and 150 mg; or preferably between 120 mg and 450 mg, more preferably between 150 mg and 400 mg.

27. The solid composition according to any one of the preceding claims, wherein the first API is carbidopa and the second API is levodopa.

28. The solid composition according to any one of the preceding claims, wherein when used, the first API is released immediately after use of the solid composition.

29. The solid composition according to any one of the preceding claims, wherein when the first API is used, it is released in less than 3 hours, preferably 2 hours, more preferably 1 hour.

30. The solid composition according to any one of the preceding claims, wherein when the second API is used, it is released in about less than 5 hours, preferably 4 hours, more preferably 3 hours, most preferably less than 1.5 hours and / or about more than 0.5 hours, preferably more than 1 hour.

31. The solid composition according to any one of the preceding claims, wherein the solid composition further comprises one or more of the following: a pharmaceutically acceptable coating, a pharmaceutically acceptable carrier, or a pharmaceutically acceptable substituent.

32. The solid composition according to any one of the preceding claims, wherein the solid composition is a tablet (10).

33. The solid composition according to any one of the preceding claims, wherein the tablet (10) has an annular, elliptical and / or rectangular shape.

34. The solid composition according to any one of claims 1 to 33, wherein the solid composition is used in the treatment of conditions associated with Parkinson's disease.

35. The solid composition used according to the preceding claims, wherein the solid composition is for oral administration.

36. The solid composition used according to any one of the preceding claims, wherein the treatment is characterized by reducing side effects associated with Parkinson's disease.

37. The solid composition used according to any one of the preceding claims, wherein the Parkinson's disease-related side effects are selected from motor symptoms and / or non-motor symptoms.

38. The solid composition used according to any one of the preceding claims, wherein the motor symptoms and / or the non-motor symptoms are selected from one or more of the following: bradykinesia, impaired mobility, tremor, rigidity, dysphagia, or frozen gait (FOG); preferably bradykinesia, impaired mobility, tremor, or FOG; more preferably FOG.

39. The solid composition used according to any one of the preceding claims, characterized in that... The stated purpose is to treat Parkinson's disease and / or prevent the progression of Parkinson's disease.

40. The solid composition used according to any one of the preceding claims, wherein the solid composition is administered daily.

41. The solid composition used according to any one of the preceding claims, wherein the first API is carbidopa and the second API is levodopa.

42. The solid composition used according to any one of the preceding claims, when dependent on claim 40, wherein the total daily dose of levodopa is between 150 mg and 2000 mg, preferably between 250 mg and 1200 mg, more preferably between 300 mg and 1000 mg.

43. The solid composition used according to any one of the preceding claims, when dependent on claim 40, wherein the total daily dose of carbidopa is between 30 mg and 300 mg, preferably between 50 mg and 250 mg, more preferably between 80 mg and 200 mg.

44. The solid composition according to any one of claims 1 to 33, or the solid composition used according to any one of claims 34 to 43, wherein the solid composition is a pharmaceutical solid composition.

Images