Oral pharmaceutical form for biphasic release, composed of a multiparticulate system, process for preparing same and therapeutic use of oral form

Abstract

The present invention relates to an oral pharmaceutical form comprising a core, a coating layer which comprises a drug, a modified release layer, an immediate release layer which comprises an active ingredient, and a polymeric layer which constitutes the outermost layer. In addition, this layer has deposited thereon a lubricant which will remain on the surface of the pharmaceutical form. The invention provides, in a single pharmaceutical form, a biphasic release system which promotes release of the active pharmaceutical ingredient in two stages. The invention further relates to a method for manufacturing said pharmaceutical form, as well as to therapeutic use of same.

Description

“ORAL PHARMACEUTICAL FORM FOR BIPHASIC RELEASE, COMPRISING A MULTIPARTICULATED SYSTEM, PROCESS FOR PREPARING IT AND THERAPEUTIC USE OF THE ORAL FORM” Field of Invention

[0001] The present invention relates to a pharmaceutical form comprising an inert core, a coating layer comprising the active pharmaceutical ingredient (API) trazodone, a modified release layer, an immediate release layer comprising the API, and a polymeric layer, which refers to the outermost layer. Furthermore, a glidant will be deposited on this layer, which will remain on the surface of the pharmaceutical form, eliminating the static energy of the microgranules and providing desirable differentials in the production process.

[0002] The present invention also relates to a controlled drug release system capable of promoting the biphasic release of trazodone. Said controlled drug release system is also capable of promoting the biphasic release of other compounds such as, for example, mirtazapine, cannabidiol, zolpidem, zopiclone, cyclobenzaprine, quetiapine, clonazepam, among others.

[0003] Furthermore, the invention relates to a process for manufacturing said pharmaceutical form, as well as its therapeutic use.

[0004] The invention relates to multiparticulate systems containing the drug subdivided into functional units, which may be pellets, granules or mini-tablets. These systems offer technological and biopharmaceutical advantages when compared to monolithic systems, and also provide therapeutic benefits for patients. For this reason, they have increasingly stood out among the new pharmaceutical forms and drug delivery systems. Fundamentals of the Invention

[0005] Trazodone is a triazolopyridine derivative that belongs to the class of serotonin type 2 (5-HT2) receptor antagonist and serotonin reuptake inhibitor (SERT). Although its mechanism of action is not fully understood, the main pharmacological action of trazodone is the blockade of the 5-hydroxytryptamine 2A (5-HT2A) receptor. Higher doses of trazodone cause antagonism at histamine H1 and a1-adrenergic receptors. It is believed that the blockade of 5-HT2A, histamine H1 and alpha receptors produces the hypnotic effect reported for low doses of trazodone. At low doses, trazodone induces and maintains sleep, without causing daytime drowsiness or tolerance, mainly due to its short half-life (3 to 6 hours). For the antidepressant effects of the medication to be effective, simultaneous blockade of 5-HT2A and SERT is necessary, which occurs at higher doses (150 to 600 mg). Tolerance may occur during the combined antagonism actions of 5-HT2A and SERT.

[0006] Trazodone is a psychoactive compound with sedative and antidepressant properties that is rapidly absorbed from the upper gastrointestinal tract and extensively metabolized after oral administration. Trazodone is typically used to relieve symptoms of depression, such as feelings of sadness, worthlessness, or guilt; loss of interest in daily activities; changes in appetite; tiredness; and thoughts of death or suicide.

[0007] Trazodone is normally used in its hydrochloride form as formula I below. The preparation of this compound was first disclosed in U.S. patent 3,381,009, Formula I

[0008] Trazodone's solubility is pH-dependent and has a pKa of 6.74 in water. As a result, trazodone is highly soluble in acidic media (as found in the stomach and upper intestine), i.e. when the pH of the medium is below its pKa. In contrast, when above its pKa, its solubility is very low, e.g. in the neutral and basic conditions of the large intestine. Such insolubility obviously has an effect on its dissolution and hence on the availability of the active pharmaceutical ingredient for absorption in the large intestine. These characteristics would therefore be expected to hinder the development of long-acting forms of trazodone (e.g. more than 8 hours), which require substantially uniform absorption throughout the gastrointestinal tract, in particular absorption during passage through both the upper and lower intestinal tracts.

[0009] As with many medications, trazodone is typically prescribed as an immediate-release form for twice-daily (BID) or three times-daily (TID) use, with all the drawbacks and disadvantages that this entails. For example, multiple daily doses may result in blood concentrations of the active pharmaceutical ingredient that do not remain within the normal range. called the therapeutic range and which, therefore, may be associated with greater risks of dose-related adverse effects when reaching high levels, or a lower degree of efficacy when reaching low levels.

[0010] As a result, there is a need for new trazodone release systems capable of making this active ingredient available more effectively, promoting the optimization of the distribution of the API throughout the body, avoiding undesirable fluctuations in its concentration and, thus, influencing the duration of the drug's action and side effects resulting from its use.

[0011] Document US 2006 / 172006 relates to a composition in the form of a controlled-release tablet of tramadol hydrochloride that provides analgesic effect within 2 hours after oral administration and for at least 24 hours after administration. The 200 mg dose of this controlled-release composition of the invention would provide a rapid onset of analgesic effect within 2 hours after oral administration and an average plasma concentration of tramadol between 100 ng / mL and 200 ng / mL for at least 24 hours after a single dose. The tablet core of said document would comprise at least one active ingredient and a matrix, and these components would be associated in such a way that the release of the pharmaceutical ingredient from the matrix would be controlled. In one embodiment of the invention, the matrix of the core would be a cross-linked starch with high amylose content (Contramid ©).The composition of the core may also include binders, lubricants, disintegrating agents and pharmaceutically acceptable carriers.

[0012] The Penumatcha Document, Kiran, 2003 1 refers to a tablet preparation comprising a controlled-release trazodone hydrochloride matrix, in which trazodone is dispersed in a hydroxypropylmethyl cellulose (HPMC) matrix. The tablet further comprises excipients such as microcrystalline cellulose (Avicel©), magnesium stearate and silica dioxide 1 Penumatcha, Kiran, 2003, Trazodone hydrochloride controlled release matrix and matrix-mini tablets. Open Access Master's Theses. Paper 280. University of Rhode Island, https: / / digitalcommons.uri.edu / theses / 280 colloidal (Cab-O-Sil©). These controlled release tablets would provide desired plasma levels within the therapeutic range over a long period of time (24 hours).

[0013] Document BR PI 0615860-9 discloses a solid monolithic extended-release pharmaceutical composition in tablet form that, when subdivided into smaller dosage forms, would present substantially the same drug release profile as the composition from which it was derived. The solid extended-release composition of said document would comprise an extended-release matrix including a controlled-release excipient, preferably a cross-linked starch with high amylose content such as Contramid© and an active pharmaceutical ingredient disposed in the matrix, trazodone, in which the composition releases this active ingredient for at least 24 hours and, in which the composition has a hardness of 100 N to 350 N. The composition further comprising a binding agent, a solubilizing agent, an acidifying agent, a pore-forming agent, a lubricant and a glidant.

[0014] As can be seen, different oral pharmaceutical forms have been developed to control the release profile of trazodone, particularly tablet pharmaceutical forms using controlled release strategies of the active pharmaceutical ingredient to achieve stable and effective concentrations for 24 hours or more.

[0015] It is based on this scenario that the invention in question arises, which provides a stable pharmaceutical form and a biphasic release system that promotes the release of the active pharmaceutical ingredient trazodone in two stages to maintain therapeutic levels, particularly for the treatment of sleep disorders, minimizing nocturnal awakenings and improving the induction and maintenance of sleep throughout the night.

[0016] It should also be noted that the proposed IFA release system is innovative because it combines, in a single pharmaceutical form, a core, an active ingredient coating layer, a modified release layer and an immediate release layer of the active ingredient in order to release the active pharmaceutical ingredient at different times in two immediate release peaks of the active ingredient, the first release peak being up to two hours after administration and the second peak between four and seven hours after administration. A polymeric film is also deposited on the immediate release layer and a glidant is added to this outermost layer, which will remain on the surface of the pharmaceutical form.

[0017] Thus, the invention offers a new drug release system, which provides the desired therapeutic effect for inducing and maintaining sleep throughout the night through a biphasic release technology, which consists of two peaks of immediate drug release that behave like a prolonged release, favoring the induction of sleep after ingestion of the medication and promoting the maintenance of sleep, which is sustained with the second peak of release of the active ingredient.

[0018] Trazodone is currently indicated for the treatment of depression, and to obtain antidepressant effects it is necessary to simultaneously block 5-HT2A and serotonin reuptake, which occurs at higher doses (150-600 mg).

[0019] Increasing the dose of trazodone causes antagonism at histamine H1 and adrenergic α1 receptors. However, trazodone has moderate antihistamine activity and low anticholinergic activity, and moderates cortisol suppression of the hypothalamic-pituitary-adrenal axis, which probably contributes to its efficacy in insomnia. Blockade of 5-HT2A, histamine H1 and alpha receptors is thought to produce the hypnotic effect reported for low doses of trazodone (25–100 mg), in which it induces and maintains sleep without causing daytime somnolence (Jaffer et al, 2017).

[0020] Data described in the scientific literature describe that trazodone may have the potential to be effective and safe in improving sleep quality.

[0021] The sedative effects of trazodone at doses of 50 mg / day for the treatment of insomnia were evaluated in 67 pregnant women, with a report of efficacy during the third trimester of pregnancy (Khazaie et al, 2013). The dose of 50 mg / day was also effective in patients with Alzheimer's disease (Camargos et al, 2014), and was also effective in maintaining sleep in a double-blind controlled study (Roth et al, 2011).

[0022] A double-blind controlled study in patients with Alzheimer's disease demonstrated that a dose of 50 mg / day was safe and effective in treating insomnia in this patient population (Camargos et al, 2014). Another cohort study of postmenopausal women reported that both zopiclone and trazodone (50-100 mg / day) improved sleep quality and sexual dysfunction (Eraslan et al, 2014).

[0023] Doses of 25-150 mg / day have been shown to improve sleep quality in patients with primary insomnia with a mean age of 46 years (Wichniak et al, 2007).

[0024] Trazodone increased slow waves during sleep in healthy volunteers at daily doses of 50 and 100 mg (Yamadera et al, 1999). Improvement in sleep quality was also observed in a study with daily doses of 50-100 mg for the treatment of antidepressant-induced secondary insomnia (Nierenberg et al, 1994).

[0025] In summary, the proposal to develop formulations with biphasic release is based on the premise that trazodone has effects on sleep quality at lower doses than those indicated for the treatment of depression.

[0026] As already reported, there are reports in the literature about its antihistamine activity and low anticholinergic activity, believing that the blockade of 5-H2A, histamine H1 and alpha receptors produces the hypnotic effect in doses between 25- 100 mg.

[0027] Based on the above, a clinical trial was conducted using a double-blind design, with the aim of evaluating the impact of medication on the quality and total time of sleep, in addition to quantifying the decrease in sleep latency in patients diagnosed with comorbid insomnia, through actigraphy and assessment scales.

[0028] In order to prove the effectiveness of the developed formulation, a RANDOMIZED, CONTROLLED, CROSSOVER CLINICAL TRIAL was carried out to evaluate the quality of sleep in patients with secondary insomnia treated with trazodone or placebo. The objective of the clinical trial was to evaluate the impact of the medication on the quality and total time of sleep, in addition to quantifying the decrease in sleep latency in patients diagnosed with comorbid insomnia, through actigraphy and assessment scales. The study was carried out with 30 patients.

[0029] The results of the questionnaire analyses, as well as the subjective perception of sleep latency, total sleep time, sleep efficiency and awakenings are in the Table below. Table 1: Results of the analysis of the questionnaires and subjective perception of sleep.

[0030] The use of Trazodone improved the scores of the Hamilton Depression Scale, the Pittsburgh Sleep Quality Questionnaire, the Athens Insomnia Index, the Insomnia Severity Scale, sleep latency, total sleep time and days of the week with awakenings.

[0031] Of the 29 patients, 24 correctly completed the proposed actigraphy use time. The results are shown in Table 2. Table 2: Actigraphy analysis results.

[0032] Improvements in sleep efficiency and the number of awakenings were observed in patients after using the developed formulations.

[0033] In summary, the study data associated with the data available in the scientific literature demonstrate the safety of the trazodone formulations developed and their possible efficacy in sleep disorders, mainly with regard to improving sleep quality, demonstrated by the results obtained in the Pittsburgh sleep quality questionnaires, Athens insomnia index, insomnia severity scale, sleep latency, total sleep time and reduction in the number of awakenings through actigraphy.

[0034] In addition to this, this innovation includes the use of an excipient in the layers containing the active ingredient that acts as an antioxidant, which helps to stabilize the medication, given that, despite the active ingredient Trazodone is not susceptible to oxidative degradation, when in process, it presented a change in color and in the impurity profile.

[0035] Unlike conventional formulations, the formulation and production process proposed in the present invention present specific characteristics that could induce degradation of the product in suspension during industrial production, due to direct contact with oxygen during the production process, due to the use of a micronized active ingredient, in a long process and with high oxygen flow, which was overcome with the addition of the antioxidant in the formulation.

[0036] Still in the layers containing the active ingredient, the invention consists of having a wetting agent capable of improving the wettability of the active ingredient in an aqueous vehicle by providing a smaller contact angle between the active ingredient and the liquid, which results in a larger surface area wetted by the vehicle.

[0037] In summary, the developed formulation has technology that allows the release of two doses at different times, being an innovative treatment concept in which sleep induction is achieved at a low dose, when compared to the available literature, making it possible to release an additional dose during the night so that the patient maintains a longer period of sleep and does not wake up and, at the same time, does not experience drowsiness the following morning. Objectives of the invention

[0038] The main objective of the invention is to provide an oral pharmaceutical form for biphasic release of trazodone. Said pharmaceutical form comprises a core, an active ingredient coating layer, a modified release layer, an immediate release layer of the active ingredient and a polymeric layer, the latter being the outermost layer. Furthermore, a glidant is deposited on said pharmaceutical form, which will remain on the surface of the pharmaceutical form.

[0039] Furthermore, it is also one of the objectives of the invention to prepare a oral pharmaceutical form having a biphasic release system of the active pharmaceutical ingredient.

[0040] System in which we have an immediate release of a dose, a latency period in the release and a second dose release, which can generate a second peak in plasma concentration or a plateau in plasma concentration for a certain time.

[0041] It is a further object of the invention to provide a medicament in an oral pharmaceutical form for the treatment or prevention of disorders or diseases in an individual, particularly for the treatment of insomnia or improving the quality of sound.

[0042] Another objective of the invention is to provide drug release using a multiparticulate system, which promotes drug release in a specific manner through a pharmaceutical form. Summary of the Invention

[0043] The objectives mentioned above are, in their entirety, achieved by the oral pharmaceutical form, by the biphasic release system of the active ingredient, by the process for preparing these and by the therapeutic use of the present invention.

[0044] According to the present invention in question, the oral pharmaceutical form comprises a core, a coating layer comprising an active pharmaceutical ingredient, a modified release layer, an immediate release layer of the active ingredient, a polymeric layer, and a glidant will be deposited on this outermost layer, which will remain on the surface of the pharmaceutical form.

[0045] In one embodiment of the invention, the core and the active coating layer form pellets obtained by coating cores with the coating layer.

[0046] The term “active pharmaceutical ingredient”, API or “active”, as defined in the invention, refers to trazodone or a pharmaceutically acceptable salt, hydrate, solvate or polymorph thereof, preferably trazodone hydrochloride.

[0047] In one embodiment of the invention, said pharmaceutical form is in the form of a unit dose, such as a capsule, a tablet, sachet, sprinkle, suspension, orodispersible tablet, dragee, dispersible tablet.

[0048] Also according to the invention, the process for preparing the oral pharmaceutical form comprises the steps of: (i) prepare a nucleus; (ii) applying the coating layer comprising the active pharmaceutical ingredient to the core to form pellets coated with the active; (iii) applying the modified release layer to the pellets prepared in (ii); and (iv) apply the immediate release layer to the pellets prepared in (iii).

[0049] In one embodiment of the invention, said process further comprises: (v) applying a polymeric coating layer to the pellets prepared in (iv).

[0050] In another embodiment of the invention, said process comprises depositing a glidant on the surface of the oral pharmaceutical form.

[0051] In another embodiment of the invention, said process further comprises transforming the product into a final pharmaceutical form.

[0052] The invention also relates to the use of the oral pharmaceutical form in the preparation of a medicament for the treatment or prevention of disorders and diseases in an individual.

[0053] In one embodiment of the invention, said treatment is treatment of sleep disorders in patients. Brief description of the drawings

[0054] Figure 1 represents the in vitro dissolution profile of a first OAD formulation of trazodone 50 mg. The dissolution method is performed in two stages, the first of which is the acid stage, where the dissolution medium is 0.1 M hydrochloric acid, at 37 °C, with a medium volume of 500 ml, using the Basket, agitated at 75 rpm, for 60 minutes and the second stage, the buffer stage, which uses as medium the Potassium Phosphate Buffer pH 6.8, at 37 °C, with a medium volume of 1000 ml, using a basket agitated at 75 rpm, for 60 minutes. The profile result presented corresponds to the sum of the two stages.

[0055] Figure 2 depicts the plasma concentration of trazodone derived from a 50 mg trazodone OAD first formulation capsule as a function of time when administered to a human subject in the fed state.

[0056] Figure 3 depicts the plasma concentration of trazodone derived from a 50 mg trazodone OAD first formulation capsule as a function of time when administered to a human subject in the fasted state.

[0057] Figure 4 represents the in vitro dissolution profile of a first 75 mg trazodone OAD formulation.

[0058] Figure 5 depicts the plasma concentration of trazodone derived from a 75 mg trazodone OAD first formulation capsule as a function of time when administered to a human subject in the fed state.

[0059] Figure 6 depicts the plasma concentration of trazodone derived from a 75 mg trazodone OAD first formulation capsule as a function of time when administered to a human subject in the fasted state.

[0060] Figure 7 represents the results of the Sleep Latency study, in minutes, demonstrating the patient's condition at the beginning of the treatment and after the intervention, which was the administration of the formulation proposed in this patent application. Figure 8 is a graph representing Total Sleep Time, in minutes, demonstrating the patient's condition at the beginning of treatment and after the intervention, which was the administration of the formulation proposed in this patent application.

[0061] Figure 9 represents the Awakenings per Night, demonstrating the patient's condition at the beginning of the treatment and after the intervention, which was the administration of the formulation proposed in this patent application.

[0062] Figure 10 represents the Athens Insomnia Scale, demonstrating the patient's condition at the beginning of treatment and after the intervention, which was the administration of the formulation proposed in this patent application.

[0063] Figure 11 represents the Insomnia Severity Index, demonstrating the patient's condition at the beginning of treatment and after the intervention, which was the administration of the formulation proposed in this patent application.

[0064] Figure 12 represents the quality of sleep based on the Pittsburgh Sleep Quality Index, demonstrating the patient's condition at the beginning of treatment and after the intervention, which was the administration of the formulation proposed in this patent application.

[0065] Figure 13 represents the results of the Polysomnography, evaluating the Micro-awakenings per night, demonstrating the patient's condition before and after the intervention, which was the administration of the formulation proposed in this patent application.

[0066] Figure 14 represents the results of the Polysomnography, evaluating the Total Sleep Time, in minutes, demonstrating the patient's condition before and after the intervention, which was the administration of the formulation proposed in this patent application.

[0067] Figure 15 represents the results of the Polysomnography, evaluating the Time Awake, in minutes, demonstrating the patient's condition before and after the intervention, which was the administration of the formulation proposed in this patent application. Detailed Description of the Invention

[0068] In view of the objectives of the present invention, an oral pharmaceutical form for biphasic release of trazodone, its therapeutic use and a process for manufacturing said pharmaceutical form are disclosed.

[0069] The oral pharmaceutical form developed comprises: - a nucleus; - a coating layer comprising an active pharmaceutical ingredient (API); - a modified release layer; - an immediate release layer comprising the IFA; - a polymeric layer; - a blending layer.

[0070] In one embodiment of the invention, the active pharmaceutical ingredient is trazodone hydrochloride.

[0071] In the context of the present invention, the term “core” is to be understood as a biocompatible core in which there is substantially no active pharmaceutical ingredient. The core materials may be insoluble or soluble materials.

[0072] In one embodiment of the invention, the core is selected from the group comprising glass, biocompatible polymers such as cellulose acetate, methyl methacrylate or other acrylics, nylon, polypropylene, silicone, SBR copolymers and the like, polyethylene glycols such as POLYOX® (Union Carbide) or KLUCEL® (Hercules), cellulose spheres, silicon dioxide spheres and spherical starch and sugar granules, preferably spherical starch and sugar granules.

[0073] In a preferred embodiment of the invention, the core is coated by the active coating layer.

[0074] In one embodiment of the invention, the active coating layer is a solution or suspension comprising the API and at least one of the group comprising one or more solvents, a diluent, a wetting agent, a polymer, a glidant, an antioxidant or a combination thereof.

[0075] In one embodiment of the invention, the immediate release layer of the active is a solution or suspension comprising the API and at least one of the group comprising one or more solvents, a diluent, a wetting agent, a polymer, a glidant, an antioxidant or a combination thereof.

[0076] In a particular embodiment of the invention, the active ingredient coating layer and the active ingredient immediate release layer have the same or different components / materials, preferably the same ones.

[0077] In one embodiment of the invention, the modified release layer is a solution or suspension comprising at least one of the group comprising a solvent, a polymer, a glidant, a plasticizer, or a combination thereof.

[0078] In a particular embodiment of the invention, there is substantially no active pharmaceutical ingredient in the modified release layer.

[0079] In a preferred embodiment of the invention, said oral pharmaceutical form further comprises a polymeric coating layer.

[0080] In one embodiment of the invention, the polymeric coating layer is a solution or suspension comprising at least one solvent and one polymer, for the purpose of photoprotecting the active ingredient.

[0081] In another embodiment of the invention, said oral pharmaceutical form further comprises the deposition of a glidant in the final formulation.

[0082] In one embodiment of the invention, the blending layer is applied to reduce the electrostatic charge of the pellets, facilitating the encapsulation process, ensuring adequate dosage and content uniformity in the final product. The blending layer may be selected from the group consisting of talc, polyethylene glycol, simethicone, titanium dioxide, stearic acid, magnesium, sodium stearyl fumarate, hydrogenated vegetable oil, carnauba wax, cornstarch, magnesium oxide, magnesium silicate, silicon dioxide, calcium phosphate, microcrystalline cellulose and combinations thereof, preferably talc.

[0083] In another embodiment of the invention, said oral pharmaceutical form further comprises the transformation into a pharmaceutical form of the final formulation.

[0084] In a preferred embodiment of the invention, the solvent is selected from the group comprising purified water, deionized water, distilled water, methanol, ethanol, glycerin, sorbitol, acetone, methyl ethyl ketone, methylene chloride, isopropanol, butylene glycol, benzyl alcohol, dibutyl phthalate, ethyl acetate, ethyl lactate, ethyl oleate, isopropyl myristate, isopropyl palmitate, mineral oil, medium chain triglycerides, methyl lactate, monoethanolamine, octyldodecanol, polyethylene glycol, propylene carbonate, polyethylene glycol 35 castor oil, pyrrolidone, corn oil, olive oil, peanut oil, cottonseed oil, sunflower oil, canola oil, soybean oil, grape seed oil, sesame oil, safflower oil, linseed oil, coconut oil, palm oil, triacetin, tricaprylin, triethanolamine, triethyl citrate, triolein, propylene glycol, 2-(2-ethoxyethoxy)ethanol (transcutol), N-methyl-2- pyrrolidone (Pharmasolve),fish oil (omega 3) and combinations thereof, preferably water and ethanol.,

[0085] In a particular embodiment of the invention, the diluent is selected from the group comprising microcrystalline cellulose, lactose monohydrate, mannitol, xylitol, sucrose, cyclodextrin, calcium carbonate, magnesium carbonate, di- or tri-basic calcium phosphate, calcium hydrogen phosphate, pregelatinized starch, low-substituted hydroxypropyl cellulose, alginate, calcium lactate, calcium silicate, calcium sulfate, cellulose acetate, dextrate, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, isomalt, kaolin, lactitol, sodium carbonate, magnesium, magnesium oxide, maltodextrin, maltose, polydextrose, sodium chloride, sorbitol, talc, trehalose and combinations thereof, preferably sucrose.

[0086] In a particular embodiment of the invention, the wetting agent is selected from the group comprising polyethylene glycol (PEG), propylene glycol, glycerol, sorbitol, sodium lauryl sulfate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium docusate, sodium cetearyl sulfate, saponin and glycerin and combinations thereof, preferably polysorbate.

[0087] In a preferred embodiment of the invention, the antioxidant is selected from the group comprising acetylcysteine, alpha tocopherol, ascorbyl palmitate, butyl hydroxyanisole (BHA), butyl hydroxytoluene (BHT), monothioglycerol, potassium nitrate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, disodium edetate (EDTA), diethylenetriamine pentaacetic acid (DTPA), triglycolmate (NT), ascorbic acid, citric acid, erythorbic acid, ethyl oleate, fumaric acid, malic acid, methionine, resveratrol, phosphoric acid, potassium metabisulfite, propionic acid, tert-butylhydroquinone, sodium sulfite, sodium thiosulfate, vitamin E polyethylene glycol succinate, and combinations thereof. same, preferably propyl gallate.

[0088] In a preferred embodiment of the invention, the polymer is selected from the group comprising polyesters such as polylactic acid (PLA), polycaprylactone, polylactide-co-glycolide (PLGA), polyhydroxybutyrate, poly[3-malic acid); polyanhydrides such as poly(adipic)anhydride (PAA), poly(fumaric-co-sebacic)anhydride or (PFA:SA), poly(sebacic)anhydride (PSA); cellulosic polymers such as water-soluble cellulose ethers such as hypromellose or hydroxypropylmethylcellulose, propylcellulose and / or hydroxypropylcellulose, hydroxyethylcellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol and its derivatives such as block copolymers of polyvinyl alcohol and polyethylene glycol commercially available as Kollicoat© IR or Kollicoat© Protect, acrylate and methacrylate polymers such as Eudragit RS 100, RL 100, E100 PO, L100-55, L100, S100, 1100, hypromellose (HPMC) and composition based on hydroxypropylmethyl cellulose or polyvinyl alcohol obtained under the trade name Opadry© and combinations thereof, preferably hypromellose, or a polymer derived from it, and methacrylate copolymer.

[0089] In a particular embodiment of the invention, the glidant is selected from the group comprising talc, silica, such as colloidal silica, magnesium oxide, powdered cellulose, silicates, such as magnesium silicate, magnesium trisilicate, magnesium aluminum silicates, fumed silica, CAB-O-SIL© M-5P, AEROSIL©, starch and combinations thereof, preferably talc.

[0090] In another embodiment of the invention, the plasticizer is selected from the group comprising polyethylene glycol, propylene glycol, glycerin, simethicone, triacetin, citric acid esters such as tributyl citrate, triethyl citrate, sebacic acid esters such as dibutyl sebacate, phthalic acid esters such as dimethyl phthalate, mono, di and triglycerides of medium chain fatty acids, castor oil, long chain fatty acids and combinations thereof, preferably triethyl citrate.

[0091] In one embodiment of the invention, the oral pharmaceutical form is selected from the group comprising a capsule, a tablet, sachet, sprinkle, suspension, orodispersible tablet, dragee, dispersible tablet.

[0092] In a preferred embodiment of the invention, the oral pharmaceutical form is a capsule or a tablet.

[0093] In an even more preferred embodiment of the invention, the oral pharmaceutical form is a capsule.

[0094] In a particular embodiment of the invention, the pharmaceutical form presents the first release with about 5 mg to about 120 mg of the ingredient active pharmaceutical ingredient, preferably about 25 mg to about 75 mg of the API, even more preferably about 25 mg to about 50 mg of the API. Furthermore, the same pharmaceutical form presents the second release with about 5 mg to about 120 mg of the active pharmaceutical ingredient, preferably about 25 mg to about 75 mg of the API, even more preferably about 25 mg to about 50 mg of the API.

[0095] In one embodiment of the invention, the core is present in the pharmaceutical form in a proportion ranging from about 10% to about 60% by weight based on the total weight of said pharmaceutical form, preferably from 20 to 40% by weight.

[0096] In one embodiment of the invention, the active pharmaceutical ingredient is present in the active coating layer in a proportion ranging from about 1% to about 40% by weight, based on the total weight of said pharmaceutical form, preferably 5% to about 20% by weight.

[0097] In one embodiment of the invention, the active pharmaceutical ingredient is present in the immediate release layer of the active in a proportion ranging from about 10% to about 80% by weight based on the total weight of the active pharmaceutical ingredient of said pharmaceutical form, preferably between 45 and 65% by weight.

[0098] In one embodiment of the invention, the blending layer is present in a proportion ranging from about 0.1 to about 10% by weight of the pharmaceutical form.

[0099] In one embodiment of the invention, the process for preparing the pharmaceutical form comprises previously preparing a coating layer of the active by forming a solution or suspension comprising the API and at least one of the group comprising one or more solvents, a diluent, a wetting agent, a polymer, a glidant, an antioxidant or a combination thereof.

[0100] In one embodiment of the invention, the process comprises previously preparing a core by preheating said core.

[0101] In one embodiment of the invention, the process further comprises applying the coating layer comprising the API to the preheated core to form pellets coated with the active.

[0102] In one embodiment of the invention, the process for preparing the pharmaceutical form comprises previously preparing a modified release layer by forming a solution or suspension comprising at least one of the group comprising a solvent, a polymer, a glidant, a plasticizer or a combination thereof.

[0103] In a particular embodiment of the invention, the process comprises applying the modified release layer to pellets previously coated with a first active coating layer.

[0104] In one embodiment of the invention, the process for preparing the pharmaceutical form comprises preparing an immediate release layer of the active by forming a solution or suspension comprising the API and at least one of the group comprising one or more solvents, a diluent, a wetting agent, a polymer, a glidant, an antioxidant or a combination thereof.

[0105] In a preferred embodiment of the invention, the process comprises applying the immediate release layer of the active to pellets previously coated with a first active coating layer and a second modified release layer.

[0106] In another embodiment of the invention, said process further comprises applying a polymeric coating layer to pellets previously coated with a first active coating layer, a second modified release layer and a third modified release layer. immediate asset.

[0107] In a particular embodiment of the invention, said process further comprises depositing a glidant on the surface of pellets previously coated with a first active ingredient coating layer, a second modified release layer, a third immediate active ingredient release layer and a fourth polymeric coating layer.

[0108] In another particular embodiment of the invention, said process further comprises incorporating into a final pharmaceutical form the pellets previously coated with a first active ingredient coating layer, a second modified release layer, a third immediate release active ingredient layer and a fourth polymeric coating layer, on which the glidant is superficially deposited.

[0109] In one embodiment of the invention, the process for preparing the pharmaceutical form comprises the following steps: (i) prepare a core to receive the film; (ii) applying the coating layer comprising the active pharmaceutical ingredient to the core to form pellets coated with the active; (iii) applying the modified release layer to the pellets prepared in (ii); and (iv) apply the immediate release layer to the pellets prepared in (iii).

[0110] In one embodiment of the invention, the cores are fed into the fluidized bed chamber and subsequently suspended by a stream of hot air. A polymeric suspension or solution is sprayed onto the cores, producing the formation of a film, which will promote the adhesion of the drug to the core and / or modulate its release from a system formed by the parameters of air intake volume, product temperature and spray rate. In this way, the steps of the production process are carried out continuously in a single equipment.

[0111] In one embodiment of the invention, the pharmaceutical form is for the treatment or prevention of sleep disorders, post-traumatic stress disorder, depression and anxiety, preferably for the treatment of insomnia and / or improving the quality of sleep in patients with depressive disorders.

[0112] The term bioavailability as defined herein refers to the extent and rate at which a drug reaches the circulatory system after administration.

[0113] The present invention is described below with reference to the following examples, which are not intended to limit the scope of the present invention in any way.

[0114] In order that the modalities described herein may be understood more fully, the following examples are provided. It should be understood that these examples are for illustration purposes only and should not be construed as limiting. Example 1: Pharmaceutical form according to the invention comprising 50 mg of the API

[0115] In a preferred embodiment, the pharmaceutical form of the present invention comprises the ingredients in Table 3 below. Table 3 - Exemplary formulation of the pharmaceutical form Step Material Description Function _ Composition , Y ão quant.it.at .Yiva % p / p Trazodone hydrochloride Ifa 27,000 mg 14,282 Sucrose / starch spheres Diluent 70,000 mg 37,027 Talc Glidant 3,500 mg 1,851 Propyl gallate Antioxidant 0,200 mg 0,106 Hypromellose layer 2910 Polymer 9,000 mg 4,761 Polysorbate 80 coating Wetting agent 1,500 mg 0,793 active Sucrose granular type k Diluent 2,800 mg 1,481 Ethyl alcohol (96 gl)* Solvent 0.002 ml Purified water* Solvent 0.230 ml Eudragit 1100 layer) Polymer 17,000 mg 8,992 release Talc Slip 8,500 mg 4,496 modified Triethyl citrate Plasticizer 1,700 mg 0,899 Ethyl alcohol (96 gl)* Solvent 0.200 ml Trazodone hydrochloride Ifa 23.000 mg 12.166 Talc Sliding 3.700 mg 1.957 Propyl gallate layer Antioxidant 0.200 mg 0.106 Hypromellose 2910 Polymer 8,800 mg 4,655 immediate release of Polysorbate 80 Wetting agent 1,500 mg 0.793 active Sucrose granular type k Diluent 2,800 mg 1,481 Ethyl alcohol (96 gl)* Solvent 0.002 ml Purified water* Solvent 0.230 ml Opadry white layer Polymer 7,500 mg 3.967 polymeric Purified water* Solvent 0.040 ml Ethyl alcohol (96 gl)* Solvent 0.040 ml Talc Slip Blend 0.350 mg 0.185 *Evaporates during the process Example 2: Pharmaceutical form according to the invention comprising 75 mg of IFA

[0116] In a preferred embodiment, the pharmaceutical form of the present invention comprises the ingredients in Table 4 below. of the pharmaceutical form r» . _ . . . . . - _ Composition n / Material Description Quantitative Function Trazodone hydrochloride Ifa 23,000 mg 10,000 Sucrose / starch spheres Diluent 70,000 mg 30,435 Talc Slip 3,500 mg 1,522 Propyl gallate layer Antioxidant 0.200 mg 0.087 Hypromellose 2910 Polymer coating 7.700 mg 3.348 Active Polysorbate 80 Wetting agent 1 ,400 mg 0.609 Granular sucrose type k Diluent 2.200 mg 0.957 Ethyl alcohol (96 gl)* Solvent 0.002 ml Purified water* Solvent 0.230 ml „ . . Eudragit LWO Polymer 17,000 mg 7,391 ^diiidud u Ta|co Slider 8,000 mg 3,478 Hoeração Triethyl citrate Plasticizer 1,600 mg 0,696 moaincaaa Ethyl alcohol (96 gl)* Solvent 0,200 ml Trazodone hydrochloride Ifa 52,000 mg 22,609 Talc Slip 7.100 mg 3.087 Propyl gallate layer Antioxidant 0.350 mg 0.152 Hypromellose 2910 Polymer 19.500 mg 8.478 immediate release of Polysorbate 80 Wetting agent 2.700 mg 1.174 active Sucrose granular type k Diluent 5.000 mg 2.174 Ethyl alcohol (96 gl)* Solvent 0.002 ml Purified water* Solvent 0.600 ml p . Opadry white Polymer 8.500 mg 3.696 uamaoa Water purificada * Solvent 0.060 ml potion Ethyl alcohol (96 gl)* Solvent 0.060 ml Talc Slip Blend 0.250 mg 0.109 *Evaporates during the process Example 3: Process for preparing a pharmaceutical form comprising the API according to the invention

[0117] In a particular embodiment of the invention, the preparation of the pharmaceutical forms comprising the API according to the formulations of Example 1 and Example 2 was carried out by the production processes detailed below. Preparation of the active coating layer

[0118] The process for preparing the pharmaceutical form comprises previously preparing a coating layer of the active ingredient in accordance with the following steps: (i) disperse the excipients propyl gallate, polysorbate 80, granular sucrose type K, talc and the active ingredient in purified water; (ii) add (i) hypromellose and keep stirring until completely dissolved; (iii) add to (ii) ethyl alcohol (96°GL) and leave the suspension of the active ingredient under agitation throughout the application of the active ingredient coating layer. Application of the active coating layer

[0119] The process for preparing the pharmaceutical form further comprises applying the active ingredient coating layer to a core, in accordance with the following steps: (i) add the spheres to a fluidized bed; (ii) heating the spheres of (i) until they reach the temperature range of 38 °C to 46 °C; (iii) apply to the spheres of (ii) the coating layer of the active ingredient which is in the form of a dispersion of the active ingredient, maintaining the temperature of the system between 38 °C and 45 °C; and (iv) forming pellets of cores coated with a first coating layer of the active ingredient; (v) drying the coated pellets in (iv) in the fluidized bed.

[0120] Preparation of modified release layer

[0121] The process for preparing the pharmaceutical form comprises previously preparing a modified release layer according to the following steps: (i) disperse the excipients talc, triethyl citrate and methacrylic acid copolymer (Eudragit L 100) in ethyl alcohol (96°GL) and keep under agitation, thus forming a suspension that constitutes the modified release layer of the present pharmaceutical form. Application of modified release layer

[0122] The process for preparing the pharmaceutical form further comprises applying the modified release layer as a second layer to the core pellets coated with a first active ingredient coating layer. The application of the modified release layer was carried out according to the following steps: (i) adding, in a fluidized bed, pellets coated with the first active coating layer; (ii) heating the pellets from (i) until they reach the temperature range of 30 °C to 35 °C; (iii) applying to the pellets of (ii) the modified release layer, maintaining the temperature of the system between 28 °C and 35 °C; and (iv) forming pellets of cores coated with a first active coating layer and a second modified release layer. (v) drying the coated pellets in (iv) in the fluidized bed.

[0123] The process comprises, after drying the pellets coated with the second modified release layer, sieving the pellets. Preparation of the immediate release layer of the active ingredient

[0124] The process for preparing the pharmaceutical form involves previously preparing an immediate release layer of the active ingredient in accordance with the following steps: (i) Disperse / dissolve the excipients propyl gallate, polysorbate 80, granular sucrose type K, talc and the active ingredient in purified water; (ii) add (i) hypromellose and keep stirring until completely dissolved; (iii) add (ii) ethyl alcohol (96°GL) and leave the active ingredient suspension under agitation throughout the application of the immediate release layer of the active ingredient. Application of the immediate release layer of the active ingredient

[0125] The process for preparing the pharmaceutical form further comprises applying the immediate release layer of the active ingredient as a third layer to the core pellets coated with a first active ingredient coating layer and a second modified release layer. The application of the immediate release layer of the active ingredient was carried out according to the following steps: (i) adding, in a fluidized bed, pellets coated with the first active coating layer and second modified release layer; (ii) heating, in the fluidized bed, the pellets of (i) until they reach the temperature range of 42 °C to 46 °C; (iii) apply, in the fluidized bed, to the pellets of (ii) the immediate release layer of the active ingredient, maintaining the temperature of the system between 38 °C and 45 °C; and (iv) forming pellets of cores coated with a first active ingredient coating layer, a second modified release layer and a third immediate release active ingredient layer. (v) drying the coated pellets in (iv) in the fluidized bed.

[0126] The process involves, after drying the pellets coated with the third layer of immediate release of the active ingredient, sieving the pellets^ Preparation of the polymer coating layer

[0127] The process for preparing the pharmaceutical form comprises previously preparing a polymeric coating layer according to the following steps: (i) prepare a hydroalcoholic solution; (ii) disperse the opadry white polymer in the solution of (i) and keep it under stirring, thus forming a dispersion that constitutes the polymeric coating layer of the present pharmaceutical form. Application of the polymer coating layer

[0128] The process for preparing the pharmaceutical form further comprises applying the polymeric coating layer as a fourth layer to the core pellets coated with a first active ingredient coating layer, a second modified release layer and a third immediate release layer of the active ingredient. The application of the polymeric coating layer was carried out according to the following steps: (i) add, in a fluidized bed, pellets coated with the third immediate release layer of the active ingredient; (ii) heating, in the fluidized bed, the pellets of (i) until they reach the temperature range of 40 °C to 45 °C; (iii) apply, in the fluidized bed, to the pellets of (ii) the polymeric coating layer, maintaining the temperature of the system between 38 °C and 45 °C; and (iv) forming pellets of cores coated with a first active ingredient coating layer, a second modified release layer, a third immediate release active ingredient layer and a fourth polymeric coating layer. (v) drying the coated pellets in (iv) in the fluidized bed.

[0129] The process involves, after drying the pellets coated with the fourth layer of polymeric coating, classifying the pellets by sieving.

[0130] The process also involves blending the coated pellets with the fourth layer of polymeric coating in order to deposit talc on the surface of the pellets and a physical interaction.

[0131] The process also includes transforming the pellets coated with the fourth layer of polymeric coating into a pharmaceutical form.

[0132] Having described the embodiments of the pharmaceutical form, use and manufacturing process, it must be understood that the scope of protection in question also covers variations that are not described, but are derived or equivalent.

Claims

CLAIMS 1. Oral pharmaceutical form CHARACTERIZED by the fact that it comprises: a core; a coating layer comprising an active pharmaceutical ingredient (API); a modified release layer; an immediate release layer comprising the API; in which the active pharmaceutical ingredient is trazodone or an acceptable salt and, a polymeric layer.

2. Pharmaceutical form, according to claim 1, CHARACTERIZED by the fact that the core is coated by the active coating layer.

3. Pharmaceutical form, according to claim 1 or 2, CHARACTERIZED by the fact that it promotes two peaks of release of the IFA, considering the interval between releases of 1 to 6 hours.

4. Pharmaceutical form, according to claim 1 or 2, CHARACTERIZED by the fact that the active ingredient coating layer and the active ingredient immediate release layer have the same concentration of the API.

5. Pharmaceutical form, according to claim 1 or 2, CHARACTERIZED by the fact that the active ingredient coating layer and the active ingredient immediate release layer present different concentrations of the API.

6. Pharmaceutical form according to any one of claims 1 to 5, CHARACTERIZED by the fact that the IFA is trazodone hydrochloride.

7. Pharmaceutical form according to any one of claims 1 to 6, CHARACTERIZED by the fact that the active coating layer is a suspension comprising the API and at least one excipient selected from the group comprising one or more solvents, a diluent, a wetting agent, a polymer, a glidant, an antioxidant or a combination thereof.

8. Pharmaceutical form according to any one of claims 1 to 7, CHARACTERIZED by the fact that the immediate release layer of the active is a suspension comprising the API and at least one excipient selected from the group comprising one or more solvents, a diluent, a wetting agent, a polymer, a glidant, an antioxidant or a combination thereof.

9. Pharmaceutical form, according to claim 7 or 8, CHARACTERIZED by the fact that the active ingredient coating layer and the active ingredient immediate release layer have the same components / materials.

10. Pharmaceutical form according to any one of claims 1 to 9, CHARACTERIZED by the fact that the modified release layer is a solution or suspension, comprising at least one of the group comprising a solvent, a polymer, a glidant, a plasticizer or a combination thereof.

11. Pharmaceutical form according to any one of claims 7 to 10, CHARACTERIZED by the fact that: (i) the solvent is selected from the group comprising purified water, deionized water, distilled water, methanol, ethanol, glycerin, sorbitol, acetone, methyl ethyl ketone, methylene chloride, isopropanol, butylene glycol, benzyl alcohol, dibutyl phthalate, ethyl acetate, ethyl lactate, ethyl oleate, isopropyl myristate, isopropyl palmitate, mineral oil, medium chain triglycerides, methyl lactate, monoethanolamine, octyldodecanol, polyethylene glycol, propylene carbonate, polyethylene glycol 35 castor oil, pyrrolidone, corn oil, olive oil, peanut oil, cottonseed oil, sunflower oil, canola oil, soybean oil, grapeseed oil, sesame oil, safflower oil, linseed oil, coconut oil, palm oil, triacetin, tricaprylin, triethanolamine, triethyl citrate, triolein, propylene glycol, 2-(2-ethoxyethoxy)ethanol (transcutol), N-methyl-2-pyrrolidone (Pharmasolve), fish oil (omega 3) and combinations thereof; (ii) the diluent is selected from the group comprising microcrystalline cellulose, lactose monohydrate, mannitol, xylitol, sucrose, cyclodextrin, calcium carbonate, magnesium carbonate, di- or tri-basic calcium phosphate, calcium hydrogen phosphate, pregelatinized starch, low-substituted hydroxypropyl cellulose, alginate, calcium lactate, calcium silicate, calcium sulfate, cellulose acetate, dextrate, erythritol, ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, isomalt, kaolin, lactitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, polydextrose, sodium chloride, sorbitol, talc, trehalose, and combinations thereof; (iii) the wetting agent is selected from the group comprising polyethylene glycol (PEG), propylene glycol, glycerol, sorbitol, sodium lauryl sulfate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodium docusate, sodium cetearyl sulfate, saponin and glycerin and combinations thereof; (iv) the antioxidant is selected from the group comprising acetylcysteine, alpha tocopherol, ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), monothioglycerol, potassium nitrate, sodium ascorbate, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium bisulfite, vitamin E or a derivative thereof, propyl gallate, disodium edetate (EDTA), diethylenetriamine pentaacetic acid (DTPA), triglycolmate (NT), ascorbic acid, citric acid, erythorbic acid, ethyl oleate, fumaric acid, malic acid, methionine, resveratrol, phosphoric acid, potassium metabisulfite, propionic acid, tert-butylhydroquinone, sodium sulfite, sodium thiosulfate, vitamin E polyethylene glycol succinate, and combinations thereof; (v) the polymer is selected from the group comprising polyesters such as polylactic acid (PLA), polycaprylactone, polylactide-co-glycolide (PLGA), polyhydroxybutyrate, poly[3-malic acid); polyanhydrides such as poly(adipic)anhydride (PAA), poly(fumaric-co-sebacic)anhydride or (PFA:SA), poly(sebacic)anhydride (PSA); cellulosic polymers such as water-soluble cellulose ethers such as hypromellose or hydroxypropylmethyl cellulose, propyl cellulose, hydroxyethyl cellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol and its derivatives such as block copolymers of polyvinyl alcohol and polyethylene glycol, acrylate and methacrylate polymers, hypromellose (HPMC) and composition based on hydroxypropylmethyl cellulose or polyvinyl alcohol and combinations thereof; (vi) the glidant is selected from the group comprising talc, silica, such as colloidal silica, magnesium oxide, powdered cellulose, silicates, such as magnesium silicate, magnesium trisilicate, magnesium aluminum silicates, fumed silica, starch, and combinations thereof; and (vii) the plasticizer is selected from the group comprising polyethylene glycol, propylene glycol, glycerin, simethicone, triacetin, citric acid esters such as tributyl citrate, triethyl citrate, sebacic acid esters such as dibutyl sebacate, phthalic acid esters such as dimethyl phthalate, mono, di and triglycerides of medium chain fatty acids, castor oil, long chain fatty acids and combinations thereof.

12. Pharmaceutical form according to any one of claims 1 to 11 , CHARACTERIZED by the fact that the oral pharmaceutical form further comprises a polymeric coating layer and / or incorporation into a final formulation.

13. Pharmaceutical form according to any one of claims 1 to 12, CHARACTERIZED by the fact that the amount of IFA present in the active ingredient coating layer comprises 25 to 60% (w / w) of the amount of total IFA present in the formulation.

14. Pharmaceutical form, according to any one of claims 1 to 12, CHARACTERIZED by the fact that the amount of the IFA, present in the immediate release layer of the active, comprises from 40 to 70% (w / w) of the amount of the total IFA. present in the formulation.

15. Pharmaceutical form according to any one of claims 1 to 14, CHARACTERIZED by the fact that it comprises 20 to 100 mg of trazodone hydrochloride.

16. Pharmaceutical form according to any one of claims 1 to 15, CHARACTERIZED by the fact that the pharmaceutical form presents a pharmaceutical form selected from the group comprising a capsule, a tablet, sachet, sprinkle, suspension, orodispersible tablet, dragee, dispersible tablet.

17. Pharmaceutical form according to any one of claims 1 to 16, CHARACTERIZED by the fact that it provides a controlled release system of the API that promotes the biphasic release of trazodone.

18. Pharmaceutical form according to any one of claims 1 to 17, CHARACTERIZED by the fact that the pharmaceutical form is composed of a multiparticulate system.

19. Process for preparing the pharmaceutical form, as defined in any one of claims 1 to 18, CHARACTERIZED by the fact that it comprises the following steps: (i) prepare a nucleus; (ii) applying the coating layer comprising the active pharmaceutical ingredient to the core to form pellets coated with the active; (iii) applying the modified release layer to the pellets prepared in (ii); (iv) applying the immediate release layer to the pellets prepared in (iii) and, (vi) apply the polymeric layer to the pellets prepared in (iv). (vii) incorporation of the multiparticulate system into a pharmaceutical form.

20. Use of the pharmaceutical form, as defined in any one of claims 1 to 18, CHARACTERIZED by the fact that it is in the preparation of a medicine for the treatment or prevention of insomnia in an individual.

21. Use according to claim 20, CHARACTERIZED by the fact that the treatment or prevention of insomnia consists of improving the quality of sleep, increasing total sleep time, decreasing sleep latency, reducing nocturnal awakenings, improving total sleep efficiency, treating or preventing depression, comorbid insomnia, primary and / or secondary insomnia, reducing the severity of insomnia, inducing and / or maintaining sleep.

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