Multicompartment compositions in the treatment of parkinson's disease

Abstract

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

Description

[0001] Multicompartment compositions in the treatment of Parkinson’s disease

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to a solid composition and its use in the treatment of Parkinson’s disease, comprising at least two compartments, a first active pharmaceutical ingredient (API) and a second API, preferably for increasing uptake of the second API thereby optimizing its use in the treatment of Parkinson’s disease, in particular improving its clinical activity and reducing its side effects associated with the treatment of Parkinson’s disease.

[0004] BACKGROUND

[0005] Parkinson’s disease (PD) is a chronic and progressive neurodegenerative disorder that affects movement control. PD is characterized by the gradual loss of dopamine- producing cells. Dopamine is a neurotransmitter crucial for coordinating controlled muscle movements. The main symptoms of PD include tremors, bradykinesia (slowness of movement), rigidity, and postural instability. While these motor symptoms are the most evident, 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.

[0006] Although there is currently no cure for PD, various treatment options, including medication, physical therapy, and in some cases, surgical interventions, can help manage symptoms and improve the quality of life for individuals. The common medical therapeutic measure for PD is levodopa (L-DOPA or L-dopa). Levodopa is converted into dopamine in the brain, compensating for the dopamine deficiency in PD patients and is a key medication in the management of PD, and it is often combined with other medications to enhance its effectiveness and address various aspects of the condition. Some common medications that include levodopa or work in conjunction with it include carbidopa / levodopa (Sinemet). This is one of the most widely used medications for PD. Carbidopa helps prevent the breakdown of levodopa in the bloodstream, allowing more levodopa to reach the brain where it can be converted into dopamine. Sinemet comes in different formulations, including immediate-release and extended- release versions. As of now, only few other formulations of levodopa / carbidopa exist, such as extended-release formulations, gel formulations or orally disintegrating tablets.

[0007] Another approach in the treatment of PD is the combination of levodopa with so called catechol-O-methyltransferase (COMT)-inhibitors. For example, Stalevo is a medication that combines levodopa with carbidopa and entacapone. Entacapone is a COMT inhibitor, and it works by preventing the breakdown of levodopa in the peripheral tissues, extending its effectiveness.

[0008] In this context, several documents describe the prior art. For example, WO 2019 / 136306 Ai relates to methods for treating “off’ -episodes in a patient with PD administering an effective dose of a dry pharmaceutical composition comprising levodopa, wherein the dose is administered by an intranasal delivery device. Further, WO 2023 / 059716 relates to a method which includes intranasally administering a nanoparticle formulation comprising a pharmaceutically effective amount of levodopa or a pharmaceutically acceptable salt thereof. WO 2022 / 107125 is directed to a method for the treatment of a neurological or movement disorder, in an individual in need thereof, by parenteral administration of levodopa and a dopa decarboxylase inhibitor (DDCI), such as carbidopa, benserazide or any combination thereof, concomitantly with oral administration of levodopa, a DDCI, such as carbidopa, benserazide, or any combination thereof.

[0009] As PD advances, 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 treatment with levodopa 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 refers to the diminishing effect of levodopa before the next dose is due, leading to a return of symptoms. Specifically, patients often suffer from the so-called freezing of gait symptom in this context. Accordingly, a common disadvantage of the prior art in treating PD with levodopa is that higher doses are necessarily required as the disease progresses. With long-term use of levodopa, individuals may experience “end-of-dose” periods where the effects of the drug before the next dose is taken, leading to a return of symptoms. In particular, patients may experience a decline in the therapeutic effects of levodopa towards the end of each dosing interval. This is known as “end-of-dose wear-off’ and can manifest as a return of PD symptoms, such as freezing of gait, before the next dose is due. In addition, some patients may experience 'on-off fluctuations, characterized by unpredictable swings between improved mobility (“on state”) and worsening symptoms (“off state”). Another common drawback is that they have limited effect on non-motor symptoms such as cognitive impairment, depression and autonomic dysfunction.

[0010] Levodopa increases dopamine levels in the brain, alleviating motor symptoms like bradykinesia and rigidity. However, it comes with significant limitations and complications. Within 5 years of levodopa treatment, 40% to 50% of patients develop dyskinesias and motor fluctuations (including off-symptoms), increasing to 70% to 80% after 10 years (Rizek P et al. CMAJ (2016), 188: 1157-65). It is widely accepted that the pulsatile levodopa blood levels induced by conventional LD formulations are associated with the development of fluctuations and motor complications. Thus, there is a need for levodopa formulations that can provide continuous levodopa delivery for continuous dopamine production in the brain.

[0011] Therefore, the underlying problem of the present invention is to provide an improved treatment of PD in order to at least partly overcome the above-mentioned deficiencies of the prior art.

[0012] SUMMARY OF THE INVENTION

[0013] A solution is provided according to the subject matter of the independent claims.

[0014] The above-outlined problems are addressed by the aspects of the present invention. The above-mentioned objects are at least partially achieved by the subject-matter of the independent claims. Preferred embodiments are subject of the dependent claims, and other suitable aspects of the present invention are described through the overall disclosure of the present application.

[0015] The headings provided in the present disclosure are included solely for the purpose of facilitating readability and maintaining an overview. These headings are not intended to limit the scope of the disclosure, nor do they preclude the combination of features from the respective embodiments.

[0016] While in the following, several compositions and its use in the treatment of a disease are described, it is to be noted that the described subject-matter is to be understood as equivalents to methods of treatment, methods in treating, mode of treatment or any alternative wording.

[0017] Composition for use

[0018] The above-mentioned problem is at least partly solved by a solid composition for use in the treatment of a condition associated with Parkinson’s disease, the composition comprising: at least two compartments separately arranged in the solid composition; a first active pharmaceutical ingredient, API, provided in a first compartment of the at least two compartments, wherein the first API is selected from the group of DOPA- decarboxylase inhibitors or catechol-O-methyltransferase (C0MT-) inhibitors; and a second API provided in a second compartment of the at least two compartments, wherein the second API is an amino acid.

[0019] In the prior art mentioned above, the treatment of PD is based on orally administered formulations which usually requires increasing the individual dose during the course of the disease. In order to lower the symptoms of the individuals, the number of daily doses of the medical formulation is usually raised. This leads inevitably to increased side effects and “end of dose wearing off’ phenomena, in particular the “early morning off state” (EMO) such as freezing of gait. The patients experience a return of Parkinson's symptoms in the morning, which is usually the period just before the next scheduled dose.

[0020] The present invention is based on a different approach. The advantageous effect is in particular that the pharmacokinetic characteristic of the solid composition is significantly altered. Furthermore, the bioavailability properties of the APIs in the solid composition are enhanced as compared to conventional compositions in the art. Specifically, the solid composition allows for a sequential release of the APIs, which maybe desired when administering one or more individual APIs. In this manner, the solid composition allows for a convenient and efficient administration. In particular, the inventors have found that the solid composition according to present disclosure exhibits a 50 to 120% increase in the bioavailability as assessed by the area under the curve (AUC) of the second API when using the solid composition according to present disclosure. Moreover, when using the solid composition according to present disclosure, the total number of intakes of API is reduced in the course of the disease. This is based on the longer duration of action, which is directly associated with the increased bioavailability. The resulting continuous blood profile of the second API likely results in another positive effect, the solid composition may substantially prolong the time patients live without experiencing motor complications associated with pulsatile blood levels of the second API of conventional formulations including fluctuations (e.g., off periods, and dyskinesias. In addition, when using the solid composition according to present disclosure, side effects associated with the second API are reduced or even removed. This is due to the fact that, prior availability of APIi, e.g.carbidopa compared to concomitant availability of APIi (e.g. carbidopa) and API2 (e.g. levodopa) more comprehensively blocks API2 activity in the periphery, and, in turn, APl2-associated side effects (immediate benefit).

[0021] Furthermore, the inventors have found that the solid composition allows for reducing the total dosage, for example required to reach a therapeutic benefit as compared with common compositions in the art. Furthermore, when, for example, a patient who is suffering from PD is treated with the solid composition according to present disclosure, a reduced number of daily doses is required as compared with the common compositions as known in the art. This leads to reduced side effects in the patients when treating according to the method of present disclosure. Moreover, the solid composition reduces “end of dose wearing off’ phenomena, and in particular EMO such as freezing of gait. Accordingly, when for example patients are treated with the solid composition according to the present disclosure, the patients won’t suffer from returning PD symptoms, particularly in the morning. The inventors have found that the treatment of patients with PD by using the solid composition according to present disclosure increases and at the same time may enhance the bioavailability of the second API within the patients. Through this, the inevitable increase in dosage of the API during the course of the disease is postponed or even diminished. The inventors could show that due to this postponement and reduction in dosage, the total daily doses are further reduced as compared to the total daily doses required with conventional compositions. Accordingly, when using the solid composition of present disclosure, undesired side effects associated with the treatment by the specific APIs are successfully reduced and moreover, disease specific symptoms alleviated.

[0022] “Using the solid composition”, “the solid composition when used” and / or “administering the solid composition” or “the solid composition when administered” according to present disclosure is to be understood and not limited to, as the intake and / or the ingestion of the solid composition by an individual. Furthermore, “Using the solid composition”, “the solid composition when used” and / or “administering the solid composition” or “the solid composition when administered” according to present disclosure is to be understood and not limited to, the process of dissolution of the solid composition. In some embodiments, use maybe prevention and / or treatment of Parkinson’s disease.

[0023] The group of DOPA-decarboxylase inhibitors according to present disclosure comprises for example one or more of benserazide, carbidopa, methyl dopa, alpha-Difluoro methyl - 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 present disclosure comprises for example one or more of entacapone, nitecapone, opicapone or tolcapone. The amino acid according to present disclosure may be preferably an aromatic amino acid, a non-proteinogenic amino acid, and / or an a-amino acid. The amino acid according to present disclosure maybe preferably levodopa.

[0024] In some embodiments, the first and / or second API may be selected from the groups of dopamine agonists, anticholinergics and / or MAO inhibitors.

[0025] The compartments are preferably constituted such that they dissolve upon use. For example, when the composition is orally administered, the compartments dissolve in body fluids. The compartments may also dissolve in water. Accordingly, the compartments may comprise a base component being soluble in body liquids and / or water. The composition itself may thus also be soluble in body liquids and / or water.

[0026] In some embodiments, the first compartment is arranged adjacent to the second compartment. The inventors have found that such an arrangement of the compartment positively impacts and increases the bioavailability of the APIs, and in particular the AUC of the APIs. Further, the adjacent arrangement of the compartments allows for a precise design of the composition to provide for customized and desired release characteristics of the APIs. The APIs may each be homogeneously arranged within the respective compartment.

[0027] “Adjacent” according to present disclosure is to be understood and not limited to, as being arranged next to each other, either in direct contact, or separated from each other 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 also arranged under the second compartment. The first compartment may be in direct contact with the second compartment. The first and the second compartment may be separated from each other by an additional layer which is located between the compartments. This additional layer maybe for example a coating layer. In some embodiments the first compartment may encompass the second compartment. For instance, the first compartment may be covering the second compartment such that the second compartment forms a core of the composition, while the first compartment forms a shell around the second compartment. In this manner, when using and / or administering the solid composition, the first compartment may dissolve before the second compartment.

[0028] In some embodiments, the composition may have a plate-like structure, wherein a length of the structure may be larger than a height of the structure. This allows for convenient arrangement of the compartments, for example in an adjacent arrangement. Specifically, release and dissolution characteristics of the plate-structures can be easily modified in this way. “Plate-like structure” according to present disclosure is to be understood and not limited to as a structure being rather planar, i.e., having a planar dimension being larger than its height. For instance, a plate-like structure may be a rectangular, squared or oval structure.

[0029] In some embodiments, the compartments maybe arranged adjacent to one another along the height of the plate-like structure of the composition. For example, the compartments may also be plate-like, and be arranged on top of each other to form the composition. This allows for specifically designing the solid composition in terms of its compartments. For instance, the same and / or different compartments maybe arranged adjacent to each other. In this manner, individual compositions can be achieved thereby allowing for efficient and patient-individualized usage (e.g., treatment). Moreover, the manufacturing process is simplified, as the compartments can be manufactured with similar manufacturing procedures. It is also conceivable that the composition maybe manufactured by using one single manufacturing step.

[0030] In some embodiments, the second compartment may provide for at most 20%, preferably for at most 15%, more preferably for at most 10% of the total surface of the solid composition. The total surface of the solid composition impacts the pharmacokinetics, and in particular the bioavailability of the APIs. Specifically, in this way, the release characteristics of the second API is improved. Specifically, it has been found that the pharmacokinetic characteristic of the solid composition is improved. The solid composition comprising at most 20%, preferably at most 15%, more preferably at most 10%, for example of the second compartment, allows for an increase in total bioavailability of the second API. In some embodiments, the first API may be further arranged in a third compartment of the at least two compartments. Thus, the composition may comprise at least three separate compartments. In this way, the bioavailability of the second API is further improved (when compared with the bioavailability of the concomitant API release of conventional formulations). The provision of the first API in a third compartment allows for better tailoring of the release profile of the first API.

[0031] In some embodiments the first and third compartments may have the same dimensions and API release characteristics. For example, the first and third compartment may have the same structural dimensions (length, width, height, form), and may consist of the same composition. This allows for simple manufacturing of the composition, and simple design of the release characteristics.

[0032] In some embodiments, the first and third compartments may provide for at least 8o%, preferably for at least 85%, more preferably for at least 90% of the total surface of the solid composition. The inventors have found that the total surface of the solid composition impacts the pharmacokinetics of the solid composition. Moreover, in this way, the bioavailability and the release characteristics of the different APIs is improved. Specifically, it has been found that in this way the pharmacokinetic characteristic of the solid composition is improved. The solid composition comprising at least 80%, preferably for at least 85%, more preferably for at least 90% for example of the first and third compartment allows for an increase in total bioavailability of both APIs.

[0033] In some embodiments, the second compartment may be located between the first and the third compartment. For example, the second compartment maybe arranged as a layer in between the first and the third compartment leading to a sandwich-like structure. In this context, the first and third compartment may be also arranged in layers. It is also conceivable that the second compartment is encapsulated within the first and third compartment. The inventors discovered that the bioavailability of the second API is increased as a consequence and that the therapeutic benefit is significantly increased.

[0034] In some embodiments, the second compartment may have the same width and the same length as the first compartment. This has a positive impact on the dissolution characteristics, as well as on the release characteristics. Accordingly, these characteristics have a beneficial effect on the therapeutic use of the solid composition. In some embodiments, the first compartment is free of the second API, and wherein the second compartment is free of the first API. In this manner, it is ensured that the bioavailability of the second API is increased.

[0035] In some embodiments, the composition for use maybe administered orally. For example, the solid composition may be orally administered by an individual. The individual may be a patient. Oral administration represents the most convenient and safest route of drug administration. In this way, convenient, non-invasive and patient compliant administration is enabled. Moreover, the independency of the patient during the course of the treatment is maintained. Furthermore, it has been found that the oral bioavailability of the APIs is increased as compared with the bioavailability of the individual APIs.

[0036] In some embodiments, the first compartment maybe 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 can be patient-individual designed. This allows for a better compliance and possibly to a beneficial course during the usage, i.e., treatment of the disease.

[0037] In some embodiments, the first API and the second API may be released simultaneously or sequentially. “Sequential release”, “released sequentially” or “releasing in a sequential manner”, according to present disclosure is to be understood and not limited to as a subsequent and / or ordered release. For example, the first API is released first and / or before the second API. However, the second API may be also released meanwhile the first API is released. The sequential release allows for a more efficient dosage regimen during the course of the treatment. For example, the sequential release allows that the patient may not need to increase the dosage of the APIs to achieve the same therapeutic effect for example during the course of the disease. Accordingly, higher doses are not necessarily required as the disease progresses. Furthermore, the inventors have found that a sequential release reduces ”end-of-dose” periods. Accordingly, a decline in the therapeutic effect of the APIs towards the end of each dosing interval is diminished and / or even prevented. For example, freezing of gait symptoms, in particular in the morning before the first dose is due, is relieved.

[0038] In some embodiments, the release of the first API may have a first peak maximum of API release in % over time, and the release of the second API may have a different, IO second peak maximum of API release in % over time. In this way, the individual peak maxima of API release in % occur in a sequential manner. The sequential release allows for a more efficient dosage regimen during the course of the treatment.

[0039] In some embodiment, the second peak maximum may be subsequent to the first peak maximum. This has the particular advantage that the first API is released and can pharmacologically affect in higher concentrations than the second API. This is because the second peak maximum of API release in % for the second API is delayed as compared with the first peak maximum of API release in % for the first API.

[0040] In some embodiments, the treatment may be characterized in a reduction of a side effect associated with Parkinson’s disease. The side effect maybe related to API 1 and / or API 2. Further, the side effect maybe a long-term and / or a short-term side effect. Accordingly, side effects associated with Parkinson’s disease are reduced. This has the advantage, that the therapeutic and clinical benefit is increased in patients when treating with the solid composition according to present invention.

[0041] In some embodiments, the side effect associated with Parkinson’s disease may be a side effect selected from a motor and / or a non-motor symptom. The treatment in particular reduces motor and / or non-motor symptoms. These symptoms occur usually in the course of the disease and negatively affect the therapeutic benefits. Accordingly, by reducing motor and / or non-motor symptoms, the therapeutic benefit can be raised.

[0042] In some embodiments, the motor and / or the non-motor symptom may be selected from one or more of 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, the compliance and the overall therapeutic benefit is increased.

[0043] In some embodiments, the use may be in prevention and / or treatment of Parkinson’s disease. In particular, it is desirable to prevent and / or treat Parkinson’s disease, which can result in an improved quality of life.

[0044] In some embodiments, the total dosage of the first API may be between 5 mg and 50 mg, preferably between 10 mg and 40 mg, more preferably between 15 mg and 35 mg. Specifically, it has been shown that these dosages impact the pharmacokinetics and moreover, allow for an increased bioavailability of the APIs. Moreover, this allows for an improved course in the treatment. In some embodiments, the total dosage 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 shown that these dosages for the second API improve the pharmacokinetics of the API and of the solid composition and in particular improves the bioavailability of the APIs.

[0045] In some embodiments, the first API may be carbidopa and the second API may be levodopa. The inventors have found that when the first and the second API may be carbidopa and levodopa, the therapeutic benefit as compared to a conventional composition is increased.

[0046] In some embodiments, the solid composition according to present disclosure may be administered daily, and wherein the total daily dose of carbidopa may be between 30 mg and 300 mg, preferably between 50 mg and 250 mg, more preferably between 80 mg and 200 mg. This allows for reduced side effects as compared to conventional total daily doses. Moreover, this leads to reduced intakes of the solid composition during the day. For example, the solid composition may be administered 5 times during the day, preferably 4 times, more preferably 3 times.

[0047] In some embodiments, the solid composition according to present disclosure may be administered daily, and wherein the total daily dose of levodopa maybe between 150 mg and 2000 mg, preferably between 250 mg and 1200 mg, more preferably between 300 mg and 1000 mg. In this way, side effects associated with levodopa are decreased while maintaining the same or even enhanced therapeutic effect. Moreover, it has been shown that freezing of gait symptoms can be significantly reduced in patients during the course of the treatment.

[0048] In some embodiments, when used, the first API may be released immediately upon use of the composition. Accordingly, this enhances the bioavailability of the APIs and lead to an improved treatment of PD.

[0049] In some embodiments when the solid composition is used, the first API is released in less than 3 hours, preferably 2 hours, more preferably 1 hour. In this manner, an immediate release of the first API takes place. This has shown to lead to an enhanced bioavailability of the second API and, overall, of the solid composition. In some embodiments when the solid composition is used, the second API is released approximately in less than 5 hours, preferably 4 hours, more preferably 3 hours, most preferred less than 1.5 hours and / or approximately more than 0.5 hour, preferably more than 1 hour. Accordingly, the extended release of the second API allows for the enhancement in bioavailability of the API.

[0050] In some embodiments, the solid composition may further comprise one or more of: 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 for the pharmaceutical application of the solid composition for an improved treatment.

[0051] In some embodiments the composition maybe a tablet. In this way, a user-friendly and convenient administration is provided. In particular, this embodiment can be manufactured in a time and cost-efficient way.

[0052] In some embodiments, the tablet may have a toroidal, oval and / or rectangular shape. The inventors have found that the shape may impact the pharmacokinetics of the solid composition. In this way, it is possible to design and tailor a therapeutic treatment based on individual needs of the patients.

[0053] We emphasize that all aspects, features, and options discussed and disclosed above within the context of the first aspect may be applied to, or combined with, the discussion and disclosure of the following second aspect, and vice versa, unless physically or technically ruled out, even if not every possible combination or subcombination of features is explicitly spelled out in the following. The technical advantages of such options and features that have already been discussed above are therefore not repeated, at least not to the same degree of detail, and reference is instead made to the corresponding explanations above, for conciseness.

[0054] Composition

[0055] In a second aspect, present invention relates to a solid composition comprising at least two compartments separately arranged in the composition; a first active pharmaceutical ingredient, API, provided in a first compartment of the at least two compartments, wherein the first API is selected from the group of DOPA-decarboxylase inhibitors and / or catechol-O-methyltransferase (C0MT-) inhibitors; and a second API provided in a second compartment of the at least two compartments, wherein the second API is an amino acid.

[0056] By using the solid composition of the present invention, enhanced bioavailability of the second API is achieved. Furthermore, the solid composition allows for a sequential release of the first API and the second API, which increases the bioavailability of the second API. In particular, by using the solid composition of the present invention an increase in bioavailability of up to approximately 120 % is achieved as compared to a conventional composition. In addition, the duration of the effective level of the second API is increased. The blood level of the second API induced by the solid composition of the present invention outlasts the blood level of conventional compositions by at least 120 min. Furthermore, a uniform blood level of the APIs is reached. A uniform blood level is associated with better efficacy of the API. By using the solid composition of the present invention, a reduction of dose of the second API is achieved. The sequential release achieves higher and more consistent blood levels for the second API as compared to conventional dosage forms. The conventional daily dose which is associated with treatment complications can be reduced in consequence. Accordingly, the solid composition of the present invention significantly changes the side effect profile of conventional dosage forms. Moreover, the solid composition of the present inventions allows for a reduction of the dose of the first API. The sequential release of the APIs also leads to a higher blood level for the first API. Accordingly, an increase in blood levels similar to conventional formulations and sufficient for the effect of the solid composition of the present invention can be achieved with a lower dose. A reduction in side effects mediated with the intake of the first API is achieved as a positive side effect.

[0057] The first compartment maybe arranged adjacent to the second compartment. The solid composition may have a plate-like structure, wherein a length of the structure may be larger than a height of the structure. The compartments may be arranged adjacent to one another along the height of the plate-like structure of the solid composition.

[0058] This arrangement allows for a geometry-driven increase of bioavailability of the second API. For example, the solid composition may have a 2-layered design. In this manner, the release characteristics of the APIs may be impacted by the shape of the composition. The first compartment may have a height of at least 0.3 cm. Preferably, the first compartment may have a height of at least 0.5 cm. More preferably, the first compartment may have a height of at least 0.7 cm. In addition, or alternatively, the first compartment may have a height of at most 1.4 cm. Preferably, the first compartment may have a height of at most 1.2 cm. More preferably, the first compartment may have a height of at most 1.0 cm.

[0059] The second compartment may have a height of at least 1.8 cm. Preferably, the second compartment may have a height of at least 2.2 cm. More preferably, the second compartment may have a height of at least 2.4 cm. In addition, or alternatively, the second compartment may have a height of at most 3.8 cm. Preferably, the second compartment may have a height of at most 3.6 cm. More preferably, the second compartment may have a height of at most 2.8 cm.

[0060] These specific heights allow for an improved bioavailability for the first and second API. In particular, the thickness of the layers (compartments) may be adjusted with different height length. To aim for a thicker layer, the height may be increased. This may affect the dissolution and / or bioavailability of the API.

[0061] The ratio between the height of the first compartment to the second compartment may be of at least 0.1 to 1. Preferably, the ratio between the height of the first compartment to the second compartment maybe of at least 0.2 to 1. More preferably, the ratio between the height of the first compartment to the second compartment may be of at least 0.3 to 1. The ratio between the surface of the first compartment to the second compartment may be of at least 0.1 to 1. Preferably, the ratio between the surface of the first compartment to the second compartment maybe of at least 0.2 to 1. More preferably, the ratio between the surface of the first compartment to the second compartment may be of at least 0.3 to 1.

[0062] In addition, or alternatively, the ratio between the height of the first compartment to the second compartment may be of at most 0.8 to 1. Preferably, the ratio between the height of the first compartment to the second compartment maybe of at most 0.6 to 1. More preferably, the ratio between the height of the first compartment to the second compartment may be of at most 0.5 to 1. In addition, or alternatively, the ratio between the surface of the first compartment to the second compartment may be of at most 0.8 to i. Preferably, the ratio between the surface of the first compartment to the second compartment maybe of at most 0.6 to i. More preferably, the ratio between the surface of the first compartment to the second compartment maybe of at most 0.5 to 1.

[0063] These specific ratios of the height and / or surface of the first and / or second compartments provide for an improved bioavailability for the first and / or second API. For example, the solid composition may have a third compartment, e.g. a 3-layered design. In this manner, the release characteristics of the APIs may be impacted by the surface of the compartments of the three layers.

[0064] The first compartment may comprise an immediate release formulation. The immediate release formulation may be characterized in that the first API may be released in an amount of substantially 50 wt.-% as compared to the total weight of the first compartment and / or third compartment in less than 30 min at pH 1.2. Preferably, the immediate release formulation may be characterized in that the first API may be released in an amount of substantially 50 wt.-% as compared to the total weight of first compartment and / or third compartment in less than 25 min at pH 1.2. More preferably, the immediate release formulation may be characterized in that the first API may be released in an amount of substantially 50 wt.-% as compared to the total weight of first compartment and / or third compartment in less than 20 min at pH 1.2. Most preferred, the immediate release formulation may be characterized in that the first API may be released in an amount of substantially 50 wt.-% as compared to the total weight of first compartment and / or third compartment in less than 15 min at pH 1.2.

[0065] The second compartment may comprise an extended-release formulation. The extended- release formulation may be characterized in that the second API may be released in an amount of substantially 50 wt.-% as compared to the total weight of the second compartment in less than 380 min, preferably 240 min at pH 1.2 and / or at pH 6.8 after 120 min. Preferably, the extended-release formulation may be characterized in that the second API may be released in an amount of substantially 50 wt.-% as compared to the total weight of the second compartment in less than 200 min at pH 1.2 and / or at pH 6.8 after 120 min. More preferably, the extended- release formulation may be characterized in that the second API may be released in an amount of substantially 50 wt.-% as compared to the total weight of the second compartment in less than 180 min at pH 1.2 and / or at pH 6.8 after 120 min. Most preferred, the extended-release formulation may be characterized in that the second API may be released in an amount of substantially 50 wt.-% as compared to the total weight of the second compartment in less than 160 min at pH 1.2 and / or at pH 6.8 after 120 min.

[0066] This sequential release (sequential arrangement of peak maxima) of the APIs allows for enhanced bioavailability due to the optimized interval between the releases of the first and second API from the first (and third, if available) and second compartment.

[0067] The first and / or second compartment may comprise 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 third compartment may comprise 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 long-chain polymer comprises HPMC, poly ethylene glycol, PEG, sodium carboxymethylcellulose, NaCMC, hydrophobic polymers e.g., ethylcellulose, Eudragit, matrix-forming agents e.g., carbomer, xanthan gum, coating agents e.g., cellulose derivatives, shellac, plasticizers e.g., glycerin, propylene glycol, disintegrants e.g., croscarmellose sodium, crospovidone, pH modifiers e.g., citric acid, sodium bicarbonate, release modifiers e.g., lecithin, and / or surfactants. The short-chain polymers comprise polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC) and / or polyethylene glycol (PEG).

[0068] The polymer may comprise Hydroxypropyl methylcellulose (HPMC), Ethyl cellulose (EC), Cellulose Acetate Phthalate (CAP), Carboxymethylcellulose (CMC), or Polyvinyl Acetate Phthalate (PVAP) or any combination thereof. Additionally, methacrylic acid copolymers such as Eudragit® L, S, RS, and / or RL may also be considered

[0069] The long-chain polymers may control the release of APIs. In particular, the long-chain polymers allow for an extended release of the API(s). The short-chain polymers may control the release of APIs. In particular, the short-chain polymers allow for an immediate release of the API(s). The ratio of short-chain polymer to long-chain polymer maybe of at most 1:9, preferably 1:7, more preferably 1:6.

[0070] In this manner, a formulation-driven improvement of bioavailability is achieved. Moreover, the interval between the releases of the first and second API is optimized in order to provide for an improved bioavailability. Together with the geometry-driven improvement of bioavailability, the overall bioavailability is enhanced in a synergistic manner.

[0071] The solid composition may be coated. The coating may be pH dependent. The solid composition maybe pH dependent. The solid composition and / or coating may comprise cellulose acetate phthalate, CAP, hydroxypropyl methyl cellulose phthalate, HPMCP, and methacrylic acid copolymers (i.e., Eudragit).

[0072] The second compartment may provide for at most 70 % of the total surface of the solid composition. Preferably, the second compartment may provide for at most 65 % of the total surface of the solid composition. More preferably, the second compartment may provide for at most 60 % of the total surface of the solid composition. Most preferred, the second compartment may provide for at most 50 % of the total surface of the solid composition.

[0073] Specifically, the second compartment (12) may provide for 0% of the total surface of the solid composition and the first compartment (11) may provide for 100% of the total surface of the tablet (10). In this manner, when the tablet is used, the first API is released completely before the second API is released. Accordingly, the uptake of the first API occurs before the uptake of the second API. In this way, the bioavailability for the second API is enhanced

[0074] The specific surface values provide for an improvement of bioavailability for the APIs. Moreover, and in this manner, the interval between the releases of the first and second API is optimized in order to provide for improved bioavailability. 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 advantageous for a shape-induced improvement of bioavailability of the APIs. For example, a 3-layered solid composition can guide the release and subsequent uptake of the APIs due to its geometry. It is further conceivable that the third compartment has the same dimension as the first compartment.

[0075] The third compartment may comprise 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 the third compartment may have the same and / or different polymer and / or polymer mixture, preferably the same polymer and / or polymer mixture.

[0076] The first and third compartment may comprise an immediate release formulation. The immediate release formulation may be characterized in that the first API is released in an amount of substantially 50 wt.-% as compared to the total weight of the first and third compartment in less than 30 min at pH 1.2. Preferably, the immediate release formulation may be characterized in that the first API is released in an amount of substantially 50 wt.-% as compared to the total weight of the first and third compartment in less than 25 min at pH 1.2. More preferably, the immediate release formulation may be characterized in that the first API is released in an amount of substantially 50 wt.-% as compared to the total weight of the first and third compartment in less than 20 min at pH 1.2. Most preferred, the immediate release formulation may be characterized in that the first API is released in an amount of substantially 50 wt.-% as compared to the total weight of the first and third compartment in less than 15 min at pH 1.2.

[0077] The second compartment may comprise an extended-release formulation. The extended-release formulation may be characterized in that the second API is released in an amount of substantially 50 wt.-% as compared to the total weight of the second compartment in less than 280 min at pH 1.2 and / or at pH 6.8 after 120 min. The second compartment may comprise an extended-release formulation. The extended- release formulation may be characterized in that the second API is released in an amount of substantially 50 wt.-% as compared to the total weight of the second compartment in less than 240 min at pH 1.2 and / or at pH 6.8 after 120 min. In particular, the extended- release formulation may be characterized in that the second API is released in an amount of substantially 50 wt.-% as compared to the total weight of the second compartment in less than 200 min at pH 1.2 and / or at pH 6.8 after 120 min. Preferably, the extended-release formulation may be characterized in that the second API is released in an amount of substantially 50 wt.-% as compared to the total weight of the second compartment in less than 180 min at pH 1.2 and / or at pH 6.8 after 120 min. More preferably, the extended- release formulation may be characterized in that the second API is released in an amount of substantially 50 wt.-% as compared to the total weight of the second compartment in less than 150 min at pH 1.2 and / or at pH 6.8 after 120 min. Most preferred, the extended-release formulation may be characterized in that the second API is released in an amount of substantially 50 wt.-% as compared to the total weight of the second compartment in less than 130 min at pH 1.2 and / or at pH 6.8 after 120 min.

[0078] In some embodiments, the extended- release formulation may be characterized in that the second API is released in an amount of substantially 50 wt.-% as compared to the total weight of the second compartment in less than 280 min at pH 1.2 and / or at pH 6.8 after 120 min. Preferably, the extended-release formulation may be characterized in that the second API is released in an amount of substantially 50 wt.-% as compared to the total weight of the second compartment in less than 240 min at pH 1.2 and / or at pH 6.8 after 120 min.

[0079] The first and third compartments may provide for at least 80% of the total surface of the solid composition. Preferably, the first and third compartments may provide for at least 85% of the total surface of the solid composition. More preferably, the first and third compartments may provide for at least 90% of the total surface of the solid composition.

[0080] The second compartment may be arranged between the first compartment and third compartment. The second compartment may have the same width and length as the first compartment. The first compartment may be free of the second API, and wherein the second compartment may be free of the first API. The first compartment may be characterized by a first dissolution rate. The second compartment may be characterized by a second dissolution rate. The second dissolution may be different from the first dissolution rate. The first API and the second API may be released simultaneously or sequentially.

[0081] In some embodiments, when using the solid composition, the release of the first API may have a first peak maximum of API release in % over time, and the release of the second API may have a different, second peak maximum of API release in % over time. The second peak maximum may be subsequent to the first peak maximum.

[0082] This sequential arrangement of peak maxima (sequential release) of the APIs provides for an improved bioavailability as compared to conventional compositions.

[0083] The amount of the first API may be between 5 mg and 50 mg. Preferably, the amount of the first API may be between 10 mg and 40 mg. More preferably, the amount of the first API may be between 15 mg and 35 mg. The amount of the second API may be between 50 mg and 500 mg. Preferably, the amount of the second API may be between 80 mg and 250 mg. More preferably, the amount of the second API may be between 90 mg and 150 mg.

[0084] In addition, or alternatively, 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.

[0085] These specific dosages of the first and / or second API have shown to allow for the optimized interval in release kinetic, which enhances the bioavailability of the APIs.

[0086] In some embodiments, when using the solid composition, the first API may be released immediately upon use of the solid composition. In some embodiments, when using the solid composition, the first API may be released in less than 3 hours. Preferably, when using the solid composition, the first API may be released in less than 2 hours. More preferably, when using the solid composition, the first API may be released in less than 1 hour. In some embodiments, when using the solid composition, the second API may be released approximately in less than 5 hours. Preferably, when using the solid composition, the second API maybe released in less than 4 hours. More preferably, when using the solid composition, the second API maybe released in less than 3 hours. Most preferred, when using the solid composition, the second API may be released in less than 1.5 hours. Preferably, when using the solid composition, the second API may be released in approximately more than 0.5 hour. Preferably, when using the solid composition, the second API may be released in approximately more than 1.0 hour.

[0087] These specific release characteristics allow for the provision of the optimized interval, which enhances the bioavailability of the APIs.

[0088] The solid composition may further comprise one or more of: 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 toroidal shape. The tablet may have an oval shape.

[0089] The tablet may have a rectangular shape. The composition maybe a solid composition. The composition for use maybe 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.

[0090] The solid composition is for use in the treatment of a condition associated with Parkinson’s disease. In some embodiments, the solid composition for use may be characterized in that the use may be in the treatment of Parkinson’s disease and / or the prevention of progress in Parkinson’s disease.

[0091] We emphasize that all aspects, features, and options discussed and disclosed above within the context of the first aspect may be applied to, or combined with, the discussion and disclosure of the second aspect, and vice versa, unless physically or technically ruled out, even if not every possible combination or sub-combination of features is explicitly spelled out in the following. The technical advantages of such options and features that have already been discussed above are therefore not repeated, at least not to the same degree of detail, and reference is instead made to the corresponding explanations above, for conciseness.

[0092] SHORT DESCRIPTION OF THE FIGURES

[0093] Possible embodiments of the present invention are further described in the following detailed description, with reference to the following figures, wherein:

[0094] Fig. 1: illustrates schematically a solid composition according to an embodiment of the present disclosure.

[0095] Figs. 2a and 2b: illustrate the release characteristics and the bioavailability of a solid composition according to an embodiment of the present disclosure and illustrates the improvement in bioavailability of a solid composition according to an embodiment of the present disclosure.

[0096] Fig. 3: illustrates the dissolution profile of a solid composition in comparison with conventional release modified compositions (immediate and extended).

[0097] Fig. 4a and 4b: illustrate multicompartment compositions according to an embodiment of the present disclosure.

[0098] Fig. 5: illustrates the dissolution profiles and AUCs of a composition comprising levodopa and carbidopa according to an embodiment of the present disclosure in comparison to conventional release modified compositions.

[0099] Fig. 6: illustrates the dissolution profiles of shaped tablets comprising different compartments according to an embodiment of the present disclosure. Fig. 7: illustrates the dissolution profiles of shaped tablets comprising different compartments according to an embodiment of the present disclosure.

[0100] Figs. 8a-8c: illustrates the dissolution and pharmacokinetic profiles of shaped tablets comprising three compartments according to an embodiment of the present disclosure in a comparative manner.

[0101] Figs. 9a-9c: illustrates the dissolution and pharmacokinetic profiles of shaped tablets with different formulations comprising two compartments according to an embodiment of the present disclosure in a comparative manner.

[0102] Fig. 10: shows the influence of the interval between the first and the second API release on bioavailability and duration of blood levels of the second API for the shaped tablets of Figs. 9A-9C.

[0103] DETAILED DESCRIPTION OF THE EMBODIMENTS

[0104] In the following only some possible embodiments of the invention are described in detail. However, the present invention is not limited to these, and a multitude of other embodiments are applicable without departing from the scope of the invention.

[0105] The presented embodiments can be modified in a number of ways and combined with each other whenever compatible and certain features may be omitted in so far as they appear dispensable. In particular, the disclosed embodiments may be modified by combining certain features of one embodiment with one or more features of another embodiment.

[0106] It is to be understood that not all features of the described aspects / embodiments have to be present for realizing the technical advantages provided by the present disclosure, which is defined by the subject-matter of the claims. The disclosed aspects / embodiments may be modified by combining certain features of one aspect / embodiment with one or more features of another aspect / embodiment. Specifically, the skilled person will understand that features, and / or functional elements of one aspect / embodiment can be combined with technically compatible features, and / or functional elements of any other aspect / embodiment of the present disclosure given that the resulting combination falls within the definition of the present disclosure.

[0107] While the embodiments below are described primarily with reference to a composition for use, the skilled person will recognize that the disclosure according to the invention can equally be applied in a plurality of different technical fields and / or use cases.

[0108] Throughout the present figures and specification, the same reference numerals refer to the same elements. For the sake of clarity and conciseness, certain features, parts, elements, aspects, components and / or steps of certain embodiments are presented without undue detail where such detail would be apparent to those skilled in the art in the art in light of the teachings herein and / or where such detail would obfuscate an understanding of more pertinent aspects of the embodiments.

[0109] As understood by the skilled person and / or in order to avoid redundancies, reference is also made to the explanations in the preceding sections, which also apply to the following detailed description. Further, not all features, parts, elements, aspects, components and / or steps are expressly indicated by reference signs for the sake of brevity and clarity. This particularly applies, where the skilled person recognizes that such features, parts, elements, aspects, components and / or steps are present in a plurality.

[0110] In Fig. 1, a tablet (io) being a solid composition (left in Fig. 1) is shown next to a conventional composition in the art (right in Fig. 1). Specifically, Fig. 1 illustrates a tablet (io) for use in the treatment of a condition associated with Parkinson’s disease is shown. The tablet comprises three compartments (11, 12, 13), which are separately arranged in the tablet (10).

[0111] A first API is provided in the first compartment (11), wherein the first API is carbidopa, which is a DOPA-decarboxylase inhibitor. In the embodiment shown in Fig. 1, carbidopa is further arranged in the third compartment (13). The second API is provided in the second compartment (12) of the tablet (10), wherein the second API is levodopa. Accordingly, in the embodiment of Fig. 1, the first API is carbidopa which is provided in the first (11) and the third (13) compartment, and the second API is levodopa which is provided in the second compartment (12). The compartments are arranged adjacent to each other, such that the second compartment (12) is arranged between the first (11) and third (13) compartment. The compartments are in direct contact with each other and are of the same structure. The tablet (io) as shown in Fig. i comprise a plate-like structure and has an oval shape. Specifically, the plate-like structure has a length that is greater than the height of the structure. The three compartments (11, 12, 13) are also plate-like, and are arranged such that they are stacked on top of each other. The three compartments (11, 12, 13) are arranged adjacent to one another along the height of the plate-like structure, i.e., they are arranged on top of one another. As can be seen, the first (11) and the third (13) compartment have the same structural dimensions. In particular, the first (11) and the third (13) compartment have the same length, width and height. The second compartment (12) has the same planar characteristics as the first (11) and the third (13) compartment, i.e., the same length and width, but has a different height. The second compartment (12) provides for 20% of the total surface of the tablet (10), namely at the edge of the tablet (10). The first (11) and third (13) compartment together provide for 80% of the total surface of the tablet (10).

[0112] The top and bottom surfaces of the tablet (10) are defined by the first compartment (11) and the third compartment (13), respectively. The main surfaces of the second compartment (12) are fully covered by the first compartment (11) and the third compartment (13). The side of the tablet (10) is defined by all three compartments. At its side, the second compartment (12) is not covered by the other two compartments (11, 13)-

[0113] The compartments are constituted such that they dissolve when used, for example when orally administered. Accordingly, when the tablet (10) is used, the tablet is dissolving. As will be appreciated by the skilled person, when the compartments are dissolving, the respective APIs are released. The initial dissolution phase is characterized by release of the carbidopa arranged in the outer compartments of the tablet (10). Minor amounts of levodopa are also be released during the initial dissolution phase, at the edge side of the tablet (10). When the first and third compartments are fully dissolved, the subsequent dissolution phase is characterized by a strong release of the levodopa.

[0114] In the embodiment shown in Fig. 1, the first compartment (11) has the same dimensions and API release characteristics as the third compartment (13). They differ from the dimensions and API release characteristics of the second compartment (12). This is in particular illustrated in Fig. 2a. Fig. 2a illustrates the release dissolution data for the APIs. Returning to Fig. i, 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) is free of the second API, and the second compartment (12) is free of the carbidopa. Also, the third compartment (13) is free of the levodopa. However, it is conceivable that in some embodiments the third compartment (13) also comprises the levodopa.

[0115] The following table illustrates preferred characteristics (diameter d, height h, width b, surface area SA, hardness in N, mass in g and the dissolution in %) of a tablet according to the present disclosure: h [mm] 3-85 + 0.04 d <m l 13.52 40.05 (0.4%) b [mm] 4.69 + 0.05 (1.0%)

[0116] Dissolution 100 % CAR release after 60 min 100% LEV release after 120 min Comparative dissolution studies

[0117] Fig. 2b shows in a comparative manner the AUC profile of a conventional composition (top in Fig. 2b) in the art as compared to the solid composition of present disclosure (bottom in Fig. 2b). Specifically, it can be seen that the AUC curves for carbidopa (API 1) and levodopa (API 2) in the solid composition are arranged in a sequential manner (“sequential release”; Fig. 2b on the bottom right). Particularly, the APIs can reach a higher increase in the maximum concentration (Cmax) as compared to the conventional composition in vivo (Cmax). Moreover, Fig. 2b shows that the use of the solid composition not only leads to an increase in concentration of levodopa which is present after use but also in the total AUC of the APIs. These results show that the solid composition according to present disclosure can effectively increase the bioavailability of levodopa in vivo.

[0118] The additional blood level duration of the APIs for the solid composition resulting from the “sequential release” is illustrated with arrows (in Fig 2b, between dashed lines).

[0119] In Fig. 3 the dissolution profiles of the solid composition are compared to conventional compositions known in the art. In particular, dissolution profiles for a tablet are shown. The material released (shown as average API content in %) of the tablet comprising carbidopa (API i) and levodopa (API 2) of two conventional compositions has been measured in vitro over 300 minutes. The conventional compositions shown in Fig. 3 are 1) an immediate release formulation and 2) a retard formulation. As can be seen in Fig. 3, the release characteristics of the two compartments in the tablet are comparable with the release characteristics of an immediate and extended release formulation. In particular, it is shown that carbidopa in the tablet is quickly released resembling the conventional immediate composition. This quick release can be seen in the steep rise of the first graph. Levodopa (API 2) is, on the other hand, released more slowly as compared to carbidopa (API 1). Levodopa resembles a release-modified composition, such as a retard formulation. Accordingly, the tablet combines the release characteristics of two different formulations. In a further embodiment, the tablet combines more than two release characteristics.

[0120] Multicompartment compositions

[0121] In Figs. 4a and 4b several preferred embodiments are shown. In particular, tablets (10) are shown that comprise two or three compartments. These compartments comprise either the same or different APIs and release characteristics. Particularly, tablets (10) in form of a multi compartment tablet are shown. These multicompartment tablets are produced by using common printing methods. Printing methods comprise screen printing, 3D printing, or 3D screen printing. As can be seen, the compartments of the tablets (10) are either adjacent to each other along the plate-like structure (in the Figs. 4a and 4b, on the right) or arranged in a coating manner (in the Figs. 4a and 4b, on the left). In Fig. 4a on the left, a tablet (io) is shown in which the first compartment (11) encompasses the second compartment (12). The first compartment (11) comprises the first API, and the second compartment (12) comprises the second API. The first compartment (11) is free of the second API and the second compartment (12) is free of the first API. In this particular embodiment, the first (11) and the second (12) compartment have different dimensions and API release characteristics. In particular, the compartments have different height, width and length. Specifically, the second compartment (12) provides for 0% of the total surface of the solid composition and the first compartment (11) provides for 100% of the total surface of the tablet (10). In this manner, when the tablet is used, the first API is released completely before the second API is released. Accordingly, the uptake of the first API occurs before the uptake of the second API. In this way, the bioavailability for the second API is enhanced.

[0122] In Fig. 4a on the right, a tablet (10) is shown in which the first compartment (11) is adjacent to the second compartment (12) along the 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 larger than the height of the second compartment (12). As can be seen, the second compartment (12) is arranged on top of the first compartment (11). The compartments are in direct contact to each other. The first compartment (11) comprises the first API, and the second compartment (12) comprises the second API. The first compartment (11) is free of the second API and the second compartment (12) is free of the first API. In this particular embodiment, the compartments have different API release characteristics.

[0123] Further embodiments may comprise a third compartment (13), which is illustrated in Fig. 4b

[0124] Specifically, Fig. 4b on the left shows a tablet (10) for use according to present disclosure, and in particular a tablet (10) which can be orally administered. The tablet comprises three compartments (11, 12, 13). The third compartment (13) of the at least two compartments is encompassed by the second compartment (12), which itself is encompassed by the first compartment (11). In this manner, the first compartment (11) provides for 100% of the total surface of the tablet (10). On the other hand, the second (12) and the third compartment (13) provide for 0% of the total surface of the tablet (10). In particular, the compartments have different height, width and length. The tablet (10) shown in Fig. 4b, comprises a first API, which is arranged in the first (11) and the third compartment (13). These compartments are free from the second API, which is arranged in the second, middle, compartment (12). In this manner, the total amount of the first API is not released before the second API. In this particular embodiment, the second API is released when the first API has completely been released from the first compartment (11). After complete release of the second API, the first API is further released from the third compartment (13). It is conceivable, that the third compartment (13) comprise a third API which is different from the first and second API.

[0125] In this particular embodiment shown in Fig. 4b on the left, the compartments are arranged in a centrosymmetric manner. It is conceivable, that the compartments are differently arranged, which changes the release characteristics.

[0126] In Fig. 4b on the right, a tablet (10) is shown which comprises three compartments. The first (11), second (12) and third (13) compartment are arranged on top of 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 to each other. The first (11) and third (13) compartments have the same dimensions and API release characteristics. The second compartment (12) has different dimensions and API release characteristics. Specifically, the first (11) and the third (13) compartment provide for at least 80% of the total surface of the tablet (10). In this particular embodiment, when the tablet is used, the two APIs are released simultaneously. However, the first API is released in a larger amount, which is due to the larger portion of the total surface. During this stage, small amount of the second API is released. After the first API is released completely from the first (11) and the third (13) compartment, the second API is released in a larger amount (“sequential”). In this way, the peak maxima of the AUC curves for the first and the second APIs occur subsequently, i.e., the peak maximum of the first API occurs before the peak maximum of the second API.

[0127] Increased bioavailability and reduction of dose

[0128] In vitro dissolution testing

[0129] Dissolution experiments were performed according to the USP monograph “Acetaminophen tablets” section dissolution of the US Pharmacopeia. A Vankel® VK 7000 dissolution paddle apparatus equipped with a VK750D heater were used for the dissolution experiments. Dissolution was performed using 900 mL phosphate buffer, pH = 5.8 at 37.0 ± 0.5 °C, with stirring at 50 rpm. Wire claps were used to fix the tablets at the bottom of the vessel during the experiment. Analysis (n=6) was performed using a Thermo® Evolution 300 UV / Vis spectrophotometer equipped with flow-through cuvettes run by an Ismatec® IPS multichannel peristaltic pump. Absorption at =243 nm was measured continuously over 8h using the Thermo vision Pro software. A calibration curve in the range of 2 - i50mg Paracetamol was made, which correlated with R = 0.9999.

[0130] In vivo testing

[0131] Tablet administration:

[0132] • Measurement of drug uptake after tablet application using gastroscopic technique directly into the stomach of pigs

[0133] • Active ingredient concentrations are measured in the blood up to 24 hours after application.

[0134] • Measuring points: 30, 60, 90, 120, 180, 240, 360, 480 minutes and 24 hours

[0135] Analytical method:

[0136] Plasma samples were prepared according to Cesar 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 by protein precipitation with perchlorate and addition of methyldopa as an internal standard; centrifugation was performed at 2000 rpm and 5°C for 15 minutes.

[0137] Samples were analyzed by ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry using a THERMO (Bremen, Germany) UltiMate HPG-3400 RS binary pump and a WPS-3000 auto-sampler set at 10 °C and equipped with a 25 pL injection syringe and a too pL sample loop. The column was stored at 25 °C in the column chamber TCC-3200. THERMO Accucore® C-18 RP (too x 2.1 mm; 2.6 pm) was used as the chromatography column using the gradient in Table 2 at a constant flow rate of 0.4 mL / min. Eluent A was water with 2% acetonitrile and 0.1% formic acid. Eluent B was pure acetonitrile.

[0138] Mass spectra were recorded using a THERMO QExactive plus Orbitrap mass spectrometer coupled to a heated electrospray source (HESI). The solid composition of present disclosure has been studied towards its release characteristics in vitro and its bioavailability in vivo. For the in vitro and in vivo experiments, the tablet (io) has been used and administered. Following dosages were used and administered respectively: a tablet with the total dosage of carbidopa between io mg and 15 mg, and the total dosage of the levodopa between 90 mg and 150 mg was used in the in vitro study and administered in the in vivo study. The average API content in % of the tablet comprising carbidopa as the first API (“API 1 in a solid composition”) and levodopa as the second API (“API 1 in a solid composition”) has been measured in vitro over 200 min and were compared to two conventional compositions (“API 1 conventional / API 2 conventional” and “API 1 in a solid composition / API 2 in a solid composition” with triangular points . The corresponding dissolution profiles for these conventional formulations are depicted in Fig. 5 on the left. As can be seen, the release characteristics of carbidopa (“API 1 in a solid composition”) of the tablet is comparable with the dissolution profile of an immediate release formulation of carbidopa (“API 1 conventional”). Further, the release characteristics of levodopa (“API 1 in a solid composition”) of the tablet is comparable with the dissolution profile of an extended- release formulation of levodopa (“API 2 in a solid composition ” with triangular points). In particular, it is shown that the tablet releases carbidopa immediately upon use of the tablet. The dissolution profile for this immediate release of carbidopa upon use resembles the dissolution profile of the conventional immediate composition. Levodopa is on the other hand released slower as compared to carbidopa in the tablet and in particular is resembling a release-modified composition, such as a retard formulation (“in a solid composition ” with triangular points). Particularly, as can be seen in Fig. 5 on the left, the carbidopa of the tablet has an average API release of too wt. % in less than 1 hour, preferably 2 hours, more preferably 1 hour. Levodopa in the tablet is characterized by an average API release of too wt. % in less than 2 hours.

[0139] For the in vivo study, the tablet is administered orally. After administration, the API content has been measured over 24 hours (1600 min) after administration. In Fig. 5 on the right, the in vivo data for the tablet (indicated as “LD sandwich tablet”) as discussed in Fig. 5 on the left is shown. From these measured data, the bioavailability has been calculated by plotting the AUC which can be seen in Fig. 5 on the right. In particular, the tablet reaches 89 (AUC 89) which is an 100% increase in bioavailability for levodopa when compared to the conventional immediate release composition (AUC 40) (e.g., Sinemet). In comparison to a release-modified composition, the tablet according to the present disclosure reaches a 50% increase in bioavailability for levodopa when compared to the retard composition (“zn a solid composition ” with triangular points), which reaches (AUC 6o) (e.g., Dopadura Retard). Consequently, the AUC of the tablet is significantly different as compared to the individual AUC of the conventional formulations (indicated as “LD Dopadura retard” and “LD Sinemet” in Fig. 5 on the right).

[0140] Specifically, the AUC of levodopa when administered in the tablet is increased as compared to the conventional compositions. Accordingly, the bioavailability for levodopa when administering the tablet differs significantly in vivo from the bioavailability of the individual APIs in conventional formulations. In this way, when using the tablet of present disclosure, the treatment of a patient who requires for example 6 conventional doses per day is reduced drastically, to only 3 doses per day by using the solid composition of present disclosure. At the same time, the prolonged bioavailability reduces freezing of gait symptoms in the morning, when the first dose of the day is due.

[0141] In conclusion, the in vitro and in vivo data demonstrate the enhanced pharmacokinetics and increase in bioavailability, when compared to conventional compositions. These results further demonstrate the potential effective use of the tablet in the treatment of PD. Particularly, the solid composition is used in the prevention and treatment of PD. As a higher bioavailability is reached (Fig. 5 on the right), the dosage required to achieve a therapeutic benefit can be reduced. In this way, a treatment with reduced side effects associated with PD can be achieved. In particular, the side effects, such as motor and / or a non-motor symptom is consequently reduced. In this manner, “end of dose wearing off’ phenomena such as freezing of gait (FOG) is reduced as the bioavailability is even prolonged as compared to the conventional compositions (see Fig. 5 on the right and Fig. 2b).

[0142] Shape and composition

[0143] In Fig. 6 the dissolution profile for three preferred embodiments, i.e. for tablets with a rectangular shape, a toroidal shape and an oval shape are shown. As can be seen the different shaped tablets comprise one or more compartments with different API release characteristics. In particular and as compared to the known dissolution profiles for an immediate and extended-release formulation, the dissolution profile for the rectangular composition resembles an immediate release formulation. On the other hand, the dissolution profile of the oval shaped composition is similar to an extended-release formulation. The toroidal shaped composition is a “mixed-type”, which shows a dissolution which resembles an immediate profile in the first 20 mins and subsequently to the extended release profile.

[0144] In Fig. 7 the dissolution profiles for a toroidal shaped tablet according to present disclosure are shown. In particular, it is shown that the toroidal tablet comprises one API in two different compartments with two different API release characteristics (immediate and extended). Specifically, embodiments with the following proportions are used: 100% immediate, 75% immediate and 25% extended, 50% immediate and 50% extended, 25% immediate and 75% extended and 100% extended. By changing the proportion between the two compartments within the toroidal tablet, different dissolution profiles are achieved.

[0145] In vitro and in vivo testing for tablets with three compartments

[0146] Figs. 8a-8c illustrate the dissolution and pharmacokinetic profiles of shaped tablets comprising three compartments according to an embodiment of the present disclosure. Two embodiments of the invention are show in a comparative manner against a conventional Levodopa (“LD”) / Carbidopa (“CD”) formulation. The dosage form of the formulations is a tablet.

[0147] For the dissolution and bioavailability studies shown in Figs 8a-8c, two formulations (Formulation 1 and 2) according to the invention have been prepared:

[0148] Formulation 1:

[0149] Table 1: Composition of the Levodopa-Layer Tab 044

[0150] No. Ingredients wt% paste wt% tablet per tablet

[0151] (mg)

[0152] 1 Levodopa 33-26 60.47 too

[0153] 2 Klucel LF Pharma 2.20 4.01 6.625

[0154] 3 Avicel PH 105 13.47 24.49 40.5

[0155] 4 Starch 1500 1.91 3.48 5.75

[0156] 5 Glycerol 2.91 5.29 8.75

[0157] 6 Talc 0.83 1.51 2.5

[0158] 7 Silfar 350 0.42 0.76 1.25

[0159] 8 L- (+) -Ascorbic acid 0.11 0.20 0.325

[0160] 9 Water 44.88 Total too too 165.708

[0161] Table 2: Composition of the Carbidopa-Layer Tab 044

[0162] No. Ingredients wt% paste wt% tablet per tablet (mg)

[0163] 1 Carbidopa 23.33 50.00 25

[0164] 2 Klucel LF Pharma 2.36 5.07 2.533

[0165] 3 Avicel PH 105 14.45 30.97 15.486

[0166] 4 Starch 1500 2.05 4.40 2.199

[0167] 5 Glycerol 3.12 6.69 3-346

[0168] 6 Talc 0.89 1.91 0.956

[0169] 7 Silfar 350 0.45 0.96 0.478

[0170] 8 L- Ascorbic acid 0.12 0.25 0.124

[0171] 9 Citrus acid 1.01 2.16 1.083

[0172] 10 Water 52.22

[0173] Total 100 100 51.205 Formulation 2:

[0174] Table 3: Composition of the Levodopa-Layer Tab 273

[0175] No. Ingredients wt% paste wt% tablet per tablet

[0176] (mg)

[0177] 1 Levodopa 27.60 60.15 100

[0178] 2 Klucel LF Pharma 1.10 2.41 4

[0179] 3 Shin-Etsu AQOAT AS-LF 7.29 15.88 26.4

[0180] 4 Ammonia 25 % 0.74 1.60 2.664

[0181] 5 Avicel PH-105 4-86 10.59 17-6

[0182] 6 Talc- Luzenac Pharma M 0.88 1.92 3.2

[0183] 7 Glycerol 1.55 3.37 5.6

[0184] 8 Triethylcitrate 0.66 1.44 2.4

[0185] 9 Silfar SE 4 1.10 2.41 4

[0186] 10 L- (+) -Ascorbic acid 0.11 0.24 0.4 11 Water 54.10

[0187] Total too too 166.264

[0188] Table 4: Composition of the Carbidopa-Layer Tab 273

[0189] No. Ingredients wt% paste wt% tablet per tablet

[0190] (mg)

[0191] 1 Carbidopa 20.62 45-27 25

[0192] 2 Klucel LF Pharma 1.88 4.12 2.277

[0193] 3 Ac-Di-Sol 3.46 7.60 4-197

[0194] 4 Mannogem Emerald 12.11 26.60 14.688

[0195] 5 RxCIPIENTS® FM1000 2.37 5.21 2.878

[0196] 6 Talc- Luzenac Pharma M 0.62 1.37 0.755

[0197] 7 Silfar 350 0.21 0.46 0.252

[0198] 8 Miglyol 812 N 1.01 2.21 1.223

[0199] 9 Glycerol 2.20 4.82 2.662

[0200] 10 L- (+) -Ascorbic acid 0.12 0.27 0.150

[0201] 11 Citric acid 0.94 2.06 1-139

[0202] 12 Water 54-46

[0203] Total 100 100 55-221

[0204] The tested formulations comprise LD and CD in the following amounts: • Conventional tablet: LD too mg; CD 25 mg;

[0205] • Formulation 1 (fast release): LD too mg; CD 25 mg; with 1:7 of HPC to

[0206] HPMCAS.

[0207] • Formulation 2 (slow release): LD too mg; CD 25 mg, with 1:7 of HPC to

[0208] HPMCAS. The solid composition used in the studies shown in Figs. 8a-8c comprises at least two compartments separately arranged in the solid composition; a first active pharmaceutical ingredient (API) provided in a first compartment (11) of the at least two compartments, wherein the first API is selected from the group of DOPA-decarboxylase inhibitors and / or catechol-O-methyltransferase (C0MT-) inhibitors; and a second API provided 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 a length of the structure is larger than a height of the structure. In particular, the compartments are arranged adjacent to one another along the height of the plate-like structure of the solid composition. In particular, first compartment has a height of at least 0.3 cm, preferably 0.5 cm, more preferably 0.7 cm. In addition, or alternatively, the first compartment (11) has a height of at most 1.4 cm, preferably 1.2 cm, more preferably 1.0 cm. In particular the second compartment (13) has a height of at least 1.8 cm, preferably 2.2 cm, more preferably 2.4 cm. In addition, or alternatively, the second compartment has a height of at most 3.8 cm, preferably 3.6 cm, more preferably 2.8 cm. The ratio between the height of the first compartment (11) to the second compartment (12) is of at least 0.1 to 1, preferably 0.2 to 1, more preferably 0.3 to 1; and / or wherein the ratio between the height of the first compartment (11) to the second compartment (12) is of at most 0.8 to 1, preferably 0.6 to 1, more preferably 0.5 to 1. In particular, the first compartment (11) comprises an immediate release formulation. The immediate release formulation is characterized in that the first API is released in an amount of substantially 50 wt.-% as compared to the total weight of the first compartment (11) in less than 30 min, preferably 25 min, more preferably 20 min, most preferred 15 min at pH 1.2.

[0209] Further the second compartment comprises an extended-release formulation. The extended-release formulation is characterized in that the second API is released in an amount of substantially 50 wt.-% as compared to the total weight of the second compartment (12) in less than 380 min, preferably 240 min, more preferably 160 min, even more preferably 120 min, most preferred 90 min at pH 1.2 and / or at pH 6.8 after 120 min.

[0210] In particular the first and / or second compartment (11, 12) comprises 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 ratio of short-chain long-chain polymer to short-chain long-chain polymer is of at most 1:9, preferably 1:7, more preferably 1:6. The second compartment (12) provides for at most 70 %, preferably for at most 65 %, more preferably for at most 60%, most preferred for at most 50% of the total surface of the solid composition. The first API is further arranged in a third compartment. The solid composition according to the preceding claim, wherein the first and third compartments (11, 13) have the same dimensions API and / or API release characteristics. In particular, the first and third compartment (11, 13) comprises an immediate release formulation. In particular, the immediate release formulation is characterized in that the first API is released in an amount of substantially 50 wt.-% as compared to the total weight of the first and / or third compartment (11, 13) in less than 30 min, preferably 25 min, more preferably 20 min, most preferred 15 min at pH 1.2. The first and third compartments (11, 13) provide for at least 80 %, preferably for at least 85 %, more preferably for at least 90 % of the total surface of the solid composition. In particular, the second compartment (12) is arranged between the first compartment (11) and third compartment (13). The second compartment (12) has the same width and length as the first compartment (11) and preferably the same footprint. The first and third compartment (11, 13) is free of the second API, and wherein the second compartment (12) is free of the first API. The first compartment and third compartment (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. In particular, the release of the first API has a first peak maximum of API release in % over time, and the release of the second API has a different, second peak maximum of API release in % over time and / or the second peak maximum is subsequent to the first peak maximum. In particular, 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. In particular, the first API is carbidopa, and the second API is levodopa.

[0211] The first API is released immediately upon use of the solid composition. The first API is released in less than 3 hours, preferably 2 hours, more preferably 1 hour. The second API is released approximately in less than 5 hours, preferably 4 hours, more preferably 3 hours, most preferred less than 1.5 hours and approximately more than 0.5 hour, preferably more than 1 hour.

[0212] The solid composition further comprises a pharmaceutically acceptable coating, a pharmaceutically acceptable carrier, and a pharmaceutically acceptable substituent. The solid composition is a tablet (10). The tablet (10) has an oval shape. The tablet (10) may have a toroidal and / or rectangular shape. The solid composition is for use in the treatment of a condition associated with Parkinson’s disease. In particular, the solid composition is administered orally. In particular, the treatment is characterized in a reduction of a side effect associated with Parkinson’s disease. The side effect associated with Parkinson’s disease is a side effect selected from a motor and / or a non-motor symptom. The motor and / or the non-motor symptom is selected from one or more of bradykinesia, impaired mobility, tremor, rigidity, dysphagia, or freezing of gait, FOG, preferably bradykinesia, impaired mobility, tremor or FOG, more preferably FOG. The solid composition for use is characterized in that the use is in the treatment of Parkinson’s disease and the prevention of progress in Parkinson’s disease. In particular, the solid composition is administered daily. In particular, the first API is carbidopa, and the second API is levodopa. In particular, 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. 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. In particular, the solid composition is a pharmaceutical solid composition.

[0213] Dissolution studies were performed in 750 mL of 0.1 M HCL, at too rpm and 37 °C. After 2h, the pH value was changed to 6.88 by adding 250 mL of 0.2 M tribasic sodium phosphate solution. The samples were analyzed by HPLC (NaHPO4buffer pH 2.7 + 5 % acetonitrile (ACN) (on a C18 column (Agilent Zorbax Eclipse Plus C18 RR 150x4.6 mm 3.5 pm), UV detection wavelength of 280 nm, column temperature 40 °C, 5 pL injection volume, run time 9 min.

[0214] Bioavailability studies were performed in an animal model (pigs) with group sizes of 4 to 8 pigs each group. Pigs are fasted 24 hours before the tablets are administered, administered directly into the stomach under full narcosis. After 20-30 min, pigs are fed (hay), and blood samples are taken and processed immediately. Plasma is then stored under refrigeration and analyzed. The samples were measured using HPLC- MS / MS method for the determination of levodopa / carbidopa in plasma: C18 column (50 x 4.6 mm 5 pm) and a mobile phase of 0.2% formic acid and acetonitrile (90:10). High-resolution mass spectrometer equipped with an electrospray source in positive mode was set up in selective reaction monitoring mode to detect the ion transitions m / z 198.1 -> m / z 107.0, m / z 227.2 -> m / z 181.0 m / z 212.1 -> m / z 139.2 for levodopa, carbidopa and methyldopa, respectively, as internal standard. The plasma samples were prepared by protein precipitation with perchlorate. Centrifugation was performed at 2000 rpm at 5°C for 15 min. In Fig. 8a the average API content in % over time for formulation 1, 2 and the conventional formulation is shown (shown as “LD / CD 1” for formulation 1; “LD / CD 2” for formulation 2 and LD / CD conventional for the conventional formulation). As can be taken from Fig 8a, LD and CD from the conventional formulation are released completely in under 1 / 2 hour (data points overlap, cf. Fig. 8a). The release of the APIs, LD and CD, in formulations 1 and 2 is considerably slower. Specifically, the release of LD in formulations 1 and 2 is slower whereas CD shows a quicker, e.g. an immediate release. In particular, formulation 1 shows a complete release of CD in approximately 1 hour. The complete release of LD takes place in approximately 3 hours. Formulation 2 shows a slower release kinetic than formulation 1. The complete release of CD in formulation 2 takes place in approximately 1 V2 hours, and the complete release of LD for formulation 2 is achieved in approximately 5 hours.

[0215] Coming now to Fig. 8b, the bioavailability of LD for formulations 1, 2 and the conventional tablet (as discussed in the context of Fig. 8a) are shown. In particular, the blood level concentration of LD has been measured over time for the respective formulations and the corresponding AUC for LD has been determined with 7.54 pg*h / mL for formulation 1, 4.82 pg*h / mL for formulation 2 and 3.01 pg*h / mL for the conventional formulation.

[0216] As can be taken from Fig. 8b, the AUC value for LD of formulation 1 and 2 are increased as compared to the conventional formulation. In particular, the AUC value of LD for formulation 1 is highest (7.54 pg*h / mL) as compared to the AUC values for LD from formulation 2 and the conventional formulation. Specifically, the AUC of LD from formulation 1 increased by 2.5 as compared to the conventional formulation. Accordingly, levodopa bioavailability is increased by a factor of 2.5 (Fig. 8b) in particular due to the sequential release of carbidopa and levodopa (Fig. 8a) from formulation 1. With respect to formulation 2, AUC (4.82 pg*h / mL) for LD is increased by a factor of more than 1.5 as compared to the conventional formulation (3.01 pg*h / mL).

[0217] Likewise, AUC values for CD of formulation 1 and 2 are increased as compared to the CD value of the conventional formulation, as shown in Fig. 8c. In particular, AUC value for CD of formulation 1 is highest compared to formulation 2 and conventional.

[0218] Figs. 8a to 8c demonstrate a 2.5-fold increase in bioavailability for LD for a 3comosition with three compartments, wherein two outer compartments show an immediate release of CD (IR, short-chain polymer with fast release) and an inner second compartment with LD showing a fast or prolonged release formulation in a sandwich geometry (3-layer). The release of two active ingredients is determined by the geometry and the formulation. Fig. 8a demonstrates that a sequential release of two active ingredients can be achieved by the geometry alone. In consequence, a larger amount of LD is absorbed due to the faster release of CD. The LD blood level is constantly high over a longer period of time as demonstrated by the results shown in Fig. 8b as compared to the conventional LD / CD formulation. Furthermore, these data demonstrate that the geometry-induced levodopa blood level outlasts the blood level of commercial standard products by approximately 2 hours.

[0219] In vitro and in vivo testing pH dependent tablets with two compartments

[0220] Dissolution studies were performed in 900 mL 0.1 M HCL, at 100 rpm and 37 °C. The samples were analyzed by HPLC (NaHPOq buffer pH 2.7 + 5 % ACN on a C18 column (Agilent Zorbax Eclipse Plus C18 RR 150x4.6 mm 3.5 pm), UV detection wavelength of 280 nm, column temperature 40 °C, 5 pL injection volume, run time 9 min.

[0221] Bioavailability studies were performed in an animal model (pigs) with group sizes of 4 to 8 pigs each group. Pigs are fasted 24 hours before the tablets are administered, administered directly into the stomach under full narcosis. After 20-30 min, pigs are fed (hay), and blood samples are taken and processed immediately. Plasma is then stored under refrigeration and analyzed. The samples were measured using HPLC- MS / MS method for the determination of levodopa / carbidopa in plasma: C18 column (50 x 4.6 mm 5 pm) and a mobile phase of 0.2% formic acid and acetonitrile (90:10). High-resolution mass spectrometer equipped with an electrospray source in positive mode was set up in selective reaction monitoring mode to detect the ion transitions m / z 198.1 -> m / z 107.0, m / z 227.2 -> m / z 181.0 m / z 212.1 -> m / z 139.2 for levodopa, carbidopa and methyldopa, respectively, as internal standard. The plasma samples were prepared by protein precipitation with perchlorate; centrifugation was performed at 2000 rpm at 5°C for 15 min.

[0222] Coming now to Figs. 9a to 9c, which illustrate the dissolution and pharmacokinetic profiles of shaped tablets with different formulations comprising two compartments comprising the composition according to an embodiment of the present disclosure in a comparative manner. The dosage form used in the dissolution test of Figs. 9a and 9c combines a 2-compartment geometry with fast (carbidopa: short-chain polymer with fast CD release) and slow (levodopa: long-chain polymers with prolonged LD release) CD and LD formulations, respectively. Contrary to the embodiments discussed in the context of Figs. 8Ato 8C, the following embodiment, a 2-layered tablet with 2 compartments comprising the composition according to an embodiment of the present disclosure, was used for the dissolution and bioavailability tests shown in Fig. 9a. This 2-layered geometry has the advantage of fewer screen changes and as consequence an overall faster production. The release of the two APIs is primarily controlled by the formulation. In particular, the release of levodopa is controlled inter alia by the pH value of the environment, e.g. pH of the solution. Specifically, the formulations release LD at alkaline pH, e.g. the alkaline environment of the small intestine. This has been demonstrated by the results shown in Fig. 9c, which will be discussed in more detail below.

[0223] For the dissolution and bioavailability studies, three formulations (“Formulations A, B and C”) according to the invention have been prepared:

[0224] Formulation A has been prepared according to the following:

[0225] Table 5: Composition of the Levodopa-Layer Tab 044

[0226] No. Ingredients wt% paste wt% tablet per tablet

[0227] (mg)

[0228] 1 Levodopa 33-26 60.47 100

[0229] 2 Klucel LF Pharma 2.20 4.01 6.625

[0230] 3 Avicel PH 105 13.47 24.49 40.5

[0231] 4 Starch 1500 1.91 3.48 5.75

[0232] 5 Glycerol 2.91 5.29 8.75

[0233] 6 Talc 0.83 1.51 2.5

[0234] 7 Silfar 350 0.42 0.76 1.25

[0235] 8 L- (+) -Ascorbic acid 0.11 0.20 0.325

[0236] 9 Water 44.88

[0237] Total 100 100 165.708

[0238] Table 6: Composition of the Carbidopa-Layer Tab 044

[0239] No. Ingredients wt% paste wt% tablet per tablet (mg)

[0240] 1 Carbidopa 23.33 50.00 25

[0241] 2 Klucel LF Pharma 2.36 5-07 2-533 3 Avicel PH 105 14.45 30.97 15 86

[0242] 4 Starch 1500 2.05 4-40 2.199

[0243] 5 Glycerol 3.12 6.69 3-346

[0244] 6 Talc 0.89 1.91 0.956

[0245] 7 Silfar 350 0.45 0.96 0.478

[0246] 8 L-Ascorbic acid 0.12 0.25 0.124

[0247] 9 Citrus acid 1.01 2.16 1.083

[0248] 10 Water 52.22

[0249] Total 100 100 51-205

[0250] Formulation B has been prepared according to the following:

[0251] Table 7: Composition of the Levodopa-Layer Tab 273

[0252] No. Ingredients wt% paste wt% tablet per tablet

[0253] (mg)

[0254] 1 Levodopa 27.60 60.15 100

[0255] 2 Klucel LF Pharma 1.10 2.41 4

[0256] 3 Shin-Etsu AQOAT AS-LF 7.29 15.88 26.4

[0257] 4 Ammonia 25 % 0.74 1.60 2.664

[0258] 5 Avicel PH-105 4-86 10.59 17-6

[0259] 6 Talc- Luzenac Pharma M 0.88 1.92 3.2

[0260] 7 Glycerol 1.55 3.37 5.6

[0261] 8 Triethylcitrate 0.66 1.44 2.4

[0262] 9 Silfar SE 4 1.10 2.41 4

[0263] 10 L- (+) -Ascorbic acid 0.11 0.24 0.4

[0264] 11 Water 54-10

[0265] Total 100 100 166.264

[0266] Table 8: Composition of the Carbidopa-Layer Tab 273

[0267] No. Ingredients wt% paste wt% tablet per tablet

[0268] (mg) 1 Carbidopa 20.62 45-27 25

[0269] 2 Klucel LF Pharma 1.88 4.12 2.277

[0270] 3 Ac-Di-Sol 3.46 7.60 4-197

[0271] 4 Mannogem Emerald 12.11 26.60 14.688

[0272] 5 RxCIPIENTS® FM1000 2.37 5.21 2.878

[0273] 6 Talc- Luzenac Pharma M 0.62 1.37 0.755

[0274] 7 Silfar 350 0.21 0.46 0.252

[0275] 8 Miglyol 812 N 1.01 2.21 1.223

[0276] 9 Glycerol 2.20 4.82 2.662

[0277] 10 L- (+) -Ascorbic acid 0.12 0.27 0.150

[0278] 11 Citric acid 0.94 2.06 1-139

[0279] 12 Water 54-46

[0280] Total 100 100 55-221

[0281] Formulation C has been prepared according to the following:

[0282] Levodopa:

[0283] Table g: Composition of the I^evodopa-Layer

[0284] No. Ingredients wt% paste wt% tablet per tablet

[0285] (mg)

[0286] 1 Levodopa 24.36 59-27 100

[0287] 2 Klucel LF Pharm 0.74 1.81 3.05

[0288] 3 Ac-Di-Sol 1.67 4.06 6.86

[0289] 4 Shin-Etsu AQOAT AS- ,o

[0290] MF7 61 18 5131.24

[0291] 5 Ammonia 25% 0.61 1.50 2.52

[0292] 6 Avicel PH-105 1-67 4.06 6.86

[0293] 7 Aerosil 200 W Phamra 0.37 0.90 1.52

[0294] 8 Glycerol 0.74 1.81 3.05

[0295] 9 Triethylcitrate 0.93 2.26 3.81

[0296] 10 Silfar SE 4 2.32 5.64 9.52 11 L-(+)-Ascorbic acid 0.07 0.18 0.30

[0297] Water 58.89

[0298] Carbidopa (as Formulation 2):

[0299] Table 10 : Composition of the Levodopa-Layer

[0300] No. Ingredients wt% paste wt% tablet per tablet

[0301] (mg)

[0302] 1 Carbidopa 20.62 45-27 25

[0303] 2 Klucel LF Pharma 1.88 4.12 2.277

[0304] 3 Ac-Di-Sol 3.46 7.60 4-197

[0305] 4 Mannogem Emerald 12.11 26.60 14.688

[0306] 5 RxCIPIENTS® FM1000 2.37 5.21 2.878

[0307] 6 Talc- Luzenac Pharma M 0.62 1.37 0.755

[0308] 7 Silfar 350 0.21 0.46 0.252

[0309] 8 Miglyol 812 N 1.01 2.21 1.223

[0310] 9 Glycerol 2.20 4.82 2.662

[0311] 10 L- (+) -Ascorbic acid 0.12 0.27 0.150

[0312] 11 Citric acid 0.94 2.06 1-139

[0313] 12 Water 54-46

[0314] Total 100 100 55-221 The tested formulations comprise the APIs LD and CD in the following amounts:

[0315] • Conventional tablet (prolonged- release): LD 250 mg; CD 25 mg;

[0316] • Formulation A (fast release): LD too mg; CD 25 mg;

[0317] • Formulation B (slow release): LD too mg; CD 25 mg;

[0318] • Formulation C (slow release): LD too mg; CD 25 mg. Formulations A, B and C are embodiments of the present invention. As can be taken from Fig. 9a, CD is completely released in under approximately 1 hour in all three formulations. Formulation A shows a release of 50 % in under approximately 60 min, and a complete release of LD in approximately 2 hours. In particular, LD (and also CD) is released at acidic pH (pH 1.2), e.g. in gastric medium. Formulation B shows a slower release for LD as compared to Formulation A. In particular, the LD release for Formulation B reaches a release of approximately 30 % of LD in approximately 2 hours at a pH of 1.2.

[0319] As can be taken from Fig. 9a, further LD is released in alkaline environment, at pH 6.8, e.g. in the small intestine medium, wherein a release of too % of LD is achieved in less than 240 min. In particular, the release curve for LD at pH 6.8 considerably rises. Formulation C, which shows the slowest release for LD as compared to Formulations A and B, releases less than 40 % of LD in approximately 2 hours at a pH of 1.2. At a pH of 6.8, and as can be taken from Fig. 9a, the release curve considerably rises, suggesting a faster dissolution in alkaline medium, too % of LD of Formulation C is released in approximately 4 hours.

[0320] The alkaline pH may be at least 5.8. Preferably, the alkaline pH may be at least 6.2. More preferably, the alkaline pH maybe at least 6.8. Most preferred, the alkaline pH maybe at least 7.2. Even more preferred, the alkaline pH maybe at least 7.8.

[0321] The dissolution characteristics of all three embodiments differ from each other. It follows that Formulation A exhibits a fast release of LD as compared to the release characteristics of Formulations B and C. Ergo Formulations B and C exhibit a slower release as compared to Formulation A. In particular, the release of LD in Formulations B and C is pH dependent. In particular, the LD release in Formulations B and C increases with higher pH, e.g. alkaline pH. The LD release is the slowest in Formulation C.

[0322] The bioavailability of the tested formulations (conventional, Formulation A, B and C) has been tested, and the results are shown in Figs. 9b and 9c.

[0323] Fig. 9b shows the bioavailability of a conventional prolonged-release formulation comprising 250 mg of LD and 25 mg of CD. The blood level concentration of CD and LD has been measured over time and the corresponding AUC for LD has been determined with 431.5 pg*min / mL. In Fig. 9c, the bioavailability of Formulation B comprising 100 mg of LD and 25 mg of CD is shown. The blood level concentration of CD and LD has been measured over time and the corresponding AUC for LD has been determined with 542 pg*min / mL. The data shown in Figs. 9b and 9c prove that the bioavailability for LD in Formulation B is considerably increased as compared to a conventional formulation comprising a higher amount of LD. In other words, the composition of the present invention reaches higher bioavailability with considerably less LD in the formulation. In this manner, the therapeutic effect is enhanced while decreasing side-effects associated with LD intake.

[0324] This data further proves that under the protection of carbidopa, a larger amount of LD is absorbed, and the LD blood level is consistently high over a longer period of time.

[0325] In conclusion, the following advantages over the conventional formulation are achieved by using the composition of the present invention:

[0326] 1) Enhanced Bioavailability - The sequential release of the first and second API, carbidopa and levodopa (Fig. 9B), increases the bioavailability of the second API, levodopa, too mg LD of the composition of the present invention achieves an AUC that exceeds that of a conventional 250 mg LD prolonged-release tablet by approximately 20 %.

[0327] 2) Duration of effective level - The blood level of the second API, levodopa, induced by the composition of the present invention outlasts the blood level by at least 120 min.

[0328] 3) Uniform blood level - A uniform blood level is achieved with the composition of the present invention for the second API, levodopa. Uniform LD blood levels, e.g. from the duodenal pump, have a better efficacy in the therapeutic treatment of a patient.

[0329] 4) Reduction of API dose - Due to the sequential release, higher and more consistent blood levels are achieved, in particular for the second API, as compared to conventional dosage forms. The conventional daily dose of the second API, levodopa is associated with side-effects and / or treatment complications such as dyskinesia. In consequence, the composition of the present invention significantly changes the side effect profile for the second API, levodopa, as compared to conventional dosage forms.

[0330] 5) Reduction of total dose - The sequential release of the APIs, LD and CD, also leads to a higher blood level for the first API. Accordingly, a similar increase in blood levels for the second API can be achieved with a lower dose of the first API. In consequence, this achieves a reduction in side effects mediated by the first API. Interval-mediated increase in bioavailability

[0331] Fig. 10 shows blood levels and bioavailability of LD after administration of three formulations (Formulations B, C and D) according to the invention and one conventional formulation. The Formulations B, C and D differ only in the interval between CD and LD release.

[0332] Formulation D has been prepared according to the following:

[0333] Levodopa:

[0334] Table 11: Composition of the I^evodopa-Layer

[0335] No. Ingredients wt% paste wt% tablet per tablet

[0336] (mg)

[0337] 1 Levodopa 24.36 59-27 100

[0338] 2 Klucel LF Pharm 0.74 1.81 3.05

[0339] 3 Ac-Di-Sol 1.67 4.06 6.86

[0340] 4 Shin-Etsu AQOAT AS- ,o

[0341] MF7'61 18'5131.24

[0342] 5 Ammonia 25% 0.61 1.50 2.52

[0343] 6 Avicel PH-105 1-67 4.06 6.86

[0344] 7 Talc Phamra M 0.37 0.90 1.52

[0345] 8 Glycerol 0.74 1.81 3.05

[0346] 9 Triethylcitrate 0.93 2.26 3.81

[0347] 10 Silfar SE 4 2.32 5.64 9.52

[0348] 11 L-(+)-Ascorbic acid 0.07 0.18 0.30

[0349] Water 58.89

[0350] Carbidopa (as Formulation 2)

[0351] Table 12: Composition of the Levodopa-Layer

[0352] No. Ingredients wt% paste wt% tablet per tablet (mg)

[0353] 1 Carbidopa 20.62 45-27 25

[0354] 2 Klucel LF Pharma 1.88 4.12 2.277 3 Ac-Di-Sol 3.46 7.60 4-197

[0355] 4 Mannogem Emerald 12.11 26.60 14.688

[0356] 5 RxCIPIENTS® FM1000 2.37 5-21 2.878

[0357] 6 Talc- Luzenac Pharma M 0.62 1-37 0-755

[0358] 7 Silfar 350 0.21 0.46 0.252

[0359] 8 Miglyol 812 N 1.01 2.21 1.223

[0360] 9 Glycerol 2.20 4.82 2.662

[0361] 10 L- (+) -Ascorbic acid 0.12 0.27 0.150

[0362] 11 Citric acid 0.94 2.06 1-139

[0363] 12 Water 54-46

[0364] Total 100 100 55-221

[0365] As can be taken from Fig. 10, the bioavailability of LD for the conventional formulation (n=4) is of 35.48 pg*min / mL*kg. Formulation B shows the highest AUC value for LD with (n=4) 61.32 pg*min / mL*kg. Formulation C shows an AUC for LD of (n=4) 28.21 pg*min / mL*kg. Formulation D shows an AUC for LD of (n=4) 15.49 pg*min / mL*kg.

[0366] Formulation B is characterized by complete LD release in approximately 160 min after complete CD release (dashed line in Fig. 9a). Formulation C has a 20-30 min longer interval (180-190 min; dashed line in Fig. 9a). Formulation D shows a 30-40 min longer interval (i90-200min; not shown in Fig. 9a).

[0367] The bioavailability of LD is controlled by the length of the interval between CD and LD release. In particular the interval between CD and LD for Formulations B and C. These data demonstrate that based on the selected conditions (interval 160 min, 180-190 min or 190-200 min), an interval between CD and LD release of 160 min is optimal for an enhanced bioavailability and duration of effective LD blood levels.

[0368] It is to be noted that the above-described features of the system apply to the respective method steps, and vice versa. In other words, any feature disclosed in the context of the composition for use of the present invention is to also disclosed for the composition itself. It is further noted that the above embodiments and / or examples may be combined with further aspects as described herein and details of the embodiments and / or examples may also be omitted, as will be understood by the skilled person. The scope of protection is determined by the claims and is not limited by the embodiments and / or examples disclosed in the above figures.

Claims

Claims1. A solid composition comprising: at least two compartments separately arranged in the solid composition; a first active pharmaceutical ingredient (API) provided in a first compartment (n) of the at least two compartments, wherein the first API is selected from the group of DOPA-decarboxylase inhibitors and / or catechol-O-methyltransferase (C0MT-) inhibitors; and a second API provided in a 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 a length of the structure is larger than a height of the structure.

4. The solid composition according to the preceding claim, wherein the compartments are arranged adjacent to one another 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 first compartment (11) has a height of at least 0.3 cm, preferably 0.5 cm, more preferably 0.7 cm; and / or wherein the first compartment (11) has a height of at most 1.4 cm, preferably 1.2 cm, more preferably 1.0 cm.

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

7. The solid composition according to the preceding claim, wherein the ratio between the height of the first compartment (11) to the second compartment (12) is of at least 0.1 to 1, preferably 0.2 to 1, more preferably 0.3 to 1; and / or wherein the ratio between the height of the first compartment (11) to the second compartment (12) is of at most 0.8 to 1, preferably 0.6 to 1, 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 claim, wherein the immediate release formulation is characterized in that the first API is released in an amount of substantially 50 wt.-% as compared to the total weight of the first compartment (11) in less than 30 min, preferably 25 min, more preferably 20 min, most preferred 15 min at pH 1.2.

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

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

12. The solid composition according to the preceding claim, wherein the first and / or second compartment (11, 12) comprises 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.13- The solid composition according to the preceding claim, wherein the ratio of short-chain polymer to long-chain polymer is of at most 1:9, preferably 1:7, more preferably 1:6.

14. The solid composition according to any one of the preceding claims, wherein the second compartment (12) provides for at most 70 %, preferably for at most 65 %, more preferably for at most 60%, most preferred for at most 50% of the total surface of the solid composition.

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

16. The solid composition according to the preceding claim, wherein the first and third compartments (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 and third compartment (11, 13) comprises an immediate release formulation.

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

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

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

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

24. The solid composition according to the preceding claim, wherein, when used, the release of the first API has a first peak maximum of API release in % over time, and the release of the second API has a different, second peak maximum of API release in % over time; wherein the second peak maximum is subsequent to the first peak maximum.

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, 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 upon use of the solid composition.

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

31. The solid composition according to any one of the preceding claims, further comprising one or more of: 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 the preceding claim, wherein the tablet (10) has a toroidal, oval and / or rectangular shape.

34. The solid composition according to any one of claims 1 to 33 for use in the treatment of a condition associated with Parkinson’s disease.35- The solid composition for use according to the preceding claim, wherein the solid composition is administered orally.

36. The solid composition for use according to any one of the preceding use claims, wherein the treatment is characterized in a reduction of a side effect associated with Parkinson’s disease.

37. The solid composition for use according to the preceding claim, wherein the side effect associated with Parkinson’s disease is a side effect selected from a motor and / or a non-motor symptom.

38. The solid composition for use according to the preceding claim, wherein the motor and / or the non-motor symptom is selected from one or more of bradykinesia, impaired mobility, tremor, rigidity, dysphagia, or freezing of gait, FOG, preferably bradykinesia, impaired mobility, tremor or FOG, more preferably FOG.

39. The solid composition for use according to any one of the preceding use claims, characterized in that the use is the treatment of Parkinson’s disease and / or the prevention of progress in Parkinson’s disease.

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

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

42. The solid composition for use according to the preceding claim 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 for use according to claim 41 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 for use according to any one of claims 34 to 43, wherein the solid composition is a pharmaceutical solid composition.

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