Pharmaceutical compositions containing safinamide

Abstract

The present invention relates to pharmaceutical compositions comprising safinamide, more particularly to taste-masked particles comprising the active ingredient or a pharmaceutically acceptable salt thereof, oral dosage formulations comprising the particles, and methods for preparing them.

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical compositions comprising safinamide, and more particularly to taste-masked particles comprising the active ingredient or a pharmaceutically acceptable salt thereof, oral administration formulations comprising the particles, and methods for preparing them. [Background technology]

[0002] Safinamide, i.e., (2S)-2-[[4-[(3-fluorophenyl)methoxy]phenyl]methylamino]propanamide, shown in the formula below. [ka] Safinamide is a highly selective, reversible MAO-B inhibitor that causes an increase in extracellular levels of dopamine in the striatum. Safinamide is involved in the state-dependent inhibition of voltage-gated sodium channels (Na+) and modulation of stimulated glutamate release.

[0003] Safinamide methanesulfonate is the active ingredient in the EMA-approved drug, Xadago®, which is administered in the form of an oral tablet.

[0004] Xadago® is approved as an add-on therapy for the treatment of adult patients with idiopathic Parkinson's disease to a fixed dose of levodopa (L-dopa) alone or in combination with other medications for patients with moderate to late stage Parkinson's disease, and safinamide acts by both dopaminergic and non-dopaminergic mechanisms.

[0005] Orally swallowable film-coated tablets of safinamide methanesulfonate are currently available commercially in doses of 50 to 100 mg.

[0006] These tablets feature an immediate release profile.

[0007] These tablets are intended to be swallowed, and therefore the patient undergoing treatment must be able to perform the swallowing action correctly.

[0008] However, swallowing is known to be difficult for some categories of patients, for example elderly patients or those with little access to paramedical assistance, especially due to conditions that cause progressive hypokinesia such as Parkinson's disease.

[0009] In these clinical situations, the patient has difficulty coordinating the actions required for swallowing, i.e., closing the glottis and simultaneously contracting the laryngeal muscles to force the entire tablet through the esophagus (dysphagia).

[0010] In these cases, it may be desirable to replace tablets swallowed with water with other oral dosage forms that are easier to swallow.

[0011] Patent document 1 (EP 1613296, Newron Pharmaceuticals) describes novel compositions and methods for treating Parkinson's disease, specifically a method for treating Parkinson's disease by administering safinamide in combination with levodopa.

[0012] This patent describes generic pharmaceutical compositions containing the active ingredient, namely formulations for oral administration such as tablets, capsules, elixirs, syrups and oral suspensions.

[0013] WO 2011 / 098456 (Merck Serono SA) relates to the treatment and prevention of dyskinesia, preferably dyskinesia associated with dopaminergic therapy. The document discloses a tablet composition having a core containing safinamide, a binder and other excipients, and an HPMC coating.

[0014] The presence of particles in the core is not explicitly disclosed.

[0015] The approval letter issued by the EMA for Xadago® describes it as a film-coated tablet, 7 mm in diameter, round, biconcave, orange to copper colour, with a metallic luster, embossed on one side with the 50 mg dose (or a different colour for 100 mg), the qualitative composition of which is shown in Table 1 below.

[0016] Table 1: [Table 1]

[0017] The manufacturing process may involve dry-compressing the active ingredient mixed with excipients (internal phase), mixing the compressed material with further excipients (external phase), compressing the final mixture into tablets and coating the latter with a colored polymer film.

[0018] Patent Document 3 (China Patent Application Publication No. 106983730, Foshan City Hongtai Pharmaceutical R&D CO LTD) discloses a safinamide micropellet tablet and a preparation method thereof, in which safinamide is prepared into gastrosoluble coated micropellets through a fluidized bed coating process and then converted into film-coated swallowable tablets through a dry tableting technique. The resulting tablets can be swallowed directly or rapidly disintegrate into micropellets in water, making them suitable for intake by patients with swallowing difficulties, especially children.

[0019] The application does not describe what suitable gastrosoluble coating polymers can be used to improve the stability of the drug and to facilitate storage.

[0020] Patent Document 4 (China Patent Application Publication No. 104546747, Xiamen Meijisi Pharmaceutical Co., Ltd.) describes a pharmaceutical composition containing safinamide methanesulfonate, which has a good dissolution profile achieved by adjusting the ratio of excipients and mainly by controlling the particle size of the active ingredient through ultrafine grinding (D90: 5-50 μm). In a broad sense, the composition comprises safinamide mesylate, as well as a hydrophilic diluent, a water-soluble polymeric binder, a disintegrant, a flavoring, and a lubricant, and the active ingredient is contained in an amount of about 20-30% by weight.

[0021] In particular, Example 5 describes an orally dispersible tablet containing 50 mg of safinamide methanesulfonate, the qualitative and quantitative composition of which is shown in Table 2 below.

[0022] Table 2: [Table 2]

[0023] As noted above, in clinical conditions where Xadago® is indicated, particularly in Parkinson's disease, it would be desirable to replace the tablets swallowed with water with other oral dosage forms that are easier to swallow.

[0024] Although these oral dosage forms are easy for patients to swallow, they present a potential technical challenge in that they result in direct contact between the active ingredient molecules and the taste buds on the patient's tongue and other receptors in the oral cavity that affect overall palatability.

[0025] For this reason, they must be formulated in such a way that the patient does not perceive the taste of the active ingredient or other possible negative sensory effects such as irritation of the oral mucosa; some pharmaceutical molecules are characterized by a very unpleasant taste and, in the worst cases, actually cause irritation of the tongue and palate.

[0026] To the best of the inventors' knowledge, it is believed that the problems associated with the organoleptic properties of the active ingredient safinamide or a pharmaceutically acceptable salt thereof have not been disclosed in the prior art to date.

[0027] The aforementioned Patent Document 3 (China Patent Application Publication No. 106983730) mentions that the bitter taste of safinamide can be covered by an outer film coating of a swallowable tablet.

[0028] In particular, the above-mentioned Patent Document 4 (CN 104546747) provides an example of preparing an orally dispersible tablet that is easier to swallow by a method of wet granulation and subsequent compression, but it does not appear to disclose any attempt to modify the organoleptic properties of the active ingredient.

[0029] The inventors have noted that safinamide in its free base form and / or in its pharmaceutically acceptable salt form, specifically safinamide methanesulfonate, is a molecule characterized by a very unpleasant taste, it is apparently a very strong, astringent, bitter component, and furthermore has a marked tendency to irritate the mucosa of the first compartment of the oropharynx.

[0030] To avoid patients refusing treatment with safinamide, it is essential to completely mask the taste of the active ingredient during administration. If safinamide is prepared into a tablet that rapidly disintegrates in the oral cavity without masking its taste and mouthfeel, the patient will directly experience the unpleasant sensation of the active ingredient, which will lead to intolerance of the dosage form and refusal of treatment, resulting in a worsening clinical pattern.

[0031] In addition to known technical problems, the undesirable organoleptic properties of some active pharmaceutical ingredients present one major problem encountered when attempting to formulate them into oral dosage forms that are easier to swallow.

[0032] In an attempt to ensure effective taste masking, commonly used techniques include many methods of chemical and physical nature, which necessarily must take into account the characteristics of the particular active ingredient and the dosage form employed.

[0033] Indeed, those skilled in the art of formulation are well aware of the technical limitations regarding the inherent organoleptic properties, size, shape, particle size distribution, solubility, etc. of the active ingredients to be added to a selected dosage form.

[0034] To address these unfavourable organoleptic properties, a common formulation technique known to those skilled in the art is to include flavourings and sweeteners in the formulation to mask the unpleasant notes of the active ingredient.

[0035] Furthermore, it is known in the prior art that the irritating effect of some active ingredients can be reduced or completely eliminated by optimally altering the pH of the formulation.

[0036] The applicant's patent application EP 2594266 describes how the irritating effect of ibuprofen or its pharmaceutically acceptable salts can be eliminated by appropriate adjustment of the pH.

[0037] In the case of safinamide methanesulfonate, although technical practices of appropriately combining sweeteners and flavorings are possible, it has not been possible to effectively mask its sensory properties, and furthermore, attempts to adjust the pH of the formulation have not resulted in a reduction in the irritating effect in the oral cavity.

[0038] As a result, when safinamide methanesulfonate is included in an oral dosage form that is easier to swallow, patients will perceive the unpleasant taste and irritating effect of the active ingredient in the oral cavity, which is detrimental to the patient.

[0039] The reasons why taste masking of safinamide methanesulfonate is difficult are, firstly, that safinamide generally has a very strong bitter component that is associated with strong astringency and tends to irritate the tongue and palate, and further, because safinamide methanesulfonate is soluble in saliva, patients directly sense its taste.

[0040] Very bitter drug molecules are often actually poorly soluble in saliva and are not immediately perceived as is the case with safinamide.

[0041] Alternatively, other taste-masking techniques could be considered, such as the use of a physical barrier between the active ingredient and the oral mucosa (highly viscous colloidal systems), reducing its solubility by, for example, adjusting the pH of the pharmaceutical formulation or encapsulation techniques (granulation, coating, microencapsulation, etc.), and those skilled in the art are also familiar with other taste-masking methods, such as the so-called ion exchange resin method, which is based on the chemical interaction of the active ingredient with molecules that can strongly interact with it, or the formation of reversible complexes between molecules of the active ingredient and those in the form of cyclic polyols (cyclodextrins).

[0042] However, many of the above approaches involve some chemical and / or physical modification of the active pharmaceutical ingredient, which affects its stability, dosage form and, above all, its activity and bioavailability manifestations. [Prior art documents] [Patent documents]

[0043] [Patent Document 1] European Patent No. 1613296 [Patent Document 2] International Publication No. 2011 / 098456 Brochure [Patent Document 3] Chinese Patent Application Publication No. 106983730 [Patent Document 4] Chinese Patent Application Publication No. 104546747 [Patent Document 5] European Patent No. 2594266 Summary of the Invention [Problem to be solved by the invention]

[0044] Although various techniques are known for preparing dosage forms that are easier to swallow, there is a need to explore innovative methods that allow for the preparation of pharmaceutical compositions containing safinamide or a pharmaceutically acceptable salt thereof that can disintegrate rapidly in the oral cavity while having excellent organoleptic properties, and that allow the release of the active ingredient in the gastrointestinal tract with kinetics comparable to those of currently available dosage forms. [Means for solving the problem]

[0045] The inventors of the present invention have unexpectedly found that by converting safinamide or a pharmaceutically acceptable salt thereof, particularly safinamide methanesulfonate, into a plurality of solid particles and by applying a taste-masking polymeric coating composition onto every particle, the drawbacks associated with the highly objectionable organoleptic properties of the active ingredient are overcome.

[0046] When administered in an oral formulation for easier swallowing, the particles constituting the subject of the present invention can pass through the patient's oral cavity without causing the perception of the unpleasant organoleptic properties of safinamide or its pharmaceutically acceptable salts, an important result that allows patients who complain of swallowing difficulties to fully benefit from the drug treatment. DETAILED DESCRIPTION OF THE INVENTION

[0047] Thus, the present invention relates to a pharmaceutical composition and a method for producing the same, in which safinamide or a pharmaceutically acceptable salt thereof, preferably safinamide methanesulfonate, is added to an oral administration formulation that is easy to swallow, such as, for example, a rapidly disintegrating tablet, an orodispersible film, a chewable tablet, an orodispersible microtablet, an effervescent tablet, a water-dispersible tablet, an orodispersible powder, or a wettablet, in the oral cavity; in these preparations, safinamide or a pharmaceutically acceptable salt thereof is present in a form that ensures complete masking of the highly undesirable organoleptic properties of the active ingredient without impairing the release kinetic profile in the gastrointestinal tract.

[0048] Accordingly, the present invention relates to a plurality of particles, each of which comprises: a. A core comprising safinamide or a pharmaceutically acceptable salt thereof b. a taste-masking polymer composition forming a coating on said cores wherein the core comprises inert particles layered with the safinamide or a pharmaceutically acceptable salt thereof in the presence of a binder.

[0049] The particles according to the present invention consist essentially of a core containing an active ingredient suitably coated with a taste-masking polymer composition capable of masking the organoleptic properties of said active ingredient.

[0050] Generally, the particles have a moderate size of 500 μm or less to avoid any unpleasant sensory perception when the selected pharmaceutical dosage form itself, or a portion thereof, is introduced into the oral cavity.

[0051] The core of the present invention comprises inert particles layered with safinamide or a pharmaceutically acceptable salt thereof in the presence of a binder, and optionally one or more pharmaceutical excipients, and the core is typically prepared by a common layering technique and formed into a bead, pearl, spheroid, micropellet, or other shape.

[0052] Typically, the core has a size (preferably not polydisperse) in the range of 150 to 500 μm, and preferably in the present invention, the core has a particle size in the range of 200 to 450 μm.

[0053] Safinamide is preferably used in the form of a crystalline solid having an average particle size in the range of 5 to 50 μm.

[0054] Pharmaceutically acceptable salts of safinamide according to the present invention include addition salts with inorganic acids such as nitric acid, hydrochloric acid, sulfuric acid, perchloric acid, and phosphoric acid, or addition salts with organic acids such as acetic acid, propionic acid, glycolic acid, lactic acid, oxalic acid, malonic acid, malic acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, and salicylic acid, and safinamide methanesulfonate is a preferred salt.

[0055] Preferably, the particles formulated and produced according to the present invention contain 10-80% by weight of safinamide base, preferably 20-60% by weight of safinamide, or an equivalent salt thereof.

[0056] Preferably, dosage forms containing particles formulated and produced according to the present invention contain 50 or 100 mg of safinamide base or an equivalent salt thereof.

[0057] The term inert particles according to the present invention means microspheres of uniform diameter on the surface of which one or more active ingredients are deposited.

[0058] The inert particles are characterized by the fact that they have a more or less smooth surface, may be water soluble or insoluble, and have a high resistance to crushing and high density, thereby making them resistant to the physical stresses encountered during processes commonly used to layer active ingredients.

[0059] The inert particles are characterized by not having a discrete particle size distribution, and they may optionally be of particle size starting from about 50 μm.

[0060] Non-limiting examples of suitable pharmaceutically acceptable inert particles according to the present invention are particles of microcrystalline cellulose (e.g., Vivapur MCC prepared by JRS), sucrose (e.g., Suglets prepared by Colorcon), starch (e.g., Nonpareil-101 prepared by Freund), mannitol (e.g., Nonpareil-108 prepared by Freund), silica (e.g., AS sprayspheres™ prepared by Umang), calcium carbonate (e.g., CS sphere sprayspheres™ prepared by Umang), as well as particles of other excipients.

[0061] In a preferred embodiment of the invention, the inert particles are particles of microcrystalline cellulose, starch and sucrose, with microcrystalline cellulose being more preferred.

[0062] The inert particles have a particle size in the range of 50 to 400 μm, preferably they have a particle size in the range of 100 to 200 μm.

[0063] In a more preferred embodiment, the inert particles are microcrystalline cellulose particles and have a particle size in the range of 100 to 200 μm.

[0064] The term binder according to the present invention means a pharmaceutical excipient suitable for binding crystals of safinamide or a pharmaceutically acceptable salt thereof to the surface of inert particles.

[0065] Non-limiting examples of binders according to the present invention include, for example, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, polyethylene glycol (PEG), methylcellulose (MC), povidone (PVP), polyethylene oxide (PEO), polyvinyl alcohol (PVA), modified starch, and others, alone or in combination.

[0066] Preferred binders of the present invention are selected from povidone (PVP), polyethylene glycol (PEG), pregelatinized starch, hydroxypropyl methylcellulose (HPMC) and microcrystalline cellulose.

[0067] The core of the particles of the present invention preferably comprises a binder in a percentage in the range of 0.5 to 40% by weight, more preferably in the range of 2 to 10% by weight.

[0068] Pharmaceutically acceptable excipients that may optionally be present in the core of the particles of the invention include, for example, microcrystalline cellulose (MCC), lactose (anhydrous or monohydrate), pregelatinized starch, mannitol, isomalt, sorbitol and similar carbohydrates, dicalcium phosphate (anhydrous or dihydrate), maltodextrin and other diluents, such as crospovidone, croscarmellose sodium, sodium starch glycolate, partially pregelatinized starch and other disintegrants, such as colloidal silica, calcium silicate, magnesium trisilicate, talc and other anti-agglomerating agents, and plasticizers, such as triethyl citrate (TEC), dibutyl sebacate, glycerol monostearate, polyethylene glycol (PEG) and other plasticizers.

[0069] These optional excipients of the particles of the invention are preferably contained in the core in a percentage ranging from 0 to 10% by weight, preferably from 0 to 5% by weight.

[0070] In a preferred embodiment, the core of the particles of the present invention comprises one or more binders and one or more anti-agglomerating agents.

[0071] In another preferred embodiment, the core of the particles of the present invention is characterized by a bulk density in the range of 0.50 to 0.90 g / ml, preferably 0.60 to 0.80 g / ml, in a round shape with a smooth surface.

[0072] The core of safinamide or a pharmaceutically acceptable salt thereof is obtained by conventional layering methods in which inert particles are layered with a binding solution.

[0073] In one aspect of the present invention, a core of safinamide or a pharmaceutically acceptable salt thereof is obtained by a wet layering method, which envisages layering inert particles with a binder solution containing the active ingredient dissolved or dispersed in a suitable vehicle liquid in the presence of at least one binder as described above.

[0074] Non-limiting vehicle liquids include water, buffered aqueous solutions, organic solvents suitable for pharmaceutical processing, such as alcohols (methanol, ethanol, isopropanol) and aprotic solvents (e.g., acetone), and mixtures thereof.

[0075] Preferably, the suitable vehicle liquid is an aqueous vehicle liquid such as water, or a mixture of water with an alcohol or a ketone, preferably acetone.

[0076] The mass of solids contained in the binding solution is preferably 15 to 30% by weight, of which preferably 0.5 to 10% by weight is the binder and 0.5 to 2.0% by weight is the anti-agglomerating agent.

[0077] Those skilled in the art will appreciate the useful technical measures required to ensure optimum performance in the lamination process carried out for the purposes of the present invention in a variety of vehicle liquids.

[0078] Thus, for example, when water is used as the vehicle liquid for the bonding solution, it is desirable to heat the solution and not allow the temperature to fall below 27°C during the entire lamination process in order to completely dissolve and maintain the active ingredient.

[0079] This approach allows a larger amount of active ingredient to be dissolved in the binding solution than would be possible at room temperature, thereby significantly reducing the time required for the lamination process, improving yields, and reducing the amount of water required to prepare the binding solution.

[0080] Alternatively, when a buffered aqueous solution is used, it is preferable to obtain a pH of around 7.0, which provides adequate conditions for the active ingredient to be fully dispersed in the binding solution.

[0081] In another aspect of the present invention, the core of safinamide or a pharmaceutically acceptable salt thereof is obtained by a method known as dry layering, in which the active ingredient is layered onto inert particles by direct deposition of a dry powder, in which the binding solution comprises at least one binder dissolved or dispersed in a suitable vehicle liquid as described above.

[0082] The at least one binder is present in a concentration of about 0.5 to 10% by weight, preferably 0.5 to 5% by weight, and optionally the anti-agglomerating agent is present in a concentration of about 0.2 to 2.0% by weight of the solution.

[0083] The taste masking polymer composition that forms the coating on the core according to the present invention may comprise a water soluble polymer, a water insoluble polymer, or a mixture thereof.

[0084] Suitable polymers according to the present invention are pH-dependent water-soluble polymers, as well as water-soluble and water-insoluble celluloses, such as basic polymethacrylate butyrate, ethylcellulose alone or in admixture with hydroxypropylmethylcellulose, and mixtures of ethylcellulose with basic polymethacrylate butyrate.

[0085] The taste masking polymer composition may be used directly as a powder, or in the form of an aqueous dispersion or a solution in a suitable organic solvent.

[0086] Some commercially available compositions that can be used in the present invention include copolymers of methacrylic acid and cellulose, which are commercially available under the trademarks Eudragit® L100, Eudragit® S100, Eudragit® L30D, Eudragit® E100, Eudragit® EPO (Evonik), Kollicoat® Smartseal 30D, Kollicoat® IR, Kollicoat® MAE 30D, Aquacoat® ECD, Aquacoat® ARC, Aquacoat® CPD (FMC), Surelease® (Colorcon), METHOCEL™, and the like, as well as suitable mixtures thereof.

[0087] In a preferred form of the invention, the polymer film applied to the core is comprised of a mixture of cellulosic polymers, which may be water-insoluble or water-soluble, the latter of which will generally be understood by those skilled in the art to be release modulators.

[0088] In a further preferred embodiment of the invention, the above mixture consists of ethyl cellulose and hydroxypropyl methylcellulose as release modulators, the latter preferably in a proportion of 5 to 40% by weight, more preferably 10 to 30% by weight, of the polymer film applied to the core of safinamide or a pharmaceutically acceptable salt thereof.

[0089] In a practical embodiment of the present invention, the polymer mixture is dispersed in water or in an organic solvent.

[0090] First, the water-soluble polymer is incorporated into the solution by continuous stirring at room temperature until it is completely solubilized in water. Next, the insoluble polymer is introduced and uniformly dispersed in the solution under the action of a planetarium agitator and any other functional excipients that may be present. The polymer suspension is maintained under constant stirring during film formation of the safinamide methanesulfonate or pharmaceutically acceptable salt thereof core.

[0091] In the second preparation procedure, an organic solvent such as ethanol or an ethanol / water mixture is assumed as the vehicle liquid, and the water-soluble and water-insoluble polymers are added at room temperature with continuous stirring, and functional excipients are added as needed to completely solubilize the polymers.

[0092] The taste-masking polymer composition may also include one or more functional excipients for coatings selected from plasticizers, lubricants, and anti-agglomerating agents.

[0093] In a preferred embodiment of the invention, the polymer coating comprises an excipient that functions as a plasticizer.

[0094] The introduction of said excipients allows the particles to be partially deformed during the tablet manufacturing process without being damaged, thereby preserving the valuable taste-masking effect.

[0095] Non-limiting examples of plasticizer excipients include polyethylene glycol (PEG) of various molecular weights, triethyl citrate (TEC), dibutyl sebacate (DBS), and the like.

[0096] The plasticizer is contained in an amount of 0 to 20% by weight based on the particles containing safinamide or a pharmaceutically acceptable salt thereof.

[0097] In a preferred embodiment of the invention, the plasticizer is present in a concentration ranging from 2 to 10% by weight of the particles.

[0098] Since plasticizers contained in the coating film can alter the release of the active ingredient from the safinamide methanesulfonate particles, those skilled in the art will fully recognize that the type of plasticizer excipient must be carefully combined with the qualitative and quantitative composition of the coating polymer film to ensure that the release of the active ingredient is equivalent to that of the Xadago swallowable tablets.

[0099] The content of the taste-masking polymer coating composition is usually in the range of 10 to 70% by weight, preferably 20 to 40% by weight of the particles.

[0100] In a preferred embodiment of the invention, the particles according to the invention have the qualitative and quantitative composition shown in Table 3 below:

[0101] Table 3: [Table 3]

[0102] In another preferred embodiment, the particles of the invention are characterized by a bulk density in the range of 0.40 to 0.80 g / ml, preferably in the range of 0.50 to 0.70 g / ml.

[0103] The particles of the present invention are prepared by a method comprising: a. layering an active pharmaceutical ingredient onto inert particles to obtain a core; b. Coating said core with a taste-masking polymer composition.

[0104] The particles according to the invention are prepared using known layering and coating methods, but their application to the active ingredient safinamide in particular has proven to be of great significance, far beyond the routine work of a person skilled in the art, due to its physicochemical properties.

[0105] The process of layering the active ingredient onto inert particles to obtain a core of safinamide or a pharmaceutically acceptable salt thereof has been achieved by a conventional method based on fluidized bed coating technology. For extensive experimental work, the inventors have been able to apply various methodologies, such as wet layering when the active ingredient is dissolved or dispersed in a binder solution, or dry layering when the active ingredient is used directly as a powder.

[0106] The inventors have applied the polymer-based coating to the core of the present invention, thereby enabling taste masking of the active ingredient.

[0107] The taste masking polymer composition can be applied to the cores of the present invention by common coating techniques used in the field of pharmaceutical manufacturing, such as fluidized bed coating, pan coating and spray coating.

[0108] In applying the coating polymer, the inventors adopted, as a preferred embodiment, fluidized bed technology well known to those skilled in the art, and as a result of conducting a large number of tests, the inventors have found that by applying a taste-masking polymer coating composition having the above-mentioned qualitative and quantitative composition to a core of safinamide or a pharmaceutically acceptable salt thereof, it is possible to effectively mask its organoleptic properties.

[0109] The application of a taste-masking polymer coating composition onto the core containing the active ingredient is a technique known to those skilled in the art.

[0110] However, what is important is that in the case of safinamide methanesulfonate, even an oral administration formulation that provides good swallowing must have a dissolution profile equivalent to that of already commercially available swallowable tablets, i.e., a rapid dissolution profile in a preferred embodiment, and therefore requires the application of a coating film of a type that lasts for only a few minutes, thereby functioning only while the drug is moving in the oral cavity, and disintegrates immediately after swallowing, thereby exhibiting a release profile equivalent to that of a swallowable tablet.

[0111] In one embodiment of the present invention, the lamination and coating with the taste masking polymer composition are carried out in the same equipment, preferably in the same fluidized bed.

[0112] In this case, the inert particles are first fluidized and then layered by spraying a binder solution containing safinamide or a pharmaceutically acceptable salt thereof (wet layering), or the layering can be carried out by applying safinamide or a pharmaceutically acceptable salt thereof as a powder directly to the inert particles while rotating the fluidized bed and simultaneously spraying the binder solution as described above (dry layering).

[0113] The cores thus obtained are extruded, optionally sieved to recover the granulometric fraction of interest, reloaded into the fluidized bed, and further coated with a taste-masking polymer composition by spraying, followed by a drying step.

[0114] These particles are preferably suitable for incorporation into all types of oral dosage forms, whether or not intended to be compressed, and are characterized by their easy obtainability, pseudospherical shape, and excellent flowability.

[0115] It is indeed desirable for particles of this type to have specific physical properties so that they do not deform and / or cleave during the compression process, thereby eliminating the protective benefits of the coating film, and it is also desirable to use layering techniques that allow for the formation of cores with particularly smooth surfaces and spherical geometries, in order to allow efficient coating of the particles with the taste-masking polymer system.

[0116] The inventors of the present invention have surprisingly found that by applying the technology according to the present invention, which allows the formation of a dense core, to safinamide or a pharmaceutically acceptable salt thereof, particles of this optimum type have been obtained, which are also characterized by a suitable shape required for coating with a taste-masking polymer composition.

[0117] The layering process on inert particles according to the present invention allows for an improvement in the process yield in terms of active ingredient loading, desired particle size and shape of the resulting particles.

[0118] In a further preferred embodiment, the core of the particles according to the invention has the composition shown in Table 4 below:

[0119] Table 4: [Table 4]

[0120] In a practical, non-limiting embodiment of the present invention, wet layering is envisioned as follows: inert particles are added to a suitable device, preferably a fluidized bed; a binder solution containing optional excipients is separately prepared; and safinamide or a pharmaceutically acceptable salt thereof is added to the solution. In this process, the inert particles are fluidized and the binder solution containing safinamide is sprayed onto them using a gun equipped with a nozzle, which can be arranged on the fluidized bed in a top-spray or bottom-spray manner. After wet layering of the active ingredient is completed, the resulting core is discharged and dried.

[0121] Alternatively, the active ingredient can be used in solid form (dry layering) without dispersing it in a binder solution.

[0122] In a practical, non-limiting embodiment, the method is envisioned using a rotor-configured fluidized bed apparatus, in which safinamide or a pharmaceutically acceptable salt thereof is added as a powder directly to the rotor-fluidized inert particles while simultaneously spraying the binder solution. After dry layering of the active ingredient is complete, the resulting cores are dried and extruded.

[0123] From a technical point of view, the above lamination procedure ensures the formation of a dense, regularly shaped core, which is particularly suitable for the subsequent coating and optional compression steps.

[0124] As described by the inventors, the layering of active ingredients onto inert particles offers several advantages over common techniques for producing microparticles containing active ingredients (e.g., granulation or pelleting), the main advantages being related to the very high process yield in terms of deposited active material, resulting particle size and spherical shape.

[0125] Furthermore, the particles obtained are particularly uniform. The manufacturing process is much more reproducible than those previously described, ensuring the high quality of the particles prepared.

[0126] The layering process of safinamide methanesulfonate onto inert particles described by the inventors allows for a reduction in the amount of polymer applied to their surface for taste-masking coating, due to their highly spherical shape and uniformity, thereby significantly minimizing the unavoidable loss of polymer that occurs during the coating process.

[0127] Reducing the amount of taste-masking polymer reduces the time and cost of the coating process, but also means a reduction in particle weight, which is particularly beneficial when the particles are added to orodispersible tablets. Limiting the tablet weight and size while maintaining a constant drug dose can help maintain patient compliance.

[0128] Additionally, by providing more space for functional excipients in orally disintegrating (ultrafine) tablets, the polymer film is better protected during the compression process, preserving the taste-masking effect in the patient's mouth.

[0129] Finally, the above layering procedure has been found to be surprisingly useful in maintaining the crystalline structure and stability of the active ingredient safinamide or a pharmaceutically acceptable salt thereof.

[0130] In a practical, non-limiting embodiment, for the taste-masking polymer coating of the core of the present invention, the safinamide methanesulfonate core is fluidized with air in a suitable device (preferably a fluidized bed), and separately, an aqueous suspension containing a coating polymer (e.g., ethyl cellulose, hydroxypropyl cellulose, and a plasticizer excipient) is prepared and sprayed onto the core using a gun equipped with a nozzle that can be positioned in the fluidized bed as a top spray or a bottom spray. After the coating process is completed, the safinamide methanesulfonate particles are dried and extruded.

[0131] Importantly, the above-described properties of the particles of the present invention, i.e., an optimally formulated compact core and an effective taste-masking coating, have been shown to be perfectly matched to the desired dissolution behavior.

[0132] As mentioned above, the particles of the present invention may then be used directly in an easy-to-swallow pharmaceutical dosage form, such as an orodispersible or water-dispersible sachet.

[0133] Preferably, the particles of the present invention are incorporated into an easy-to-swallow dosage form (eg an orodispersible sachet) either neat or optionally in the presence of suitable pharmaceutically acceptable excipients.

[0134] Alternatively, the particles of the present invention may be in a rapidly disintegrating yet easy to swallow combination dosage form such as, for example, orally disintegrating tablets (ODT), chewable tablets, orodispersible microtablets, water-dispersible effervescent tablets and orodispersible films.

[0135] Therefore, the present invention further relates to the use of a plurality of particles as described above in the preparation of an oral dosage formulation.

[0136] The preferred dosage form of the present invention is an orally disintegrating tablet.

[0137] The term orally disintegrating tablet according to the present invention means an orodispersible tablet as defined in Ph.Eur., which is an uncoated tablet for oral administration that disperses rapidly before being swallowed.

[0138] Therefore, in a practical embodiment of the present invention, safinamide or a pharmaceutically acceptable salt thereof is layered with at least one binder solution by a dry method or, preferably, a wet method, the core thus obtained is then coated with a suitable taste-masking polymer composition, and the particles of the present invention are then mixed with suitable excipients and converted into an orally disintegrating tablet that has taste-masking properties even after long-term storage.

[0139] Therefore, the present invention further relates to the use of the taste-masked particles obtained above in the preparation of orally disintegrating tablets.

[0140] The particles have good compression resistance and flow properties and can be used directly, optionally after subsequent mixing with suitable pharmaceutical excipients, in the preparation of oral dosage forms.

[0141] Extraparticulate excipients that may be included in the dosage forms of the present invention are diluents such as mannitol, lactose, isomalt, sorbitol, xylitol, starch, maltodextrin, or combinations thereof; binders such as microcrystalline cellulose, ethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, medium molecular weight polyethylene glycol, lactose, dicalcium phosphate, alginic acid, and combinations thereof; disintegrants such as crospovidone, sodium starch glycolate, croscarmellose; lubricants such as magnesium stearate, sodium stearyl fumarate, polyethylene glycol, sodium benzoate, and the like.

[0142] In a preferred embodiment of the present invention, the diluent is selected from mannitol, isomalt, xylitol, starch, and combinations thereof, the binder is selected from microcrystalline cellulose, medium molecular weight polyethylene glycol, and alginic acid, the disintegrant is selected from crospovidone, sodium starch glycolate, and croscarmellose, and the lubricant is selected from magnesium stearate, sodium stearyl fumarate, and polyethylene glycol.

[0143] In a preferred embodiment of the invention, the orally disintegrating tablet of the invention has the qualitative and quantitative composition shown in Table 5 below:

[0144] Table 5: [Table 5-1]

[0145] The compositions in Table 5 are the result of extensive research conducted by the inventors to evaluate various effects related to the qualitative and quantitative composition of orally disintegrating tablets that may affect the integrity of the particles of the present invention during the compression process.

[0146] In the above studies, it has been found that the use of an appropriate combination of ultrafine particle excipients that exhibit brittle, flexible and elastic behavior is successful in maintaining the integrity of the taste-masking polymer film of the particles during the manufacturing process of orally disintegrating tablets.

[0147] Suitable diluents which have a predominantly brittle behaviour are, for example, mannitol, isomalt and xylitol, and those which have a predominantly soft behaviour are, for example, starch.

[0148] Suitable binders that exhibit a predominantly elastic behavior are, for example, medium molecular weight polyethylene glycol and alginic acid.

[0149] Furthermore, in order to avoid the risk of damaging the particles of safinamide methanesulfonate during compression, it is preferred to have a plasticizer excipient present in the taste masking polymer film, which is preferably applied to the core in an amount of at least 2% by weight relative to the particles.

[0150] The preferred plasticizers of the present invention are triethyl citrate (TEC) and polyethylene glycol (PEG).

[0151] In a preferred embodiment of the present invention, the orally disintegrating tablet of the present invention has the qualitative and quantitative composition shown in Table 5-2 below: Table 5-2: [Table 5-2]

[0152] As noted above, particularly in clinical conditions such as Parkinson's disease where Xadago® is indicated, it would be desirable to replace the tablets swallowed with water with other oral dosage forms that are easier to swallow.

[0153] To the best of the inventors' knowledge, the problems associated with the organoleptic properties of the active ingredient safinamide or a pharmaceutically acceptable salt thereof have not been previously disclosed in the prior art.

[0154] The present invention makes it possible to prepare particles containing safinamide or a pharmaceutically acceptable salt thereof, and to formulate pharmaceutical compositions that have excellent organoleptic properties, can disintegrate rapidly in the oral cavity, and can release the active ingredient in the gastrointestinal tract with pharmacokinetics equivalent to that of so-called immediate release.

[0155] Those skilled in the art face many difficulties when formulating orodispersible dosage forms, especially when the dosage form contains active ingredients that have unfavourable physicochemical and / or organoleptic properties.

[0156] To date, there is no general purpose technology in the art that is suitable for application to any active ingredient.

[0157] In particular, the taste-masking technology selected must meet many criteria related to the preparation process, primarily related to the specific product; stability of the active ingredient, particle size and shape, structural and physical properties, and the qualitative and quantitative composition of the taste-masking polymer coating system are just a few of the many variables that must be considered and controlled in the formulation approach.

[0158] The use of multiple solid particles as described in the present invention makes it possible to prepare an easily swallowed oral dosage formulation in which the unpleasant sensory profile of safinamide or a pharmaceutically acceptable salt thereof, preferably safinamide methanesulfonate, is sufficiently masked without altering the desired dissolution profile when the drug is ingested by a patient.

[0159] The advantages of the compositions of the present invention compared to those already described in the literature are therefore evident.

[0160] To this end, the tablets of the present invention have physical properties that meet the requirements set out in the official pharmacopoeias, such as an in vivo disintegration time of less than 1 minute.

[0161] Furthermore, the tablets claimed herein have in vitro dissolution properties comparable to current commercially available immediate release tablets.

[0162] The kinetic properties of the particles of the present invention and orally disintegrating tablets comprising said particles with respect to immediate release in the stomach were assessed by measuring the percentage release of the active ingredient when testing the dissolution of the dosage form in artificial gastric fluid or 0.1 N hydrochloric acid, with more than 80% of the dose released in about 30 minutes, which is considered a good result.

[0163] Finally, the taste masking properties of the particles of the present invention and orally disintegrating tablets comprising said particles were assessed by measuring the percentage release of the active ingredient when testing the dissolution of the dosage form in artificial saliva at a pH of about 6.8, which showed that less than 10% of the dose was released in 1 minute, which is considered a good result.

[0164] In order to more clearly illustrate the present invention, the following non-limiting examples are presented. [Example]

[0165] Example 1: Core preparation: Wet lamination a. Fluidized bed (top spray addition): The binding solution was prepared by adding the binder excipients to water at 30° C. with continuous stirring, and after solubilization was complete, adding safinamide methanesulfonate followed by the deflocculating agent excipients.

[0166] Meanwhile, the inert particles were placed in a fluidized bed (GPCG 1.1; manufactured by Glatt Co.) and heated to approximately 40-45°C for 50 min. 3 The mixture was flowed at a flow rate of 1 / h.

[0167] Once the temperature was reached, a binder solution containing safinamide methanesulfonate was sprayed onto the core using a gun equipped with a 1.0 mm diameter nozzle at a flow rate of approximately 10 g / min. After the lamination process was completed, the core was heated at 45°C for 30 minutes, then cooled to room temperature and extruded.

[0168] After the drying step was completed, the product was discharged and sieved to collect the fraction in the range of 200 to 450 μm.

[0169] Using the above procedure, cores of the following compositions were prepared: Core 1 Safinamide methanesulfonate 68.6% MCC100 25.0% PVP K30 4.3% Talc 2.1% Core 2 Safinamide methanesulfonate 70.1% MCC100 24.0% Pregelatinized starch RX 1500 3.8% Talc 2.1% Core 3 Safinamide methanesulfonate 69.2% MCC100 24.0% PEG 6000 4.5% Talc 2.3%

[0170] b. Fluidized bed (bottom spray addition):

[0171] The binding solution was prepared by adding the binder excipients to water at 30° C. with continuous stirring, and after solubilization was complete, adding safinamide methanesulfonate followed by the deflocculating agent excipients.

[0172] Meanwhile, the inert particles were placed in a fluidized bed (GPCG 1.1; manufactured by Glatt Co.) and heated to approximately 40-45°C for 50 min. 3 The mixture was flowed at a flow rate of 1 / h.

[0173] Once this temperature was reached, a binder solution containing safinamide methanesulfonate was sprayed onto the core using a gun equipped with a 1.0 mm diameter nozzle at a flow rate of approximately 15 g / min. After the lamination process was completed, the core was heated at 45°C for 30 minutes, then cooled to room temperature and extruded.

[0174] After the drying step was completed, the product was discharged and sieved to collect the fraction in the range of 200 to 450 μm.

[0175] Using the above procedure, cores of the following compositions were prepared: Core 4 Safinamide methanesulfonate 68.7% MCC100 24.8% PVP K90 4.3% Talc 2.2% Core 5 Safinamide methanesulfonate 70.9% MCC100 23.0% Hydroxypropyl methylcellulose 4.0% Talc 2.1% Core 6 Safinamide methanesulfonate 69.5% MCC100 24.1% PEG 6000 4.4% Talc 2.0%

[0176] Example 2: Core preparation: Dry lamination: a. Fluidized bed (rotor): The binder solution was prepared by adding the binder excipients to water at room temperature with continuous stirring until complete solubilization. The inert particles were placed in a fluidized bed (VFC-LAB3 with GXR-35 rotor insert, Freund Vactor) operated at 350 rpm and maintained at room temperature. Safinamide methanesulfonate was introduced into a K-tron pneumatic powder feed system and added to the fluidized bed at a flow rate of approximately 25 g / min. Simultaneously, the binder solution was sprayed at a flow rate of approximately 15 g / min. After the process was completed, the resulting cores were dried at 60°C for approximately 30 minutes. After the granulation process was completed, the product was discharged and sieved to collect the particle size fraction in the 200-450 μm range. Using the above procedure, cores with the following compositions were prepared: Core 10 Safinamide methanesulfonate 67.2% MCC100 26.0% PEG6000 4.8% Talc 2.0% Core 11 Safinamide methanesulfonate 68.0% MCC100 2.0% PVP K30 4.3% Talc 2.7% Core 12 Safinamide methanesulfonate 67.8% MCC100 24.9% Starch RX1500 5.2% Talc 2.1%

[0177] Example 3: Coating of the core a. Polymer Coating Composition: pH Dependent Safinamide methanesulfonate cores prepared according to the teachings of Examples 1 and 2 were loaded into a fluidized bed system (GPCG 1.1) and coated with a suspension of Eudragit® EPO and functional excipients. The coating process was carried out at a spray rate of 4-5 ml / min and a spray pressure of 2.0 bar, while maintaining the core temperature at approximately 30-35°C. After the deposition process, the particles were dried inside the fluidized bed at 45-50°C for approximately 30 minutes.

[0178] Table 6a: Composition of Eudragit® EPO coated cores [Table 6a]

[0179] b. Polymer Coating Composition: Cellulose Safinamide methanesulfonate cores prepared according to the teachings of Examples 1 and 2 were loaded into a fluidized bed system (GPCG 1.1) and coated with a suspension of ethyl cellulose / hydroxypropyl methylcellulose (Clear / Methocel® E5). The coating process was carried out at a spray rate of 7-10 ml / min and a spray pressure of 2.0 bar, while maintaining the temperature of the granulation at approximately 44-48°C. After the deposition process, the granulation was dried in the fluidized bed at 45-50°C for approximately 30 minutes.

[0180] Table 6b: Composition of ethylcellulose coated cores [Table 6b]

[0181] Example 4: Following the procedure described in Example 3, particles of the present invention were prepared having the following composition: particle 1 Core 1 52.5% Eudragit® EPO 31.5% Sodium dodecyl sulfate 2.5% Stearic acid 3.5% Talc 10.0% particle 2 Core 1 68.40% Surelease® Clear 26.90% Methocel® E5 4.70% particle 3 Core 1 63.90% Surelease® Clear 27.30% Methocel® E5 4.80% TEC 4.00% particle 4 Core 5 63.70% Surelease® Clear 22.50% Methocel® E5 9.70% TEC 4.10% particle 5 Core 11 66.20% Surelease® Clear 25.10% Methocel® E5 4.40% PEG 6000 4.30% particle 6 Core 1 80.00% Surelease® Clear 12.40% Methocel® E5 5.30% TEC 2.30% particle 7 Core 11 80.10% Surelease® Clear 15.00% Methocel® E5 2.70% TEC 2.20% particle 8 Core 4 81.60% Surelease® Clear 15.60% Methocel® E5 2.80%

[0182] Example 5: Preparation of an orally disintegrating tablet (ODT) containing multiple particles according to the present invention

[0183] Granules containing safinamide methanesulfonate and appropriate additional granular excipients prepared according to the teachings of Examples 3-4 were mixed in a rotary mixer (Cyclops Lab, IMA) for 20 minutes. The lubricant was then added to the mixer's container, and the resulting mixture was mixed for an additional 3 minutes. The mixture was then fed into an automatic rotary tablet press EA8 (Ronchi) to obtain biconvex round tablets with a diameter of 11 mm. The compression force was set at 10 kN, and the rotation speed was set at 45 rpm.

[0184] Table 7: Composition of ODT containing safinamide methanesulfonate [Table 7]

[0185] Example 6: Following the procedure described in Example 5, orally disintegrating tablets were prepared having the following composition: 1 tablet Particle 2 57.60% Mannitol 21.80% Starch 4.40% PEG 6000 3.70% Crospovidone 10.00% Magnesium stearate 2.50% Tablet 2 Particle 3 56.00% Mannitol 23.50% Starch 4.80% PEG 6000 3.20% Crospovidone 10.00% Magnesium stearate 2.50% Tablet 3 Particle 5 58.60% Mannitol 20.00% Starch 4.30% PEG 6000 3.80% Crospovidone 10.00% Magnesium stearate 2.50% 4 tablets Particle 8 53.80% Mannitol 25.10% Starch 5.10% PEG 6000 4.00% Crospovidone 9.60% Magnesium stearate 2.40%

[0186] Example 7: Preparation of an orodispersible powder containing multiple particles according to the present invention

[0187] Sachets were filled with the particles prepared according to the procedures described in Examples 3 and 4 to provide an orally soluble oral dosage formulation of safinamide methanesulfonate. The powder was filled into a tumbling mixer Cyclops Lab (IMA) and mixed with appropriate ultrafine excipients for 15 minutes, after which the powder was dispensed into sachets in net amounts of 1.0 g.

[0188] Table 8: Composition of orodispersible powder containing particles of safinamide [Table 8]

[0189] Example 8: Following the procedure described in Example 7, sachets were prepared with the following composition: Orally dispersible powder 1 Particle 1 36.6% Mannitol 38.0% Calcium carbonate 25.4% Orally dispersible powder 2 Particle 4 29.2% Mannitol 42.5% Calcium carbonate 28.3% Orally dispersible powder 3 Particle 5 29.3% Mannitol 42.4% Calcium carbonate 28.3%

[0190] Example 9: Sensory evaluation of the active ingredient safinamide To evaluate the unpleasant taste and irritation of the active pharmaceutical ingredient, safinamide methanesulfonic acid, an in vivo study was conducted using an amount of safinamide methanesulfonic acid equivalent to 100 mg of safinamide base.

[0191] In the sensory evaluation, two subjects were asked to hold the above amount of drug in their mouths without swallowing the drug mass.

[0192] Both subjects experienced an immediate bitter taste followed a few seconds later by a sensory profile that was characterized by an extremely bitter taste and a very strong stinging sensation.

[0193] After the test, the participants rinsed their mouths with plenty of drinking water, but five minutes later their tongues and palates were still sore.

[0194] The sensory evaluation was intended to identify any undesirable organoleptic properties of the active ingredients.

[0195] Example 10: Sensory evaluation of orally disintegrating tablets containing particles of safinamide: An in vivo study was conducted to evaluate taste masking of the active pharmaceutical ingredient (safinamide methanesulfonate) using orally disintegrating tablets prepared according to the teachings described in Example 6.

[0196] In the sensory evaluation, five subjects were asked to hold a tablet in their mouths for one minute or less until they perceived a certain taste, and to report the sensation they perceived using the following criteria. 1 = No unpleasant taste or irritation 2 = Bitter notes and some perceptible stinging 3 = Bitter and clearly perceptible irritation 4 = bitter and very pungent 5 = Extremely bitter and intolerably irritating

[0197] After holding the tablet in the mouth for 1 minute, participants were instructed to rinse their mouths with plenty of drinking water to avoid swallowing any boluses from the tablet.

[0198] Each assessment session was conducted in an environment where subjects were not affected by the presence of other subjects.

[0199] Table 9 shows the test results for the evaluation of orally disintegrating tablets containing particles of safinamide methanesulfonate according to the present invention.

[0200] Table 9: Sensory evaluation of ODT tablets containing safinamide: [Table 9]

[0201] Sensory evaluation tests confirmed that the undesirable organoleptic properties of the active ingredient were effectively masked and that administration of the active pharmaceutical ingredient in the form of an orally disintegrating tablet was possible.

[0202] Example 11: Sensory evaluation of orodispersible powders containing particles of safinamide methanesulfonate: An in vivo study was conducted to evaluate the taste masking of the active pharmaceutical ingredient (safinamide methanesulfonate) using an orodispersible powder prepared according to the teachings described in Example 8.

[0203] In the sensory evaluation, five subjects were asked to place 1 gram of the orally dispersible powder in their mouths, hold it in their mouths for 20 seconds (the time required to form a semi-fluid mass that could be swallowed), and report the sensation they perceived using the following scale: 1 = No unpleasant taste or irritation 2 = Bitter notes and some perceptible stinging 3 = Bitter and clearly perceptible irritation 4 = bitter and very pungent 5 = Extremely bitter and intolerably irritating

[0204] After holding the powder in the mouth for 20 seconds, participants were instructed to rinse their mouths with plenty of drinking water to avoid swallowing any lumps from the powder.

[0205] Each assessment session was conducted in an environment where subjects were not affected by the presence of other subjects.

[0206] Table 10 shows the test results for evaluating the orodispersible powder containing particles of safinamide methanesulfonate according to the present invention.

[0207] Table 10: Sensory evaluation of orally dispersible powders containing safinamide [Table 10]

[0208] Sensory evaluation tests confirmed that the unwanted organoleptic properties of the active ingredient were effectively masked and that administration of the active pharmaceutical ingredient in the form of an orodispersible powder was possible.

[0209] Example 12: Comparative test: Sensory evaluation of orally disintegrating tablets of Examples 5 and 6 of Chinese Patent Application No. 104546747 Comparative tests were carried out in vivo using orally disintegrating tablets prepared according to the teachings of Examples 5 and 6 of the cited Chinese Patent Application Publication No. 104546747.

[0210] The sensory evaluation was carried out as described above in Example 10 of the present invention.

[0211] The results of the comparative tests are shown in Tables 11 and 12 below.

[0212] Table 11: Sensory evaluation of orally disintegrating tablets containing safinamide according to Example 5 of CN'747 [Table 11]

[0213] Table 12: Sensory evaluation of orally disintegrating tablets containing safinamide according to Example 6 of CN'747 [Table 12]

[0214] Comparative tests confirmed the presence of undesirable organoleptic properties of the active ingredient (safinamide methanesulfonic acid) and the fact that said negative sensory notes were not at all masked by the orodispersible compositions of the cited documents.

[0215] Example 13: Comparative test: In vitro evaluation of taste masking of orally disintegrating tablets of Example 5 of Chinese Patent Application Publication No. 104546747: The taste-masking properties of orally disintegrating tablets prepared according to the teachings of Example 5 of the cited Chinese Patent Application No. 104546747 were evaluated by measuring the % release of the active ingredient when the dosage form was tested for solubility in artificial saliva at a pH of about 6.8, where a release of 10% or less within 1 minute after ingestion is considered satisfactory.

[0216] The results of the dissolution test are shown in Table 13 below, where a comparison was made with the % release of safinamide from orally disintegrating tablets prepared according to the teachings set forth in Example 6 of the present invention.

[0217] Table 13: Disintegration of orally disintegrating tablets containing safinamide mesylate [Table 13]

[0218] The above comparative studies confirmed that the problem of unfavourable organoleptic properties associated with the active ingredient safinamide or a pharmaceutically acceptable salt thereof was neither recognised nor addressed by the prior art, and the comparative studies provided evidence that in the absence of effective taste-masking of safinamide or a pharmaceutically acceptable salt thereof, orally disintegrating tablets of the prior art would result in a complete perception of the taste of the active ingredient by patients, together with an unacceptable dosage form, leading to patient refusal of treatment and consequent worsening clinical patterns.

Claims

1. An orally disintegrating tablet comprising a plurality of particles, wherein the plurality of particles comprises: a. A core containing safinamide or a pharmaceutically acceptable salt thereof b. a taste-masking polymer composition coated onto said core each including 1. An orally disintegrating tablet, wherein the core comprises inert particles layered with the safinamide or a pharmaceutically acceptable salt thereof in the presence of a binder, and the taste-masking polymer composition is present in an amount of 10 to 40% by weight and comprises a mixture of insoluble and water-soluble cellulose-based polymers.

2. 2. The orally disintegrating tablet of claim 1, wherein the particles have a particle size of 500 μm or less.

3. 3. The orally disintegrating tablet according to claim 1 or 2, wherein the core comprises safinamide methanesulfonate.

4. 2. The orally disintegrating tablet according to claim 1, wherein the binder is selected from povidone (PVP), polyethylene glycol (PEG), pregelatinized starch, hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, and mixtures thereof.

5. 2. The orally disintegrating tablet according to claim 1, wherein the inert particles are particles of microcrystalline cellulose.

6. 2. The orally disintegrating tablet of claim 1, wherein the taste-masking polymer composition is present in an amount of 20 to 40% by weight.

7. 10. The orally disintegrating tablet of claim 1, wherein the taste-masking polymer composition comprises a plasticizer.

8. 8. The orally disintegrating tablet of claim 7, wherein the plasticizer is present in an amount of at least 2% by weight.

9. An orally disintegrating tablet according to any one of claims 1 to 8, having the qualitative and quantitative composition shown in Table 5: (Table 5)

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