Orally dispersible pharmaceutical solid dosage forms of safinamide

Abstract

The present invention relates to an oral dispersible pharmaceutical composition of safinamide, the pharmaceutical composition comprising safinamide or a pharmaceutically acceptable salt thereof, an ion exchange resin and one or more pharmaceutically acceptable excipients, where the oral dispersible pharmaceutical composition of safinamide is used for the treatment of Parkinson's disease.

Description

[0001] Related applications This application relates to Indian Provisional Application No. IN202321050162, filed on 25 July 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This invention relates to an orally dispersible pharmaceutical composition of safenamide, the pharmaceutical composition comprising safenamide or a pharmaceutically acceptable salt thereof, an ion exchange resin and one or more pharmaceutically acceptable excipients, wherein the orally dispersible pharmaceutical composition of safenamide is used to treat Parkinson's disease. Background Technology

[0003] Parkinson's disease (PD) is one of the most common neurodegenerative disorders, affecting an estimated 6.2 million people worldwide. In Europe, over one million people have PD, while in the United States, nearly one million suffer from the disease. However, these numbers are likely much higher, as many may remain undiagnosed. With the incidence of PD rising significantly with age and life expectancy increasing, its prevalence is believed to be rising dramatically in the near future – reaching nearly 13 million people by 2040. The economic impact of the disease is enormous – estimated at €13.9 billion annually in Europe and $52 billion annually in the United States.

[0004] Parkinson's disease is a progressive disorder that may begin with mild rigidity and occasional tremors, progressing over a period of ten years or more to frequent tremors and memory impairment, and eventually to uncontrollable tremors and dementia. The disease causes a slowly increasing disability in purposeful movement. Current drug treatments or therapies may include levodopa, carbidopa, bensarazide, entacapone, dopamine agonists (like rotigotine, pramipexole, ropinirole, apomorphine), monoamine oxidase (MAO-B) inhibitors (like selegiline, rasagiline, safenamide, tranylcypromine); COMT inhibitors (like entacapone, tocapone); and glutamate antagonists (like amantadine).

[0005] Unfortunately, over time, such drug therapies often become less effective or ineffective. Often, PD patients may require a combination of multiple medications to prolong the duration of the drug therapy's effectiveness.

[0006] Safenamide is an MAO-B inhibitor and is chemically described as N2-{4-[(3-fluorobenzyl)oxy]benzyl}-L-propanamide.

[0007]

[0008] Formula I In Europe, the European Medicines Agency (EMA) approved safinamide (XADAGO®) in February 2015 for the treatment of adult patients with idiopathic Parkinson's disease (PD), as an adjunct therapy to a stable dose of levodopa (L-DOPA) alone or in combination with other PD medications for patients with intermediate to advanced fluctuating disease. XADAGO® is available only in 50 mg and 100 mg immediate-release, standard film-coated tablets.

[0009] In the United States, XADAGO® was approved in March 2017 for use as adjunctive therapy to levodopa / carbidopa in patients with Parkinson's disease (PD) experiencing "off" episodes, and it is available only in 50 mg and 100 mg strengths of immediate-release conventional film-coated tablets.

[0010] XADAGO®'s immediate-release, standard film-coated tablets require swallowing – meaning patients receiving the therapy should be able to swallow correctly. However, swallowing can be difficult for some patient groups, such as elderly or pediatric patients, or those who are unable to cooperate with healthcare professionals due to the progression of disabling disease. In particular, patients with Parkinson's disease face swallowing difficulties, and it is known that over 80% of Parkinson's patients experience swallowing difficulties during the course of the disease (see I. Suttrup. Dysphagia [Dysphagia]. Feb 2016;31(1):24-32). Therefore, there is an urgent need to develop more easily swallowable drug formulations, which is particularly important in the field of Parkinson's disease. In fact, according to clinical reports, 80% of physicians believe that drug formulations with easier-to-swallow administration methods will increase treatment adherence and / or compliance in Parkinson's disease patients.

[0011] A specific solid drug dosage form that disintegrates rapidly is the orally dispersible tablet (also known as ODT: orally disintegrating tablet), which does not require water, is easier to swallow, and can therefore be consumed when the patient needs an easy-to-administer dosage form.

[0012] There are prior art disclosures attempting to obtain orally dispersible compositions containing safenamide. For example, patent application CN111821268 discloses an orally disintegrating tablet composition of safenamide mesylate and a method for preparing the same, wherein the orally disintegrating tablet composition comprises safenamide mesylate, silicified microcrystals, croscarmellose sodium, and magnesium stearate. Patent application CN 106667940 discloses a safenamide dispersible tablet composition and a method for preparing the same, wherein the safenamide dispersible tablet further comprises a safenamide-hydrophilic material blend, a filler, a disintegrant, a binder, a lubricant, and a corrective agent. Patent application CN 104546747, in Example 5, discloses an orally dispersible tablet containing 50 mg of safenamide mesylate, a diluent, a water-soluble polymer binder, a disintegrant, a flavoring agent, and a lubricant.

[0013] However, many of the aforementioned prior art documents involve more or less complex manufacturing processes, making the entire process lengthy and costly. Furthermore, the manufacturing techniques of those prior art may require more or less significant chemical and / or physical modifications to safenamide as the active ingredient, which may affect the stability of the finished dosage form and the bioavailability of safenamide.

[0014] While orally dispersed drug formulations are beneficial for Parkinson's disease patients, they present considerable challenges because they allow direct contact between the active ingredient and the patient's taste buds on the tongue, as well as other oral receptors that contribute to palatability. In this regard, safenamide, known to be in its free base form and / or pharmaceutically acceptable salt form (such as safenamide mesylate), has a very unpleasant taste, with the bitter component being particularly strong. Furthermore, safenamide and its pharmaceutically acceptable salts tend to irritate the oropharyngeal mucosa.

[0015] The aforementioned prior art literature does not address the technical issues of providing orally dispersible safenamide compositions that provide sufficient sensory characteristics for Parkinson's disease patients, or alternatively, those prior art literatures simply use flavorings that are actually insufficient to provide an effective masking of the unpleasant and strong unpleasant taste of safenamide and its pharmaceutically acceptable salts.

[0016] Prior art patents EP 3558261 and EP 3703665 disclose particles comprising a core containing safenamide (or a pharmaceutically acceptable salt) and a binder, wherein the particles are coated with a polymer composition. These safenamide-coated particles are compressed into orally dispersible tablets, which are claimed to provide excellent sensory properties, thereby providing effective masking of safenamide and its pharmaceutically acceptable salts.

[0017] However, both existing technologies EP 3558261 and EP 3703665 involve more or less complex manufacturing steps, making the entire process lengthy and costly. Specifically, the manufacturing method disclosed in EP 3558261 requires the use of a Rotocube 60 IMA (which performs dry agglomeration via a rotary granulator-single pot), followed by particle coating in a fluidized bed system (FBP). The use of this machinery makes the manufacturing process very lengthy and complex. EP 3703665 requires the use of a VFC-LAB3 equipped with a rotor insert GXR-35 Freund Vector (which performs wet stratification using a fluidized bed system with a rotor insert assembly), followed by particle coating in a fluidized bed system (FBP). Again, using such machinery is not cost-effective for manufacturing orally dispersed safenamide compositions.

[0018] Furthermore, the stability of pharmaceutical compositions of safenamide and its pharmaceutically acceptable salts is a known concern in the prior art. For example, EP 2474521 discloses that large-scale formulations of safenamide contain an undesirable impurity, (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]acrylamide (referred to as compound (IIa) or also as the “dimeric impurity”), which is highly cytotoxic when compared to safenamide mesylate. In addition, obtaining pharmaceutical compositions of safenamide and its pharmaceutically acceptable salts with the lowest possible total amount of impurities is crucial. In Europe, the approved dosimetry for XADAGO® requires starting treatment with 50 mg of safenamide (or an equivalent amount of safenamide mesylate) daily, and the daily dose can be increased to 100 mg of safenamide (or an equivalent amount of safenamide mesylate) daily based on individual clinical needs. Therefore, to maintain the efficacy and safety of safenamide pharmaceutical compositions, and particularly orally dispersible safenamide compositions, in the treatment of Parkinson's disease, it is crucial to avoid safenamide dimer impurities and to obtain safenamide compositions with the lowest possible total impurity content. In this regard, the aforementioned prior art EP 3558261 and EP3703665 disclose that, although those skilled in the art are aware of other techniques for masking unpleasant / irritating tastes, those other techniques are based on strong chemical interactions between the active ingredient and certain molecular and / or pharmaceutically acceptable excipients. However, those other techniques involve significant chemical and / or physical modifications to the active ingredient, which affects the stability of the active ingredient.

[0019] As stated above, XADAGO® is only commercially available in the form of immediate-release conventional film-coated tablets. When developing new oral dispersible drug formulations, it should be remembered that regulatory standards require demonstrating the stringent bioequivalence of the newly developed oral dispersible drug formulation compared to conventional film-coated tablets of a reference product. Therefore, this bioequivalence requirement presents additional challenges to the development of new oral dispersible tablets. Prior art EP 3558261 and EP 3703665 also disclose that other techniques for masking unpleasant / irritating tastes (more precisely, the manufacture of particles comprising a core containing safenamide and a binder, wherein said particles are coated with a polymer composition) significantly affect the onset of action and bioavailability of safenamide, and therefore, those skilled in the art will understand that these other techniques are not suitable for obtaining safenamide oral dispersible drug formulations with kinetics equivalent to those of currently commercially available formulations (i.e., XADAGO®).

[0020] Therefore, given the existing technology, there is a need to provide safenamide oral dispersion dosage forms with overall improved characteristics. In this regard, there is room for improvement in the prior art to provide safenamide oral dispersion compositions with improved disintegration time, stability, friability, and hardness, while having sufficient masking properties of safenamide and its pharmaceutically acceptable salts, thereby providing suitable sensory characteristics for Parkinson's disease patients administering those oral dispersion safenamide compositions. Furthermore, there is a need to provide efficient and cost-effective manufacturing methods for obtaining said safenamide oral dispersion dosage forms. Additionally, said safenamide oral dispersion dosage forms must be sufficiently stable to meet stringent regulatory requirements regarding impurities, and in particular, those safenamide oral dispersion dosage forms must avoid the formation of safenamide-related cytotoxic impurities or keep the formation and total amount of impurities to the lowest possible level. Finally, there is also a need to provide safenamide oral dispersion dosage forms that, from a regulatory perspective, exhibit reliable and adequate dissolution profiles of safenamide, resulting in bioequivalence to XADAGO® immediate-release film-coated tablets.

[0021] In fact, despite the appeal of rapidly disintegrating formulations to Parkinson's patients, there are currently no commercially available orally dispersible formulations of safenamide in Europe and the United States, highlighting the challenging task of formulating safenamide in an orally dispersible form.

[0022] The present invention unexpectedly solves the aforementioned objectives / problems. In particular, the inventors have been able to design novel oral dispersion solid dosage forms comprising safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix. It has been unexpectedly found that this provides a new way to stabilize safenamide or the pharmaceutically acceptable salt, thus preventing the formation of degradation products over time; for example, the major undesirable impurity (S)-2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]acrylamide (referred to as the "dimeric impurity"), and providing low levels of total impurities. The oral dispersion solid dosage forms of the present invention meet the impurity limit specifications required by European pharmaceutical regulatory agencies.

[0023] Furthermore, the inventors have unexpectedly discovered that the oral dispersible solid dosage form of the present invention provides effective and adequate masking of safenamide and its pharmaceutically acceptable salts, thereby providing suitable sensory characteristics for Parkinson's disease patients administering the oral dispersible safenamide composition of the present invention.

[0024] Furthermore, the inventors have unexpectedly discovered that the oral dispersion dosage form of the present invention also possesses the overall improved technical features summarized below. In particular, the safenamide oral dispersion dosage form of the present invention has sufficient rigidity and low friability, which is an important advantage for withstanding physical shocks along the manufacturing process and for storage and transportation. The oral dispersion composition of the present invention does indeed satisfyingly disintegrate rapidly, particularly within less than three minutes, as required by the European Pharmacopoeia, 10.0, page 939.

[0025] Furthermore, despite comments beyond the teachings of EP 3558261 and EP 3703665, the inventors have unexpectedly discovered that the safenamide oral dispersion dosage form of the present invention (in which safenamide or a pharmaceutically acceptable salt thereof is captured within a matrix formed of a pharmaceutically acceptable polymer) allows for a reliable and adequate dissolution profile of safenamide, thereby releasing safenamide in a manner sufficiently equivalent to that of XADAGO® immediate-release film-coated tablets (i.e., exhibiting comparable pharmacokinetic parameters such as Cmax, Tmax, and AUC0-t in terms of bioavailability).

[0026] Therefore, the inventors of this invention have unexpectedly discovered that the safenamide oral dispersion dosage form of this invention comprises a pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, the pharmaceutically acceptable polymer interacting with safenamide or a pharmaceutically acceptable salt thereof and stabilizing it physically and chemically, thus serving as a suitable taste-masking technique for obtaining a safenamide oral dispersion composition that not only disintegrates in the oral cavity and exhibits good sensory characteristics and low levels of total impurities, but also has in vivo pharmacokinetics equivalent to safenamide film-coated tablets (XADAGO®). Summary of the Invention

[0027] This invention relates to an orally dispersible pharmaceutical composition of safenamide, the composition comprising safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer adapted to form a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, and wherein the orally dispersible pharmaceutical composition of safenamide is used to treat Parkinson's disease.

[0028] Therefore, the main objective of this invention is to provide an orally dispersible pharmaceutical composition of safenamide comprising safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer adapted to form a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix.

[0029] Another object of the present invention is to provide an orally dispersible pharmaceutical composition of safenamide, the composition comprising safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer adapted to form a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, and wherein the pharmaceutically acceptable polymer adapted to form a matrix with safenamide or a pharmaceutically acceptable salt thereof is an ion exchange resin.

[0030] Another object of the present invention is to provide an orally dispersible pharmaceutical composition of safenamide comprising safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer adapted to form a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein the amount of safenamide or a pharmaceutically acceptable salt thereof in each dosage form is from 5 to 150 mg, preferably from 25 to 125 mg, and more preferably from 50 to 100 mg, based on the weight of the free base of safenamide.

[0031] Another object of the present invention is to provide an orally dispersible pharmaceutical composition of safenamide comprising safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer adapted to form a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein the solid dosage form is an orally dispersible tablet.

[0032] Another object of the present invention is to provide an orally dispersible pharmaceutical composition of safenamide comprising safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer adapted to form a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein the pharmaceutically acceptable salt of safenamide is safenamide mesylate.

[0033] Another object of the present invention is to provide an orally dispersible pharmaceutical composition for safenamide, the composition comprising safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein the pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof is an ion exchange resin, and wherein the weight ratio of safenamide or a pharmaceutically acceptable salt thereof to the ion exchange resin is from 1:0.05 to 1:10, preferably from 1:0.1 to 1:5; more preferably from 1:0.25 to 1:3, and even more preferably from 1:0.5 to 1:2.

[0034] Another object of the present invention is to provide an orally dispersible solid dosage form of a drug comprising safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein the pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof is an ion exchange resin, wherein the weight ratio of the ion exchange resin to the safenamide or a pharmaceutically acceptable salt thereof is from 1:0.05 to 1:10, preferably from 1:0.1 to 1:5; more preferably from 1:0.25 to 1:3, and even more preferably from 1:0.5 to 1:10. 2, wherein the ion exchange resin is selected from the group consisting of sodium, potassium, magnesium, or calcium salts or partially sodium, potassium, magnesium, or calcium salts of sulfonated polystyrene polymers, sulfonated styrene-divinylbenzene copolymers, polymethacrylic acid polymers, methacrylic acid-divinylbenzene copolymers, protonated sulfonated polystyrene polymers, protonated sulfonated styrene-divinylbenzene copolymers, protonated polymethacrylic acid polymers, and protonated methacrylic acid-divinylbenzene copolymers.

[0035] Another object of the present invention is to provide an orally dispersible pharmaceutical composition of safenamide comprising safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer adapted to form a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein the ion exchange resin is a methacrylic acid-divinylbenzene copolymer.

[0036] Another object of the present invention is to provide an orally dispersible pharmaceutical composition of safenamide comprising safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer adapted to form a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein the methacrylic acid-divinylbenzene copolymer is polacrine potassium.

[0037] Another object of the present invention is to provide an orally dispersible pharmaceutical composition of safenamide, the composition comprising safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer adapted to form a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein at least 85% w / w of safenamide or a pharmaceutically acceptable salt thereof present in the orally dispersible solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, preferably, at least 90% w / w of safenamide or a pharmaceutically acceptable salt thereof present in the orally dispersible solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, more preferably, at least 95% w / w of safenamide or a pharmaceutically acceptable salt thereof present in the orally dispersible solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, and even more preferably, at least 97% w / w of safenamide or a pharmaceutically acceptable salt thereof present in the orally dispersible solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer.

[0038] Another object of the present invention is to provide an orally dispersible pharmaceutical composition of safenamide, the composition comprising safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer adapted to form a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein the one or more pharmaceutically acceptable excipients are selected from one or more diluents, one or more binders, one or more disintegrants, one or more flavoring agents, one or more sweeteners, one or more solvents, one or more lubricants, or mixtures thereof.

[0039] Another object of the present invention is to provide an orally dispersible pharmaceutical composition of safenamide comprising safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer adapted to form a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein the one or more disintegrants are one or more intraparticle disintegrants.

[0040] Another object of the present invention is to provide an orally dispersible pharmaceutical composition of safenamide comprising safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer adapted to form a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, and wherein, when the orally dispersible composition is subjected to a dissolution test in 900 mL of 0.1 M hydrochloric acid at 50 rpm using a USP Type 2 apparatus method, at least 90% of safenamide is released within 10 minutes.

[0041] Another object of the present invention is to provide an orally dispersible pharmaceutical composition of safenamide comprising safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer adapted to form a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, and wherein, when the orally dispersible composition is subjected to a dissolution test using a USP Type 2 apparatus method at a rotation of 50 rpm in a 900 mL volume of phosphate buffer at pH 6.8, at 10 minutes, at least 50% of the safenamide is released.

[0042] Another object of the present invention is to provide an oral dispersible pharmaceutical composition of safenamide according to the present invention, wherein the composition, after being stored in an Alu Alu Blister Pack for 1 month at a temperature of 40°C and a relative humidity of 75%, has a total amount of safenamide-related impurities of less than 0.50% w / w, more preferably less than 0.25% w / w, and even more preferably less than 0.1% w / w.

[0043] Another object of the present invention is to provide an oral dispersible pharmaceutical composition of safenamide according to the present invention, wherein the composition, after being stored in an Alu Alu Blister Pack for 1 month at a temperature of 40°C and a relative humidity of 75%, has an amount of safenamide-related dimer impurities of less than 0.05% w / w, preferably less than 0.03% w / w, and more preferably equal to or less than 0.025% w / w.

[0044] Another object of the present invention is to provide an orally dispersible pharmaceutical composition of safenamide according to the invention, wherein, after a single oral dose of the dosage form, safenamide or a pharmaceutically acceptable salt thereof equivalent to 100 mg of safenamide exhibits a time (Tmax) to reach maximum plasma concentration from 3 h to 6 h, preferably from 4 h to 5 h.

[0045] Another object of the present invention is to provide an orally dispersible pharmaceutical composition of safenamide according to the invention, wherein, after a single oral dose of the dosage form, safenamide or a pharmaceutically acceptable salt thereof equivalent to 100 mg of safenamide exhibits a maximum plasma concentration (Cmax) from 660 ng / mL to 920 ng / mL.

[0046] Another object of the present invention is to provide an orally dispersible pharmaceutical composition of safenamide according to the invention, wherein, after a single oral dose of the dosage form, safenamide or a pharmaceutically acceptable salt thereof equivalent to 100 mg of safenamide exhibits an area under the time / plasma concentration curve (AUC(0-72)) from time 0 to 72 hours, ranging from 18,000 ng / mL to 28,600 ng / mL.

[0047] Another object of the present invention is to provide an oral dispersible pharmaceutical composition of safenamide according to the present invention, wherein the oral dispersible pharmaceutical dosage form disintegrates in less than 3 minutes, preferably in less than 2 minutes, and more preferably in less than 1 minute, wherein the disintegration test is performed using a European Pharmacopoeia disintegration apparatus A, wherein the dosage form is placed in water at pH 7 at 37°C and 30 cycles per minute.

[0048] Another object of the present invention is to provide a method for preparing an oral dispersible drug solid dosage form as defined according to the present invention, the method comprising: (i) Dissolve safenamide or a pharmaceutically acceptable salt thereof in water until a clear solution is obtained. (ii) Add ion exchange resin to the solution from step (i) until a homogeneous suspension is achieved. (iii) Provide an adhesive, one or more disintegrants or mixtures thereof, and a diluent, respectively. (iv) Granulate the mixture from step (iii) with the suspension from step (ii) using a fluidized bed processor to obtain wet granules. (v) Drying the wet particles obtained in step (iv) using a fluidized bed processor, thereby obtaining dried particles. (vi) The dry granules obtained in step (v) are mixed with an exonucleating agent, one or more lubricants, and optionally with sweeteners and flavorings. (vii) The mixture obtained in step (vi) is compressed to form an oral dispersion drug solid dosage form.

[0049] Another object of the present invention is to provide a method for preparing an oral dispersible drug solid dosage form as defined according to the present invention, the method comprising: (i) Dissolve safenamide or a pharmaceutically acceptable salt thereof in water until a clear solution is obtained. (ii) Add ion exchange resin to the solution from step (i) until a homogeneous suspension is achieved. (iii) Add adhesive to the solution from step (ii). (iv) Provide one or more disintegrants or mixtures thereof, and a diluent, (v) Granulate the mixture from step (iv) with the suspension from step (iii) using a fluidized bed processor to obtain wet granules. (vi) The wet particles obtained in step (v) are dried using a fluidized bed processor, thereby obtaining dried particles. (vii) The dry granules obtained in step (vi) are mixed with an ex-granule disintegrant, one or more lubricants, and optionally with sweeteners and flavorings. (viii) Compress the mixture obtained in step (vii) to form an oral dispersion drug solid dosage form.

[0050] Another objective of the present invention is to provide an oral dispersible pharmaceutical composition of safenamide according to the present invention for use in the treatment of adult patients with idiopathic Parkinson's disease (PD), as an adjunct therapy to a stable dose of levodopa (L-DOPA) alone or in combination with other PD drug products for patients with mid-to-late-stage fluctuating disease. Attached Figure Description

[0051] Figure 1 shows the average plasma concentrations over 72 hours following oral single-dose administration of the following: a) oral dispersible tablets according to Example 5 of the invention, administered with water (Test-T1, points are shown as squares); b) oral dispersible tablets according to Example 5 of the invention, administered without water (Test-T2, points are shown as triangles); and c) 100 mg tablets of XADAGO® (reference, points are shown as circles). Detailed Implementation

[0052] Unless otherwise stated, the terms used in this specification are intended to have their common meaning in the relevant field.

[0053] This invention relates to an orally dispersible pharmaceutical composition of safenamide, the pharmaceutical composition comprising safenamide or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients.

[0054] The term "safenamide" as used throughout this specification refers not only to their bases themselves, but also to their other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs, and pharmaceutically acceptable prodrugs.

[0055] The term "pharmaceutically acceptable" means salts, carriers, excipients, and other formulation ingredients that are compatible with all other pharmaceutical components of the composition and are harmless to the individual being treated with the composition.

[0056] As used herein, the term "orally dispersible tablet" is defined, according to the European Pharmacopoeia, 10.0, page 939, as an uncoated tablet intended to be placed in the mouth and rapidly dispersed in the mouth before being swallowed; more precisely, an orally dispersible tablet disintegrates within three minutes in a disintegration test. Based on this definition, the term "orally dispersible tablet" is intended to be synonymous with solid oral dosage forms named orally dispersible tablets, orally disintegrating or disintegrating tablets (ODT), rapidly disintegrating tablets, rapidly dissolving tablets, and chewable tablets, etc.

[0057] As used herein, the term "polymer" is defined as any pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof, which interacts with and stabilizes safenamide or a pharmaceutically acceptable salt thereof, thus acting as a suitable taste-masking excipient for obtaining a safenamide oral dispersion composition that not only disintegrates in the oral cavity and exhibits good sensory characteristics and low levels of total impurities, but also has kinetics equivalent to safenamide film-coated tablets (XADAGO®). In particular, the polymer is capable of forming a matrix that allows safenamide or a pharmaceutically acceptable salt thereof to be trapped within the formed matrix. As used herein, the term "polymer" includes any of a broad range of matrix-forming polymers, including hydrophilic polymers, hydrophobic polymers, and water-insoluble polyelectrolytes such as ion exchange resins, including sulfonated polystyrene polymers, sulfonated styrene-divinylbenzene copolymers, polymethacrylic acid polymers, methacrylic acid-divinylbenzene copolymers, etc.

[0058] Polymers suitable for forming a matrix with safenamide or its pharmaceutically acceptable salts according to the invention are preferably not those polymers selected from the group consisting of: disintegrants such as croscarmellose sodium, HMPC, croscarmellose sodium and carboxymethyl starch sodium, Parteck ODT (a combination of 93% spray-dried mannitol and 5.4% croscarmellose sodium), methacrylate copolymer Eudragit EPO, N-vinylpyrrolidone of crosspovidone and copovidone, polyvinyl alcohol, polyvinyl acetate and / or copolymers thereof, and Pharmabust C1 (a co-spray-dried sugar alcohol (mannitol, sorbitol) / disintegrant (copovidone) / flow aid (silica)). In other words, in the context of the invention, the term "polymer" suitable for forming a matrix most preferably does not cover those polymers from the group mentioned above in this paragraph. This is because they are less suitable for providing stable safenamide compositions. Therefore, in preferred embodiments, these polymers are not included.

[0059] As used herein, the term "ion exchange resin" is defined as any pharmaceutically acceptable water-insoluble polymer capable of exchanging its mobile ions with ions in the surrounding medium. As used herein, the term includes sodium or potassium or magnesium or calcium or iron or zinc salts, or partially sodium or potassium or magnesium or calcium or iron or zinc salts, of sulfonated polystyrene polymers, sulfonated styrene-divinylbenzene copolymers, polymethacrylic acid polymers, methacrylic acid-divinylbenzene copolymers, etc. As used herein, the term also includes protonated sulfonated polystyrene polymers, protonated sulfonated styrene-divinylbenzene copolymers, protonated polymethacrylic acid polymers, protonated methacrylic acid-divinylbenzene copolymers, etc.

[0060] As used herein, the term "cation exchange resin" is defined as any pharmaceutically acceptable water-insoluble polymer capable of exchanging its mobile cations with cations in the surrounding medium. As used herein, the term includes sodium, potassium, magnesium, or calcium salts, or partially sodium, potassium, magnesium, or calcium salts, of sulfonated polystyrene polymers, sulfonated styrene-divinylbenzene copolymers, polymethacrylic acid polymers, methacrylic acid-divinylbenzene copolymers, etc. As used herein, the term also includes protonated sulfonated polystyrene polymers, protonated sulfonated styrene-divinylbenzene copolymers, protonated polymethacrylic acid polymers, protonated methacrylic acid-divinylbenzene copolymers, etc.

[0061] As used herein, the term "acidic cation exchange resin" is defined as any pharmaceutically acceptable water-insoluble polymer that can exchange its mobile cations with cations in the surrounding medium and has acidic functional groups (such as sulfonic acid groups or carboxylic acid groups). The term as used herein includes sodium, potassium, magnesium, or calcium salts, or partially sodium, potassium, magnesium, or calcium salts of sulfonated polystyrene polymers, sulfonated styrene-divinylbenzene copolymers, etc. The term as used herein also includes protonated sulfonated polystyrene polymers, protonated sulfonated styrene-divinylbenzene copolymers, protonated polymethacrylic acid polymers, protonated methacrylic acid-divinylbenzene copolymers, etc.

[0062] As used herein, the term "weakly acidic cation exchange resin" is defined as any pharmaceutically acceptable water-insoluble polymer that can exchange its mobile cations with cations in the surrounding medium and has a weakly acidic functional group (such as a carboxylic acid group). As used herein, the term includes sodium, potassium, magnesium, or calcium salts, or partially sodium, potassium, magnesium, or calcium salts, of polymethacrylic acid polymers, divinylbenzene methacrylate copolymers, etc.

[0063] As used herein, the term "partially polacrine potassium" is defined as a partially potassium salt of a methacrylic acid-divinylbenzene copolymer, wherein the weakly acidic salt is formed by the carboxylic acid functional group of methacrylic acid. In the following text, the term "partially polacrine potassium" is commercially known under several trade names such as Purolite® C115KMR, Amberlite® IRP88, etc.

[0064] As used herein, the term "partial sodium polaclin" is defined as a fractional sodium salt of a sulfonated styrene-divinylbenzene copolymer, wherein the acidic salt is formed by the sulfonic acid functional groups of styrene. In the following text, the term "fractional sodium polaclin" is commercialized under several trade names such as Purolite® C100NaMR.

[0065] As used herein, the term "matrix" is defined as a combination of a polymer and safinamide or a pharmaceutically acceptable salt thereof, wherein the safinamide or a pharmaceutically acceptable salt thereof is bound to the polymer by intermolecular forces such as electrostatic interactions, hydrogen bonds, and van der Waals forces. Clearly, due to these forces, the matrix allows safinamide or a pharmaceutically acceptable salt thereof to be trapped within the formed matrix. Specifically, when the polymer is an ion exchange resin, the safinamide or a pharmaceutically acceptable salt thereof is bound primarily by electrostatic interactions. More specifically, when the polymer is a cation exchange resin, the safinamide or a pharmaceutically acceptable salt thereof is bound primarily by electrostatic interactions to the negatively charged functional groups of the cation exchange resin. More specifically, when the polymer is an acidic cation exchange resin, the safinamide or a pharmaceutically acceptable salt thereof is bound primarily by electrostatic interactions to the negatively charged acidic functional groups of the acidic cation exchange resin. Even more specifically, when the polymer is a polymethacrylic acid polymer, the safinamide or a pharmaceutically acceptable salt thereof is bound primarily by electrostatic interactions to the negatively charged carboxylic acid groups of the polymethacrylic acid polymer.

[0066] The term "captured within the matrix" means that substantially all of safenamide or its pharmaceutically acceptable salts are contained within the matrix. In other words, safenamide or its pharmaceutically acceptable salts are substantially absent outside the matrix. In this way, improved dissolution and disintegration characteristics of the orally dispersed solid dosage form can be obtained. "Substantially all" means at least 85% w / w, preferably at least 90% w / w, more preferably at least 95% w / w, and even more preferably at least 97% w / w. Preferably, substantially all of safenamide or its pharmaceutically acceptable salts are uniformly contained within the matrix. In other words, the safenamide or its pharmaceutically acceptable salts contained within the matrix are uniformly distributed throughout the matrix.

[0067] As used throughout this specification, the term "stable" means a pharmaceutical composition in which the active pharmaceutical ingredient safenamide is present at least 90% of the amount specified on the original label for each such ingredient during specific storage conditions.

[0068] As used throughout this specification, the term "specific storage conditions" means that the pharmaceutical compositions of the present invention are stored in the Alu Alu Blister Pack at 40°C and 75% relative humidity for at least one month.

[0069] As used in this article, the term "disintegration" is defined as the process by which a solid dosage form is brought to a state of complete disintegration from a solid state.

[0070] According to the present invention, the term "about" should mean a variation of up to 10% (plus or minus 10%) in a particular term.

[0071] As used herein, the term "friability" refers to the tendency of a tablet to break, crumble, or fracture during processing. Friability testing is performed in accordance with the guidelines in European Pharmacopoeia, 10.0, pp. 336-337. For most products, a maximum mass loss of no more than 1.0% is considered acceptable.

[0072] According to the present invention, after stability studies were conducted in accordance with ICH guidelines, the safenamide content in the pharmaceutical composition was within the limit of 95% to 105%, which was comparable to the reference product XADAGO®.

[0073] In an embodiment, the oral dispersible drug solid dosage form of the present invention comprises safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer adapted to form a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix.

[0074] In an embodiment, the oral dispersible drug solid dosage form of the present invention comprises safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein the pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof is an ion exchange resin.

[0075] In embodiments, the oral dispersible drug solid dosage form of the present invention comprises safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein the pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof is an ion exchange resin, wherein the weight ratio of the ion exchange resin to the safenamide or a pharmaceutically acceptable salt thereof is from 1:0.05 to 1:10, preferably from 1:0.1 to 1:5; more preferably from 1:0.25 to 1:3, and even more preferably from 1:0.5 to 1:2.

[0076] In a preferred embodiment, the oral dispersible drug solid dosage form of the present invention comprises safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein the pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof is an ion exchange resin, wherein the weight ratio of the ion exchange resin to the safenamide or a pharmaceutically acceptable salt thereof is from 1:0.05 to 1:10, preferably from 1:0.1 to 1:5; more preferably from 1:0.25 to 1:3, and even more preferably from 1:0.5 to 1:2, wherein the ion exchange resin is a methacrylic acid-divinylbenzene copolymer, and wherein the methacrylic acid-divinylbenzene copolymer is polacrine potassium.

[0077] In a preferred embodiment, the oral dispersible drug solid dosage form of the present invention comprises safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer adapted to form a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein at least 85% w / w of safenamide or a pharmaceutically acceptable salt thereof present in the oral dispersible drug solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, preferably, at least 90% w / w of safenamide or a pharmaceutically acceptable salt thereof present in the oral dispersible drug solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, more preferably, at least 95% w / w of safenamide or a pharmaceutically acceptable salt thereof present in the oral dispersible drug solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, and even more preferably, at least 97% w / w of safenamide or a pharmaceutically acceptable salt thereof present in the oral dispersible drug solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer.

[0078] In a preferred embodiment, the oral dispersible drug solid dosage form of the present invention comprises safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein the pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof is an ion exchange resin, wherein the weight ratio of the ion exchange resin to safenamide or a pharmaceutically acceptable salt thereof is from 1:0.05 to 1:10, preferably from 1:0.1 to 1:5; more preferably from 1:0.25 to 1:3, and even more preferably from 1:0.5 to 1:2, wherein at least 85% w / w of safenamide or a pharmaceutically acceptable salt thereof present in the oral dispersible drug solid dosage form is trapped within the matrix formed by the pharmaceutically acceptable polymer, preferably at least 90% present in the oral dispersible drug solid dosage form. The w / w safenamide or a pharmaceutically acceptable salt thereof is trapped in a matrix formed with the pharmaceutically acceptable polymer. More preferably, at least 95% w / w safenamide or a pharmaceutically acceptable salt thereof present in the oral dispersible solid dosage form is trapped in a matrix formed with the pharmaceutically acceptable polymer. Even more preferably, at least 97% w / w safenamide or a pharmaceutically acceptable salt thereof present in the oral dispersible solid dosage form is trapped in a matrix formed with the pharmaceutically acceptable polymer.

[0079] In a more preferred embodiment, the oral dispersible drug solid dosage form of the present invention comprises safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein the pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof is an ion exchange resin, wherein the weight ratio of the ion exchange resin to the safenamide or a pharmaceutically acceptable salt thereof is from 1:0.05 to 1:10, preferably from 1:0.1 to 1:5; more preferably from 1:0.25 to 1:3, and even more preferably from 1:0.5 to 1:2, wherein the ion exchange resin is a methacrylic acid-divinylbenzene copolymer, and wherein the methacrylic acid-divinylbenzene copolymer is potassium polacrine, wherein at least 85% of the oral dispersible drug solid dosage form is present. The safenamide or a pharmaceutically acceptable salt thereof, present in w / w, is trapped within a matrix formed of the pharmaceutically acceptable polymer. Preferably, at least 90% w / w of the safenamide or a pharmaceutically acceptable salt thereof present in the oral dispersible solid dosage form is trapped within a matrix formed of the pharmaceutically acceptable polymer. More preferably, at least 95% w / w of the safenamide or a pharmaceutically acceptable salt thereof present in the oral dispersible solid dosage form is trapped within a matrix formed of the pharmaceutically acceptable polymer. Even more preferably, at least 97% w / w of the safenamide or a pharmaceutically acceptable salt thereof present in the oral dispersible solid dosage form is trapped within a matrix formed of the pharmaceutically acceptable polymer.

[0080] In an embodiment, the oral dispersible drug dosage form comprises safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, wherein the one or more pharmaceutically acceptable excipients are selected from one or more diluents, one or more binders, one or more disintegrants, one or more flavoring agents, one or more sweeteners, one or more solvents, one or more lubricants, or mixtures thereof.

[0081] As used herein, the term "diluent" is defined as a pharmaceutically acceptable excipient used as a diluent in a pharmaceutical composition. The term "diluent" includes one or more combinations selected from the group consisting of: mannitol, maltol, sorbitol, maltitol, xylitol, isomaltitol, erythritol, lactose (preferably lactose monohydrate), starch and its derivatives, cellulose and its derivatives, particularly microcrystalline cellulose or mixtures thereof, more preferably mannitol and microcrystalline cellulose. The diluent may be present at a concentration from about 10% to about 40% by weight of the total composition.

[0082] As used herein, the term "lubricant" is defined as a pharmaceutically acceptable excipient used as a lubricant in a pharmaceutical composition. The term "lubricant" includes one or more combinations selected from the group consisting of talc, sodium benzoate, sodium stearoyl fumarate, calcium stearate, magnesium stearate, zinc stearate, glyceryl betaine, stearic acid, and glyceryl monostearate, or mixtures thereof, more preferably sodium stearoyl fumarate and magnesium stearate. The lubricant may be present at a concentration from about 0.5% to about 2% by weight of the total composition.

[0083] As used herein, the term "binder" is defined as a pharmaceutically acceptable excipient used as a binder in a pharmaceutical composition. The term "binder" includes one or more combinations selected from the group consisting of: polyvinylpyrrolidone, povidone, copovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, corn starch, or mixtures thereof, more preferably hydroxypropyl methylcellulose. The binder may be present at a concentration from about 1% to about 5% by weight of the total composition.

[0084] As used herein, the term "disintegrant" is defined as a pharmaceutically acceptable excipient used as a disintegrant in a pharmaceutical composition. The term "disintegrant" includes one or more combinations selected from the group consisting of: crospovidone sodium, crospovidone, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, corn starch, sodium carboxymethyl starch, pregelatinized starch, or mixtures thereof, more preferably crospovidone and crospovidone sodium. Disintegrants may be present at a concentration from about 5% to about 15% by weight of the total composition.

[0085] As used herein, the term "flavoring agent" is defined as a pharmaceutically acceptable excipient used as a flavoring agent in a pharmaceutical composition. The term "flavoring agent" includes one or more combinations selected from the group consisting of: cherry, raspberry, apricot, pear, strawberry, bitter masking agent, pineapple, lemon, honey, mint, orange, peppermint, menthol, blackcurrant, vanilla, banana, red fruit, wild berries, and caramel flavor, more preferably vanilla flavoring. Flavoring agents may be present at a concentration from about 0.5% to about 2% by weight of the total composition.

[0086] As used herein, the term "sweetener" is defined as a pharmaceutically acceptable excipient used as a sweetener in a pharmaceutical composition. The term "sweetener" includes one or more combinations selected from the group consisting of aspartame, acesulfame potassium, sodium saccharin, neohesperidin dihydrochalcone, sucralose, sucrose, fructose, or a mixture thereof with monoammonium glycyrrhizate, more preferably acesulfame potassium. Sweeteners may be present at a concentration from about 0.5% to about 2% by weight of the total composition.

[0087] As used herein, the term "solvent" is defined as a pharmaceutically acceptable excipient used as a solvent in a pharmaceutical composition. The term "solvent" includes one or more combinations of two or more selected from the group consisting of purified water, dichloromethane, isopropanol, or mixtures thereof.

[0088] In the embodiments, following a single oral dose of the oral dispersible pharmaceutical solid dosage form of the present invention under fasting conditions, safenamide equivalent to 100 mg of safenamide or a pharmaceutically acceptable salt thereof exhibited a time to reach maximum plasma concentration (Tmax) from 3 h to 6 h. In the preferred embodiments, following a single oral dose of the oral dispersible pharmaceutical solid dosage form of the present invention under fasting conditions, safenamide equivalent to 100 mg of safenamide or a pharmaceutically acceptable salt thereof exhibited a time to reach maximum plasma concentration (Tmax) from 4 h to 5 h. The term "Tmax" refers to the time in hours to achieve Cmax after a single oral dose of the composition of the present invention under fasting conditions.

[0089] In the examples, after a single oral dose of the oral dispersible pharmaceutical solid dosage form of the present invention under fasting conditions, safenamide equivalent to 100 mg of safenamide or a pharmaceutically acceptable salt thereof exhibited a maximum plasma concentration (Cmax) ranging from 660 ng / mL to 920 ng / mL. The term "Cmax" refers to the maximum concentration of safenamide in the blood after a single oral dose of the composition under fasting conditions.

[0090] In the examples, following a single oral dose of the oral dispersible pharmaceutical solid dosage form of the present invention under fasting conditions, safenamide or a pharmaceutically acceptable salt thereof, equivalent to 100 mg safenamide, exhibited an area under the time / plasma concentration curve (AUC(0-72)) from time 0 to 72 hours, ranging from 18000 µg·h / mL to 28600 µg·h / mL. The term "AUC" refers to the area under the time / plasma concentration curve following a single oral dose of the composition of the present invention. "AUC0-t" represents the plasma concentration from time 0 to time t as a percentage of the area under the time curve, where t represents 72 hours.

[0091] In an embodiment, the oral dispersible drug solid dosage form comprises safenamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer suitable for forming a matrix with safenamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein the solid dosage form has a disintegration time of not more than 3 minutes.

[0092] In the embodiments, the method for preparing the oral dispersible drug solid dosage form of the present invention includes: (i) Dissolve safenamide or a pharmaceutically acceptable salt thereof in water until a clear solution is obtained. (ii) Add ion exchange resin to the solution from step (i) until a homogeneous suspension is achieved. (iii) Provide an adhesive, one or more disintegrants or mixtures thereof, and a diluent, respectively. (iv) Granulate the mixture from step (iii) with the suspension from step (ii) using a fluidized bed processor to obtain wet granules. (v) Drying the wet particles obtained in step (iv) using a fluidized bed processor, thereby obtaining dried particles. (vi) The dry granules obtained in step (v) are mixed with an exonucleating agent, one or more lubricants, and optionally with sweeteners and flavorings. (vii) The mixture obtained in step (vi) is compressed to form an oral dispersion drug solid dosage form.

[0093] In another embodiment, one method for preparing a pharmaceutical composition of safenamide according to the present invention includes the following steps: (i) Dissolve safenamide or a pharmaceutically acceptable salt thereof in water until a clear solution is obtained. (ii) Add ion exchange resin to the solution from step (i) until a homogeneous suspension is achieved. (iii) Add adhesive to the solution from step (ii). (iv) Provide one or more disintegrants or mixtures thereof, and a diluent, (v) Granulation of the mixture from step (iv) and the suspension from step (iii) using a fluidized bed processor to obtain dried granules. (vi) The wet particles obtained in step (v) are dried using a fluidized bed processor, thereby obtaining dried particles. (vii) The dry granules obtained in step (vi) are mixed with an ex-granule disintegrant, one or more lubricants, and optionally with sweeteners and flavorings. (viii) Compress the mixture obtained in step (vii) to form an oral dispersion drug solid dosage form.

[0094] In an embodiment, the present invention provides an orally dispersed pharmaceutical composition of safenamide comprising safenamide or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within a matrix formed with an ion exchange resin, and wherein, when the orally dispersed composition is subjected to a dissolution test in 900 mL of 0.1 M hydrochloric acid at 50 rpm using a USP Type 2 apparatus method, more than 90% of the safenamide is released within 10 minutes.

[0095] In an embodiment, the present invention provides an orally dispersed pharmaceutical composition of safenamide comprising safenamide or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within a matrix formed with an ion exchange resin, and wherein, when the orally dispersed composition is subjected to a dissolution test using a USP Type 2 apparatus method at 50 rpm rotation in a 900 mL volume of phosphate buffer at pH 6.8, more than 50% of the safenamide is released at 10 minutes.

[0096] In an embodiment, the present invention provides an orally dispersible pharmaceutical composition of safenamide comprising safenamide or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within a matrix formed with an ion exchange resin, and wherein the composition, after being stored under specific storage conditions, does not have more than 2.0% w / w of total safenamide impurities.

[0097] In an embodiment, the present invention provides an orally dispersible pharmaceutical composition of safenamide comprising safenamide or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within a matrix formed with an ion exchange resin, and wherein the composition, after being stored in an Alu Alu Blister Pack for one month at storage conditions of 40°C and 75% relative humidity, does not have more than 0.50% w / w total safenamide impurities.

[0098] In an embodiment, the present invention provides an orally dispersible pharmaceutical composition of safenamide comprising safenamide or a pharmaceutically acceptable salt thereof, an ion exchange resin, and one or more pharmaceutically acceptable excipients, wherein safenamide or a pharmaceutically acceptable salt thereof is trapped within a matrix formed with an ion exchange resin, and wherein the composition, after being stored in an Alu Alu Blister Pack for one month at storage conditions of 40°C and 75% relative humidity, does not have more than 0.05% w / w of safenamide-related dimer impurities.

[0099] The invention has been described by way of example only. It should be understood that modifications falling within the scope and spirit of the claims (which will be obvious to those skilled in the art based on the disclosure herein) are also considered to be included within the scope of the invention. The scope of the invention is by no means limited to the disclosed examples.

[0100] Example Example 1:

[0101] Manufacturing method: (i) Dissolve safenamide or a pharmaceutically acceptable salt thereof in water until a clear solution is obtained. (ii) Add ion exchange resin to the solution from step (i) until a homogeneous suspension is achieved. (iii) Provide an adhesive, one or more disintegrants or mixtures thereof, and a diluent, respectively. (iv) Granulate the mixture from step (iii) with the suspension from step (ii) using a fluidized bed processor to obtain wet granules. (v) Drying the wet particles obtained in step (iv) using a fluidized bed processor, thereby obtaining dried particles. (vi) The dry granules obtained in step (v) are mixed with an ex-granule disintegrant, one or more lubricants, and optionally with sweeteners and flavorings. (vii) The mixture obtained in step (vi) is compressed to form an oral dispersion drug solid dosage form.

[0102] Example 2:

[0103] Examples 3, 4 and 5:

[0104] - Not present in the final composition.

[0105] Manufacturing methods for Examples 2, 3, and 4: (i) Dissolve safenamide methanesulfonate in purified water until a clear solution is obtained. (ii) Add Polaklin potassium to the solution from step (i) until a homogeneous suspension is achieved. (iii) Provide HPMC, crosspovidone or croscarmellose sodium carboxymethyl cellulose, mannitol and microcrystalline cellulose respectively. (iv) Granulate the mixture from step (iii) with the suspension from step (ii) using a fluidized bed processor to obtain wet granules. (v) Drying the wet particles obtained in step (iv) using a fluidized bed processor, thereby obtaining dried particles. (vi) The dry granules obtained in step (v) are mixed with the granule-exposed polyvinylpyrrolidone or croscarmellose sodium, sodium stearoyl fumarate or magnesium stearate, and Optionally contains acesulfame potassium and vanilla flavoring. (vii) The mixture obtained in step (vi) is compressed to form an oral dispersion drug solid dosage form.

[0106] Manufacturing method of Example 5: (i) Dissolve safenamide methanesulfonate in purified water until a clear solution is obtained. (ii) Add Polaklin potassium to the solution from step (i) until a homogeneous suspension is achieved. (iii) Add HPMC to the solution from step (ii) while stirring. (iv) Provide croscarmellose sodium cellulose, mannitol and microcrystalline cellulose respectively. (v) Granulation of the mixture from step (iv) and the suspension from step (iii) using a fluidized bed processor to obtain dried granules. (vi) The wet particles obtained in step (v) are dried using a fluidized bed processor, thereby obtaining dried particles. (vii) The dry granules obtained in step (vi) are mixed with cross-linked sodium carboxymethyl cellulose, magnesium stearate, and optionally potassium acesulfame potassium and vanilla flavoring. (viii) Compress the mixture obtained in step (vii) to form an oral dispersion drug solid dosage form.

[0107] Friability test and disintegration test: In accordance with the guidelines in European Pharmacopoeia 10.0, pages 336-337, the preparations of Examples 3, 4, and 5 were submitted for friability testing. The results are shown in Table 1.

[0108] The disintegration times of the formulations in Examples 3, 4, and 5 were also tested following Test A (water at pH 7, 37°C, and 30 cycles per minute) on page 323 of the European Pharmacopoeia 10.0. The results are also shown in Table 1.

[0109] Table 1: Friability results and disintegration time of the preparations in Examples 3, 4 and 5.

[0110]

[0111] As shown in Table 1, all orally dispersible tablets in Examples 3, 4, and 5 meet the requirement of having less than 1% friability according to the guidelines of the European Pharmacopoeia. Furthermore, all of the stated orally dispersible tablets meet the requirements for being orally dispersible tablets, conforming to the definition given in European Pharmacopoeia 10.0, page 939, whereby an orally dispersible tablet is defined as an uncoated tablet intended for placement in the mouth that rapidly disintegrates before being swallowed. According to the disintegration test A (water at pH 7, 37°C, and 30 cycles per minute) on page 323 of European Pharmacopoeia 10.0, it also establishes 3 minutes as the time at which they must disintegrate in the disintegration test for tablets and capsules.

[0112] Dissolution studies: Dissolution profiles of safenamide ODT compositions in Examples 3, 4 and 5 were measured under different pH conditions: (i) using 900 mL of 0.1 M hydrochloric acid at 50 rpm according to USP device 2 (paddle type); and (ii) using 900 mL of phosphate buffer at pH 6.8 at 50 rpm according to USP device 2 (paddle type).

[0113] The dissolution curves obtained in both cases are shown in Table 2 below.

[0114] Table 2: Dissolution curves of the formulations of the present invention.

[0115]

[0116] Stability study: The formulations obtained in Examples 3, 4, and 5 were analyzed to quantify the amount of the most relevant impurities present after storage under controlled temperature and relative humidity (RH) conditions for a certain period of time. The results are presented in Table 3.

[0117] Table 3: Stability data of safenamide tablets (Examples 3, 4 and 5) in Alu Alu Blister Pack at 1-month time intervals under 40°C / 75% RH conditions.

[0118]

[0119] The above data show that the total impurities in the preparation do not exceed 2%, and the measured values ​​are within the range of ICH guidelines, indicating the stability of safenamide in the pharmaceutical product.

[0120] Percentage of active ingredients captured within the matrix formed using ion exchange resin The percentage of active ingredients trapped in the matrix formed by ion exchange resin in the formulation was analyzed.

[0121] The binder dispersion solution containing safenamide methanesulfonate in Example 5 was centrifuged at 3000 RPM for 10 min. Then, 1.0 mL of the supernatant was taken and diluted to 20 mL with a diluent (prepared sequentially by thoroughly mixing 60 volumes of water and 40 volumes of acetonitrile). The liquid sample was thoroughly mixed and then analyzed by HPLC to quantify the amount of safenamide; i.e., the safenamide not captured in the matrix formed with the ion exchange resin. The corresponding percentage of safenamide captured in the formed matrix was calculated by subtracting the amount of safenamide not captured in the matrix from the total amount of safenamide. The results are given in Table 4.

[0122] Table 4: Safenamide captured in a matrix formed with ion exchange resin.

[0123]

[0124] Bioavailability testing: The bioavailability of the safenamide composition of the present invention (Example 5) was investigated.

[0125] Research Design This trial was conducted as an open-label, balanced, randomized, three-treatment, three-sequence, three-time-period, crossover, single-dose comparative bioavailability study in non-smokers, normal, healthy, adults, and human subjects under fasting conditions.

[0126] For this comparative bioavailability study and palatability test, a crossover design was followed. Each subject received the test drug (T1 and T2) and the reference drug (R) during the study period (three time periods, with a 14-day washout period between the dosing days of any two consecutive time periods). Thus, each subject acted as his own control, and no separate subject group was required to serve as the control group.

[0127] volunteer With consent, a sufficient number of healthy, adult, human volunteers were screened to recruit 18 participants for the study, who met the following inclusion criteria in order: Non-smokers, normal, healthy adults, human subjects aged 18 to 45 years (inclusive).

[0128] - Body mass index (BMI) is between 18.5 and 30.0 (inclusive), calculated as weight (kg) / height (m)².

[0129] - No major diseases or clinically significant abnormalities were found during screening, medical history, clinical examination, laboratory evaluation, 12-lead ECG and chest X-ray (rear / front view) recording.

[0130] - From the researcher's perspective, being able to understand and follow research procedures.

[0131] - Able to provide voluntary written informed consent for participation in research.

[0132] -In the case of female subjects: o underwent surgical sterilization at least 6 months prior to participating in the study; or o If they are of fertility potential and willing to use appropriate and effective double-barrier contraception or intrauterine devices during the study; and The serum pregnancy test result must be negative.

[0133] The plan was to include 18 participants in the bioavailability and palatability study. Referring to the bioavailability study, 17 of the 18 participants were ultimately considered for analysis.

[0134] sample The following are the samples used in the bioavailability test: a) Test Sample 1 (Test Product T1): The composition of Example 5, in the form of an orally dispersible tablet, administered with water.

[0135] b) Test Sample 2 (Test Product T2): The composition of Example 5, in the form of an orally dispersible tablet, applied without water.

[0136] c) Reference sample: XADAGO® 100 mg tablets.

[0137] Test methods It is important to note that this testing method is used in bioavailability studies and palatability assessments. For this purpose, at ambient temperature, test samples T1 and T2, along with a reference sample, are administered to subjects in a seated position at predetermined times, using either 240 ± 0.2 mL of drinking water (test T1 and reference) or without drinking water (test T2).

[0138] In all cases, during each time period of administration, subjects avoided drinking water from 0.1 hour before administration until 0.1 hour after administration (except for test product T2, where the mouth was moistened with 20 ± 0.2 mL of drinking water before administration, and for reference and test products T1, where 240 ± 0.2 mL of drinking water was administered before administration). Lunch was served 0.4 hours after administration.

[0139] For the reference sample: After an overnight fast of at least 10 hours, subjects were given a single oral dose (100 mg) of the reference product at ambient temperature with 240 ± 0.2 mL of drinking water. The tablets were swallowed whole without chewing or crushing.

[0140] For test sample T1 (water application): After an overnight fast of at least 10 hours, the test product T1 was administered to the subjects. For each subject, the tablet was placed on the tongue (dose time) and allowed to disintegrate for 30 seconds, but under no circumstances should it be swallowed, chewed, crushed, or broken as a whole. After that 30 seconds, an oral examination was performed to ensure complete disintegration of the tablet, and the subject was then asked to swallow the contents with saliva. If the sample did not disintegrate completely, the oral examination was repeated every 30 seconds until complete disintegration was achieved. The time taken for the subject to swallow saliva was recorded. The subject was then instructed to consume approximately half the amount of water (from 240 ± 0.2 mL of drinking water) by swirling it in their mouth. Following this activity, an intermediate oral examination was performed by a trained researcher using a flashlight to assess adherence to the administration. Finally, the subject was asked to consume the remaining amount of water, and the mouth was checked again to ensure that the drug particles were no longer available.

[0141] For test sample T2 (anhydrous application): After an overnight fast of at least 10 hours, the test product T2 was administered to the subjects. Before administration, subjects were asked to moisten their mouths with approximately 20 ± 0.2 mL of room temperature water for about 5 seconds and then swallow the water. No additional water was provided during the administration procedure. For each subject, the tablet was placed on the tongue (dose time) and allowed to disintegrate for 30 seconds, but swallowing, chewing, crushing, or breaking the tablet whole was strictly prohibited. After the 30 seconds, an oral examination was performed to confirm complete disintegration of the tablet, and the subject was then asked to swallow the contents of their mouth along with their saliva. If the sample did not completely disintegrate, the oral examination was repeated every 30 seconds until complete disintegration was achieved. The time taken for the subject to swallow saliva was recorded. After swallowing, the subject was asked to move their tongue around in their mouth and swallow saliva to ensure that all residual product was ingested. Finally, a trained researcher performed an oral examination with a flashlight to assess adherence to the administration.

[0142] sampling Blood samples were collected at the time before administration (0.000 hours - corresponding to 60 minutes before administration) and at 0.167, 0.250, 0.333, 0.500, 0.750, 1.000, 1.333, 1.667, 2.000, 2.333, 2.667, 3.000, 3.333, 3.667, 4.000, 4.500, 5.000, 6.000, 8.000, 10.000, 12.000, 16.000, 24.000, 36.000, 48.000 and 72.000 hours after administration within each time period.

[0143] Blood samples were collected via an indwelling venous catheter placed in a vein in the subject's forearm. The catheter was removed 16,000 hours after sample collection. Blood samples were also collected via fresh venipuncture 16,000 hours after administration. After each tube of blood was drawn, it was immediately and gently inverted several times to ensure mixing of the tube contents (i.e., the anticoagulant).

[0144] To prevent occlusion, the intravenous catheter was kept in place for as long as possible by injecting 0.5 mL of normal saline solution for the collection of all blood samples up to 16,000 hours after drug administration. All blood samples were kept in ice-cold water.

[0145] Blood samples were centrifuged at 3000 rcf for 5 minutes at 3°C ​​to separate plasma. The separated plasma was transferred in singlet form to pre-labeled polypropylene tubes and stored upright in a freezer at -55°C or lower for temporary storage. Finally, the samples were transferred by keeping them in a dry freezer and then stored in a bioanalytical freezer at -55°C.

[0146] Sure This method involves measuring the plasma concentration of safenamide over a predetermined period of 72 hours.

[0147] The average plasma concentration of safenamide was determined. The safenamide concentrations after once-daily administration of the test samples T1 and T2 of this invention, as well as the reference sample, are summarized in Table 5.

[0148] Furthermore, the plasma concentration-time curve after daily administration of the test sample of the present invention is shown in Figure 1.

[0149] Table 5

[0150] In addition, the main pharmacokinetic parameters exhibited by once-daily administration of the orally dispersible tablets according to the invention (Example 5) with and without water (Test-T1 and Test-T2 samples, respectively), and once-daily administration of the reference product (XADAGO® 100 mg tablets) were measured by LC-MS / MS. In particular, the values ​​of Cmax, Tmax, and AUC0-72, as well as the standard deviation (SD), for the test and reference samples are summarized in Table 6.

[0151] The term "AUC" refers to the area under the time / plasma concentration curve following a single oral dose of the composition of the present invention. Specifically, "AUC0-t" represents the area under the time curve from time 0 to time t, where t represents 72 hours. The term "Tmax" refers to the time, in hours, to achieve Cmax after a single oral dose of the composition of the present invention under fasting conditions. Finally, the term "Cmax" refers to the maximum concentration of safenamide in the blood after a single oral dose of the composition under fasting conditions.

[0152] Table 6

[0153] The pharmacokinetic parameters described above and the mean plasma concentrations of safenamide shown in the table above indicate that once-daily administration of the composition of the present invention (in the form of orally dispersible tablets of Example 5, with and without water (Test T1 and Test T2 products, respectively) under fasting conditions) is bioequivalent to the total drug exposure obtained after once-daily administration of 100 mg XADAGO® tablets. This means that the composition of the present invention administered with and without water has comparable bioavailability, as safenamide is absorbed from the composition of the present invention at the same rate and extent to which it becomes available at the site of drug action as the reference sample.

[0154] Palatability studies: The taste of the safenamide composition of the present invention (prepared according to Example 5) (with and without water) and the reference product XADAGO® (100 mg tablets) was evaluated in order to assess overall subject compliance, monitor adverse events, and ensure subject safety.

[0155] As previously stated, 18 subjects were recruited for bioavailability and palatability testing, and the palatability assessment was conducted concurrently with the bioavailability study. Therefore, the methods used in these tests are consistent with those described in the Testing Methods section (see pages 25-26).

[0156] Specifically, for this sensory evaluation, subjects are given the oral dispersible tablets of the present invention in test T1 (with water) or test T2 (without water), and are asked to report their feedback according to the following scale by indicating bitterness, sweetness, mouthfeel, and flavor sensation: 1 = Very bad 2 = difference 3 = Acceptable 4 = Happy 5 = Excellent In addition, the same experiment was repeated by asking subjects to place the oral dispersible tablet in their mouths and hold it for 5 minutes, followed by sensory evaluation. Descriptive statistics for each subject are summarized in Tables 7 (after 10 seconds) and 8 (after 5 minutes), while the mean (i.e. average) values ​​for all subjects for each evaluation parameter and test formulation are summarized in Table 9.

[0157] Table 7: Individual sensory evaluation of the safenamide ODT of the present invention after 10 seconds as Example 5 (Test T1 and Test T2 products).

[0158]

[0159] Table 8: Individual sensory evaluation of the safenamide ODT of the present invention after 5 minutes as Example 5 (Test T1 and Test T2 products).

[0160]

[0161] Table 9: Average sensory evaluation of the safenamide ODT of the present invention as Example 5 (Test T1 and Test T2 products).

[0162]

[0163] The treatments performed with the products of Test T1 and Test T2 were generally acceptable (no unpleasant taste), thus confirming that the formulation of the safenamide orally dispersible tablets of the present invention prepared according to Example 5 provides sufficient masking of safenamide mesylate. Therefore, by providing suitable sensory characteristics for Parkinson's disease patients administering those orally dispersible safenamide compositions, good adherence to treatment and appropriate patient compliance are ensured.

Claims

1. An orally dispersing pharmaceutical solid dosage form comprising safinamide or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer suitable for forming a matrix with safinamide or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, wherein safinamide or a pharmaceutically acceptable salt thereof is entrapped within the matrix.

2. The orally dispersing pharmaceutical solid dosage form according to claim 1, wherein the pharmaceutically acceptable polymer suitable for forming a matrix with safinamide or a pharmaceutically acceptable salt thereof is an ion exchange resin.

3. The orally dispersing pharmaceutical dosage form according to any one of claims 1-2, wherein the amount of safinamide or a pharmaceutically acceptable salt thereof per dosage form is from 5 to 150 mg, preferably from 25 to 125 mg, and more preferably from 50 to 100 mg, based on the weight of safinamide free base.

4. The orally dispersing pharmaceutical dosage form according to any one of claims 1-3, wherein the solid dosage form is an orally dispersing tablet.

5. The orally dispersing pharmaceutical dosage form according to any one of claims 1-4, wherein the safinamide or a pharmaceutically acceptable salt thereof is safinamide mesylate.

6. The orally dispersing pharmaceutical dosage form according to any one of claims 2-5, wherein the weight ratio of safinamide or a pharmaceutically acceptable salt thereof to the ion exchange resin is from 1 : 0.05 to 1 : 10, preferably from 1 : 0.1 to 1 : 5; more preferably from 1 : 0.25 to 1 : 3, and even more preferably from 1 : 0.5 to 1 :

2.

7. The orally dispersing pharmaceutical dosage form according to any one of claims 2-6, wherein the ion exchange resin is selected from the group consisting of sulfonated polystyrene polymers, sulfonated styrene-divinylbenzene copolymers, polymethacrylic acid polymers, methacrylic acid-divinylbenzene copolymers, protonated sulfonated polystyrene polymers, protonated sulfonated styrene-divinylbenzene copolymers, protonated polymethacrylic acid polymers, and sodium or potassium or magnesium or calcium salts or partial sodium or potassium or magnesium or calcium salts of protonated methacrylic acid-divinylbenzene copolymers.

8. The orally dispersing pharmaceutical dosage form according to any one of claims 2-7, wherein the ion exchange resin is a methacrylic acid-divinylbenzene copolymer.

9. The orally dispersing pharmaceutical dosage form according to claim 8, wherein the methacrylic acid-divinylbenzene copolymer is polacrillin potassium.

10. The orodispersible pharmaceutical dosage form according to any one of claims 1-9, wherein at least 85% w / w of the safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is entrapped within the matrix formed with the pharmaceutically acceptable polymer, preferably at least 90% w / w of the safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is entrapped within the matrix formed with the pharmaceutically acceptable polymer, more preferably at least 95% w / w of the safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is entrapped within the matrix formed with the pharmaceutically acceptable polymer, and even more preferably at least 97% w / w of the safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is entrapped within the matrix formed with the pharmaceutically acceptable polymer.

11. The orodispersible pharmaceutical solid dosage form according to any one of claims 1-10, wherein the dosage form comprises one or more disintegrants in an amount from 5% to 20% w / w with respect to the total weight of the dosage form.

12. The orodispersible pharmaceutical solid dosage form according to claim 11, wherein the one or more disintegrants is one or more intragranular disintegrants.

13. The orodispersible pharmaceutical solid dosage form according to any one of claims 1-12, wherein the dosage form exhibits a dissolution profile according to which: (i) at least 90% w / w of the safinamide is dissolved, relative to the total safinamide content of the dosage form, after 10 minutes when the orodispersible pharmaceutical solid dosage form is subjected to dissolution testing using the USP Apparatus Type 2 method in 900 mL volume of 0.1 M hydrochloric acid at a rotation of 50 rpm, and (ii) at least 50% w / w of the safinamide is dissolved, relative to the total safinamide content of the dosage form, after 10 minutes when the orodispersible pharmaceutical solid dosage form is subjected to dissolution testing using the USP Apparatus Type 2 method in 900 mL volume of Phosphate Buffer pH 6.8 at a rotation of 50 rpm.

14. The orodispersible pharmaceutical solid dosage form according to any one of claims 1-13, wherein the total amount of impurities related to safinamide is lower than 0.50% w / w, preferably 0.30% w / w, more preferably lower than 0.25% w / w, and even more preferably lower than 0.1% w / w, after a period of 1 month at a temperature of 40°C and a relative humidity of 75% under storage conditions in Alu Alu Blister Pack.

15. The orodispersible pharmaceutical solid dosage form according to any one of claims 1-14, wherein the amount of dimer impurities related to safinamide is lower than 0.05% w / w, preferably lower than 0.03% w / w, and more preferably equal to or lower than 0.025% w / w, after a period of 1 month at a temperature of 40°C and a relative humidity of 75% under storage conditions in Alu Alu Blister Pack.

16. The orally dispersed pharmaceutical solid dosage form according to any one of claims 1-15, wherein safinamide or a pharmaceutically acceptable salt thereof equivalent to 100 mg of safinamide exhibits a time to maximum plasma concentration (Tmax) from 3 h to 6 h, preferably from 4 h to 5 h, after oral administration of a single dose of the dosage form.

17. The orally dispersed pharmaceutical solid dosage form according to any one of claims 1-16, wherein safinamide or a pharmaceutically acceptable salt thereof equivalent to 100 mg of safinamide exhibits a maximum plasma concentration (Cmax) from 660 ng / mL to 920 ng / mL, after oral administration of a single dose of the dosage form.

18. The orally dispersed pharmaceutical solid dosage form according to any one of claims 1-17, wherein safinamide or a pharmaceutically acceptable salt thereof equivalent to 100 mg of safinamide exhibits an area under the curve from time 0 to 72 hours / time plasma concentration (AUC(0-72)) from 18000 ng.h / mL to 28600 pg.h / mL, after oral administration of a single dose of the dosage form.

19. The orally dispersed pharmaceutical dosage form according to any one of claims 1-18, wherein the orally dispersed pharmaceutical dosage form disintegrates in less than 3 minutes, preferably in less than 2 minutes, and more preferably in less than 1 minute, wherein the disintegration test is performed using the European Pharmacopeia Disintegration Apparatus A, by placing the dosage form in water at pH = 7 at 37 °C and performing 30 cycles per minute.

20. A process for preparing the orally dispersed pharmaceutical solid dosage form according to any one of claims 1-19, the process comprising: (i) dissolving safinamide or a pharmaceutically acceptable salt thereof in water until a clear solution is obtained, (ii) adding an ion exchange resin to the solution of step (i) until a homogeneous suspension is achieved, (iii) providing separately a binder, one or more disintegrants or a mixture thereof, and a diluent, (iv) granulating the mixture of step (iii) with the suspension of step (ii) using a fluid bed processor to obtain wet granules, (v) drying the wet granules obtained in step (iv) using a fluid bed processor, thereby obtaining dry granules, (vi) mixing the dry granules obtained in step (v) with extra-granular disintegrants, one or more lubricants, and optionally with a sweetener and a flavoring agent, (vii) compressing the mixture obtained in step (vi) to form the orally dispersed pharmaceutical solid dosage form.

21. A process for preparing the orally dispersed pharmaceutical solid dosage form according to any one of claims 1-19, the process comprising: (i) dissolving safinamide or a pharmaceutically acceptable salt thereof in water until a clear solution is obtained, (ii) adding an ion exchange resin to the solution of step (i) until a homogeneous suspension is achieved, (iii) adding a binder to the solution of step (ii), (iv) granulating the mixture of step (iii) using a fluid bed processor to obtain wet granules, (v) drying the wet granules obtained in step (iv) using a fluid bed processor, thereby obtaining dry granules, (vi) mixing the dry granules obtained in step (v) with extra-granular disintegrants, one or more lubricants, and optionally with a sweetener and a flavoring agent, (vii) compressing the mixture obtained in step (vi) to form the orally dispersed pharmaceutical solid dosage form. (iv) providing one or more disintegrants or a mixture thereof, and a diluent, respectively, (v) granulating the mixture of step (iv) with the suspension of step (iii) using a fluid bed processor to obtain wet granules, (vi) drying the wet granules obtained in step (v) using a fluid bed processor, thereby obtaining dry granules, (vii) mixing the dry granules obtained in step (vi) with extra-granular disintegrants, one or more lubricants, and optionally with a sweetener and a flavoring agent, (viii) compressing the mixture obtained in step (vii) to form an orally dispersed pharmaceutical solid dosage form.

22. The orally dispersed pharmaceutical solid dosage form according to any one of claims 1-19, for use in the treatment of adult patients with idiopathic Parkinson’s Disease (PD), as an additional therapy to a stable dose of levodopa (L-dopa) alone or in combination with other PD medicinal products, for patients with advanced fluctuations.

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