Orodispersible clonazepam pharmaceutical composition

Abstract

The present invention relates to an immediate-release orodispersible pharmaceutical composition comprising a eutectic mixture of clonazepam and a hydrophilic polymer matrix. The invention further discloses methods for producing the composition and the use thereof in the preparation of a drug suitable for treating neurological disorders.

Description

[0001] PHARMACEUTICAL COMPOSITION OF ORODISPERSIBLE CLONAZEPAM

[0002] TECHNICAL FIELD OF THE INVENTION

[0003] The present invention pertains to the field of human health and relates to pharmaceutical compositions for medical use and processes for preparing such compositions, wherein the pharmaceutical compositions are suitable for the delivery of clonazepam with improved dissolution and bioavailability properties. The pharmaceutical compositions are useful for the treatment of neurological disorders, particularly epilepsy.

[0004] BACKGROUND OF THE INVENTION

[0005] Epilepsy is one of the most common neurological disorders worldwide, estimated to affect more than 70 million people, and of these, approximately 20% to 30% have drug-resistant or refractory epilepsy. People with epilepsy are at increased risk for injury, psychosocial dysfunction, and impaired quality of life. Epilepsy is a disorder characterized by transient but recurrent disturbances in brain function that may or may not be associated with impaired or loss of consciousness and abnormal movements or behavior.

[0006] Epileptic seizures are often classified into two broad types: primary generalized seizures, which begin with a widespread electric shock affecting both hemispheres of the brain, and partial seizures, which affect only one area of ​​the brain. Primary generalized seizures include absence seizures, also known as petit mal seizures, myoclonic seizures, atonic and tonic seizures, clonic seizures, and clonic-tonic seizures, also known as grand mal seizures. Partial seizures include simple seizures (without loss of alertness or alteration in mental function) and complex seizures (with impaired consciousness), as well as secondary generalized seizures.An epileptic seizure or convulsion can vary in duration, lasting from seconds to a few minutes; some partial seizures have also been documented, lasting from days to weeks.

[0007] Treatment for patients with epilepsy aims to restore functional capacity. Various antiepileptic drug (AED) regimens have been used for this purpose. The choice of drug is based on the efficacy and safety of the drug, the type of epilepsy, and each patient's personal circumstances, such as age, occupation, other medical conditions, etc.

[0008] Antiepileptic drug monotherapy can achieve long-term remission in 50% to 70% of patients. 10% to 20% will experience significant improvement, while the remainder will experience minimal or no improvement and will therefore undergo combination therapy. If seizure control is not achieved with combination therapy, the epilepsy will be considered drug-resistant or refractory, and the patient should be evaluated for alternative treatments such as surgery or neurostimulation.

[0009] In general terms, and without limiting ourselves to any mechanism, terminology, or classification, seizures result from a loss of balance between excitatory and inhibitory signals in cells (i.e., increased excitation or decreased inhibition); the result is an imbalance of electrical activity in a group of active neurons. Seizures can produce a variety of clinical characteristics and symptoms and can remain localized or generalize throughout the brain. In summary, epilepsy is a neural network disorder in which normal physiological connections between cortical and subcortical regions are interrupted or altered.

[0010] Benzodiazepines are widely known in the art and have been widely used for their central nervous system depressant effects. They are therefore used in the treatment of depression, panic attacks, and anxiety, as muscle relaxants to relieve seizures and muscle spasms, or to induce sleep. Some of the best-known benzodiazepines are clonazepam, alprazolam, chlordiazepoxide, diazepam, oxazepam, estazolam, midazolam, among others.

[0011] Clonazepam is a BCS (Biopharmaceutics Classification System) class II medication. Clonazepam is a benzodiazepine primarily used for the treatment of epilepsy. Although it shares many of the pharmacological actions of benzodiazepines, it is notable for its effectiveness as an anticonvulsant. Clonazepam is indicated for the treatment of epilepsy, both chronic partial and chronic generalized, restless legs syndrome (RLS), chronic fatigue syndrome, Tourette syndrome, Lennox-Gastaut syndrome, REM behavior disorder, anxiety disorders, panic attacks, and night terrors. In the treatment of anxiety disorders, long-term treatment with low doses of clonazepam may be necessary due to the chronic nature of the anxiety disorder. Clonazepam is also used for the initial treatment of mania in combination with other medications.It is also prescribed to treat the symptoms of Parkinson's disease and schizophrenia, to treat insomnia, and to control spasms and pain. It has also been used to treat hallucinogen persisting perception disorder (HPPD).

[0012] Clonazepam exhibits potent anxiolytic activity and euphoric side effects; therefore, it is considered a potent benzodiazepine. For example, a 0.25 mg dose of clonazepam is approximately equal to 1.0 mg of loperazam and 5.0 mg of diazepam. Clonazepam's sedative effects are relatively weak compared to its strong anticonvulsant and anxiolytic effects. It acts as an agonist of brain B2 receptors, potentiating the inhibitory neurotransmitter effect of GABA and suppressing the spread of seizure activity produced by an epileptic focus. Patent US3121076 describes various benzodiazepines, among which is the active ingredient clonazepam. Currently, the active ingredient is marketed as a medicine under the distinctive name of Rivothl®, in a pharmaceutical form of tablets (0.5 and 2.0 mg) and solution (2.5 mg / ml), and is considered the reference medicine.

[0013] One of the main treatment goals for patients with epilepsy is maintaining adequate antiepileptic drug levels and preventing subsequent seizures. In patients with mood disorders such as bipolar disorder, the goal is to prevent relapses and stabilize mood. In both cases, adherence to the prescribed dosage regimen is essential for maintaining therapeutic blood levels. However, the difficulty of swallowing solid oral formulations and the painstaking manual dexterity required to administer oral solutions lead to incorrect dosing or poor treatment compliance, resulting in inadequate adherence and reduced efficacy of oral treatments.

[0014] On the other hand, there are 0.5 and 2.0 mg scored tablets, in which the tablets can be divided into halves or quarters to facilitate dose adjustment. Despite their great advantages, they have the disadvantage that they dissolve or disintegrate in the gastrointestinal tract for the release of the active ingredient, which must dissolve to be available for absorption and, from there, it will pass into the portal circulation, where it will be subject to first-pass hepatic metabolism before reaching systemic circulation. Evidently, the bioavailability of the active ingredient depends on dissolution, absorption, and hepatic metabolism.

[0015] A person skilled in the art will be aware that these pharmaceutical forms of clonazepam are readily absorbed through the gastrointestinal mucosa, with peak plasma concentrations between 3 and 12 hours. The onset of action after oral administration is between 20 and 60 minutes, lasting between 6 and 8 hours in children and up to 12 hours in adults; it has a half-life of approximately 18 to 50 hours. It is finally metabolized by the liver through oxidation and hydroxylation, reducing it to inactive metabolites that are excreted in urine (0.5%), and a fraction is excreted unchanged in feces (9% to 27%).

[0016] In addition, solid oral forms of clonazepam are limited by the dissolution rate of the active ingredient, which is classified as poorly soluble (Biopharmaceutical Classification II). This, in turn, affects its absorption and bioavailability. Consequently, the dissolution stage of clonazepam affects both the onset and the intensity and duration of the response.

[0017] In general, and without intending to be limited to any mechanism, it has been observed that during drug dissolution, 3 thermodynamic steps are required, which involve energies and energy changes to: 1) create openings (cavities) within the solvent molecules with the change in Gibbs free energy (AH1) and an entropy change (AS1); 2) the elimination of a solute molecule to a particle (AH2, AS2); and 3) the insertion of the particle into the solvent cavity (AH3, AS3), therefore, it is extremely complex to obtain a solid pharmaceutical form with the same speed and amount of bioavailable drug as that obtained from a solution, where the drug is already dissolved.

[0018] In view of the above arguments, there is a need for an immediate-release solid dosage form that allows for drug delivery with improved dissolution and bioavailability properties and, of course, without the drawbacks associated with traditional dosage forms previously indicated.

[0019] Various techniques and / or mechanisms have been reported in the state of the art that aim to improve the dissolution of a poorly soluble active ingredient. Among the various conventional techniques are: i) the formation of salts and / or complexes, ii) particle size reduction, iii) the use of hydrophilic agents, iv) the modification of the crystalline state of the active ingredient, v) solid dispersions and vi) micellar solubilization, with the aim of improving the dissolution rate.

[0020] Although solid dispersions have advantages in terms of supersaturation solubility, dissolution, and improved bioavailability, one of the major disadvantages of this technique lies in the stability of the active ingredient and its physicochemical characteristics, which can consequently modify the dissolution and permeability. A person skilled in the art will recognize that, generally, solid dispersions are based on the fusion of the active ingredient with a polymer; however, if the drug is not miscible with the polymer, then rapid crystallization can occur and generate phase separation, giving rise to drug-rich domains and polymer-rich domains. Furthermore, amorphous solid dispersions are per se thermodynamically unstable, compared to the crystalline form of the active ingredient, given that it has a lower internal energy (C. Ahlneck, G.Zografi, The molecular basis of moisture effects on the physical and chemical stability of drugs in the solid state, Int. J. Pharm. 62 (2-3) (1990) 87-95). Theoretically, amorphous solid dispersions are kinetically stable over their expected shelf life, but in reality they have been observed to eventually revert to their crystalline form. In contrast, although crystalline solid dispersions are kinetically more stable than amorphous forms, such crystalline forms present solubilization problems due to their high lattice energy; therefore, amorphous forms offer an advantage over crystalline forms with respect to solubility.

[0021] Furthermore, when solid dispersions are exposed to moisture (e.g., during storage under high humidity conditions), the presence of water significantly increases the diffusion of the active ingredient towards the crystal surface, favoring heterogeneous nucleation of the sites, so the system reduces the ability of the polymers to inhibit crystallization and spherical hindrance within the hydrophilic polymer matrix.

[0022] It is well known that the fundamental principle of pharmacological therapeutics is to ensure that the drug reaches the site of action and remains there at adequate concentrations for the time necessary to achieve the therapeutic effect. To achieve this, it is necessary to achieve the appropriate dissolution of the active ingredient, which is influenced by various factors such as pH, particle size, and crystalline environment. Any variation in the in vitro dissolution profile will directly impact the in vivo behavior of the pharmaceutical form.

[0023] Thus, the present invention faced various challenges, such as the problem of clonazepam solubility (BCS Class II), to achieve the same dissolution rate and bioavailability as an oral solution through solid dispersions. It also faced the challenge of maintaining clonazepam stability under storage conditions, while providing an improved dissolution profile compared to conventional solid forms. These challenges must be consistent and provide in vitro behavior similar to that of clonazepam oral solution.

[0024] Orally disintegrating tablets (ODTs) are tablets that disintegrate / dissolve rapidly in the mouth, due to the action of saliva in the oral cavity, without requiring the administration of water. Furthermore, since the formulation disintegrates in the mouth, the drug can be absorbed in the oral, pharyngeal, and gastrointestinal regions, so pregastric absorption of the drug avoids first-pass hepatic metabolism.

[0025] These dosage forms, due to their ease of administration and pleasant mouthfeel, can even encourage patients, especially pediatric, geriatric, and schizophrenic patients who have difficulty swallowing conventional tablets, and thus improve treatment adherence through much more precise dosing than conventional pharmaceutical forms. Another advantage of the novel pharmaceutical form according to the present invention occurs when water is not available to aid in its intake under specific conditions.

[0026] In the technical area, different technologies are known to generate oral rapid dissolution systems, some of the most used are freeze-drying, molding and compaction technologies.

[0027] In lyophilization technology, the solvent is removed from a drug solution or suspension containing structure-forming excipients. Tablets are characterized by a highly porous network; they rapidly absorb water and dissolve, releasing the incorporated drug. The lyophilization process occurs at low temperatures, which eliminates adverse thermal reactions that can affect drug stability. However, the lyophilization process increases production costs and makes it difficult to scale up to an industrial level. Furthermore, the resulting dosage form exhibits very high friability, low stability at high temperatures and humidity levels, and poor mechanical properties. Furthermore, it often requires special packaging.

[0028] In terms of molding technology, two different processes are typically employed: the solvent method and the heat method. The solvent molding process involves the preparation of a drug solution or suspension containing the drug and excipients, followed by evaporation of the solvent at ambient pressure and drying. In the heat molding method, tablets are formed using a matrix composed of monosaccharides or polysaccharides transformed into amorphous threads by the simultaneous action of instant melting and centrifugal forces. In general, molding technology produces rapidly dissolving tablets with high drug doses. However, one disadvantage is their low mechanical strength, which is why they are prone to erosion and breakage during handling.

[0029] Granulation followed by compression is considered the conventional process for preparing fast-dissolving tablets. Granulation can be wet, dry, or in-mold, followed by a compression step. In this step, the resulting granules are mixed with a superdisintegrant and other appropriate excipients, and finally, the mixture is subjected to compression. In this technology, the dissolution of the active ingredient correlates with the tablet hardness and may be slower than that observed in lyophilized tablets. Furthermore, problems with the stability of the active ingredient after granulation have been observed. In this regard, patent document WO2012 / 075455 describes fast-dispersing microgranules, having an average particle size of between 100 and 300 µm, comprising at least one sugar alcohol, a saccharin, or a mixture thereof, at least one superdisintegrant, and at least one functional additive.In one embodiment, it refers to an orally disintegrating tablet comprising rapidly dispersing microgranules, microparticles comprising a therapeutically effective amount of an active ingredient (clonazepam).

[0030] For its part, document W02008 / 027993 discloses a composition comprising synchronized-pulsatile release (TPR) spheres, comprising a solid dispersion of at least one active ingredient in at least one solubility-enhancing polymer. In one embodiment, the composition is an orally disintegrating tablet containing the active ingredient clonazepam. The immediate-release spheres comprise a solid dispersion of the active ingredient and the solubility-enhancing polymer. Meanwhile, the rapidly dissolving microgranules comprise particles of at least one disintegrant and a sugar alcohol and / or saccharin.

[0031] Hot melt extrusion (HME) is one of the most efficient technologies for generating solid dispersions. In this process, the active ingredient is mixed with a matrix-forming polymer to generate a physical mixture that can be extruded. This process offers several advantages over other conventional methods, such as the absence of a solvent, continuous operation with fewer processing steps, the absence of compression, and the possibility of improving bioavailability by dispersing the drug at the molecular level. For these and other reasons, HME technology has gained significant popularity for generating pharmaceutical drug delivery systems such as granules, immediate and modified-release tablets, rapid oral dissolution systems, transdermal and topical administration, among others.However, HME formulations have also been shown to present stability problems under high humidity and temperature conditions, due to the very nature of the polymers used in this technology. This means that the resulting amorphous dispersions are thermodynamically unstable compared to the crystalline form of the active ingredient. Therefore, the polymers used to form the matrix cannot inhibit the recrystallization of amorphous drugs under high humidity conditions, since the presence of water significantly increases drug mobility and reduces the polymers' ability to inhibit recrystallization.

[0032] Based on the above, document US5939099 was identified, which describes solid preparations obtained by melt extrusion of (A) at least one active compound; (B) a mixture of (B1) a water-soluble thermoplastic polymer and (B2) a water-insoluble low-substitution hydroxypropylcellulose; and (C) common pharmaceutical auxiliaries. Among the list of active ingredients, clonazepam is disclosed.

[0033] In contrast, document MX231185 discloses rapidly disintegrating oral tablets, preferably sublingual, obtained through a specific process. Said process comprises forming a solution of the biologically active agent (clonazepam) in a solvent (selected from water, ethanol, methylene chloride, a mixture of ethanol-methanol chloride and ethanol-water), together with a crystallization-inhibiting agent (formed by a mixture of the binder and part of the lubricant); impregnating a mixture of the filler components and excipients with said solution until a granulated mass is formed; grinding the previously dried granulated mass until a ground mass of uniform granulometry is obtained; adding the remaining lubricant and other components to it; mixing and compressing. Document US8545890, in turn, discloses orally disintegrating tablets, which have optimal mechanical resistance and disintegrate within 60 seconds in the oral cavity.These tablets are characterized by the incorporation of a directly compressible composite excipient prepared with calcium silicate coated with a carbohydrate (e.g. mannitol), wherein the carbohydrate and calcium silicate may be present in the composite excipients in a ratio of 1:50 to 50:1.

[0034] Document AU2011231645 discloses rapidly dissolving drug delivery systems. Specifically, it relates to a rapidly dissolving oral film comprising a bioactive agent (e.g., clonazepam), a hydrophilic binder, and / or water-soluble diluents for the treatment of patients suffering from critical oral conditions that cause swallowing difficulties, where no added water is required to facilitate the dissolution of said rapidly dissolving film.

[0035] WO 2009086046 relates to an orally disintegrating tablet composition. Specifically, it discloses a composition comprising drug particles (temazepam) and rapidly dispersing microgranules, wherein the rapidly dispersing microgranules comprise sugar alcohols and / or sugars in combination with disintegrants, the drug particle comprising at least one drug, a polymer binder (ODT), wherein the drug is selected from benzodiazepines and others.

[0036] WO2015016727 discloses an orally dispersible film, which includes a drug (clonazepam), a film-forming hydrophobic polymer (polyvinyl acetate, shellac or a methacrylate copolymer), a disintegrant (cellulose derivative, cellulose ether, carboxymethylcellulose or a salt thereof, or sodium carboxymethylcellulose), a stabilizer (PVA and HPMC) and a plasticizer, which include, but are not limited to, phthalate derivatives, citrate derivatives, polyalkylene oxides, glycerol, glycerol monoacetate, glycerol diacetate, triacetate, acetate, polysorbate, cetyl alcohol, propylene glycol, sorbitol and sodium diethylsulfosuccinate, among others.

[0037] Although various solid dispersions are known in the state of the art that include as active ingredient at least one benzodiazepine (such as clonazepam) and one or more polymers, there is a need for suitable pharmaceutical compositions that maintain stability during a satisfactory storage time, and in particular, improved dissolution and permeability in vitro - compared to conventional solid compositions, even more, substantially similar to the oral solution of clonazepam.

[0038] The article by Minhanz, A. (2012), discloses solid dispersions of clonazepam, through which the increase in solubility and dissolution of clonazepam was analyzed. Different solid matrices of clonazepam were evaluated using PEG 6000 and 3 water-soluble polymers as carriers: HPMC, HPC and Poloxamer, in different drug-carrier ratios (1:2, 1:4, 1:6, 1:8 and 1:10). Furthermore, it is reported that solid dispersions with poloxamer reduce the crystalline structure, improving the wettability of the active ingredient, thereby increasing the solubility and dissolution of clonazepam. Likewise, it is important to highlight that in the state of the art, it is well known that HPMC, HPC and PVP polymers are crystallization inhibitors.Table 3 of the cited article shows the solid dispersion compositions comprising the carrier drug (CLZN:PEG 6000) in a 1:2 ratio, and, in turn, the polymer is combined with the poloxamer (PEG 6000:poloxamer) in ratios 1:5, 1:4, 1:3, 1:2, and 1:0, respectively. The result is shown in Figure 5, from which it is clearly evident that a higher concentration of poloxamer increases the release of clonazepam. Likewise, it should be noted that said graph clearly shows that, at 60 minutes, less than 40% of clonazepam was released.

[0039] Note that one of the great advantages of the present invention compared to the state of the art is that in just 5 minutes a dissolution of between 70% and more than 90% of clonazepam was reached (see Figure 8 of the present application), which is clearly equivalent to the dissolution profile of a “clonazepam solution”.

[0040] The paper by Jagdale, et al. (2012) discloses solid dispersions (SDs) of clonazepam using the amphiphilic carrier Gelucire 50 / 13 (G50), a polyglycolyzed glyceride, and the preparation of orally disintegrating tablets from the solid dispersion using the superdisintegrant crospovidone or Doshion P544. The solid dispersions (SDs) were prepared by various techniques including physical mixing (PM), solvent evaporation (SE), co-milling (COG), co-precipitation (COP), kneading (KN), and melting (CM) with drug:carrier ratios of 1:0.25, 1:0.5, and 1:1. In conclusion, the results of this research showed that SDs significantly improved the drug dissolution rate.Likewise, the characterization of the solid dispersion (SD) by X-ray diffraction (XRD) showed that clonazepam was in amorphous form, which explains the improvement in the dissolution rate of the drug; Table 2 clearly shows that the solid dispersions generated by the KN and COP techniques (G50-KN and G50+COP) were the ones that showed the best dissolution at both 60 and 120 minutes, while the SDs generated with the fusion technique (G50-CM) and solvent evaporation (G50-SE) were the ones that showed the lowest dissolution rate of the active clonazepam. Specifically, SDs G50-KN1, G50-KN2, G50-COP1 and G50-COP1 were the only ones that practically reached 100% dissolution at 120 minutes.

[0041] The document by Monzurul, et al (2011 ) describes solid dispersions of clonazepam (CLZ) with HPMC or poloxamer 407. The solid dispersions were prepared using polyethylene glycol 6000 as a vehicle in a ratio of 1 : 20 by melt granulation. It also discloses the production of tablets by compressing the solid dispersions adding microcrystalline cellulose, sodium starch glycolate and talc. The results of the in vitro dissolution tests of the tablets were obtained after 60 minutes; in all formulations the dissolution increased significantly compared to pure clonazepam (4.2%). The clonazepam:HPMC formulations (1 : 0.5, 1 : 1 ; and 1 : 1.5) showed a release of 81.96%, 83.33% and 98.68%, respectively. For their part, the clonazepam:poloxamer formulations (1:0.5, 1:1; and 1:1.5) showed a release of 98.86%, 89.4% and 87.31%, respectively.Of all the formulations, those that released the greatest amount of the active ingredient and in the fastest way were formula L3 (CLZ:PEG:HPMC, 1:20:1.5) and formula L4 (CLZ:PEG:Poloxamer, 1:20:0.5) where ±83% of the drug was released in 30 minutes (Figure 3), which implies that formulation L4 presents 2 important proportions, the first proportion corresponds to the active ingredient:CLZ:PEG polymer (1:20), which is critical to increase the solubility of the active ingredient, and the second proportion corresponds to the PEG:poloxamer (20:0.5). Furthermore, it is found that PEG:poloxamer formulations show that CLZ release is inversely proportional to the amount of poloxamer, thus the highest release rate is observed with the PEG:poloxamer ratio of 20:0.5, decreasing with 20:1 and decreasing further with 20:1.5, respectively.

[0042] The document by Bhalerao, et al. (2009) discloses an orally dispersible tablet of clonazepam, through a solid dispersion of clonazepam and PVP K30, by solvent evaporation method. Different combinations of superdisintegrants such as croscarmellose sodium, sodium starch glycolate and crospovidone were used. Among all the formulations, formulation F10 prepared in a drug:PVP K30 ratio (1:4) and a combination of croscarmellose sodium 5% (w / w) and sodium starch glycolate 5% (w / w) showed a minimum dispersion time of 8 seconds and faster dissolution. Also, Bhalerao states that those tablets that used a combination of superdisintegrants other than croscarmellose and sodium starch glycolate showed a longer dispersion time.

[0043] In light of the foregoing, the present invention addresses one or more of the problems described above by providing an immediate-release orodispersible pharmaceutical composition that is rapidly released and dispersed in saliva and absorbed through the mucosa of the oral cavity. This makes it suitable for situations where conventional solid forms such as tablets are difficult to swallow and where administering liquids poses challenges with adherence and proper dosage. Furthermore, the compositions of the present invention are safe and effective in achieving a therapeutic effect.

[0044] OBJECTS OF THE INVENTION

[0045] Taking into account the defects of the prior art, it is an object of the present invention to provide an immediate release orodispersible pharmaceutical composition comprising a eutectic mixture of clonazepam and a hydrophilic polymeric matrix, wherein the orodispersible pharmaceutical composition has improved dissolution and bioavailability properties compared to conventional solid dosage forms.

[0046] Another object of the present invention relates to a process for obtaining an orodispersible pharmaceutical composition with immediate release from a eutectic mixture of clonazepam and a hydrophilic polymeric matrix.

[0047] A further object of the present invention relates to an immediate release orodispersible pharmaceutical composition for use in the preparation of a medicament useful for the treatment of neurological disorders.

[0048] BRIEF DESCRIPTION OF THE INVENTION

[0049] A first aspect of the present invention relates to a clonazepam eutectic mixture, comprising clonazepam in a concentration of between 0.30 and 0.67% (w / w), at least one surfactant in a concentration of between 0.67 and 1.33% (w / w), at least one cosolvent in a concentration of between 10.00 and 16.67% (w / w), and at least one non-ionic disintegrating agent in a concentration of between 1.33 and 2.67% (w / w).

[0050] A second aspect of the present invention relates to an orodispersible pharmaceutical composition comprising the clonazepam eutectic mixture according to the present invention; and a hydrophilic polymeric matrix comprising at least one glidant in a concentration of between 1.00 and 2.00% (w / w), at least one sweetening agent in a concentration of between 1.00 and 2.00% (w / w), at least one anionic disintegrating agent in a concentration of between 1.67 and 3.00% (w / w), at least one diluting agent in a concentration of between 69.33 and 82.33% (w / w), and at least one lubricating agent in a concentration of between 1.33 and 2.33% (w / w).

[0051] A third aspect of the present invention relates to the use of the orodispersible pharmaceutical composition according to the present invention, for the preparation of a medicament useful in the treatment of neurological disorders.

[0052] A fourth aspect of the present invention relates to a method for obtaining the orodispersible pharmaceutical composition according to the present invention, comprising the steps of: (a) obtaining a clonazepam eutectic mixture; and (b) incorporating the clonazepam eutectic mixture into a hydrophilic polymer matrix. BRIEF DESCRIPTION OF THE FIGURES

[0053] The novel aspects considered characteristic of the present invention will be set forth with particularity in the appended claims. However, the features and advantages thereof will be better understood in the examples, when read in conjunction with the appended figures, where:

[0054] Figure 1 shows the X-ray diffraction pattern of clonazepam raw material.

[0055] Figure 2 shows the X-ray diffraction pattern of the orodispersible pharmaceutical composition C201 1353 according to the present invention.

[0056] Figures 3 to 6 show the Differential Calorimetry (DSC) analysis curves corresponding to clonazepam (Figure 3), polyethylene glycol (Figure 4), poloxamer (Figure 5) and croscarmellose (Figure 6).

[0057] Figure 7 shows the Differential Calorimetry (DSC) analysis curve of the orodispersible pharmaceutical composition C201 1353 according to the present invention.

[0058] Figure 8 shows the dissolution profiles of the orodispersible pharmaceutical composition C201 1353 according to the present invention versus the commercial products Rivothl® Solution (2.5 mg / mL, one drop equals 0.1 mg) and Rivothl® Tablets (2 mg) in a volume of 900 mL.

[0059] Figure 9 shows the dissolution results in a method simulating physiological conditions of the orodispersible pharmaceutical composition C201 1353 according to the present invention versus the pharmaceutical compositions C2001028 and C1902034; and its comparison with the commercial product Rivothl® solution.

[0060] Figure 10 shows the comparative bioavailability profile on a semi-logarithmic scale of the average plasma concentration of clonazepam vs. time; for the comparison of (B) the orodispersible pharmaceutical composition C201 1353 and (A) the commercial product Rivothl®.

[0061] DETAILED DESCRIPTION OF THE INVENTION

[0062] The present invention offers certain advantages over the prior art, including the bioequivalence of the orodispersible pharmaceutical composition with the commercial product Rivothl® solution due to its immediate release profile, thus promoting improved bioavailability of the drug in the body. Furthermore, it comes in a scored orodispersible tablet form, allowing the patient to titrate the dose from 0.5 mg to 2.0 mg and ingest it without the need for water.

[0063] A first aspect of the present invention relates to a clonazepam eutectic mixture, comprising clonazepam in a concentration of between 0.30 and 0.67% (w / w), at least one surfactant in a concentration of between 0.67 and 1.33% (w / w), at least one cosolvent in a concentration of between 10.00 and 16.67% (w / w), and at least one non-ionic disintegrating agent in a concentration of between 1.33 and 2.67% (w / w).

[0064] In a preferred embodiment, the clonazepam eutectic mixture comprises clonazepam at a concentration of 0.67% (w / w), at least one surfactant at a concentration of 1.00% (w / w), at least one cosolvent at a concentration of 14.67% (w / w), and at least one non-ionic disintegrant at a concentration of 2.00% (w / w).

[0065] Preferably, the surfactant is poloxamer, the cosolvent is polyethylene glycol and the non-ionic disintegrating agent is croscarmellose.

[0066] A second aspect of the present invention relates to an orodispersible pharmaceutical composition comprising the clonazepam eutectic mixture according to the present invention; and a hydrophilic polymeric matrix comprising at least one glidant in a concentration of between 1.00 and 2.00% (w / w), at least one sweetening agent in a concentration of between 1.00 and 2.00% (w / w), at least one anionic disintegrating agent in a concentration of between 1.67 and 3.00% (w / w), at least one diluting agent in a concentration of between 69.33 and 82.33% (w / w), and at least one lubricating agent in a concentration of between 1.33 and 2.33% (w / w).

[0067] In a preferred embodiment, the hydrophilic polymeric matrix comprises at least one glidant in a concentration of 1.5% (w / w), at least one sweetening agent in a concentration of 1.5% (w / w), at least one anionic disintegrating agent in a concentration of 2.53% (w / w), at least one diluting agent in a concentration of 74.13% (w / w), and at least one lubricating agent in a concentration of 2.00% (w / w). Preferably, the glidant is silicon dioxide, the sweetening agent is sucralose, the anionic disintegrating agent is crospovidone, the diluting agent is a combination of lactose and starch in a ratio of at least 85:15, and the lubricating agent is magnesium stearate.

[0068] Preferably, the pharmaceutical composition has an X-ray diffraction pattern with peaks at diffraction angle (°29) of 19.09, 22.92, 23.06 and 23.49 ±0.5°.

[0069] Preferably, the pharmaceutical composition has an endothermic peak at 59.06°C ± 3.0°C.

[0070] Preferably, the pharmaceutical composition is adapted for oral administration and has a th-scored tablet form that allows its titration to clonazepam concentrations from 0.5 mg to 2.0 mg.

[0071] Preferably, the pharmaceutical composition has an oral disintegration time of less than one minute.

[0072] A third aspect of the present invention relates to the use of the orodispersible pharmaceutical composition according to the present invention, for the preparation of a medicament useful in the treatment of neurological disorders.

[0073] In a preferred embodiment, the neurological disorders are selected from chronic partial and chronic generalized epilepsy, absence seizures, also known as petit mal, myoclonic seizures, atonic and tonic seizures, clonic seizures, and clonic-tonic seizures, also known as grand mal; restless legs syndrome (RLS); chronic fatigue syndrome; Tourette's syndrome; Lennox-Gastaut syndrome; REM behavior disorder; anxiety disorders; panic attacks and night terrors; for the treatment of insomnia; for the initial treatment of mania in combination with other medications; for the treatment of symptoms of Parkinson's disease and schizophrenia; for the control of spasms and pain; and for the treatment of hallucinogen persisting perception disorder (HPPD).

[0074] A fourth aspect of the present invention relates to a method for obtaining the orodispersible pharmaceutical composition according to the present invention, comprising the steps of: (a) obtaining a clonazepam eutectic mixture; and (b) incorporating the clonazepam eutectic mixture into a hydrophilic polymeric matrix.

[0075] In a preferred embodiment, the step of (a) obtaining a clonazepam eutectic mixture comprises the steps of: (i) sieving and mixing clonazepam, at least one surfactant, at least one cosolvent and at least one non-ionic disintegrating agent; (ii) heating the mixture to a temperature of between 60 and 140 °C; (iii) atomizing the previously heated mixture at a speed of between 7000 and 8000 rpm to obtain a clonazepam eutectic mixture.

[0076] In a preferred embodiment, the step of (b) incorporating the clonazepam eutectic mixture into a hydrophilic polymeric matrix comprises the steps of: (i) adding the clonazepam eutectic mixture to a hydrophilic polymeric matrix comprising at least one glidant, at least one sweetening agent, at least one anionic disintegrating agent, at least one diluting agent, and at least one lubricating agent; (ii) mixing at a speed of between 18 and 20 rpm; and (iii) compressing at a speed of between 15 and 80 rpm to obtain an immediate-release orodispersible pharmaceutical composition in the form of a th-scored tablet.

[0077] The active ingredient is preferably clonazepam, which includes any form known in the art, and may be included in its free base form and its corresponding pharmaceutically acceptable acid addition salts, for pharmaceutical use in a pharmaceutical composition. In a preferred embodiment, the pharmaceutically active ingredient is clonazepam in its free base.

[0078] For the purposes of the present invention, the term "eutectic mixture" refers to a homogeneous mixture of the active ingredient and one or more other components that melts and solidifies at a temperature lower than the melting points of the separate constituents or any other mixture thereof. Typically, the components form a polymeric matrix in which there is no interaction to form a new chemical compound, but in certain ratios, they inhibit the crystal structures from recovering their original size, so that agglomeration is phase-limited in the solid form. Such systems cannot form continuous solid solutions, but rather tend to form discontinuous solid solutions called eutectics.The term “polymer matrix” as used herein is defined as a mixture comprising one or more polymers, optionally together with one or more excipients, wherein the active ingredient is randomly dispersed or included among the polymer segments referred to as the matrix. Such a polymer matrix may comprise a homogeneous mixture or solution of a polymer, a surfactant, and a disintegrant, which are suitable for preparing the eutectic mixture and are used in the process of the invention.

[0079] For the purposes of the present invention, it should be understood that the terms “orodispersible” refer to “dispersion” and the term “orally disintegrating” refers to a solid composition or dosage form containing the active ingredient with rapid disintegration, usually within a few seconds when placed on the tongue, without the need to administer liquids or chew.

[0080] The advantages of the present invention will be better understood from the following examples, which are presented solely for illustrative purposes to allow a full understanding of the preferred embodiments of the present invention, without implying that there are no other non-illustrated embodiments that can be put into practice based on the detailed description given above.

[0081] EXAMPLES

[0082] EXAMPLE 1

[0083] This example describes a process for obtaining an orodispersible pharmaceutical composition with immediate release from a eutectic mixture of the active ingredient and a hydrophilic polymer matrix in accordance with the present invention.

[0084] The process comprised a first step of (a) obtaining a eutectic mixture of clonazepam, which in turn comprised the steps of: (i) sieving and mixing an active ingredient, a surfactant, a cosolvent and a non-ionic disintegrating agent; (ii) heating the mixture to a temperature between 60 and 140 °C; (iii) atomizing the previously heated mixture at a speed between 7000 and 8000 rpm to obtain a eutectic mixture of clonazepam.

[0085] The process also comprised a second step of (b) incorporating the clonazepam eutectic mixture into a hydrophilic polymeric matrix, which in turn comprised the steps of: (i) adding the clonazepam eutectic mixture to a hydrophilic polymeric matrix comprising a glidant, a sweetening agent, an anionic disintegrating agent, a diluting agent, and a lubricating agent at a speed of between 18 and 20 rpm; and (ii) compressing at a speed of between 15 and 80 rpm to obtain an immediate release orodispersible pharmaceutical composition in a scored tablet pharmaceutical form to deliver doses from 0.5 mg to 2.0 mg.

[0086] Below, in Table 1, the components and concentrations used in the mixture to obtain the orodispersible pharmaceutical composition in accordance with the present invention are shown.

[0087] TABLE 1

[0088] EXAMPLE 2

[0089] In order to characterize an immediate-release orodispersible pharmaceutical composition obtained in accordance with the process described in the previous example, different analytical techniques such as X-ray diffraction (XRD) and differential calorimetry (DSC) were used in the present example. Table 2 shows the components and concentrations used in the pharmaceutical composition evaluated, identified hereinafter as C2011353.

[0090] TABLE 2 In powder X-ray diffraction analysis, copper Ka was used as the radiation source using a wavelength of 1.54 A. (X-ray diffraction pattern). The crystalline form of clonazepam and the pharmaceutical composition obtained in accordance with the present invention were used as the object of analysis. The results of the crystalline form of clonazepam are shown in Table 3 and the XRPD diagram representation is illustrated in Figure 1.

[0091] TABLE 3 Likewise, the results of the pharmaceutical composition are shown in Table 4 and the representation of the XRPD diagram is illustrated in Figure 2.

[0092] TABLE 4

[0093] On the other hand, the results of differential calorimetry (DSC) analysis representing the heat absorption rate of each of the independent components and the pharmaceutical composition are shown in Table 5 and the DSC curves are illustrated in Figures 3 to 6.

[0094] TABLE 5

[0095] The pharmaceutical composition [clonazepam eutectic mixture “ME”] has an X-ray powder diffraction (XRPD) pattern as shown in Figure 2 and a differential scanning calorimetry (DSC) curve with a defined peak as shown in Figure 7.

[0096] EXAMPLE S

[0097] In the present example, the immediate release orodispersible pharmaceutical composition C201 1353 obtained from the process according to the present invention was subjected to accelerated stability studies under conditions of temperature of 40°C +2°C and relative humidity of 75% +5%, for a period of 12 months. The results are shown in Table 6.

[0098] ND: Not detected. S: seconds. *of the value indicated on the label.

[0099] As can be seen in the results of the 12-month accelerated stability test, it is demonstrated that the immediate release orodispersible pharmaceutical composition according to the present invention is physicochemically stable under high humidity and temperature conditions, such that the specifications for water content, friability and disintegration are within the specification limits of the standard (USP 43, FEUM 12). §Ed.). Furthermore, the degradation products are found at undetectable levels.

[0100] EXAMPLE 4

[0101] In this example, the aim is to evaluate the dissolution profile of the immediate release orodispersible pharmaceutical composition C201 1353 in accordance with the present invention compared to the commercial products Rivothl® Solution (2.5 mg / mL, one drop equals 0.1 mg) and Rivothl® Tablets (2 mg).

[0102] The method used was the FDA, which consists of a stirring speed of 50 rpm, a temperature of 37 ± 0.5 °C, purified water as a dissolution medium, a medium volume of 900 mL and a sampling volume of 5 mL without replacement; with sampling times of 5, 10, 15, 30, 45 and 60 minutes. The results are illustrated in Figure 8, where it can be seen that the immediate-release orodispersible pharmaceutical composition could be bioequivalent to the commercial product Rivotril® Solution, since it has a similarity factor of 73.

[0103] EXAMPLE S

[0104] The purpose of this example is to evaluate the dissolution profile, using a method that simulates physiological conditions, of the immediate-release orodispersible pharmaceutical composition C201 1353 obtained in accordance with the process described in the present invention compared to other pharmaceutical compositions with different concentrations and manufacturing processes (C2001028 and C1902034). In addition, the pharmaceutical compositions will be evaluated against the commercial product Rivothl® Solution (2.5 mg / mL, one drop equals 0.1 mg).

[0105] Table 7 shows the components and concentrations of the pharmaceutical compositions. It is important to note that C2001028 was obtained using the method described in the present invention with the additional addition of carnauba wax as a coating. C1902034, on the other hand, was obtained through a simple powder mixing and compression process.

[0106] TABLE 7 The dissolution method used comprises 3 stages that simulate the conditions of the gastrointestinal tract from the oral cavity (simulated saliva), stomach (simulated gastric fluid), to the first fraction of the small intestine in a fasting state (FaSSif-V2). The dissolution conditions are shown below: a) shake in simulated saliva (1.5 mL) for 60 seconds; b) dilute in a medium of 500 mL of simulated gastric fluid for 15 minutes; c) dilute in a medium of 415 mL of simulated intestinal fluid in a fasting state for 60 minutes. The conditions during the method are a shaking speed of 50 rpm, a temperature of 37 ± 0.5 °C, a sampling volume of 5 mL without replacement and sampling times at 5, 10, 15, 30, 45, 60 and 75 minutes.

[0107] Figure 9 shows the results of the dissolution profiles for the different pharmaceutical compositions, which shows the dissolution rate of the immediate-release orodispersible pharmaceutical composition C2011353 compared to the other compositions. In addition, the similarity factor (FS) was determined, giving the following values: C2011353 FS = 73, C1902034 FS = 38, and C2001028 FS = 50.

[0108] These results demonstrate that the dissolution profile of the immediate-release orodispersible pharmaceutical composition according to the present invention is practically the same as that obtained with the reference product, which corresponds to an oral administration solution in which the active ingredient clonazepam is already dissolved. Although the eutectic mixtures exhibit good stability, the dissolution tests determined the optimal ratio of the clonazepam eutectic mixture to the hydrophilic polymeric matrix to achieve an in vitro dissolution similar to the oral administration solution. In particular, the pharmaceutical compositions of the present invention release at least 80% by weight of clonazepam within 5 to 10 minutes, and even more particularly, they release at least 90% by weight of clonazepam within 5 minutes. EXAMPLE 6

[0109] The objective of this study was to compare the bioavailability of the immediate release orodispersible pharmaceutical composition according to the present invention (C2011353) versus the commercial product Rivotril® (2.5 mg / mL), which is presented in a pharmaceutical form of clonazepam oral drops where each drop has a concentration of 0.1 mg. In particular, its bioequivalence was demonstrated in terms of the speed and magnitude of absorption in accordance with NOM-177-SSA1 -2013. The study was conducted in a monocentric, prospective, open-label, randomized, single-dose, two-period, two-sequence (AB, BA) crossover design in 20 healthy research subjects (men and women) under fasting conditions. Table 8 shows the treatment schedule in the experimental design of the comparative bioavailability study.

[0110] TABLE 8

[0111] (A) Commercial product Rivotril®

[0112] (B) Orodispersible pharmaceutical composition C2011353

[0113] Once the plasma concentrations were determined for each of the different sampling times per subject, they were statistically evaluated. In order to show the Cp vs. t profile with its respective standard error at each sampling time, which was determined from the theoretical times indicated in the protocol, their average, median, minimum and maximum values, standard deviation, standard error, and percentage of the coefficient of variation are presented together for each sampling time as indicated by NOM-177-SSA1 -2013. Table 9 shows the average plasma concentrations reached by Clonazepam at each sampling time from the 20 research subjects after administration of the commercial product Rivotril® solution. TABLE 9

[0114] Cp: ​​Plasma concentration. %CV: Percentage coefficient of variation, h: Time NA: Not applicable

[0115] Likewise, Table 10 shows the average plasma concentrations reached by Clonazepam at each sampling time from the 20 research subjects obtained after the administration of the immediate release orodispersible pharmaceutical composition C2011353.

[0116] TABLE 10

[0117] Cp: ​​Plasma concentration. %CV: Percentage coefficient of variation, h: Time NA: Not applicable

[0118] Figure 10 shows the semilogarithmic scale profile of the average plasma concentration of Clonazepam vs. time, after administration of the treatments. The vertical bars indicate the standard error. In addition, the values ​​obtained for each of the statistical tests demonstrate the possible comparative bioavailability for Clonazepam between (B) orodispersible pharmaceutical composition C201 1353 and (A) commercial product Rivotñl® corresponding to the 20 research subjects who completed the study are shown in Table 1 1, for the data transformed to their natural logarithm. Where the criterion to accept comparative bioavailability is when the classic confidence intervals (ICCL) for the Cmax and AUCo-96 parameters are within 80 and 125% and in the Schuirmann One-Sided Double t Test (PDU) they show a value less than 0.05 of significance; all of them with a power equal to or greater than 0.8. TABLE 11

[0119] Inf.: Lower limit of the Confidence Interval.

[0120] Sup.: Upper limit of the Confidence Interval

[0121] Prob: Probability

[0122] Using ANADEVA for the 2x2 crossover design, applying the Classic Confidence Intervals (ICCL) at 90% and the Schuirmann One-Sided Double t Test (PDU); it is demonstrated that the immediate release orodispersible pharmaceutical composition C201 1353, presents comparative bioavailability with the commercial product Rivotñ® oral solution of 2.5 mg / mL, finding that the confidence interval of the pharmacokinetic parameters of Cmax and ABCo-96 are within 80 and 125% and the probability tests were less than 0.05 for the logarithmically transformed data according to NOM-177-SSA1 -2013.

[0123] In accordance with the foregoing, it can be seen that the immediate release orodispersible pharmaceutical composition, as well as its method of production, have been designed for use in the pharmaceutical industry, it being evident to any person skilled in the art that the embodiments of the invention as described above and illustrated in the accompanying Figures, are merely illustrative but not limiting of the present invention, since numerous significant changes in its details are possible without departing from the scope of the invention. For example, it is possible to use the described method to obtain an orodispersible pharmaceutical composition that uses an active ingredient different from that shown in the previously described examples.

[0124] Therefore, the present invention should not be considered as restrictive except for what concerns the previous technique and for the possibility of the previous indications. BIBLIOGRAPHY

[0125] Minhanz, A; Rahman, M; Ahsan, Q; et al. (2012). Enhancement of solubility and dissolution properties of clonazepam by solid dispersions; International Journal of Pharmacy & Life Sciences; 3(3); pp:1510-1518.

[0126] Jagdale S.C; Bhadohya, A. S. & Chabukswar, A. R. (2012). Solubility Enhancement and Formulation of Mouth Dissolving Tablet of Clonazepam with Solid Dispersion Technology; Rev Cienc Farm Básica Api; 2012; 33(1 ):83-94.

[0127] Monzurul Amin Roni, Md. Saiful Islam, Golam Kibria, Sams Mohammad Anowar Sadat; (201 1 ). Effects of Poloxamer and HPMC on the Dissolution of Clonazepam-Polyethylene Glycol Solid Dispersions and Tablets. Ind J Pharm Edu Res, Apr-Jun, 201 1 / Vol 45 / Issue 2, pp: 139-144.

[0128] Bhalerao, AV; Deshkar, SS; Shirolkar, SV; Gharge, VG; & Deshpande, AD. (2009) Development and Evaluation of Clonazepam Fast Disintigrating Tablets Using Superdisintigrates and Solid Dispersion Technique. Research J. Pharm. and Tech.2(2): April-June. 2009.

Claims

CLAIMS 1. A solid pharmaceutical composition for oral administration of clonazepam characterized in that it comprises: a) a eutectic mixture comprising clonazepam; and b) a hydrophilic polymeric matrix, wherein the pharmaceutical composition has an X-ray diffraction pattern comprising peaks expressed in terms of angles 20 to 19.09, 22.96, 23.19 and 23.43 ± 0.5 degrees using a Cuka X-ray source wavelength of 1.54 A.

2. The pharmaceutical composition according to claim 1, wherein the eutectic mixture comprises clonazepam in a concentration between 0.30 and 0.67% (w / w), at least one surfactant in a concentration between 0.67 and 1.33% (w / w), at least one cosolvent in a concentration between 10.00 and 16.67% (w / w), and at least one non-ionic disintegrating agent in a concentration between 1.33 and 2.67% (w / w); and the hydrophilic polymeric matrix comprises at least one slip agent in a concentration of between 1.00 and 2.00% (w / w), at least one anionic disintegrating agent in a concentration of between 1.67 and 3.00% (w / w), at least one diluting agent in a concentration of between 69.33 and 82.33% (w / w) and at least one lubricating agent in a concentration of between 1.33 and 2.33% (w / w).

3. The pharmaceutical composition according to claim 2, further characterized in that the eutectic mixture comprises clonazepam in a concentration of 0.67% (w / w), at least one surfactant in a concentration of 1.00% (w / w), at least one cosolvent in a concentration of 14.67% (w / w), and at least one non-ionic disintegrating agent in a concentration of 2.00% (w / w).

4. The pharmaceutical composition according to claim 2, further characterized in that in the eutectic mixture the surfactant is poloxamer, the cosolvent agent is polyethylene glycol and the non-ionic disintegrating agent is croscarmellose.

5. The pharmaceutical composition according to claim 2, characterized in that the hydrophilic polymeric matrix comprises at least one sweetening agent in a concentration of between 1.00 and 2.00% (w / w).

6. The pharmaceutical composition according to claim 2, characterized in that the hydrophilic polymeric matrix comprises at least one sliding agent in a concentration of 1.5% (w / w), at least one anionic disintegrating agent in a concentration of 2.53% (w / w), at least one diluting agent in a concentration of 74.13% (w / w) and at least one lubricating agent in a concentration of 2.00% (w / w).

7. The pharmaceutical composition according to claim 5, characterized in that the sweetening agent is in a concentration of 1.5% (w / w).

8. The pharmaceutical composition according to claim 2, further characterized in that the glidant is silicon dioxide, the anionic disintegrating agent is crospovidone, the diluent agent is a combination of lactose and starch in a ratio of at least 85:15 and the lubricating agent is magnesium stearate.

9. The pharmaceutical composition according to claim 5, characterized in that the sweetening agent is sucralose.

10. The pharmaceutical composition according to claim 1, further characterized in that it has an endothermic peak at 59.06°C ± 3.0°C determined in a ramp of 10°C per minute up to 270°C.

11. The pharmaceutical composition according to claim 1, further characterized in that it is adapted for oral administration and has a th-scored tablet form that allows its titration to clonazepam concentrations from 0.5 mg to 2.0 mg.

12. The pharmaceutical composition according to claim 1, further characterized in that it is an orodispersible tablet that has an oral disintegration time of less than one minute.

13. The use of the pharmaceutical composition according to claims 1 to 12, for the preparation of a medicament useful in the treatment of neurological disorders.

14. The use according to claim 13, wherein the neurological disorders are selected from both chronic partial and chronic generalized epilepsy, absence seizures, also known as petit mal, myoclonic seizures, atonic and tonic seizures, clonic seizures and tonic-clonic seizures, also known as grand mal; restless legs syndrome (RLS); chronic fatigue syndrome; Tourette syndrome; Lennox-Gastaut syndrome; REM behavior disorder; anxiety disorders; panic attacks and night terrors; for the treatment of insomnia; for the initial treatment of mania in combination with other medications; for the treatment of symptoms of Parkinson's disease and schizophrenia; to control spasms and pain; and for the treatment of hallucinogen persisting perception disorder (HPPD).

15. A process for obtaining a pharmaceutical composition of clonazepam, characterized in that it comprises the steps of: (a) obtaining a eutectic mixture of clonazepam; and (b) incorporating the eutectic mixture of clonazepam into a hydrophilic polymeric matrix, wherein: step (a) of obtaining a eutectic mixture of clonazepam comprises the steps of: (i) sieving and mixing clonazepam, at least one surfactant, at least one cosolvent and at least one non-ionic disintegrating agent; (ii) heating the mixture to a temperature between 60 and 140 °C;(iii) atomizing the preheated mixture at a speed of between 7000 and 8000 rpm to obtain a clonazepam eutectic mixture, and wherein the step of (b) incorporating the clonazepam eutectic mixture into a hydrophilic polymeric matrix comprises the steps of: (i) adding the clonazepam eutectic mixture to a hydrophilic polymeric matrix comprising at least one glidant, at least one anionic disintegrating agent, at least one diluent and at least one lubricating agent; (ii) mixing at a speed of between 18 and 20 rpm; and (iii) compressing; 16. The process according to claim 15, wherein step (b) step (i) further involves the addition of at least one sweetening agent.

17. The process according to claim 15, wherein step (b) step (iii) is performed at a speed between 15 and 80 rpm.

18. The process according to claim 15, wherein the resulting tablet is a th-scored orodispersible tablet.

19. A solid pharmaceutical composition for oral administration of clonazepam characterized in that it has a dissolution profile in which between 80% and 90% by weight of clonazepam dissolves in a time of between 5 and 10 minutes, at least 97% by weight of clonazepam is dissolved at 10 minutes and at least 100% by weight of clonazepam is dissolved at 30 minutes, wherein the dissolution profile is measured using the FDA method with a stirring speed of 50 rpm and a temperature of 37±0.5°C.

20. The pharmaceutical composition according to claim 19, wherein the composition has a dissolution profile wherein at least 80% of clonazepam is dissolved at 5 minutes.

21. A solid pharmaceutical composition for oral administration of clonazepam characterized in that it presents a minimum plasma concentration of clonazepam of 6.03 ng / mL and a maximum plasma concentration of clonazepam of 32.51 ng / mL after 30 minutes.

22. The pharmaceutical composition according to any of claims 19 and 21, further characterized in that it has a th-scored orodispersible tablet form.

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