DESC:FIELD OF THE INVENTION
The present invention is related to the orodispersible pharmaceutical composition of safinamide comprising safinamide or its pharmaceutically acceptable salt thereof, ion exchange resin and one or more pharmaceutically acceptable excipients, wherein the said orodispersible pharmaceutical composition of safinamide is used for the treatment of Parkinson’s disease.

BACKGROUND OF THE INVENTION
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, which is estimated to affect 6.2 million people worldwide. In Europe, more than 1 million people live with Parkinson’s disease, whereas in the US, similarly almost 1 million people suffer from the disease. However, these figures may be considerably higher as many people may go undiagnosed. As the incidence of Parkinson’s disease rises significantly with age, and the life expectancy is getting higher, the prevalence of the disease is believed to rise dramatically in the near future – nearly 13 million people with Parkinson’s by 2040. The economic impact of the disease is enormous – the annual European cost is estimated at 13.9 € billion, whereas the annual US cost is estimated at $52 billion.

Parkinson’s disease is a progressive disorder, which can begin with mild stiffness and infrequent tremors, which progress over a period of ten or more years to frequent tremors and memory impairment, and ultimately, to uncontrollable tremors and dementia. The disease produces 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, safinamide, tranylcypromine; COMT inhibitors like entacapone, tolcapone; and glutamate antagonists like amantadine.

Unfortunately, such drug therapies frequently become less effective or ineffective over the time. In general, a PD patient may require multiple drugs in combination to extend the time period of efficacy of drug therapies.
Safinamide is a MAO-B inhibitor and is chemically described as N2-{4-[(3- fluorobenzyl)oxy]benzyl}-L-alaninamide.

Formula I

In Europe, the European Medicines Agency (EMA) approved Safinamide (XADAGO®) in February 2015, indicated for the treatment of adult patients with idiopathic Parkinson’s disease (PD) as add-on therapy to a stable dose of levodopa (L-dopa) alone or in combination with other PD medicinal products in mid-to late-stage fluctuating patients. XADAGO® is only available as immediate release conventional film coated tablets in 50 mg and 100 mg strength.

In the US, XADAGO® was approved in March 2017, for the indication of adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease (PD) experiencing “off” episodes and it is only available as immediate release conventional film coated tablets in 50 mg and 100 mg strength.

Immediate release conventional film coated tablets of XADAGO® need to be swallowed – meaning that patients in therapy should be able to perform the action of swallowing correctly. However, swallowing may prove difficult for some category of patients, for example, for elderly patients or pediatric patients, or for patients who barely cooperate with medical personnel because of progression of disabling diseases. In particular, patients suffering from Parkinson disease face swallowing difficulties, and it is known that more than 80% of Parkinson patients develop dysphagia during the course of the disease (see I.Suttrup. Dysphagia. 2016 Feb;31(1):24-32). Therefore, the development of pharmaceutical dosage forms in which swallowing is made easier is highly needed, especially in Parkinson’s disease field. In fact, according to clinical reports, 80% of physicians consider that pharmaceutical dosage forms having an easier swallowing way of administration would increase compliance and/or adherence of the treatment for Parkinsonian patients.

A particular solid pharmaceutical dosage form that rapidly disintegrates are orodispersible tablets (also named ODT: orally disintegrated tablet), which do not require water, are easier to swallow and hence can be consumed in situations where patients require an easy-to-administer dosage form.

There are disclosures in the prior art which attempt to obtain orodispersible compositions comprising safinamide. For example, CN111821268 patent application discloses an orally disintegrating tablet composition of safinamide mesylate and its process for preparation, wherein the said orally disintegrating tablet composition comprises of safinamide mesylate, silicified microcrystalline, croscarmellose sodium and magnesium stearate. CN106667940 patent application discloses a safinamide dispersible tablet composition and its process for preparation, wherein the said safinamide dispersible tablet contains safinamide-hydrophilic material blend, filler, disintegrants, binding agent, lubricant and correctives in addition. CN104546747 patent application discloses, in Example 5, an orodispersible tablet that contains 50 mg of safinamide mesylate, a diluent, a water-soluble polymeric binder, a disintegrant, a flavoring agent and a lubricant.

However, many of the aforementioned prior art documents involve more or less complex manufacturing processing steps, thus making the overall process lengthy and with high cost. Furthermore, those prior art manufacturing techniques may require more or less significant chemical and/or physical modifications of safinamide as the active ingredient, which may have an impact in the stability of the finished dosage form and the bioavailability of safinamide.

Although orodispersible pharmaceutical dosage forms are advantageous for Parkinsonian patients, they pose a considerable challenge, as orodispersible compositions allow direct contact between the active ingredient and the taste buds of patient’s tongue and other receptors of the oral cavity that contribute to the effect of palatability. In this regard, it is known that safinamide in the form of free base and/or in the form of pharmaceutically acceptable salt, such as safinamide mesylate, has a very unpleasant taste, with a bitter component that it is decidedly very intense. Additionally, safinamide and pharmaceutically acceptable salts thereof have a tendency to irritate the mucosae of the oropharynx.

The aforesaid prior art documents are either silent about the technical problem of providing orodispersible safinamide compositions which provide adequate organoleptic characteristics to Parkinsonian patients, or alternatively, those prior art documents simply use flavoring agents, which indeed are not sufficient for providing effective masking of the unpleasant and intense bad taste of safinamide and pharmaceutically acceptable salts thereof.

Prior art EP3558261 patent and EP3703665 patent application disclose particles including a core comprising safinamide (or a pharmaceutically acceptable salt) and a binder, wherein said particles are coated by a polymer composition. Those safinamide coated particles are compressed into orodispersible tablets, which allegedly provide excellent organoleptic properties, thus providing an effective taste masking of safinamide and pharmaceutically acceptable salts thereof.

However, both prior art EP3558261 and EP3703665 involve more or less complex manufacturing processing steps, thus making the overall process lengthy and with high cost. In particular, manufacturing method disclosed in EP3558261 requires the use of Rotocube 60 IMA (which makes a dry agglomeration by rotary granulator- single pot) followed by particle coating in Fluid bed system (FBP). The use of this machinery makes the manufacturing process very lengthy and complex. EP3703665 requires the use VFC-LAB3 equipped with a rotor insert GXR-35 Freund Vector (which makes a wet layering by using fluid bed system with rotor insert assembly) followed by particle coating in Fluid bed system (FBP). Again, the use of this machinery is not cost- effective for manufacturing of orodispersible safinamide compositions.

Furthermore, stability of pharmaceutical compositions of safinamide and its pharmaceutically acceptable salts is known to be a matter of concern in the prior art. For example, EP2474521 patent discloses that large scale preparations of safinamide contained the undesired impurity (S)-2-[3-(3-fluorobenzyl)-4-(3- fluorobenzyloxy)-benzylamino]propenamide (referred to as compound (IIa) or also referred to as “dimer impurity”), which is highly cytotoxic when compared to safinamide mesylate. In addition to that, it is crucial to obtain pharmaceutical compositions of safinamide and its pharmaceutically acceptable salts with the lowest total amount of impurities as possible. In Europe, approved posology for XADAGO® requires starting the treatment at 50 mg of safinamide per day (or equivalent amount for safinamide mesylate), and the daily dose may be increased to 100 mg of safinamide per day (or equivalent amount for safinamide mesylate) on the basis of individual clinical need. Consequently, avoidance of safinamide dimer impurity, as well as obtaining safinamide compositions having a total amount of impurities as low as possible is of paramount importance in order to maintain efficacy and safety of safinamide pharmaceutical compositions, and in particular, to orodispersible safinamide compositions, in the treatment of Parkinson’s disease. In this regard, aforementioned prior art EP3558261 and EP3703665 disclose that although the person skilled in the art is aware of other techniques for masking bad taste/irritating taste, those other techniques are based on a strong chemical interaction between the active ingredients with certain molecules and/or pharmaceutically acceptable excipients. However, those other techniques involve significant chemical and/or physical modifications of the active ingredients, which influence the stability of said actives.

As mentioned above, XADAGO® is commercially available only in the form of immediate release conventional film coated tablets. When developing new orodispersible pharmaceutical dosage forms, it shall be borne in mind that it is a standard requirement by regulatory agencies to prove strict bioequivalence criteria of said newly developed orodispersible pharmaceutical dosage form versus the conventional film coated tablet of the reference product. Therefore, said requirement of bioequivalence poses an additional challenge for the development of new orodispersible tablets. Prior art EP3558261 and EP3703665 also disclose that other techniques (rather manufacturing particles including a core comprising safinamide and a binder, wherein said particles are coated by a polymer composition) for masking bad taste/irritating taste greatly influence the onset of action and bioavailability of safinamide, and therefore, the person skilled in the art understands that these other techniques are not eligible for obtaining safinamide orodispersible pharmaceutical dosage forms with kinetics equivalent to the dosage form currently available in the market (i.e. XADAGO®).

Therefore, in view of the prior art, there is need to provide for safinamide orodispersible pharmaceutical dosage forms having overall improved characteristics. In this regard, there is room for improvement in the prior art for providing safinamide orodispersible compositions having improved disintegration time, stability, friability and hardness, while having at the same time adequate taste masking of safinamide and pharmaceutically acceptable salts thereof, thus providing suitable organoleptic characteristics for Parkinsonian’s patients being administered with those orodispersible safinamide compositions. Furthermore, there is the need to provide efficient and cost-effective manufacturing processes for obtaining said safinamide orodispersible pharmaceutical dosage forms. Additionally, said safinamide orodispersible pharmaceutical dosage forms must be stable enough to comply with strict regulatory requirements in terms of impurities, and in particular, those safinamide orodispersible pharmaceutical dosage forms must avoid or keep at the lowest possible values the formation of cytotoxic impurities related to safinamide as well as total amount of impurities. Finally, there is also the need to provide for safinamide orodispersible pharmaceutical dosage forms which, from a regulatory standpoint, exhibit reliable and adequate dissolution profile of safinamide for resulting in being bioequivalent to XADAGO® immediate-release film-coated tablets.

Indeed, despite the attractiveness of fast disintegrating dosage forms for Parkinsonian patients, there has not been neither in Europe nor in the US, up to date, any commercially available orodispersible dosage form comprising safinamide, which highlights the difficult task of formulating safinamide in orodispersible form.

The above-mentioned objects/problems were surprisingly solved according to the present invention. In particular, the inventors have been capable of designing new orodispersible 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 trapped within the matrix, which has been surprisingly found to provide a new way of stabilizing safinamide or a pharmaceutically acceptable salt, therefore preventing formation of degradation products over time; e.g. mainly undesired impurity (S)- 2-[3-(3-fluorobenzyl)-4-(3-fluorobenzyloxy)-benzylamino]propenamide (referred to as “dimer impurity”), as well as providing low levels of total impurities. The orodispersible pharmaceutical solid dosage forms of the present invention comply with the criteria of impurities limit specifications required by the European medicine regulatory agencies.

Furthermore, the inventors have also surprisingly found that the orodispersible pharmaceutical solid dosage forms of the present invention provide an efficient and adequate taste masking of safinamide and pharmaceutically acceptable salts thereof, thus providing suitable organoleptic characteristics for Parkinsonian’s patients being administered with the orodispersible safinamide compositions of the present invention.

Even more, the inventors have surprisingly found that orodispersible pharmaceutical dosage forms of the invention also have overall improved technical characteristics as summarized hereinafter. In particular, safinamide orodispersible pharmaceutical dosage forms of the invention have adequate hardness and low friability, which are important advantages in order to withstand physical shocks along manufacturing process and for storage and handling transportation. The orodispersible compositions of the invention indeed satisfactorily disintegrate rapidly, in particular in less than three minutes, as required by the European Pharmacopeia, edition 10.0, page 939.

Furthermore, despite the teaching away comments from EP3558261 and EP3703665, the inventors have surprisingly found that the safinamide orodispersible pharmaceutical dosage forms of the invention, wherein safinamide or a pharmaceutically acceptable salt thereof is trapped within the matrix formed with a pharmaceutically acceptable polymer, allow to provide reliable and adequate dissolution profile of safinamide, thus releasing safinamide in a sufficiently equivalent manner for being bioequivalent to immediate-release film-coated tablets of XADAGO® (i.e. showing comparable pharmacokinetic parameters on bioavailability such as Cmax, Tmax, and AUC0-t).

Hence, the present inventors have unexpectedly found that safinamide orodispersible pharmaceutical dosage forms of the invention comprising a pharmaceutically acceptable polymer suitable for forming a matrix with safinamide or a pharmaceutically acceptable salt thereof, wherein safinamide or a pharmaceutically acceptable salt thereof is trapped within the matrix, interact with and stabilize, both physically and chemically, safinamide or pharmaceutically acceptable salts thereof, thus serving as an appropriate taste-masking technique for the obtention of a safinamide orodispersible composition which not only disintegrates in the oral cavity and presents good organoleptic characteristics and low levels of total impurities but also has equivalent in vivo pharmacokinetics to safinamide film-coated tablets (XADAGO®).

SUMMARY OF THE INVENTION
The present invention relates to an orodispersible pharmaceutical composition of safinamide comprising safinamide or its 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 trapped within the matrix, and wherein the said orodispersible pharmaceutical composition of safinamide is used for the treatment of Parkinson’s disease.

Thus, the primary object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide comprising safinamide or its 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 its pharmaceutically salt thereof is trapped within the matrix.

Another object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide comprising safinamide or its 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 its pharmaceutically salt thereof is trapped within the matrix, and wherein the pharmaceutically acceptable polymer suitable for forming a matrix with safinamide or a pharmaceutically acceptable salt thereof is an ion exchange resin.

Another object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide comprising safinamide or its 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 its pharmaceutically salt thereof is trapped within the matrix, wherein the amount of safinamide or a pharmaceutically acceptable salt thereof per dosage form is of from 5 to 150 mg, preferably of from 25 to 125 mg, and more preferably of from 50 to 100 mg, based on the weight of safinamide free base.

Another object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide comprising safinamide or its 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 its pharmaceutically salt thereof is trapped within the matrix, wherein the solid dosage form is an orodispersible tablet.

Another object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide comprising safinamide or its 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 its pharmaceutically salt thereof is trapped within the matrix, wherein the safinamide pharmaceutically acceptable salt thereof is safinamide mesylate.

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

Another object of the present invention is to provide an orodispersible 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 trapped within the matrix, wherein the pharmaceutically acceptable polymer suitable for forming a matrix with safinamide or a pharmaceutically acceptable salt thereof is an ion exchange resin, wherein the ion exchange resin is in a weight-to-weight ratio of safinamide or pharmaceutically acceptable salt thereof to the ion exchange resin of from 1:0.05 to 1:10, preferably of from 1:0.1 to 1:5; more preferably of from 1:0.25 to 1:3, and even more preferably of from 1:0.5 to 1:2, and wherein the ion exchange resin is selected from the group of sodium or potassium or magnesium or calcium salts or partial sodium or potassium or 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.

Another object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide comprising safinamide or its 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 its pharmaceutically salt thereof is trapped within the matrix, wherein the ion exchange resin is a methacrylic acid-divinylbenzene copolymer.

Another object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide comprising safinamide or its 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 its pharmaceutically salt thereof is trapped within the matrix, wherein the methacrylic acid-divinylbenzene copolymer is polacrilin potassium.

Another object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide comprising safinamide or its 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 trapped within the matrix, wherein at least 85% w/w of safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, preferably at least 90% w/w of safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, more preferably at least 95% w/w of safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, and even more preferably at least 97% w/w of safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer.

Another object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide comprising safinamide or its 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 its pharmaceutically salt thereof is trapped within the matrix, wherein the said one or more pharmaceutically acceptable excipients is selected from one or more diluents, one or more binders, one or more disintegrants, one or more flavouring agent, one or more sweetener, one or more solvents, one or more lubricants or the mixtures thereof.

Another object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide comprising safinamide or its 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 its pharmaceutically salt thereof is trapped within the matrix, wherein said one or more disintegrants is one or more intragranular disintegrants.

Another object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide comprising safinamide or its 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 excipient, wherein safinamide or its pharmaceutically salt thereof is trapped within the matrix, and wherein safinamide is released at least 90% at 10 minutes when the said orodispersible composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in 0.1 M Hydrochloric acid in 900 mL of volume.

Another object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide comprising safinamide or its 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 its pharmaceutically salt thereof is trapped within the matrix, and wherein safinamide is released at least 50% at 10 minutes when the said orodispersible composition is subjected to the dissolution test using USP Type 2 apparatus method at a rotation of 50 rpm in Phosphate buffer pH 6.8 in 900 mL of volume.

Another object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide according to the invention, wherein the said composition has a total amount of impurities related to safinamide below 0.50% w/w, more preferably below 0.25% w/w, and even more preferably below 0.1% w/w, after being stored under the storage conditions of 40 °C temperature and 75% relative humidity 1 month in Alu Alu Blister Pack.

Another object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide according to the invention, wherein the said composition has an amount of the dimer impurity related to safinamide below 0.05% w/w, preferably below 0.03% w/w and more preferably equal to or below 0.025% w/w, after being stored under the storage conditions of 40 °C temperature and 75% relative humidity 1 month in Alu Alu Blister Pack.

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

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

Another object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide according to the invention, wherein after an oral single-dose administration of the dosage form, wherein after an oral single-dose administration of the dosage form, safinamide or a pharmaceutically acceptable salt thereof, equivalent to 100 mg of safinamide, exhibits an area under the time/plasma concentration curve from time 0 to 72 hours (AUC (0-72)) of from 18000 ng/mL to 28600 ng/mL.

Another object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide according to the invention, wherein said orodispersible pharmaceutical dosage form is disintegrated in less than 3 minutes, preferably in less than 2 minutes, and more preferably in less than 1 minute, wherein the disintegration test was performed using a European Pharmacopeia disintegration apparatus A, placing the dosage form in water having pH=7 at 37 °C and 30 cycles per minute.

Another object of the present invention is to provide a process for the preparation of the orodispersible pharmaceutical solid dosage form as defined according to the invention, which comprises:
(i) dissolving safinamide or a pharmaceutically acceptable salt thereof in water until a clear solution is obtained,
(ii) adding to the solution of step (i) an ion exchange resin until a homogeneous suspension is achieved,
(iii) separately providing 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 fluidized bed processor, to obtain wet granules,
(v) drying the wet granules obtained in step (iv) using fluidized bed processor, thus obtaining dried granules,
(vi) mixing the dry granules obtained in step (v) with extragranular disintegrants, one or more lubricants and optionally with sweeteners and flavouring agents,
(vii) compressing the mixture obtained in step (vi) to form an orodispersible pharmaceutical solid dosage form.

Another object of the present invention is to provide a process for the preparation of the orodispersible pharmaceutical solid dosage form as defined according to the invention, which comprises:
(i) dissolving safinamide or a pharmaceutically acceptable salt thereof in water until a clear solution is obtained,
(ii) adding to the solution of step (i) an ion exchange resin until a homogeneous suspension is achieved,
(iii) adding to the solution of step (ii) a binder,
(iv) separately providing one or more disintegrants or a mixture thereof, and a diluent,
(v) granulating the mixture of step (iv) with the suspension of step (iii) using a fluidized bed processor, to obtain wet granules,
(vi) drying the wet granules obtained in step (v) using fluidized bed processor, thus obtaining dried granules,
(vii) mixing the dry granules obtained in step (vi) with extragranular disintegrants, one or more lubricants and optionally with sweeteners and flavouring agents,
(viii) compressing the mixture obtained in step (vii) to form an orodispersible pharmaceutical solid dosage form.

Another object of the present invention is to provide an orodispersible pharmaceutical composition of safinamide according to the invention for use in the treatment of adult patients with idiopathic Parkinson’s disease (PD) as add-on therapy to a stable dose of levodopa (L-dopa) alone or in combination with other PD medicinal products in mid-to late-stage fluctuating patients.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 shows the mean plasma concentration for 72 hours after an oral single-dose administration of: a) the orodispersible tablet according to Example 5 of the present invention, administered with water (Test-T1, points are depicted in square form); b) the orodispersible tablet according ot Example 5 of the present invention, administered without water (Test-T2, points are depicted in triangle form); and c) the 100 mg tablet of XADAGO® (Reference, points are depicted in circles).

DETAILED DESCRIPTION
Unless otherwise indicated, terms in this specification are intended to have their ordinary meaning in the relevant art.

The present invention is related to an orodispersible pharmaceutical composition of safinamide comprising safinamide or its pharmaceutically acceptable salt thereof, ion exchange resin and one or more pharmaceutically acceptable excipients.

The term “safinamide” used throughout the specification refers to not only their base per se, but also their other pharmaceutically acceptable salts, pharmaceutically acceptable solvates, pharmaceutically acceptable hydrates, pharmaceutically acceptable enantiomers, pharmaceutically acceptable derivatives, pharmaceutically acceptable polymorphs and pharmaceutically acceptable prodrugs thereof.

The term “pharmaceutically acceptable” means salt, carriers, excipients, and other formulation ingredients that are compatible with all other pharmaceutical ingredients of a composition and are not deleterious to an individual treated with the said composition.

The term “orodispersible tablet” as used herein is defined in accordance with the European Pharmacopeia, edition 10.0, page 939 as an uncoated tablet intended to be placed in the mouth where it disperses rapidly before being swallowed, more precisely orodispersible tablets disintegrate within three minutes in the disintegration test. In accordance with this definition the term orodispersible tablet is intended to be a synonym of solid oral dosage forms named as orodispersible tablet, orally disintegrating or disintegrated tablet (ODT), fast disintegrating tablet, fast dissolving tablet and chewable tablet, amongst others.

The term “polymer” as used herein is defined as any pharmaceutically acceptable polymer suitable for forming a matrix with safinamide or a pharmaceutically acceptable salt thereof that interact with and stabilize, both physically and chemically, safinamide or pharmaceutically acceptable salts thereof, thus serving as an appropriate taste-masking excipient for the obtention of a safinamide orodispersible composition which not only disintegrates in the oral cavity and presents good organoleptic characteristics and low levels of total impurities but also has equivalent kinetics to safinamide film-coated tablets (XADAGO®). In particular, the polymer is able to form a matrix that allows safinamide or a pharmaceutically acceptable salt thereof to be trapped within said formed matrix The term polymer as used herein comprises 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, amongst others.

Polymers suitable for forming a matrix with safinamide or a pharmaceutically acceptable salt thereof according to this invention are preferably not those selected from the group consisting of: disintegrants such as croscarmellose sodium, HMPC, crosslinked sodium carboxymethyl cellulose and sodium carboxymethyl starch, Parteck ODT (combination of 93% spray-granulated mannitol and 5.4% croscarmellose sodium), Methacrylate-Copolymer Eudragit EPO, N-vinylpyrrolidone of crospovidone and copovidone, polyvinyl alcohol, polyvinyl acetate and/or their copolymers and Pharmabust C1 (co-spray dried sugar alcohol (Mannitol, Sorbitol) / disintegrant (Copovidone) / flow agent (silicon dioxide)). In other words, in the context of the present invention, the term “polymer” suitable for forming a matrix most preferably does not encompass those in the group hereinabove mentioned in this paragraph. This is so as they are less suitable to provide stable safinamide compositions. In preferred embodiments these polymers are therefore not contained.

The term “ion exchange resin” as used herein is defined as any pharmaceutically acceptable water insoluble polymer that can exchange their mobile ions with the ions in the surrounding medium. The term as used herein comprises sodium or potassium or magnesium or calcium or iron or zinc salts or partial 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, amongst others. The term as used herein also comprises protonated sulfonate polystyrene polymers, protonated sulfonated styrene-divinylbenzene copolymers, protonated polymethacrylic acid polymers, protonated methacrylic acid- divinylbenzene copolymers, amongst others.

The term “cation exchange resin” as used herein is defined as any pharmaceutically acceptable water insoluble polymer that can exchange their mobile cations with the cations in the surrounding medium. The term as used herein comprises sodium or potassium or magnesium or calcium salts or partial sodium or potassium or magnesium or calcium salts of sulfonated polystyrene polymers, sulfonated styrene-divinylbenzene copolymers, polymethacrylic acid polymers, methacrylic acid-divinylbenzene copolymers, amongst others. The term as used herein also comprises protonated sulfonated polystyrene polymers, protonated sulfonated styrene-divinylbenzene copolymers, protonated polymethacrylic acid polymers, protonated methacrylic acid-divinylbenzene copolymers, amongst others.

The term “acidic cation exchange resin” as used herein, is defined as any pharmaceutically acceptable water insoluble polymer that can exchange their mobile cations with the cations in the surrounding medium and have acidic functional groups such as sulfonic or carboxylic groups. The term as used herein comprises sodium or potassium or magnesium or calcium salts or partial sodium or potassium or magnesium or calcium salts of sulfonated polystyrene polymers, sulfonated styrene-divinylbenzene copolymers, amongst others. The term as used herein also comprises protonated sulfonated polystyrene polymers, protonated sulfonated styrene-divinylbenzene copolymers, protonated polymethacrylic acid polymers, protonated methacrylic acid-divinylbenzene copolymers, amongst others.

The term “weakly acidic cation exchange resin” as used herein, is defined as any pharmaceutically acceptable water insoluble polymer that can exchange their mobile cations with the cations in the surrounding medium and have weakly acidic functional groups such as carboxylic groups. The term as used herein comprise sodium or potassium or magnesium or calcium salts or partial sodium or potassium or magnesium or calcium salts of polymethacrylic acid polymers, methacrylic acid-divinylbenzene copolymers, amongst others.

The term “polacrilin potassium” as used herein is defined as a partial potassium salt of a methacrylic acid-divinylbenzene copolymer wherein a weakly acidic salt is formed from the carboxylic acid functional groups of the methacryclic acid. Hereinafter, the term “partial polacrilin potassium” is commercialized under several commercial names such as Purolite® C115KMR, Amberlite® IRP88, amongst others.

The term “polacrilin sodium” as used herein is defined as a partial sodium salt of a sulfonated styrene-divinylbenzene copolymer wherein an acidic salt is formed from the sulfonic acid functional groups of the styrene. Hereinafter, the term “partial polacrilin sodium” is commercialized under several commercial names such as Purolite® C100NaMR, amongst others.

The term “matrix” as used herein is defined as the combination of a polymer and safinamide or pharmaceutically acceptable salts thereof, wherein the safinamide or the pharmaceutically acceptable salts thereof are bound to the polymer by intermolecular forces such as electrostatic interactions, hydrogen bonding and van der Waal forces, amongst others. Apparently due to these forces the matrix allows safinamide or a pharmaceutically acceptable salt thereof to be trapped within said formed matrix. Particularly, wherein the polymer is an ion exchange resin, the safinamide or pharmaceutically acceptable salts thereof are primarily bound by electrostatic interactions. More particularly, wherein the polymer is a cation exchange resin, safinamide or pharmaceutically acceptable salts thereof is primarily bound by electrostatic interactions to the negatively charged functional groups of the cation exchange resin. More particularly, wherein the polymer is an acidic cation exchange resin, safinamide or pharmaceutically acceptable salts thereof is primarily bound by electrostatic interactions to the negatively charged acidic functional groups of the acidic cation exchange resin. Even more particularly, wherein the polymer is polymethacrylic acid polymer, safinamide or pharmaceutically acceptable salts thereof is primarily bound by electrostatic interactions to the negatively charged carboxylic acid groups of the polymethacrylic acid polymer.

The term “trapped within the matrix” means that basically all of the safinamide or the pharmaceutically acceptable salt thereof is contained within the matrix. In other words, basically no safinamide or the pharmaceutically acceptable salt thereof is present outside the matrix. In this way the improved dissolution and disintegration characteristics of the orodispersible solid dosage form can be obtained. “Basically 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. It is preferred that basically all of the safinamide or the pharmaceutically acceptable salt thereof is contained within the matrix homogeneously. In other words, safinamide or the pharmaceutically acceptable salt thereof contained within the matrix is distributed throughout the matrix uniformly.

The term “stable” as used throughout the specification, refers to a pharmaceutical composition in which the active pharmaceutical ingredient safinamide is present in an amount of at least 90% of the original label specified amount for each such ingredient during specific storage conditions.

The term “specific storage conditions” as used throughout the specification, refers to the pharmaceutical composition of present invention stored for at least 1 month at 40 °C temperature and 75% relative humidity in Alu Alu Blister Pack.

The term “disintegrate” as used herein is defined as the action whereby a solid dosage form is brought from a solid state to a state of complete disintegration.
In accordance with the present invention, the term “about” shall mean a variation up to 10% (plus or minus 10%) of the particular term.

The term “friability” as used herein refers to the tendency for a tablet to chip, crumble or break during handling. The test of friability is carried out following the guidelines of the European Pharmacopeia, edition 10.0, pp. 336-337. A maximum loss of mass not greater than 1.0% is considered acceptable for most products.

In accordance with the present invention, an assay value of safinamide in pharmaceutical composition of safinamide is within the limits of 95% to 105% after stability study according to ICH guidelines which is comparable when compared with reference product XADAGO®.

In an embodiment, the orodispersible pharmaceutical solid dosage form of the invention comprises 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 the safinamide or a pharmaceutically acceptable salt thereof is trapped within the matrix.

In an embodiment, the orodispersible pharmaceutical solid dosage form of the invention comprises 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 trapped within the matrix, wherein the pharmaceutically acceptable polymer suitable for forming a matrix with safinamide or a pharmaceutically acceptable salt thereof is an ion exchange resin.

In an embodiment, the orodispersible pharmaceutical solid dosage form of the invention comprises 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 trapped within the matrix, wherein the pharmaceutically acceptable polymer suitable for forming a matrix with safinamide or a pharmaceutically acceptable salt thereof is an ion exchange resin, wherein the ion exchange resin is in a weight-to-weight ratio of safinamide or pharmaceutically acceptable salt thereof to the ion exchange resin of from 1:0.05 to 1:10, preferably of from 1:0.1 to 1:5; more preferably of from 1:0.25 to 1:3, and even more preferably of from 1:0.5 to 1:2.

In a preferred embodiment, the orodispersible pharmaceutical solid dosage form of the invention comprises 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 trapped within the matrix, wherein the pharmaceutically acceptable polymer suitable for forming a matrix with safinamide or a pharmaceutically acceptable salt thereof is an ion exchange resin, wherein the ion exchange resin is in a weight-to-weight ratio of safinamide or pharmaceutically acceptable salt thereof to the ion exchange resin of from 1:0.05 to 1:10, preferably of from 1:0.1 to 1:5; more preferably of from 1:0.25 to 1:3, and even more preferably of 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 polacrilin potassium.

In a preferred embodiment, the orodispersible pharmaceutical solid dosage form of the invention comprises 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 trapped within the matrix, wherein at least 85% w/w of safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, preferably at least 90% w/w of safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, more preferably at least 95% w/w of safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, and even more preferably at least 97% w/w of safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer.

In a preferred embodiment, the orodispersible pharmaceutical solid dosage form of the invention comprises 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 trapped within the matrix, wherein the pharmaceutically acceptable polymer suitable for forming a matrix with safinamide or a pharmaceutically acceptable salt thereof is an ion exchange resin, wherein the ion exchange resin is in a weight-to-weight ratio of safinamide or pharmaceutically acceptable salt thereof to the ion exchange resin of from 1:0.05 to 1:10, preferably of from 1:0.1 to 1:5; more preferably of from 1:0.25 to 1:3, and even more preferably of from 1:0.5 to 1:2, wherein at least 85% w/w of safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, preferably at least 90% w/w of safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, more preferably at least 95% w/w of safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, and even more preferably at least 97% w/w of safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer.

In a more preferred embodiment, the orodispersible pharmaceutical solid dosage form of the invention comprises 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 trapped within the matrix, wherein the pharmaceutically acceptable polymer suitable for forming a matrix with safinamide or a pharmaceutically acceptable salt thereof is an ion exchange resin, wherein the ion exchange resin is in a weight-to-weight ratio of safinamide or pharmaceutically acceptable salt thereof to the ion exchange resin of from 1:0.05 to 1:10, preferably of from 1:0.1 to 1:5; more preferably of from 1:0.25 to 1:3, and even more preferably of 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 polacrilin potassium, wherein at least 85% w/w of safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, preferably at least 90% w/w of safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, more preferably at least 95% w/w of safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer, and even more preferably at least 97% w/w of safinamide or pharmaceutically acceptable salt thereof present in the orodispersible pharmaceutical solid dosage form is trapped within the matrix formed with the pharmaceutically acceptable polymer.

In an embodiment, the orodispersible pharmaceutical dosage form comprises 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 the safinamide or a pharmaceutically salt thereof is trapped within the matrix, wherein the said one or more pharmaceutically acceptable excipients are selected from one or more diluents, one or more binders, one or more disintegrants, one or more flavouring agent, one or more sweetener, one or more solvents, one or more lubricants or the mixtures thereof.

The term “diluent” as used herein is defined as a pharmaceutically acceptable excipient that is used as diluent in pharmaceutical compositions. The term “diluent” comprises one or combinations of two or more selected from the group of mannitol, maltol, sorbitol, maltitol, xylitol, isomalt, erythritol, lactose, preferably lactose monohydrate, starch and its derivatives, cellulose and its derivatives, in particular microcrystalline cellulose or mixture thereof, more preferably mannitol and microcrystalline cellulose. The diluent can be present in a concentration of from about 10% to about 40% by weight of the total weight of the composition.

The term “lubricant” as used herein is defined as a pharmaceutically acceptable excipient that is used as lubricant in pharmaceutical compositions. The term “lubricant” comprises one or combinations of two or more selected from the group of talc, sodium benzoate, sodium stearyl fumarate, calcium stearate, magnesium stearate, zinc stearate, glyceryl behenate, stearic acid and glyceryl monostearate or mixture thereof, more preferably sodium stearyl fumarate and magnesium stearate. The lubricant can be present in a concentration of from about 0.5% to about 2% by weight of the total weight of the composition.

The term “binder” as used herein is defined as a pharmaceutically acceptable excipient that is used as binder in pharmaceutical compositions. The term “binder” comprises one or combinations of two or more selected from the group of polyvinylpyrrolidone, povidone, copovidone, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, maize starch or mixture thereof, more preferably hydroxypropyl methyl cellulose. The binder can be present in a concentration of from about 1% to about 5% by weight of the total weight of the composition.

The term “disintegrant” as used herein is defined as a pharmaceutically acceptable excipient that is used as disintegrant in pharmaceutical compositions. The term “disintegrant” comprises one or combinations of two or more selected from the group of croscarmellose sodium, crospovidone, carmellose sodium, carmellose calcium, corn starch, sodium starch glycolate, pregelatinized starch or mixture thereof, more preferably crospovidone and croscarmellose sodium. The disintegrant can be present in a concentration of from about 5% to about 15% by weight of the total weight of the composition.

The term “flavouring agent” as used herein is defined as a pharmaceutically acceptable excipient that is used as flavouring agent in pharmaceutical compositions. The term “flavouring agent” comprises one or combinations of two or more selected from the group of cherry, raspberry, apricot, pear, strawberry, bitter masker, pineapple, lemon, honey, mint garden, orange, peppermint, menthol, black currant, vanilla, banana, red fruits, wild berries and caramel flavor, more preferably vanilla flavour. The flavouring agent can be present in a concentration of from about 0.5% to about 2% by weight of the total weight of the composition.

The term “sweetener” as used herein is defined as a pharmaceutically acceptable excipient that is used as sweetener in pharmaceutical compositions. The term “sweetener” comprises one or combinations of two or more selected from the group of aspartame, potassium acesulfame, sodium saccharinate, neohesperidine dihydrochalcone, sucralose, sucrose, fructose or monoammonium glycyrrhizinate mixture thereof, more preferably acesulfame potassium. The sweetener can be present in a concentration of from about 0.5% to about 2% by weight of the total weight of the composition.

The term “solvent” as used herein is defined as a pharmaceutically acceptable excipient that is used as solvent in pharmaceutical compositions. The term “solvent” comprises one or combinations of two or more selected from the group of purified water, dichloromethane, isopropyl alcohol or mixtures thereof.

In an embodiment, after an oral single-dose administration of the orodispersible pharmaceutical solid dosage form of the present invention under fasting conditions, safinamide or a pharmaceutically acceptable salt thereof, equivalent to 100 mg of safinamide, exhibits a time to maximum plasma concentration (Tmax) of from 3 h to 6 h. In a preferred embodiment, after an oral single-dose administration of the orodispersible pharmaceutical solid dosage form of the present invention under fasting conditions, safinamide or a pharmaceutically acceptable salt thereof, equivalent to 100 mg of safinamide, exhibits a time to maximum plasma concentration (Tmax) of from 4 h to 5 h. The term "Tmax" refers to the time in hours when Cmax is achieved following an oral single-dose administration of the composition of the present invention under fasting conditions.

In an embodiment, after an oral single-dose administration of the orodispersible pharmaceutical solid dosage form of the present invention under fasting conditions, safinamide or a pharmaceutically acceptable salt thereof, equivalent to 100 mg of safinamide, exhibits a maximum plasma concentration (Cmax) of from 660 ng/mL to 920 ng/mL The term "Cmax" refers to the maximum concentration of safinamide in the blood following an oral single-dose administration of the composition under fasting conditions.

In an embodiment, after an oral single-dose administration of the orodispersible pharmaceutical solid dosage form of the present invention under fasting conditions, safinamide or a pharmaceutically acceptable salt thereof, equivalent to 100 mg of safinamide, exhibits an area under the time/plasma concentration curve from time 0 to 72 hours (AUC (0-72)) of from 18000 µg.h/mL to 28600 µg.h/mL. The term “AUC” refers to the area under the time/plasma concentration curve after an oral single-dose administration of the composition of the invention. “AUC0-t” denotes the area under the plasma concentration versus time curve from time 0 to time t, wherein t represents 72 hours.

In an embodiment, the orodispersible pharmaceutical solid dosage form comprises 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 said solid dosage form has disintegrating time of not more than 3 minutes.

In an embodiment, the process for the preparation of the orodispersible pharmaceutical solid dosage form of the invention comprises:
(i) dissolving safinamide or a pharmaceutically acceptable salt thereof in water until a clear solution is obtained,
(ii) adding to the solution of step (i) an ion exchange resin until a homogeneous suspension is achieved,
(iii) separately providing 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 fluidized bed processor, to obtain wet granules,
(v) drying the wet granules obtained in step (iv) using fluidized bed processor, thus obtaining dried granules,
(vi) mixing the dry granules obtained in step (v) with extragranular disintegrants, one or more lubricants and optionally with sweeteners and flavouring agents,
(vii) compressing the mixture obtained in step (vi) to form an orodispersible pharmaceutical solid dosage form.

In another embodiment, one of the processes for preparation of the pharmaceutical composition of safinamide according to the present invention comprises following steps:
(i) dissolving safinamide or a pharmaceutically acceptable salt thereof in water until a clear solution is obtained,
(ii) adding to the solution of step (i) an ion exchange resin until a homogeneous suspension is achieved,
(iii) adding to the solution of step (ii) a binder,
(iv) separately providing one or more disintegrants or a mixture thereof, and a diluent,
(v) granulating the mixture of step (iv) with the suspension of step (iii) using a fluidized bed processor, thus obtaining dried granules,
(vi) drying the wet granules obtained in step (v) using fluidized bed processor, thus obtaining dried granules,
(vii) mixing the dry granules obtained in step (vi) with extragranular disintegrants, one or more lubricants and optionally with sweeteners and flavouring agents,
(viii) compressing the mixture obtained in step (vii) to form an orodispersible pharmaceutical solid dosage form.

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

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

In an embodiment, the present invention provides an orodispersible pharmaceutical composition of safinamide comprising safinamide or its pharmaceutically acceptable salt thereof, ion exchange resin and one or more pharmaceutically acceptable excipients, wherein the safinamide or its pharmaceutically salt thereof is trapped within the matrix formed with the ion exchange resin, and wherein the said composition does not have more than 2.0% w/w of total impurity of safinamide, after being stored at specific storage conditions.

In an embodiment, the present invention provides an orodispersible pharmaceutical composition of safinamide comprising safinamide or its pharmaceutically acceptable salt thereof, ion exchange resin and one or more pharmaceutically acceptable excipients, wherein the safinamide or its pharmaceutically salt thereof is trapped within the matrix formed with the ion exchange resin, and wherein the said composition does not have more than 0.50% w/w of total impurity of safinamide, after being stored under the storage conditions of 40 °C temperature and 75% relative humidity 1 month in Alu Alu Blister Pack.

In an embodiment, the present invention provides an orodispersible pharmaceutical composition of safinamide comprising safinamide or its pharmaceutically acceptable salt thereof, ion exchange resin and one or more pharmaceutically acceptable excipients, wherein the safinamide or its pharmaceutically salt thereof is trapped within the matrix formed with the ion exchange resin, and wherein the said composition does not have more than 0.05% w/w of dimer impurity related to safinamide, after being stored under the storage conditions of 40 °C temperature and 75% relative humidity 1 month in Alu Alu Blister Pack.

The present invention has been described by way of example only. It is to be recognized that modifications falling within the scope and spirit of the claims, which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention. The scope of the invention is in no manner limited by the disclosed examples.

Examples
Example 1:
Sr. No Ingredients % w/w
1 Safinamide 20.0 - 30.0
2 Binder 1.0 - 5.0
3 Disintegrant 5.0 - 15.0
4 Diluent 10.0 - 40.0
6 Ion Exchange Resin 20.0 - 30.0
7 Sweetener 0.50 - 2.0
8 Flavouring agent 0.50 - 2.0
9 Lubricant 0.50 - 2.0
10 Solvent q.s.
Tablet weight 100

Manufacturing process:
(i) dissolving safinamide or a pharmaceutically acceptable salt thereof in water until a clear solution is obtained,
(ii) adding to the solution of step (i) an ion exchange resin until a homogeneous suspension is achieved,
(iii) separately providing 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 fluidized bed processor, to obtain wet granules,
(v) drying the wet granules obtained in step (iv) using fluidized bed processor, thus obtaining dried granules,
(vi) mixing the dry granules obtained in step (v) with extragranular disintegrants,
one or more lubricants and optionally with sweeteners and flavouring agents,
(vii) compressing the mixture obtained in step (vi) to form an orodispersible pharmaceutical solid dosage form.

Example 2:
Sr. No Ingredients mg/tab
1 Safinamide Mesylate 100.0 - 150.0
2 HPMC 5.0 - 25.0
3 Crospovidone / Croscarmellose Sodium 25.0 - 75.0
4 Mannitol/ Microcrystalline cellulose 50.0 - 200.0
5 Polacrilin potassium 100.0 - 150.0
6 Acesulfame potassium 2.5 - 10
7 Vanilla flavour 2.5 - 10
8 Sodium stearyl fumarate 2.5 - 10
9 Purified Water q.s.
Coated tablet weight 500.0

Examples 3, 4 & 5:
Sr. No Ingredients mg/tab
Example 3 Example 4 Example 5
1 Safinamide Mesylate 131.789 131.789 131.788
2 HPMC 7.500 7.500 7.500
3 Crospovidone 50.000 - -
4 Croscarmellose Sodium - 50.000 50.000
5 Mannitol 113.922 50.000 50.000
6 Microcrystalline cellulose 50.000 113.922 140.282
7 Polacrilin potassium 131.789 131.789 105.430
8 Acesulfame potassium 5.000 5.000 5.000
9 Vanilla flavour 5.000 5.000 5.000
10 Sodium stearyl fumarate 5.000 - -
11 Magnesium stearate - 5.000 5.000
12 Purified Water* q.s. q.s. q.s.
Coated tablet weight 500.000 500.000 500.000
* - Not present in final composition.

Manufacturing process of Examples 2, 3 & 4:
(i) dissolving safinamide mesylate in purified water until a clear solution is obtained,
(ii) adding to the solution of step (i) polacrilin potassium until a homogeneous suspension is achieved,
(iii) separately providing HPMC, crospovidone or croscarmellose sodium, mannitol and microcrystalline cellulose,
(iv) granulating the mixture of step (iii) with the suspension of step (ii) using a fluidized bed processor, to obtain wet granules,
(v) drying the wet granules obtained in step (iv) using fluidized bed processor, thus obtaining dried granules,
(vi) mixing the dry granules obtained in step (v) with extragranular crospovidone or croscarmellose sodium, sodium stearyl fumarate or magnesium stearate, and
optionally with acesulfame potassium, and vanilla flavour,
(vii) compressing the mixture obtained in step (vi) to form an orodispersible pharmaceutical solid dosage form.

Manufacturing process of Example 5:
(i) dissolving safinamide mesylate in purified water until a clear solution is obtained,
(ii) adding to the solution of step (i) polacrilin potassium until a homogeneous suspension is achieved,
(iii) adding to the solution of step (ii) HPMC under stirring,
(iv) separately providing croscarmellose sodium, mannitol and microcrystalline cellulose,
(v) granulating the mixture of step (iv) with the suspension of step (iii) using a fluidized bed processor, thus obtaining dried granules,
(vi) drying the wet granules obtained in step (v) using fluidized bed processor, thus obtaining dried granules,
(vii) mixing the dry granules obtained in step (vi) with extragranular croscarmellose sodium, magnesium stearate, and optionally with acesulfame potassium, and vanilla flavour,
(viii) compressing the mixture obtained in step (vii) to form an orodispersible pharmaceutical solid dosage form.

FRIABILITY TEST AND DISINTEGRATION TEST:
Formulations of Examples 3, 4 & 5 were submitted for friability test in accordance with the guidelines of the European Pharmacopeia, edition 10.0, pp. 336-337. The results are shown in Table 1.

Formulations of Examples 3, 4 & 5 were also tested for disintegration time following Test A of the European Pharmacopeia, edition 10.0, page 323), water having pH=7, at 37 °C and 30 cycles per minute. The results are also shown in Table 1.

Table 1: Friability results and disintegration time of Formulation of Examples 3, 4 & 5.
Parameter Example 3 Example 4 Example 5
Hardness (N) 59 N - 65 N 60 N - 65 N 45 N - 54 N
Thickness (mm) 3.95 mm - 4.05 mm 3.84 mm - 3.90 mm 3.96 mm - 4.03 mm
Disintegration
time 2 minutes 28
seconds 2 minutes to 2
minutes 30 seconds 2 minutes 27
seconds
Friability (%) 0.48% w/w 0.10% w/w 0.041% w/w

As shown in Table 1, all orodispersible tablets of Examples 3, 4 & 5 complied with the requirement of having a friability of less than 1% in accordance with guidelines of the European Pharmacopeia. Furthermore, all said orodispersible tablets complied with the requirement of being orodispersible tablets, in agreement with the definition given by the European Pharmacopeia, edition 10.0, page 939, wherein orodispersible tablets are defined as non-coated tablets for placing in the mouth which disintegrate quickly before they are swallowed. It also establishes 3 minutes as the time under which they must disintegrate in the disintegration test for tablets and capsules, according to the disintegration Test A of the European Pharmacopeia, edition 10.0, page 323, water having pH=7, at 37 °C and 30 cycles per minute.

DISSOLUTION STUDY:
The dissolution profiles of the Safinamide ODT compositions of Examples 3, 4 & 5 were measured at different pH conditions: (i) as per USP Apparatus 2 (Paddle type) at 50 rpm using 0.1 M Hydrochloric acid in 900 mL of volume; and (ii) as per USP Apparatus 2 (Paddle type) at 50 rpm using Phosphate buffer pH 6.8 in 900 mL of volume.

In both cases, the obtained dissolution profile results are shown in table 2 below.

Table 2: Dissolution profiles of the formulations of the invention.
Media 0.1N HCl pH 6.8 Phosphate buffer
Example 3 Example 4 Example 5 Example 3 Example 4 Example 5
Time (min) % safinamide release % safinamide release % safinamide release % safinamide release % safinamide release % safinamide release
5 73 58 87 27 22 32
10 95 97 96 62 54 68
15 97 99 99 79 78 81
20 97 100 101 83 87 88
30 98 100 102 86 92 94
45 98 100 102 87 93 98

STABILITY STUDY:
Formulations as obtained in Examples 3, 4 & 5 were analyzed to quantify the amount of most relevant impurities present after being stored for a certain period of time under controlled conditions of temperature and Relative Humidity (RH). Results are presented in Table 3.

Table 3: Stability data of safinamide tablet (Examples 3, 4 & 5) under 1 month time interval at condition of 40°C / 75% RH in Alu Alu Blister Pack.
Related substances Example 3 Example 4 Example 5 Limit
Acid impurity 0.036% 0.041% 0.074% Not more than 2%
Single max. unknown impurity 0.006% 0.028% 0.023% Not more than 2%
2-fluoro impurity 0.030% Not detected Not available Not more than 2%
4-fluoro impurity 0.106% Not detected Not available Not more than 2%
Dimer impurity 0.025% Not detected Not available Not more than 2%
Total impurities 0.208% 0.069% 0.097% Not more than 2%
Assay 96.6 % 99.3% 99.9% Between 95.0% to 105.0%

The above data shows a total impurity not more than 2% in the formulation and assay value within the range of ICH guideline, indicative of stability of safinamide in the drug product.

PERCENTAGE OF THE ACTIVE INGREDIENT TRAPPED WITHIN THE MATRIX FORMED WITH THE ION EXCHANGE RESIN
The percentage of the active ingredient trapped within the matrix formed with the ion exchange resin in the formulation was analysed.

The binder dispersion solution containing safinamide mesylate of Example 5 was centrifuged at 3000 RPM for 10 minutes. Then, 1.0 mL of the supernatant solution was taken, and it was diluted to 20 mL with diluent (in turn prepared by adequate mixing of 60 volumes of water and 40 volumes of acetonitrile). The liquid sample was mixed well and was then analysed by HPLC to quantify the amount of safinamide; i.e. safinamide not trapped within the matrix formed with the ion exchange resin. The corresponding percentage of safinamide trapped within the matrix formed was calculated by difference between total amount of safinamide minus amount of safinamide not trapped within the matrix. Results are given in Table 4.

Table 4: % of safinamide trapped within the matrix formed with the ion exchange resin.
Example 5
Free safinamide in binder dispersion – i.e. not trapped within the matrix formed 2.3%
Safinamide complexed with resin 97.7%

BIOAVAILABILITY TEST:
The bioavailability of the composition of safinamide of the present invention (Example 5) was studied.

Design of the study
The trial was carried out as an open label, balanced, randomized, three-treatment, three-sequence, three-period, crossover, single oral dose, comparative bioavailability study in non-smoker, normal, healthy, adult, human subjects under fasting conditions.

For this comparative bioavailability study as well as for the palatability test, a crossover design was followed. Each subject received the treatment test drugs (T1 and T2) and reference drug (R) during the study (three periods, with a washout phase of 14 days between the dosing days of any two consecutive periods). Hence, every subject acted as his own control and no separate group of subjects was required to act as the control group.

Volunteers
Sufficient number of healthy, adult, human volunteers was screened with their consent to enroll 18 subjects in the study, which in turn complied with the following criteria of inclusion:
- Non-smoker, normal, healthy, adult, human subjects between 18 and 45 years of age (both inclusive).
- Having a Body Mass Index (BMI) between 18.5 and 30.0 (both inclusive), calculated as weight in kg / height in m2.
- Not having any significant diseases or clinically significant abnormal findings during screening, medical history, clinical examination, laboratory evaluations, 12-lead ECG and chest X-ray (posterior/anterior view) recordings.
- Able to understand and comply with the study procedures, in the opinion of the investigator.
- Able to give voluntary written informed consent for participation in the study.
- In case of female subjects:
o Surgically sterilized at least 6 months prior to study participation; or
o If of child-bearing potential, is willing to use a suitable and effective double barrier contraceptive method or intra uterine device during the study; and
o Serum pregnancy test result must be negative.

The 18 subjects were planned for inclusion in the bioavailability as well as in the palatability studies. With reference to the bioavailability study, 17 among the 18 subjects were finally considered for analysis.

Samples
The samples used in the bioavailability test are the following:
a) Test sample 1 (Test product T1): The composition of Example 5 in the form of orodispersible tablet administered with water.
b) Test sample 2 (Test product T2): The composition of Example 5 in the form of orodispersible tablet administered without water.
c) Reference sample: XADAGO® 100 mg tablet.

Test Method
It is important to note that this test methodology was applied for the bioavailability study as well as for the palatability assessment. For that, the Test T1 and T2 and reference samples were administered to the subjects at scheduled times in sitting posture with 240 ± 02 mL of drinking water (Test T1 and reference) or without drinking water (Test T2) at ambient temperature.

In all cases, subjects refrained from drinking water from 01 hour before till 01 hour after dosing in each period administration (except 20 ± 02 mL of drinking water were used to wet the mouth prior to drug administration for Test product T2 and 240 ± 02 mL of drinking water were given with drug administration for Reference product and Test product T1). Lunch was served after 04 hours post-dose.

For Reference sample:
After an overnight fast of at least 10 hours, a single oral dose (100 mg) of the reference product was administered to the subjects with 240 ± 02 mL of drinking water at ambient temperature. The tablet was swallowed whole without chewing or crushing.

For Test T1 sample (water administration):
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 (dosing time) and was allowed to disintegrate for 30 seconds, but under no circumstances was it swallowed as a whole, chewed, bitten or broken. After those 30 seconds, mouth check was done to ensure thorough disintegration of the tablet and then subjects were asked to swallow the content along with saliva. If the sample did not disintegrate completely, mouth check was repeated every 30 seconds till complete disintegration was achieved. The time at which the subject swallowed the saliva was documented. Then the subject was instructed to consume approximately half quantity of water (from 240 ± 02 mL of drinking water) by swirling in mouth. This activity was followed by mouth check in between to assess compliance to dosing with torch by trained study personnel. Finally, subjects were asked to administer remaining quantity of water and again inspection of oral cavity was done to assure no availability of drug particles.

For Test T2 sample (administration without water):
After an overnight fast of at least 10 hours, the test product T2 was administered to the subjects. Prior to the administration, subjects were asked to wet their mouth with approximately 20 ± 02 mL of water at room temperature for about 5 seconds and then swallow the water. No further water was provided for the administration procedure. For each subject, the tablet was placed on the tongue (dosing time) and was allowed to disintegrate for 30 seconds, but under no circumstances was it swallowed as a whole, chewed, bitten or broken. After those 30 seconds, mouth check was done to ensure thorough disintegration of the tablet and then subjects were asked to swallow the content along with saliva. If the sample did not disintegrate completely, mouth check was repeated every 30 seconds till complete disintegration was achieved. The time at which the subject swallowed the saliva was documented. After swallowing, the subject was asked to move its tongue around the mouth, swallowing the saliva, to ensure that all remaining product was swallowed. Finally, mouth check with torch by trained study personnel was followed to assess compliance to dosing.

Sampling
Blood was collected at pre-dose time (0.000 hours – corresponding to 60 minutes before the dosing) 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 following drug administration in each period.

Blood samples were collected through an indwelling intravenous cannula placed in a forearm vein of the subjects. Cannula was removed after collection of the 16.000 hours post-dose sample. Blood samples after 16.000 hours post-dose was collected through a fresh vein puncture. Immediately after each tube of blood was drawn, it was inverted gently several times to ensure the mixing of tube contents (i.e. anticoagulant).

Intravenous indwelling cannula was kept in situ as long as possible by injecting 0.5 mL of normal saline solution to prevent cannula from clogging for collection of all the blood samples up to 16.000 hour post-dose. All blood samples were kept in an ice-cold water.

The blood samples were centrifuged at 3000 rcf for 5 minutes at 3 °C to separate plasma. The separated plasma was transferred to pre-labelled polypropylene tube in singlet and stored upright in a freezer at a temperature of -55 °C or below for interim storage. Finally, the samples were transferred by keeping them in dry ice box and then stored in the bioanalytical freezer at -55 °C.

Determinations
The method involved the measurement of the plasma concentration of safinamide for 72 hours at predetermined time points.

Mean plasma concentrations of safinamide were determined. Values of safinamide concentration after the once-daily administration of the test samples T1 and T2 of the present invention as well as the reference sample are summarized in Table 5.

Further, the plasma concentration-time profile after the once-daily administration of the test samples of the invention is shown in Fig.1.
Table 5
Time points (h) Mean plasma concentration of safinamide after once-daily intake of the test sample T1 (ng/mL) – administration with water Mean plasma concentration of safinamide after once-daily intake of the test sample T2 (ng/mL) – administration without water Mean plasma concentration of safinamide after once-daily intake of XADAGO® 100 mg tablet (ng/mL)
0.000 0.000 0.000 0.000
0.167 0.599 0.757 0.000
0.250 2.558 4.929 0.758
0.333 18.207 22.340 9.639
0.500 149.860 48.009 102.877
0.750 377.577 149.131 286.781
1.000 463.177 224.162 396.495
1.333 556.630 343.913 497.089
1.667 576.971 389.718 527.270
2.000 589.871 478.545 547.057
2.333 611.589 532.608 577.676
2.667 610.023 594.922 617.085
3.000 637.990 634.564 655.182
3.333 665.066 671.864 660.591
3.667 659.218 686.834 679.191
4.000 681.888 691.714 681.357
4.500 686.884 703.739 712.668
5.000 700.116 726.313 719.986
6.000 743.734 759.063 746.667
8.000 708.411 720.398 705.955
10.000 639.338 641.763 650.455
12.000 582.413 574.373 566.056
16.000 477.907 491.607 492.703
24.000 387.934 384.548 397.483
36.000 290.332 292.433 294.514
48.000 196.422 196.991 194.391
72.000 105.726 107.387 104.575

Moreover, the main pharmacokinetic parameters exhibited after the once-daily administration of the orodispersible tablet according to the present invention (Example 5) with and without water (Test-T1 and Test-T2 samples, respectively), and the once-daily administration of the reference sample product (XADAGO® 100 mg tablet) were measured by means of LC-MS/MS method. Particularly, the values of the Cmax, Tmax, and AUC0-72 as well as the standard deviation (SD) of the test samples and the reference sample are summarized in Table 6.

The term “AUC” refers to the area under the time/plasma concentration curve after an oral single-dose administration of the composition of the invention. Particularly, “AUC0-t” denotes the area under the plasma concentration versus time curve from time 0 to time t, wherein t represents 72 hours. The term "Tmax" refers to the time in hours when Cmax is achieved following an oral single-dose administration of the compositions of the present invention under fasting conditions. Finally, the term "Cmax" refers to the maximum concentration of safinamide in the blood following an oral single-dose administration of the composition under fasting conditions.
Table 6
Pharmacokinetic Parameters Mean ± SD (untransformed data)
Test Sample T1 Test Sample T2 Reference Sample
Tmax(a) 4.442
(0.750-8.000) h 4.485
(0.750-7.983) h 4.452
(1.333-8.017) h
Cmax 789.719 ± 128.7487 ng/mL 787.040 ± 140.8757 ng/mL 774.675 ± 132.8329 ng/mL
AUC0-t 23645.877 ± 4762.1393 ng.h/mL 23471.083 ± 4938.0847 ng.h/mL 23728.275 ± 4811.2373 ng.h/mL
(a) Tmax is represented in median (min-max) value.

The above pharmacokinetic parameters and the values of the mean plasma concentration of safinamide shown in Tables above demonstrate that the once-daily administration under fasting conditions of the composition of the present invention, in the form of orodispersible tablet of Example 5, both with water and without water (Test T1 product and Test T2 product, respectively) is bioequivalent to the total drug exposure obtained after once-daily administration of 100 mg tablet of XADAGO®. This means that the composition of the present invention, administered with and without water, has comparable bioavailability, because the rate and extent to which safinamide is absorbed from the composition of the invention and becomes available at the site of drug action is the same as the reference sample.

PALATABILITY STUDY:
The taste of both the safinamide composition of the present invention (prepared according to Example 5) with and without water and the reference product XADAGO® (100 mg tablet) was evaluated in order to assess overall subject compliance, to monitor the adverse events, and to ensure the safety of the subjects.

As mentioned before, the 18 subjects were recruited for both bioavailability and palatability tests, and the palatability assessment was conducted in parallel to the bioavailability study. Hence, the methodology of said test is in line with the description in test method section (see pages 25-26).

Particularly, for this sensory evaluation, subjects were administered an orodispersible tablet of either Test T1 (with water) or Test T2 (without water) of the present invention and were asked to report their feedback by means of indicating bitterness, sweetness, mouth feel and flavor sensations according to the following scale:
1 = extremely bad
2 = poor
3 = acceptable
4 = pleasant
5 = excellent

Moreover, the same experiment was repeated by requesting subjects to put the orodispersible tablet in the mouth and keep it for 5 minutes, followed by sensory evaluation. Descriptive statistics for each subject have been summarized in Table 7 (after 10 seconds) & Table 8 (after 5 minutes), while average (i.e. mean) value of all subjects for each evaluation parameter and test formulation has been summarized in Table 9.

Table 7: Individual sensory evaluation of safinamide ODT of the present invention as Example 5 (Test T1 and Test T2 products) after 10 seconds.
Subject Bitterness Sweetness Mouth Feel Flavor
T1
(with water) T2
(without water) T1
(with water) T2
(without water) T1
(with water) T2
(without water) T1
(with water) T2
(without water)
1001 3 3 3 4 4 4 3 3
1002 5 5 2 4 3 4 3 4
1003 3 3 2 3 4 3 3 4
1004 3 3 3 3 4 4 4 4
1005 5 3 3 3 3 2 4 3
1006 - 3 - 2 - 3 - 3
1007 4 3 2 2 2 2 3 2
1008 3 3 4 2 3 4 3 4
1009 3 3 2 4 3 4 4 4
1010 5 5 2 2 4 4 1 4
1011 3 3 3 4 3 3 3 4
1012 3 3 3 3 3 3 4 3
1013 4 4 3 2 3 4 3 3
1014 5 5 2 4 4 3 4 4
1015 4 4 3 3 4 4 3 4
1016 3 3 2 3 2 2 3 3
1017 3 4 3 3 4 3 4 3
1018 3 5 1 2 3 3 3 4

Table 8: Individual sensory evaluation of safinamide ODT of the present invention as Example 5 (Test T1 and Test T2 products) after 5 minutes.
Subject Bitterness Sweetness Overall acceptability
T1
(with water) T2
(without water) T1
(with water) T2
(without water) T1
(with
water) T2
(without water)
1001 5 3 2 2 4 2
1002 3 3 2 2 3 3
1003 3 5 2 2 4 4
1004 3 2 3 3 4 3
1005 5 3 3 2 3 5
1006 - 5 - 3 - 4
1007 3 3 2 3 5 3
1008 5 4 3 3 4 3
1009 3 5 3 3 4 3
1010 5 5 3 3 4 5
1011 4 5 3 2 3 4
1012 3 3 3 3 4 3
1013 5 4 2 2 4 3
1014 4 1 2 2 4 2
1015 3 5 2 3 4 4
1016 5 4 3 3 3 2
1017 4 5 3 3 3 4
1018 4 4 2 3 3 3

Table 9: Mean sensory evaluation of safinamide ODT of the present invention as Example 5 (Test T1 and Test T2 products).
Treatment After 10 seconds After 5 minutes
Bitterness Sweetness Mouth Feel Flavor Bitterness Sweetness Overall acceptability
T1
(with water) 3.7 2.5 3.3 3.2 3.9 2.5 3.7
T2
(without water) 3.6 2.9 3.3 3.5 3.8 2.6 3.3

Treatments with Test T1 and Test T2 products were overall acceptable (no unpleasant taste) thus confirming that the formulation of the safinamide orodispersible tablets of the present invention prepared according to Example 5 provides adequate taste-masking of safinamide mesylate. Hence, by providing suitable organoleptic characteristics for Parkinsonian’s patients being administered with those orodispersible safinamide compositions, a good adherence to treatment and an appropriate patient compliance is ensured. ,CLAIMS:We claim:

1. An orodispersible 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 trapped within the matrix.

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

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

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

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

7. The orodispersible pharmaceutical dosage form according to any of claims 2-6, wherein the ion exchange resin is selected from the group of sodium or potassium or magnesium or calcium salts or partial sodium or potassium or 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.

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

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

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

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

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

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

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

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

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

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

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

19. The orodispersible pharmaceutical dosage form according to any of claims 1-18, wherein said orodispersible pharmaceutical dosage form is disintegrated in less than 3 minutes, preferably in less than 2 minutes, and more preferably in less than 1 minute, wherein the disintegration test was performed using a European Pharmacopeia disintegration apparatus A, placing the dosage form in water having pH=7 at 37 °C and 30 cycles per minute.

20. A process for the preparation of the orodispersible pharmaceutical solid dosage form as defined according to any of claims 1-19, which comprises:
(i) dissolving safinamide or a pharmaceutically acceptable salt thereof in water until a clear solution is obtained,
(ii) adding to the solution of step (i) an ion exchange resin until a homogeneous suspension is achieved,
(iii) separately providing 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 fluidized bed processor, to obtain wet granules,
(v) drying the wet granules obtained in step (iv) using fluidized bed processor, thus obtaining dried granules,
(vi) mixing the dry granules obtained in step (v) with extragranular disintegrants, one or more lubricants and optionally with sweeteners and flavouring agents,
(vii) compressing the mixture obtained in step (vi) to form an orodispersible pharmaceutical solid dosage form.

21. A process for the preparation of the orodispersible pharmaceutical solid dosage form as defined according to any of claims 1-19, which comprises:
(i) dissolving safinamide or a pharmaceutically acceptable salt thereof in water until a clear solution is obtained,
(ii) adding to the solution of step (i) an ion exchange resin until a homogeneous suspension is achieved,
(iii) adding to the solution of step (ii) a binder,
(iv) separately providing one or more disintegrants or a mixture thereof, and a diluent,
(v) granulating the mixture of step (iv) with the suspension of step (iii) using a fluidized bed processor, to obtain wet granules,
(vi) drying the wet granules obtained in step (v) using fluidized bed processor, thus obtaining dried granules,
(vii) mixing the dry granules obtained in step (vi) with extragranular disintegrants, one or more lubricants and optionally with sweeteners and flavouring agents,
(viii) compressing the mixture obtained in step (vii) to form an orodispersible pharmaceutical solid dosage form.

22. An orodispersible pharmaceutical solid dosage form according to any of claims 1-19 for use in the treatment of adult patients with idiopathic Parkinson’s disease (PD) as add-on therapy to a stable dose of levodopa (L-dopa) alone or in combination with other PD medicinal products in mid-to late-stage fluctuating patients.