Orodispersible clonazepam pharmaceutical composition

Abstract

The present invention relates to new solid oral-disintegration compositions having a clonazepam release profile substantially similar or identical to that of a liquid immediate-release clonazepam composition, which also exhibit rapid disintegration, low friability and organoleptic properties pleasant for the patient. In addition, the new solid oral-disintegration compositions of the invention are useful for the treatment of neurological disorders, including epilepsy, both chronic generalised epilepsy (absence or "petit mal" seizures) and chronic partial epilepsy (focal and complex crises).

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 comprising clonazepam and processes for preparing said compositions, wherein the pharmaceutical compositions are suitable for delivering 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 behaviors.

[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 is 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 short, epilepsy is a neural network disorder in which normal physiological connections between cortical and subcortical regions are disrupted or altered.

[0010] Benzodiazepines are widely known in the state of the art and have been widely used for their depressing effect on the central nervous system, which is why they are 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. Clonazepam or 1,3-dihydro-7-nitro-5-(2-chlorophenyl)-2H-1,4.benzodiazepin-2-one is a substance classified according to the BCS (Biopharmaceutics Classification System) in class II, given its low solubility and high permeability.

[0011] Its mechanism of action has been described in the state of the art; in general, it increases the inhibitory potency of gamma-aminobutyric acid (GABA) on the GABAA receptor and ion channel complex. Although it shares many of the pharmacological actions of benzodiazepines, it stands out for its efficacy as an anticonvulsant. Clonazepam's potency and greater efficacy are due to its highly specific action on the 2-gamma subunit of the GABAA receptor in humans.

[0012] 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 anxiety. 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, and to control spasms and pain. It has also been used to treat hallucinogen persisting perception disorder (HPPD).

[0013] 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 at brain B2 receptors, potentiating the inhibitory neurotransmitter effect of GABA and suppressing the spread of seizure activity produced by an epileptic focus.

[0014] Clonazepam is primarily metabolized to 7-aminoclonazepam by nitroreduction via cytochrome P450 and is subsequently acetylated to produce 7-acetamidoclonazepam and four other metabolites. Orally dispersible tablets are placed in the oral cavity and dissolve or disintegrate rapidly, making them an excellent option for treating patients who have trouble taking regular tablets or for those patients who have difficulty taking their medication, for example, infants or the elderly who require support staff to administer their medication. They are also an excellent option when high precision in dosage of the active ingredient is required, for example, when compared with liquid dosage forms, where care and skill must be taken to administer the appropriate dose.

[0015] There are products on the market that contain high doses of the active ingredient: 2 mg tablets and 2.5 mg / mL solutions (drops). The 2 mg tablets, in particular, are difficult to swallow in older adults with dysphagia. Similarly, the product in solution form leads to incorrect dosage, which poses problems for patients with treatment due to the low or high doses of the active ingredient administered. To support this, researchers conducted a study on a clonazepam solution (drops), analyzing the weight of the dispensed doses (1 drop and 5 drops) by individuals between 29 and 66 years of age. The results of the weight variation are shown in Table 1.

[0016] TABLE 1

[0017] The results obtained show that in the study where individuals were asked to dispense one drop, there was a coefficient of variation of up to 31.12%, while in the study where they were asked to dispense five drops, the coefficient of variation was 17.46%. Both values ​​fall outside the variability acceptance (VA) value, which must be <15.0%, in accordance with the pharmacopoeia. As those skilled in the art will appreciate, patients using the reference product, which corresponds to a clonazepam solution, experience various problems in dispensing the correct dose of the medication. Therefore, one purpose of the present invention is to provide a solid pharmaceutical form of clonazepam that has the same clonazepam release profile as the liquid form of the reference medication, without the problems posed by dispensing drops to adjust the desired dose.

[0018] The design of a pharmaceutical dosage form, such as an orodispersible tablet (ODT), requires a significant amount of research to develop a tablet that dissolves or disintegrates rapidly, while maintaining the appropriate friability for unit dosage handling. Furthermore, the complexity increases when the tablet contains an active ingredient with poor dissolution and / or stability.

[0019] Specifically, an ODT (orally disintegrating tablet) composition must also provide acceptable pharmacokinetics and bioavailability to achieve the desired therapeutic effect. These desired properties in an ODT composition can be contradictory, as taste masking can inhibit or delay drug release, thus providing unacceptable pharmacokinetic properties. Conversely, composition components that promote rapid release can result in undesirable taste or mouthfeel properties. Finally, any ODT composition with suitable organoleptic and pharmacokinetic properties must also be manufactured at commercially useful rates and yields.

[0020] The ODT compositions of the present invention essentially completely disintegrate in about 60 seconds or less, about 50 seconds or less, about 40 seconds or less, about 30 seconds or less, about 20 seconds or less, or about 10 seconds or less, after administration. In one embodiment, the ODT compositions of the present invention release about 80% or more of the drug (e.g., temazepam) in 30 minutes or less when tested for dissolution using official USP methodology (USP Apparatus 2; paddles at 75 rpm in 900 mL of sodium acetate buffer (pH 4.0) with 0.05% polysorbate 80; detection: UV absorption at 310 nm). Various processes for obtaining rapidly dissolving tablets have been disclosed in the state of the art, usually through complex, elaborate and expensive techniques, such as freeze-drying, molding, and sublimation.Therefore, the state of the art remains latent in obtaining an orally disintegrating tablet that can be manufactured with low friability and using ordinary tablet production techniques, which in turn improves the dissolution of BCS class II active compounds.

[0021] There are various documents that disclose the production of rapidly disintegrating compositions. For example, document W02004091585A1 discloses oral tablets comprising an active ingredient and silicified microcrystalline cellulose, wherein said tablet has the ability to dissolve orally in no more than 60 seconds.

[0022] WO2012075455 discloses a rapidly dispersing microgranular composition with an average particle size in the range of 100 to 300 µm, comprising at least one sugar alcohol, saccharin, or a mixture thereof, at least one super-disintegrant, and at least one multifunctional additive (starch, hydroxypropylcellulose, maltodextrin, and mixtures thereof). In one embodiment, the active ingredient is clonazepam.

[0023] Document W02009027521 discloses a solid, orodispersible and / or dispersible composition comprising at least one active substance (clonazepam), with a particle size not exceeding 50 pm in an amount of 0.1 to 59% by weight; at least one non-water-soluble diluent, in an amount of 40 to 99% by weight; at least one disintegrating agent (crospovidone) in an amount of 0.1 to 15% by weight and at least one sweetening agent, with a particle size not exceeding 50 pm in an amount of 0.05 to 10% by weight (Aerosil 200® and magnesium stearate).

[0024] US20080317853A1 discloses an orally disintegrating compressed tablet composition comprising (a) an active pharmaceutical agent (clonazepam), (b) a filler, having an average particle size of 150 microns or greater, in an amount of about 42 to 72% by weight, and wherein said filler is in a directly compressible granulated, compacted, or agglomerated form; (c) silicon dioxide ranging from about 10 to 30% by weight, wherein said silicon dioxide covers the surface of said filler and does not form any adsorbate with said active pharmaceutical agent, and optionally an effervescent couple.

[0025] Document W02003061623 discloses a solid orodispersible pharmaceutical form comprising (a) granules consisting of lactose and starch that have been co-dried, in which the lactose / starch ratio is between 90 / 10 and 25 / 75, preferably between 85 / 15 and 50 / 50, and (b) at least one active substance.

[0026] Document CN110420190 describes a clonazepam tablet, which includes the following parts by weight: 0.5-1.5 parts of clonazepam, 25-50 parts of a first filler, 5-50 parts of a second filler, 0.05-1.5 parts of an adhesive, 0.05-1 part of a first lubricant, 0.05-0.5 parts of a second lubricant and sufficient amount of purified water. The first lubricant is talc and the second lubricant is magnesium stearate. The first filler is lactose and microcrystalline cellulose. The lactose-microcrystalline cellulose ratio is 0.5-1:0.8~1.2. The second filler is corn starch and pregelatinized starch in a ratio of 0.8-1.2:0.6-1.0. The dissolution rate is greater than 75% in 35 minutes.

[0027] Samreen Fathima et al (2019) describe a stable orally disintegrating tablet (ODT) formulation of clonazepam. Orally disintegrating tablets of clonazepam were prepared by the direct compression method. Six different formulations were studied by varying the concentration and combination of superdisintegrants such as croscarmellose sodium (CCS), crospovidone (CP), and sodium starch glycolate (SSG). The formulation of different batches was by utilizing three different superdisintegrants and other ingredients at varying concentrations. Formulations C1, C2 (with crospovidone + croscarmellose sodium) were prepared.

[0028] - 5%, 10%), formulations C3, C4 (with sodium starch glycolate + crospovidone

[0029] - 5%, 10%) and formulations C5, C6 (with sodium starch glycolate + croscarmellose sodium - 5%, 10%). Tablet dissolution data are shown in Table 5.

[0030] The paper by Shirsand, SB, et al (2008) describes the preparation of rapidly dissolving clonazepam tablets by the direct compression method. Three superdisintegrants, namely crospovidone, croscarmellose sodium, and sodium starch glycolate, were used in different proportions with microcrystalline cellulose (Avicel PH-102) along with directly compressible mannitol (Pearlitol SD 200) to improve mouthfeel. The prepared batches of tablets were evaluated for hardness, friability, uniformity of drug content, wetting time, water absorption ratio, and in vitro dispersion time. Based on the in vitro dispersion time (approximately 13 seconds), three formulations were tested for in vitro drug release pattern (in phosphate buffer pH 6.8), short-term stability (at 40 e / 75% relative humidity for 6 months) and drug stability and excipient interaction (IR spectroscopy).

[0031] OBJECT OF THE INVENTION

[0032] Considering the problems previously raised and the latent deficiencies of the state of the art, it is clear that there is still a need for new orodispersible solid oral compositions that exhibit rapid disintegration and provide a release profile substantially similar to that of a liquid oral composition and that can also be manufactured with low friability and using ordinary tablet production techniques.

[0033] To solve, at least in part, this problem, the present invention provides an improved orally disintegrating solid dosage form that surprisingly has a clonazepam release profile similar to or equal to the clonazepam release profile of an immediate release clonazepam liquid composition.

[0034] In another embodiment of the present invention, an improved orally administered solid pharmaceutical composition of clonazepam is provided, which dissolves rapidly and provides pleasant organoleptic properties for the patient.

[0035] In another embodiment of the present invention there is provided an improved pharmaceutical composition of clonazepam that is capable of dissolving in about 60 seconds or less in the mouth of the patient.

[0036] In another embodiment of the present invention, there is provided an improved orally administrable solid pharmaceutical composition comprising a therapeutically effective amount of clonazepam; a combination of a hydrophilic diluent with a glidant and a disintegrating agent, and one or more pharmaceutically acceptable additives.

[0037] In another embodiment of the present invention, a pharmaceutical composition is provided wherein the combination of a hydrophilic diluent agent with a glidant agent and with a disintegrating agent are in a proportion that is in percentages of 80-99:0.2-1.0:1-3, respectively, where the percentages by weight are expressed in relation to the total weight of the composition.

[0038] Another embodiment of the present invention relates to an orally administered tablet, comprising a therapeutically effective amount of clonazepam, wherein after administration said composition substantially disintegrates in the oral cavity of a patient and provides a clonazepam release profile substantially similar to or equal to the clonazepam release profile presented by an immediate release clonazepam composition.

[0039] Another embodiment of the present invention relates to an oral administration tablet, which disintegrates rapidly, in a time not exceeding 1 minute and has a friability of not more than 1%.

[0040] Another embodiment of the present invention relates to a rapidly disintegrating tablet for oral administration that has at least one or more of the following properties: hardness of 1 to 4 Kp; friability of 1.0% or less, disintegration time of 60 seconds or less, and a clonazepam release profile similar to or equal to the clonazepam release profile of a liquid formulation.

[0041] Another embodiment of the present invention relates to a process for the preparation of a tablet for oral administration by direct compression comprising a therapeutically effective amount of clonazepam, wherein after administration said composition substantially disintegrates in the oral cavity of a patient and provides a clonazepam release profile substantially similar to or equal to the clonazepam release profile presented by an immediate release clonazepam composition.

[0042] Another embodiment of the present invention relates to an orally disintegrating tablet (ODT) composition comprising a therapeutically effective amount of clonazepam, a sweetening and / or taste-masking agent, and optionally also providing a pleasing aroma and color to the patient, wherein upon administration said composition substantially disintegrates in the oral cavity of a patient and provides a clonazepam release profile that is substantially the same as the clonazepam release profile of an immediate release clonazepam composition.

[0043] BRIEF DESCRIPTION OF THE FIGURES

[0044] Figure 1 illustrates the dissolution profile of 10 tablets of 0.1 mg of the orodispersible solid pharmaceutical composition according to the present invention in 500 mL.

[0045] Figure 2 illustrates the dissolution profile of 1 tablet of 0.1 mg of the orodispersible solid pharmaceutical composition according to the present invention versus 1 drop of 0.1 mg of the commercial product Rivotril® in a volume of 500 mL.

[0046] Figure 3 illustrates the dissolution profile of different orodispersible solid pharmaceutical compositions (C1611688, C1611690 and C1711561) according to the present invention versus the commercial product Rivotril® in a volume of 500 mL.

[0047] Figure 4 illustrates the dissolution profile of 10 tablets of 0.1 mg of the orodispersible solid pharmaceutical composition according to the present invention versus 10 drops of 0.1 mg of the commercial product Rivotril® in a sequenced dissolution method with simulated saliva.

[0048] Figure 5 illustrates the bioavailability profile, where the average plasma concentration was evaluated in different subjects administered 10 tablets of the solid orodispersible pharmaceutical composition compared to other subjects administered 10 drops of 0.1 mg of the commercial product Rivotril®.

[0049] DETAILED DESCRIPTION OF THE INVENTION

[0050] The present invention exhibits certain advantages over the prior art, among which may be mentioned the production of a solid orodispersible composition in the form of tablets, preferably with a clonazepam concentration of 0.1 mg each. Furthermore, said composition has a disintegration time of less than one minute, friability <1%, and a hardness of between 1 and 4 Kp. More particularly, the pharmaceutical composition according to the present invention has the advantage of presenting a bioequivalent dissolution profile to the reference product Rivotril® (2.5 mg / mL), which is characterized by being presented in a pharmaceutical form of oral drops where each drop has a concentration of 0.1 mg.

[0051] A first aspect of the present invention relates to an orodispersible solid pharmaceutical composition, characterized in that it comprises clonazepam in a concentration of between 0.1 and 1% (w / w); at least one hydrophilic diluting agent in a concentration of between 80 and 98% (w / w); at least one glidant in a concentration of between 0.2 and 1.0% (w / w); at least one disintegrating agent in a concentration of between 1.0 and 3.0% (w / w); at least one sweetening and / or masking agent in a concentration of between 0.4 and 2.0% (w / w); and at least one hydrophilic lubricating agent in a concentration of between 0.3 and 2.5% (w / w).

[0052] In a preferred embodiment, the orodispersible solid pharmaceutical composition comprises clonazepam in a concentration of 0.33% (w / w); at least one hydrophilic diluent agent in a concentration of 94.5% (w / w); at least one glidant in a concentration of 0.67% (w / w); at least one disintegrating agent in a concentration of 1.5% (w / w); at least one sweetening and / or masking agent in a concentration of 1.0% (w / w); and at least one hydrophilic lubricating agent in a concentration of 2.0% (w / w).

[0053] Preferably, the solid orodispersible pharmaceutical composition is adapted for oral administration and is presented in tablet form.

[0054] A second aspect of the present invention relates to a method for obtaining an orodispersible solid composition according to the present invention, comprising the steps of: (i) mixing at least one hydrophilic diluent agent, at least one glidant, at least one disintegrating agent and at least one sweetening and / or masking agent; (ii) homogenizing the mixture; (iii) adding at least one active ingredient to the mixture and homogenizing; (iv) dispersing the mixture; (v) lubricating the mixture with at least one hydrophilic lubricating agent; and (vi) compressing the mixture to obtain tablets.

[0055] For the purposes of the present invention, it should be understood that the terms “orodispersible, dispersion or orally disintegrating” are used interchangeably to refer to a composition or dosage form that disintegrates in the mouth, without the need to supply water.

[0056] For the present invention, it should be understood that the terms "disintegrant" or "superdisintegrant" are used interchangeably and refer to those agents that allow a tablet to be broken down into small particles, thereby generating a larger surface area. This will favor contact of the aqueous medium with the active ingredient, thereby improving the bioavailability of the active component, that is, facilitating its dissolution in fluids and subsequent absorption. Multiple superdisintegrants, both natural and synthetic, are known in the state of the art. Of particular interest are the superdisintegrants povidone, cross-linked sodium carboxymethylcellulose or croscarmellose sodium, cross-linked polyvinylpyrrolidone or crospovidone, starch and its derivatives, such as sodium starch glycolate, low-substituted hydroxypropylcellulose, and the like, as well as combinations of one or more thereof. In a preferred embodiment, the disintegrant is crospovidone.

[0057] For the purposes of the present invention, the term “lubricant” should be understood to refer to those agents used to reduce dynamic friction. Among the suitable lubricants, those suitable for tabletting are preferred, such as sodium fumarate, a stearate (e.g., magnesium stearate, aluminum stearate, calcium stearate, zinc stearate, and the like), talc, or a fatty acid (e.g., hexanedioic acid), adipic acid, cetyl alcohol, fumaric acid, glyceryl monostearate, glyceryl palmitostearate, glyceryl tripalmitate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, magnesium lauryl sulfate, mineral oil, myristic acid, myristic alcohol, palmitic acid, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, stearyl alcohol, and triglycerides.Among the preferred lubricants are hydrophilic lubricants such as sodium stearoyl fumarate, talc, polyethylene glycol, stearic acid and its salts, and combinations of one or more of these. In a preferred embodiment, the hydrophilic lubricant is sodium stearoyl fumarate.

[0058] For the purposes of the present invention, the term "glidant" should be understood to refer to an agent that allows for a homogeneous distribution of the active ingredient within the composition and good fluidity of the final mixture. Preferably, the glidant is selected from silica and its derivatives, colloidal silica, silicon dioxide, magnesium or calcium silica, and talc, and / or combinations thereof. In a preferred embodiment, the glidant is silicon dioxide.

[0059] For the purposes of the present invention, the term “diluent” should be understood to refer to an agent that allows rapid dissolution, homogeneous distribution and filling of the tablet contents.Examples of diluents that may be used in the invention include, without limitation, saccharides such as monosaccharides, oligosaccharides or polysaccharides, and / or their oxidized and / or reduced forms; bose, lactose in its various forms, anhydrous, monohydrated, agglomerated or atomized; sugar alcohols such as mannitol, maltol, sorbitol, maltitol, xylitol, somalta and erythritol, powdered cellulose, microcrystalline cellulose, silylated microcrystalline cellulose or chemically modified cellulose derivatives, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose; somalta, starch and its derivatives, sucrose, pharmaceutically acceptable inorganic compounds such as dibasic calcium phosphate, calcium or magnesium carbonates, magnesium oxide, sugar alcohols selected from mannitol, sorbitol, maltitol, maltol, somalta, xylitol, erythritol or mixtures thereof. Hydrophilic diluents are preferred.In a preferred embodiment, the hydrophilic diluent is a carbohydrate selected from lactose, lactose derivatives, starch, starch derivatives, and / or combinations of one or more thereof; in an even more preferred embodiment, the diluent is a combination of lactose and starch (85:15).

[0060] For the purposes of the present invention, the term "pharmaceutically acceptable additive" should be understood to refer to any substance included in the formulation of a medicament and that acts as a vehicle, preservative, or modifier of some of its characteristics to enhance its efficacy, safety, stability, appearance, acceptability, processing, or manufacturing. Furthermore, it must be appropriate for the pharmaceutical form of interest. The composition of the present invention may include one or more of these conventional additives known in the art to improve the dosage form, which could include, for example, but are not limited to, sweetening agents, masking agents, flavoring agents, and natural and artificial flavoring agents.Examples of such agents include sugar and sugar substitutes, gluconate, sodium saccharin, lithium saccharin, cyclamate, or mixtures thereof; mannitol, sorbitol, maltitol, xylitol, sucralose, steviosides, aspartame, acesulfame K, ammonium glycyrrhizate, natural and synthetic flavors such as tartaric acid, etc.

[0061] Preferably, the sweetening or masking agent is selected from sucralose, steviosides, acesulfame K, ammonium glycyrrhizate, aspartame, and combinations of one or more thereof. More preferably, the sweetening or masking agent is sucralose.

[0062] Preferably, the hydrophilic diluent agent has an average particle size of at least 25 pm.

[0063] Preferably, the slip agent has an average particle size of at least 5 pm.

[0064] Preferably, the disintegrating agent has an average particle size of between 25 and 40 pm.

[0065] Preferably, the active ingredient is clonazepam and has an average particle size D90 not greater than 20 pm.

[0066] Preferably, the tablets obtained in step (vi) have a weight of at least 30 mg, a friability < 1% and a hardness of between 1 and 4 Kp.

[0067] Those skilled in the art of compounding pharmaceutical drugs will appreciate that the amount of these agents will depend on the desired properties, considering that rapidly disintegrating oral pharmaceutical compositions must have a pleasant taste and mouthfeel.

[0068] The examples shown below are for the sole purpose of illustrating some of the embodiments of the present invention, and should in no way be considered as limiting in any way, since a person skilled in the art will be able to design alternative embodiments without departing from the spirit of the present invention.

[0069] EXAMPLE 1

[0070] This example describes the process for obtaining the orodispersible solid composition of clonazepam in accordance with the present invention.

[0071] First, a hydrophilic diluent with a particle size of at least 25 µm, a glidant with a particle size of at least 5 µm, a disintegrating agent with an average particle size between 25 and 40 µm, and a sweetening and / or masking agent were mixed. Once the mixture was obtained, it was homogenized and the active ingredient with an average particle size D90 no greater than 20 µm (clonazepam) was added for further homogenization. Finally, the mixture was dispersed, lubricated with a hydrophilic lubricating agent, and compressed to obtain tablets with a weight of at least 30 mg, a hardness between 1 and 4 Kp, a friability less than or equal to 1%, and a disintegration time less than or equal to 1 minute.

[0072] Table 2 below shows the components and concentrations used in the mixture to obtain the orodispersible solid pharmaceutical composition in accordance with the present invention.

[0073] TABLE 2 EXAMPLE 2

[0074] In the present example, the in vitro dissolution profile of the orodispersible solid pharmaceutical composition of clonazepam in the form of 0.1 mg tablets obtained by the process described in example 1 in accordance with the present invention is evaluated. Furthermore, in a second test, the in vitro dissolution profile of the orodispersible solid pharmaceutical composition in the form of 0.1 mg clonazepam tablets was evaluated against the commercial product Rivotril® (2.5 mg / mL), which is characterized by being presented in a pharmaceutical form of oral drops (2.5 mg / mL), where each drop has a concentration of 0.1 mg.

[0075] For better reference, the components and concentrations of the composition evaluated, identified hereafter as C171 1561, are shown in Table 3.

[0076] TABLE 3

[0077] For the evaluation of the dissolution profile of the orodispersible solid pharmaceutical composition, the paddle method was used in accordance with the United States Pharmacopoeia (USP). The test consisted of dissolving 10 tablets of the orodispersible solid pharmaceutical composition (C171 1561 ) in a volume of 500 mL of water as a dissolution medium at a temperature of 37 °C ± 0.5 °C, with constant stirring at a speed of 50 rpm and 6 sampling times (5, 10, 15, 30, 45 and 60 minutes). The profile results are presented in Figure 1 .

[0078] The second test consisted of dissolving 1 tablet of the orodispersible solid composition (C1711561 ) against 1 drop of Rivothl® in a volume of 500 mL of water at a temperature of 37 °C ± 0.5 °C, with constant stirring at a speed of 50 rpm and 6 sampling times (5, 10, 15, 30, 45 and 60 75 minutes). The results are presented in Figure 2, where it can be seen that the behavior of the tablet dissolution profile is similar to that of the Rivotril® solution.

[0079] EXAMPLE S

[0080] In the present example, the dissolution profile of orodispersible solid pharmaceutical compositions in the form of tablets with a clonazepam concentration of 0.1 mg was analyzed with components and concentrations (C161 1688 and C161 1690) different from those used in the pharmaceutical composition evaluated in the previous examples (C171 1561). In addition, the different pharmaceutical compositions were evaluated against the commercial product Rivotril® (2.5 mg / mL), which is characterized by being presented in a pharmaceutical form of oral drops where each drop has a concentration of 0.1 mg. The different pharmaceutical compositions are presented in Table 4 for better reference.

[0081] TABLE 4

[0082] The test consisted of dissolving 10 tablets of the orodispersible solid compositions in a volume of 500 mL of water versus 10 drops of Rivotril® in a volume of 500 mL of water at a temperature of 37 °C ± 0.5 °C, with constant stirring at a speed of 50 rpm and 6 sampling times (5, 10, 15, 30, 45 and 60 minutes). The results of the profiles are presented in Figure 3. This figure also indicates the similarity factor (F2) of each profile obtained for the three compositions evaluated with respect to the commercial product Rivotril®.

[0083] The similarity factor, which is a measurement of the similarity in percentage dissolution (%) between the two curves, ensures the equality or equivalence of the 2 curves when the value of the similarity factor is greater than 50. From Figure 3 it can be seen that the dissolution profile behavior of the C171 1561 tablets is similar to that of the commercial product Rivotril® since the similarity factor is 52. This shows that the similarity factor is higher than that presented in the C1611688 tablets with a similarity factor of 38 and in the C161 1690 tablets with a similarity factor of 31. Therefore, the advantage that the C171 1561 tablets have over the others is verified. From the above it can be inferred that the lubricant is an important excipient in the orodispersible pharmaceutical composition.The use of sodium stearyl fumarate, as can be seen from the dissolution profile, is extremely effective and has a less retarding effect on tablet dissolution than other lubricants.

[0084] EXAMPLE 4

[0085] In the present example, the in vitro dissolution profile in a simulated saliva + HCI sequenced dissolution medium with a pH of 1.2 of the orodispersible solid pharmaceutical composition in the form of 0.1 mg clonazepam tablets from example 2 (C1711561) in accordance with the present invention is evaluated against the commercial product Rivotril® (2.5 mg / mL), which is characterized by being presented in a pharmaceutical form of oral drops (2.5 mg / mL), where each drop has a concentration of 0.1 mg.

[0086] The dissolution profile of the orodispersible solid pharmaceutical composition was evaluated using the paddle method in accordance with the United States Pharmacopoeia (USP). The test consisted of dissolving 10 tablets of the orodispersible solid composition in a sequenced dissolution method with simulated saliva and 500 mL of water versus 10 drops of Rivotril® in a sequenced dissolution method with simulated saliva and 500 mL of water at a temperature of 37 °C ± 0.5 °C, with constant stirring at a speed of 50 rpm and 7 sampling times (5, 10, 15, 30, 45, 60 and 75 minutes). The results of the profile are presented in Figure 4, where it can be seen that the dissolution profile behavior of the tablets is similar to that of the commercial product Rivotril®.

[0087] From the results obtained previously, it is clear that the orodispersible solid pharmaceutical composition of the present invention has a dissolution pattern "similar" to that of the reference product, which is a clonazepam solution. The dissolution profiles can be considered similar based on (1) the overall similarity of the profiles and (2) the similarity at each time point of dissolution of the sample. To quantitatively determine how "similar" the dissolution profiles are, the similarity factor was determined, considering the data shown in Table 5 of the dissolution profile.

[0088] TABLE 5

[0089] To determine the Similarity Factor (F2), the following equation was used:

[0090] F2= (LOG(((SUM / n+1 ) A -0.5)*100))*50

[0091] F2= 71

[0092] As previously indicated, the Similarity Factor “is a measurement of the similarity in percentage dissolution (%) between the two curves” that ensures the equality or equivalence of the 2 curves when the value of the similarity factor is greater than 50. In the present test the similarity factor obtained is 71. The results clearly demonstrate that the dissolution factor of clonazepam obtained from the orodispersible solid pharmaceutical composition in accordance with the present invention is practically equal to the dissolution pattern of the oral drops pharmaceutical form of the reference product RIVOTRIL® as can be seen in Figure 4.

[0093] With this result, the inventors of the present application have managed to overcome one of the problems of the state of the art, by obtaining a solid orodispersible pharmaceutical composition that presents the same dissolution pattern as a liquid pharmaceutical form of clonazepam, which represents a surprising advance since, as previously indicated, the solid oral forms of clonazepam that exist in the market have as a limitation the dissolution speed of the active ingredient, which is classified as poorly soluble (Biopharmaceutical classification II), which in turn affects its absorption and bioavailability. Consequently, the dissolution stage of clonazepam affects both the onset and the intensity and duration of its pharmacological effect.

[0094] EXAMPLE S

[0095] The objective of this study was to compare the bioavailability of the orodispersible solid pharmaceutical composition in the form of 0.1 mg tablets (C171 1561 ) 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 interchangeability in terms of absorption rate and magnitude (Cmax and AUC) was demonstrated.

[0096] Study design.

[0097] A single-dose study was designed per period, 02 treatments, 02 periods. The administration of the treatments was randomly assigned, with an approximate duration of 1 12 h per period, with a washout period of 15 days between periods and a total duration of the study of approximately 23 days, including post-study assessment. The study was carried out with a homogeneous population in terms of age, height and weight with healthy individuals (n = 26), of both genders and an age between 18 to 55 years. The above in accordance with the provisions of NOM-177-SSA1 -2013. The dose administered to the individuals was 1 mg of clonazepam. Therefore, 10 tablets of the solid orodispersible pharmaceutical composition were administered in accordance with the present invention and with respect to the commercial product, 10 drops of Rivotril® dissolved in 250 mL of water were administered.

[0098] Blood samples were collected to determine the plasma concentration of clonazepam. The active ingredient clonazepam was quantified from these blood samples (hepatic plasma) using ultra-performance liquid chromatography coupled with tandem mass spectrometry.

[0099] The results of the study are shown in Figure 5, which evaluates the average plasma concentration of clonazepam versus sampling time on an arithmetic scale. The pharmacokinetics, although slightly different, remain within the bioequivalence range: at a single dose of 1 mg, the reference formulation reaches a Cmax of 10.35 ng / mL in 0.69 h, with a ti / 2 of 42.23 h and an area under the curve (AUC) of 203.52 h-ng / mL; with orodispersible tablets, the Cmax is 8.73 ng / mL, the tmax is 0.78 h, the ti / 2 is 41.94 h and the AUC is 191.67 h-ng / mL.

[0100] The results of the statistical analysis of comparative bioavailability of clonazepam for Cmax and AUC-t are presented in Table 6 below.

[0101] TABLE 6

[0102] 90%CI, Classical 9D% confidence interval; TDU, Two-tailed T test

[0103] The results show that the standard 90% confidence intervals for Cmax and AUC-t are within the acceptance range of 80% to 125%. The probability values ​​obtained from Schulmannen's two-tailed t test for the pharmacokinetic parameters Cmax and AUC-t indicate that the compared products have similar bioavailability. Finally, the statistical power of the study is greater than 99% for Cmax and AUC-t.

[0104] In strict compliance with the comparative bioavailability acceptance criteria established in this study and NOM-177-SSA1 -2013, it is concluded that the solid orodispersible pharmaceutical composition in the form of tablets in accordance with the present invention has bioavailability similar to the reference drug RIVOTRIL®, thereby demonstrating the interchangeability of said products.

[0105] In accordance with the above, it can be seen that the orodispersible solid pharmaceutical composition according to the present invention has been designed for the administration of clonazepam, and it will be evident to any person skilled in the art that the embodiments of the pharmaceutical composition as described above and illustrated in the accompanying drawings 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.

[0106] Therefore, the present invention should not be considered as restricted except as required by the prior art and by the scope of the appended claims.

[0107] LITERATURE

[0108] SAMREEN FATHIMA, et al (2019), “Formulation and Evaluation of Clonazepam Oro Dispersible Tablets'', JOURNAL OF DRUG DEVELOPMENT AND DELIVERY, 2019, vol 2:1 , pages 19-24.

[0109] SHIRSAND, SB, et al, “Design and Evaluation of Fast Dissolving Tablets of Clonazepam'', INDIAN JOURNAL OF PHARMACEUTICAL SCIENCES, 2008, vol. Nov-Dec 70, no. 6, pages 791 -795.

Claims

CLAIMS 1. A solid orodispersible pharmaceutical composition, characterized in that it comprises clonazepam in a concentration between 0.1 and 1% (w / w); at least one hydrophilic diluting agent in a concentration between 80 and 98% (w / w); at least one glidant in a concentration between 0.2 and 1.0% (w / w); at least one disintegrating agent in a concentration between 1.0 and 3.0% (w / w); at least one sweetening and / or masking agent in a concentration between 0.4 and 2.0% (w / w); and at least one hydrophilic lubricating agent in a concentration between 0.3 and 2.5% (w / w).

2. The pharmaceutical composition according to claim 1, further characterized in that it comprises clonazepam in a concentration of 0.33% (w / w); at least one hydrophilic diluting agent in a concentration of 94.5% (w / w); at least one glidant in a concentration of 0.67% (w / w); at least one disintegrating agent in a concentration of 1.5% (w / w); at least one sweetening and / or masking agent in a concentration of 1.0% (w / w); and at least one hydrophilic lubricating agent in a concentration of 2.0% (w / w).

3. The pharmaceutical composition according to claim 1, further characterized in that the hydrophilic diluent agent is a carbohydrate selected from lactose, lactose derivatives, starch, starch derivatives and combinations of one or more thereof.

4. The pharmaceutical composition according to claim 1, further characterized in that the hydrophilic diluent agent is a combination of lactose and starch in a ratio of at least 85:

15.

5. The pharmaceutical composition according to claim 1, further characterized in that the glidant is selected from silica and its derivatives, silicon dioxide, colloidal silica and combinations of one or more thereof.

6. The pharmaceutical composition according to claim 1, further characterized in that the sliding agent is silicon dioxide.

7. The pharmaceutical composition according to claim 1, further characterized in that the disintegrating agent is selected from povidone, crospovidone, polyvinylpyrrolidone, croscarmellose, carboxymethylcellulose, starch, derivatives thereof, and combinations of one or more thereof.

8. The pharmaceutical composition according to claim 1, further characterized in that the disintegrating agent is crospovidone.

9. The pharmaceutical composition according to claim 1, further characterized in that the hydrophilic lubricating agent is selected from sodium stearate, talc, polyethylene glycol, stearic acid and their salts; and combinations of one or more thereof.

10. The pharmaceutical composition according to claim 1, further characterized in that the hydrophilic lubricating agent is sodium steahl fumarate.

11. The pharmaceutical composition according to claim 1, further characterized in that the sweetening and / or masking agent is selected from sucralose, steviosides, acesulfame k, ammonium glycyrrhizate, aspartame, and combinations of one or more thereof.

12. The pharmaceutical composition according to claim 1, further characterized in that the sweetening and / or masking agent is sucralose.

13. The pharmaceutical composition according to claim 1, further characterized in that the clonazepam particle has an average particle size D90 of no more than 20 pm.

14. The pharmaceutical composition according to claim 1, further characterized in that it is adapted for oral administration.

15. The pharmaceutical composition according to claim 1, further characterized in that it is presented in the form of a tablet.

16. The pharmaceutical composition according to claim 1, further characterized in that it has a disintegration time of less than one minute, a friability < 1% and a hardness of between 1 and 4 Kp.

17. A method for obtaining a solid orodispersible pharmaceutical composition according to claim 1, characterized in that it comprises the steps of: (i) mixing at least one hydrophilic diluent agent, at least one glidant, at least one disintegrating agent and at least one sweetening and / or masking agent; (ii) homogenizing the mixture; (iii) adding the active ingredient to the mixture and homogenizing; (iv) dispersing the mixture; (v) lubricating the mixture with at least one hydrophilic lubricating agent; and (vi) compressing the mixture to obtain tablets.

18. The method according to claim 17, further characterized in that the hydrophilic diluent agent has an average particle size of at least 25 pm.

19. The method according to claim 17, further characterized in that the slip agent has an average particle size of at least 5 pm.

20. The method according to claim 17, further characterized in that the disintegrating agent has an average particle size of between 25 and 40 pm.

21. The method according to claim 17, further characterized in that the active ingredient is clonazepam and has an average particle size D90 of no more than 20 pm.

22. The method according to claim 17, further characterized in that the tablets obtained in step (vi) have a weight of at least 30 mg, a friability < 1% and a hardness of between 1 and 4 Kp.

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