Quetiapine liquid formulations

Abstract

The invention relates to a liquid formulation, in particular to a suspension, of quetiapine or a pharmaceutically acceptable salt thereof, methods for its preparation and its use in medicine, in particular for the treatment of mental, behavioural and / or mood conditions.

Description

[0001] QUETIAPINE LIQUID FORMULATIONS

[0002] FIELD OF INVENTION

[0003] The present invention relates to a liquid formulation, in particular to a suspension, of quetiapine or a pharmaceutically acceptable salt thereof, methods for its preparation and its use in medicine, in particular for the treatment of mental, behavioural and / or mood conditions.

[0004] BACKGROUND OF THE INVENTION

[0005] Quetiapine is an anti-psychotic drug for the treatment of schizophrenia, bipolar disorder and major depressive disorders. It is classified as second-generation antipsychotic and is usually associated with fewer side effects compared with other antipsychotic agents.

[0006] Antipsychotic drugs such as quetiapine are used as well in geriatrics for the treatment of anxiety and agitation, frequent and annoying symptoms of neurological diseases such as dementia, Parkinson's disease or Alzheimer's disease, due to its sedating effect.

[0007] Quetiapine is widely used in solid form, particularly in tablets, such as in the form of immediate-release tablets and extended-release tablets for oral administration containing from 25 to 400 mg of quetiapine. Nevertheless, for its use in elder population or uncooperative patients, it is necessary to have a liquid form, given that this segment of patients usually presents difficulties in swallowing medicines in tablet or capsule form. A liquid formulation with a certain viscosity would be very suitable for these patients, as it facilitates both the initial titration and swallowing in case of dysphagia or agitation. Additionally, liquid formulations of quetiapine should be not only technically feasible, but also physicochemically stable and ideally possess good organoleptic properties.

[0008] Quetiapine is commercially available as an oral liquid formulation comprising 20 mg / mL of quetiapine (Quetiapine Rosemont 20mg / ml Oral Suspension). However, due to stability problems, this liquid form must be stored in the refrigerator, at a temperature between 2° and 8 °C, as is explained for instance in the UK MHRA Public Assessment Report of the product. Therefore, there is still a need in the art for formulations containing quetiapine in a liquid form with improved physicochemical stability, which would offer additional advantage for medical practitioners as well as patients compared to the presently available formulations. In terms of patient compliance, good organoleptic properties are also very desirable. The present invention addresses such concerns.

[0009] SUMMARY OF THE INVENTION

[0010] The authors of the present invention have surprisingly found that selection of specific excipients in specific amounts leads to oral liquid formulations (suspensions) of quetiapine that are physically and chemically stable under storage under non-refrigerated and even accelerated degradation conditions for at least 24 months and have good palatability, thus resulting in improved patient compliance (i.e. , better fulfilment of the therapeutic treatment).

[0011] The liquid formulations of the invention have a viscous texture and allow administering the lower individual doses (25-50 mg) in a very small volume (1-2 mL), features of particular significance for patients who have swallowing problems and for dosage adjustments purposes as well.

[0012] On the other hand, these formulations produce less gastric irritation than their solid counterparts, a relevant characteristic for polymedicated patients, particularly the elderly.

[0013] Furthermore, the present quetiapine liquid formulations are bioquivalent to the commercialized solid forms.

[0014] From a storage and usage point of view, the suspensions of the present invention show improved flocculation, controlled sedimentation and can be reconstituted easily through slight agitation into a uniform suspension, thus eliminating dosage variations throughout the volume of the suspension.

[0015] Surprisingly, the inventors have further found that there is no need to add neither a buffering system nor an acidifying agent to stabilize the liquid formulation of the present invention. This is advantageous as the solubility of quetiapine is pH- dependent, increasing as the medium becomes more acidic. At pHs under 4, quetiapine dissolves and a suspension cannot be obtained, and additionally a pH that is too acidic would not be suitable for patients. At pHs over 6, the dissolution profile of quetiapine becomes slower and its bioavailability could be affected.

[0016] Moreover, they found that there is not necessary to add a sweeting agent for obtaining a good-tasting liquid formulation.

[0017] Therefore, according to a first aspect, the invention is directed to a liquid formulation comprising: i) quetiapine or a pharmaceutically acceptable salt thereof, ii) a suspending agent in an amount between 0.05% and 5.0% w / v, iii) a thickener in an amount of at least 25% w / v, and iv) a wetting agent in an amount between 0.5% and 10% w / v.

[0018] A second aspect of the present invention is directed to a method for preparing the liquid formulation of the first aspect of the invention, said process comprising the following steps: a) Mixing water and the thickener; b) Adding the suspending agent and the wetting agent, previously mixed with each other, to the mixture obtained in step a) and mixing; c) Adding quetiapine or the salt thereof to the mixture obtained in step b) and mixing.

[0019] Another aspect refers to a liquid formulation obtainable by the method of the second aspect.

[0020] A further aspect of the present invention is directed to a liquid formulation according to the invention for use as a medicament.

[0021] An additional aspect of the invention is directed to a liquid formulation according to the invention, for use in the prevention and / or treatment of mental, behavioural and / or mood conditions. These aspects and preferred embodiments are additionally described further down in the description and defined in the claims.

[0022] DESCRIPTION OF THE FIGURES

[0023] Figure 1: Schematic overview of the manufacturing process of a formulation according to the present invention.

[0024] DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention provides for a quetiapine formulation. The present invention also provides methods for obtaining the quetiapine formulation of the invention and describes uses thereof.

[0026] Definitions

[0027] In order to facilitate the comprehension of the present invention, the meaning of some terms and expressions as used in the context of the invention are set forth below.

[0028] As used herein, the term “suspension” refers to a dispersed, two-phase system in which one phase (“internal” phase) is dispersed as particles in the second phase (“continuous” or “external” phase). By definition, they are thermodynamically unstable systems. Therefore, when one phase is being dispersed into the other phase, the system has the tendency to revert to an energetically more stable state, e.g., it undergoes aggregation, sedimentation, coalescence, crystal growth and caking. In the formulations of the invention, solid particles of the drug, specifically quetiapine, are dispersed in a liquid medium, preferably in an aqueous medium.

[0029] A well formulated pharmaceutical suspension should have the following properties:

[0030] 1. The dispersed particles should not settle readily and the settled particles should redisperse immediately on shaking (should not form a cake).

[0031] 2. The viscosity should be such that the preparation can be poured easily.

[0032] 3. The ingredients (active and excipients) should be chemically stable. 4. A suspension for oral use must be palatable.

[0033] As used herein, the term “flocculation” refers to the process where suspended particles agglomerate to form loosely structured flocs, which are held together in a network-like structure by physical adsorption of macromolecules or by the longer range van der Waals forces of attraction. The floccules referred to as “stable flocs” usually contain varying amounts of entrapped liquid medium within the network-like structure. In summary: flocculated particles are weakly bonded, settle rapidly, do not form a cake and are easily re-suspended. As the flocs tend to fall together, they tend to produce a distinct boundary between the sediment and the supernatant liquid. The liquid above the sediment is clear because even the small particles present in the system are associated with the flocs. If the viscosity of a flocculated system is increased by adding a suitable suspending agent, the sedimentation of the flocs is retarded and an “elegant” pharmaceutical system is obtained.

[0034] In the context of the present invention, the term “% w / v” or “g / 100mL” as applied to a solution refers to the grams of solute in 100 mL of solution, and “mg / mL” means the milligrams of solute per mL of solution; whereas as applied to a suspension it refers to the grams of dispersed solid species in 100 mL of liquid medium, and “mg / mL” means the milligrams of dispersed solid species per mL of liquid medium. Specifically, when referring to each of the components of the formulations of the present invention, “w”, “g” and “mg” refer to the component and “v” or “mL” refers to the formulation.

[0035] As used herein, quetiapine (CAS 111974-69-7, https: / / pubchem.ncbi.nlm.nih.qov / compound / 5002) is a compound of formula:

[0036] Quetiapine is slightly soluble in water therefore it is a good candidate for formulating a liquid formulation in the form of an aqueous suspension. When quetiapine is dispersed in water, it settles very rapidly. Minimizing the settling of the dispersed particles is a key requirement in suspension formulation.

[0037] In the context of the present invention, “quetiapine” may be in the form of a pharmaceutically acceptable salt.

[0038] The term “pharmaceutically acceptable salts” as used herein encompasses any salt with no limitation on the type of salt that can be used, provided that these are acceptable for administration to a patient, meaning that they do not induce undue toxicity, irritation, allergic responses, or the like. Pharmaceutically acceptable salts are well known in the art. By way of illustration, pharmaceutically acceptable salts of quetiapine can be acid addition salts, base addition salts or metal salts, and can be synthesized from the parent compounds containing a basic or acid moiety by means of conventional chemical processes known by the persons skilled in the art. Specific salts are described further below.

[0039] As used herein, the term “suspending agent” refers to an agent that increases the viscosity of the medium so that it decreases the sedimentation rate of particles in suspension and then the particles settle more slowly. Their purpose is to prevent caking I settling at the bottom of the container.

[0040] In the context of the present invention, exemplary suspending agents are xanthan gum, tragacanth gum, guar gum and other natural gums, alginates, pectins, agar-agar, carrageenans, cellulose derivatives such as hydroxypropylmethylcellulose (HMPC), sodium carboxymethylcellulose (NaCMC), methylcellulose (MC), hydroxyethylcellulose (HEC), microcrystalline cellulose and their mixtures.

[0041] As used herein, the term “thickener”, also referred to as “thickening agent”, relates to an excipient that increases the viscosity of the medium (i.e., the external or continuous phase of a suspension). Its purpose is to improve the suspension of other ingredients and, additionally, to slow the transit of fluids down the throat, allowing more time to coordinate the swallowing process safely. In the context of the present invention, exemplary thickeners are sugars (such as sucrose, fructose, maltose), sugar alcohols (such as sorbitol, xylitol, dulcitol, mannitol), or other thickeners (such as polyethylene glycol, propylene glycol) and their mixtures.

[0042] As used herein, the term “wetting agent”, also called “humectant”, refers to a liquid substance used to displace the film of air that exists on the surface of solid particles such as dry powders (e.g. the suspending agent) and that may hinder their mixing with the vehicle. Therefore, a wetting agent facilitates the mixture of insoluble solid particles such as powders in liquids, avoiding formation of lumps of said solid particles and improving the content uniformity of the final preparation. Illustrative examples of humectants include glycerol (also known as glycerine), polyethylene glycol and / or propylene glycol.

[0043] As used herein, the term “surfactant” relates to an excipient used to reduce the surface tension between a liquid (i.e. the aqueous external phase of the suspension) and a solid (i.e. the particles of quetiapine). Typically, surfactants according to the invention are non-ionic, anionic, cationic or amphoteric tensioactive agents.

[0044] As used herein, the term “preservative” relates to a compound that prevents or reduces the physical and / or chemical degradation of a composition and / or a compound that prevents or reduces the microbial contamination of a composition. Particularly, in the context of the present invention, this term refers to “antimicrobial agent” or “antimicrobial preservative”, that is a compound which inhibits at least one microorganism, preventing the growth and / or reducing the amount of and / or rate of growth of, preferably the amount of, the microorganism compared to the corresponding amount and / or rate of growth of said microorganism in the absence of said compound. Typically, preservatives according to the invention are alcohols, benzoates, parabens, phenols, quaternary ammonium compounds, sorbic acid or salts thereof selected from the group of benzoic acid, sodium benzoate, potassium benzoate, methyl-, ethyl-, propyl-, butyl- parabens, propyl-paraben sodium, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzyl alcohol, ethanol, bronopol, butylated hydroxyanisole, chlorobutanol, chlorocresol, chloroxylenol, isopropyl alcohol, monothioglycerol, phenoxyethanol, phenyl ethyl alcohol, propyl gallate, propylene glycol, potassium sorbate, calcium acetate, calcium chloride, calcium lactate, cetrimide, cetylpyridinium chloride, chlorhexidine, citric acid monohydrate, glycerin, hexetidine, chlorhexidine, imidurea, diazolidinyl urea, lactic acid, pentetic acid, propionic acid, edetic acid, malic acid, sodium acetate, sodium metabisulfite, potassium metabisulfite, sodium borate, sodium lactate, sodium propionate, sodium sulfite, sulfobutyl ether p-cyclodextrin, thimerosal, xanthan, benzalkonium chloride, cetylpyridinium chloride, or their mixtures, or any other pharmaceutically acceptable antimicrobial agent.

[0045] As used herein, the term “flavouring agent” and or “sweetening agent” relates to a compound that may be added to impart a desired taste or aroma, in particular, a sweet taste. Exemplary flavouring and / or sweetening agents are natural or artificial fruit flavours selected from mint, menthol, cinnamon, vanilla, chocolate, cherry, grape, orange, strawberry or lemon.

[0046] As used herein, the term “antifoaming agent” or “defoaming agent” relates to a chemical additive that may be added to the liquid formulation in order to reduce and hinder the formation of foam in a liquid formulation during industrial manufacturing processes. Usually “antifoaming agent” refers to an additive used to prevent formation of foam and “defoaming agent” to an excipient added to break an already formed foam. However, the terms antifoaming agent and defoamer are often used interchangeably. Commonly used antifoaming agents are certain alcohols such as cetostearyl alcohol, paraffin waxes, ester waxes and fatty alcohol waxes, mineral oil, vegetable oil, long chain fatty alcohol, fatty acid soaps or esters, insoluble oils such as castor oil, stearates, polydimethylsiloxanes and other silicones derivatives, ethers and glycols such as, for example, a simethicone emulsion, polyethylene glycol and polypropylene glycol copolymers, ethylene bis stearamide, alkyl polyacrylates and silica.

[0047] In the context of the present invention the terms “buffering system”, “buffer solution”, “pH buffer” or “hydrogen ion buffer” relate to a mixture of an acid and a base (generally an acid and its conjugate base or vice versa, commonly a weak acid and its conjugate base, or vice versa). Their purpose is to minimise pH fluctuations in the formulation, i.e. keep the pH of a solution or suspension at a constant or nearly constant value. In the context of the present invention, said pH is maintained within 4.5 to 6. Typically, buffering systems according to the invention include acetates such as acetic acid and sodium acetate; citrates such as citric acid, sodium citrate or potassium citrate; carbonates such as sodium bicarbonate and potassium bicarbonate; or phosphates such as sodium phosphate and disodium phosphate, e.g. a sodium dihydrogen phosphate dihydrate / sodium hydroxide buffering system. A common buffering combination comprises a citrate component and / or a phosphate component, such as the citrate-phosphate buffer (also known as Mcllvaine buffer), particularly citric acid monohydrate and disodium hydrogen phosphate dihydrate buffering system.

[0048] In the context of the present invention the term “acidifying agent” refers to a substance that is added to lower the pH of a liquid formulation, for example to a pH between 4.5 and 6. The acidifying agent can include one or more of sodium phosphate, sodium phosphate dibasic, adipic acid, ammonium chloride, citric acid monohydrate, citric acid, lemon juice, sodium citrate, potassium citrate, hydrochloric acid, lactic acid, propionic acid, and tartaric acid.

[0049] The term "treatment" or "to treat" in the context of this specification means administration of a formulation according to the invention to ameliorate or eliminate the condition and / or one or more symptoms associated with said condition and / or the physiological sequelae of the condition.

[0050] The term "prevention" or “to prevent” in the context of this specification means reducing the risk of acquiring or developing the condition or one or more symptoms associated with said condition.

[0051] Formulation of the invention

[0052] In a first aspect, the present invention relates to a liquid formulation comprising: i) quetiapine or a pharmaceutically acceptable salt thereof; ii) a suspending agent in amount between 0.05% and 5.0% w / v; iii) a thickener in an amount of at least 25% w / v; and iv) a humectant in an amount between 0.5% and 10% w / v.

[0053] In a preferred embodiment, the liquid formulation is in suspension form, more preferably in aqueous suspension form, even more preferably comprising at least 10% w / v, at least 20% w / v, at least 30% w / v of water, particularly at least 40% w / v water. The upper limit of % w / v of water is determined by the amount of the other components comprised in the liquid formulation, as water is generally added in an amount necessary for all the components to add up to 100% w / v.

[0054] The quetiapine suspensions of the present invention are feasible in a wide range of quetiapine or pharmaceutically acceptable salt thereof concentrations, e.g. between 10 - 40 mg / mL (1 - 4 % w / v), even though concentrations around 20 - 30 mg / mL are preferred in order to facilitate dosage adjustments and to be more adequate for elderly patients.

[0055] In a particular embodiment, the liquid formulation, preferably suspension, of the invention comprises quetiapine or a pharmaceutically acceptable salt thereof in an amount from about 15 to about 35 mg / mL (1.5 to 3.5% w / v), preferably from about 20 to about 30 mg / mL (2 to 3% w / v), more preferably from about 20 to about 25 mg / mL (2.0 to 2.5% w / v).

[0056] In the context of the present invention, the quetiapine or quetiapine salt is in a solid state, and it may be in a crystalline form or in an amorphous form. Additionally, the quetiapine or quetiapine salt may be in an anhydrous and / or solvent-free form or as solvate, particularly a hydrate.

[0057] The term “solvate” according to this invention is to be understood as meaning any form of the active compound which has another molecule (most likely a polar solvent) attached to it via non-covalent bonding. Examples of solvates include hydrates and alcoholates. Solvation methods are generally known in the state of the art.

[0058] In a particular embodiment, the quetiapine or quetiapine salt has a relative particle size distribution D90 lower than 200 pm. In a preferred embodiment the D90 is lower than 100 pm; preferably lower than 75 pm. In an embodiment, in any of these embodiments, the lower limit is 1 pm, more particularly 10 pm, even more particularly 30 pm. In a preferred particular embodiment, the D90 is between 60 and 30 pm. Said particle size distribution can be measured by laser diffraction, such as by using a laser diffraction particle size analyser such as a Malvern Mastersizer, such as the Malvern Mastersizer 3000. In a particular embodiment, the quetiapine salt is selected from the group of fumarate, benzoate, tartrate, oxalate, tosylate, naphsylate, succinate, maleate, citrate, phosphonate, methane sulphonate, formate, hydrochloride, hydrobromide, besylate, dibenzoyl-L-(+)-tartrate, di-p-toluoyl-L-(+)-tartrate, nitrate and sulfate salts. In a preferred embodiment, the salt is a fumarate salt, also known as hemifumarate salt (https: / / pubchem.ncbi.nlm.nih.gov / compound / Seroquel#section=2D-Structure).

[0059] Quetiapine and its salts are widely commercially available from a variety of chemical vendors, such as Sigma-Aldrich (Ref. PHR1856) or Smolecule (Ref. S001786), or described in US4879288, US8101597, WQ2006056772 and WQ2007102074.

[0060] In a particular embodiment, the suspending agent is selected form the group consisting of xanthan gum, tragacanth gum, guar gum and other natural gums, alginates, pectins, agar-agar, carrageenans, cellulose derivatives such as hydroxypropylmethylcellulose (HMPC), sodium carboxymethylcellulose (NaCMC), methylcellulose (MC), hydroxyethylcellulose (HEC), microcrystalline cellulose and mixtures thereof.

[0061] In a more particular embodiment, the suspending agent is a natural gum preferably xanthan gum, tragacanth gum or mixtures thereof, more preferably, the suspending agent is tragacanth gum, even more preferably in the amounts that follow below. Tragacanth gum (CAS 9000-65-1) is commercially available from a variety of chemical vendors, such as from Sigma-Aldrich (Ref. G1128), LOBA Chemie (Ref. 04002) or FARAVELLI Group.

[0062] The suspending agent is in an amount between 0.05% and 5.0% w / v. In a particular embodiment, the suspending agent is in an amount between 0.1% and 2.5%, preferably between 0.2 and 1.5%, more preferably between 0.3 and 1.0% w / v.

[0063] It has been found that the use of sorbitol or propylene glycol as thickener allows employing lower amounts of suspending agent. Thus, in an embodiment, the thickener is sorbitol and the suspending agent is in an amount between 0.05 and 2.0%, preferably between 0.1 and 1.0%, more preferably between 0.2 and 0.8%, even more preferably between 0.3 and 0.6% w / v. When sorbitol or propylene glycol is not employed, such as when a different thickener to sorbitol or propylene glycol selected from those specified herein is used instead, more particularly when polyethyleneglycol is used instead, higher amounts of suspending agent are generally preferred. In such cases, the suspending agent is preferably in an amount between 0.1 and 5.0%, preferably between 0.2 and 2.5% w / v.

[0064] In a particular embodiment, the thickener is selected from sugars, such as sucrose, fructose, maltose; sugar alcohols, such as sorbitol, xylitol, dulcitol, mannitol; or other thickeners such as propylene glycol or polyethyleneglycol; preferably the thickener is selected from sugars, such as sucrose, fructose, maltose; or from sugar alcohols, such as sorbitol, xylitol, dulcitol, mannitol; any of these preferably in the amounts that follow below.

[0065] In a preferred embodiment, the thickener is selected from sugar alcohols, such as sorbitol, xylitol, dulcitol, mannitol; any of these preferably in the amounts that follow below. In an even more preferred embodiment, the thickener is sorbitol, more preferably sorbitol in the amounts that follow below.

[0066] In an alternative embodiment, the thickener is selected from sugars, such as sucrose, fructose, maltose; any of these preferably in the amounts that follow below. In an even more preferred embodiment, the thickener is sucrose, more preferably sucrose in the amounts that follow below.

[0067] The thickener is in an amount of at least 25% w / v. In a very preferred embodiment, the thickener is in an amount of at least 27%, at least 30%, at least 35%, at least 40%, greater than 40%, at least 42%, at least 45%, w / v. Any of these amounts may include an upper limit of up to 75%, in particular up to 73%, more in particular 70%, even more in particular up to 67%, yet more in particular up to 60%, more particularly up to 55%, even more particularly up to 53% w / v.

[0068] In a particular embodiment, the thickener is in an amount between 25 and 75%, preferably between 27 and 73%, more preferably between 27 and 70%, even more preferably between 30 and 67%, yet more preferably between 30 and 60%, preferably between 35 and 55%, more preferably between 42 and 53% w / v. In a more particular embodiment, the thickener is sorbitol, preferably as an aqueous solution, preferably as a non-crystallising aqueous solution, of sorbitol at 65 to 75%, such as at 70 %, w / w (weight of sorbitol over weight of solution). Such solutions are commercially available from a variety of chemical vendors, such as from Roquette (Ref.: NEOSORB® 70 / 70 B Non-crystallizing Liquid Sorbitol), Tereos, Brenntag Quimica, S.A.U. or Azelis Spain, S.A.

[0069] Surprisingly, the inventors have found that the inclusion of sorbitol as thickener results in remarkable physical characteristics, such as density and viscosity, of the liquid formulation, preferably suspension, of the present invention, as well as a good mouth-feel in spite of the bitterness of quetiapine, thus providing an excellent result in terms of stability, physicochemical properties and palatability, even though a sweetening agent is not added. Additionally, sorbitol is an acceptable substitute for sugars, such as sucrose and fructose, that are not recommended for patients suffering from hyperglycemia, such as diabetic patients.

[0070] In a particular embodiment, the humectant is selected from the group consisting of glycerol (also known as glycerine), polyethylene glycol and / or propylene glycol. In a particular embodiment, the humectant is glycerol. In a particular embodiment, the humectant is polyethylene glycol. In a particular embodiment, the humectant is propylene glycol. In a preferred embodiment, any of these wetting agents is present in the amounts that follow below.

[0071] The humectant is in an amount between 0.5 and 10%, preferably between 1 and 5%, more preferably between 2 and 4% w / v. In an embodiment, in any embodiment described herein, when the formulation of the present invention comprises glycerol, it is present as a humectant, i.e. in amounts as described in this paragraph.

[0072] Said humectants are commercially available from a variety of chemical vendors, such as Sigma-Aldrich (Refs. G9012, 1576708, 202398), Azelis Spain S.A. or llnivar Solutions.

[0073] In a particular embodiment, the liquid formulation, preferably suspension, of the present invention further comprises a surfactant. In a preferred embodiment, the surfactant is selected from the group of polyoxyethylene sorbitan fatty acid esters (e.g., polysorbates), polyoxyethylene fatty acids (e.g., polyoxyethylene stearates), polyoxyethylene alkyl ethers (or ethoxylated fatty alcohols), or poloxamers.

[0074] In a more preferred embodiment of the invention the surfactant is a polysorbate selected from Polysorbate 20 (also referred to as Tween 20), Polysorbate 40 (also referred to as Tween 40), Polysorbate 80 (also referred to as Tween 80) and / or sodium lauryl sulphate (also referred to as sodium dodecyl sulfate); any of them in the following amounts; yet more preferably is Polysorbate 20, preferably in the following amounts.

[0075] Preferably, the surfactant is in an amount between 0.001 and 3%, preferably between 0.005 and 0.5%, more preferably between 0.01 and 0.3% w / v.

[0076] The inventors have importantly found that a combination of a suspending agent with a thickener as described above, the humectant and, optionally the surfactant results in an improved physical stability of the liquid formulation, particularly suspension, of quetiapine (i.e., improved flocculation) without worsening other parameters such as the chemical stability, the organoleptic properties, the foaming capacity and / or the antimicrobial activity.

[0077] The liquid formulation, preferably suspension, of the invention may comprise a preservative. However, unexpectedly, it has been found that the efficacy of preventing a microbial proliferation can be achieved in the formulations of the present invention even in the absence of a preservative.

[0078] In a particular embodiment, the liquid formulation, preferably suspension, of the invention may further comprise a preservative.

[0079] In a preferred embodiment, the preservative is selected from the group of methyl, ethyl and propyl parabens, benzoic acid, sodium benzoate, or their mixtures, or any other pharmaceutically acceptable antimicrobial agent. In a particularly preferred embodiment, the preservative is sodium benzoate, more preferably in the following amounts. In a preferred embodiment, the preservative is present in an amount between about 0.01 and about 0.5%, preferably between 0.05 and about 0.2% w / v.

[0080] In a particular embodiment, the formulation, preferably suspension, of the invention does not further comprise an antimicrobial preservative, such as a preservative which inhibits microorganisms, e.g. a preservative which inhibits bacteria, such as gram-negative and / or gram-positive bacteria, e.g. of the Pseudomonas aeruginosa, Staphylococcus aureus or Escherichia coli species; yeasts, such as of the Candida albicans species; and / or molds, such as of the Aspergillus brasiliensis (formerly Aspergillus niger) species.

[0081] In one embodiment, the amount of and / or rate of growth of the microorganism in the presence of the preservative is at least 10% lower than, at least 25% lower than, at least 50% lower than, at least 75% lower than or at least 90% lower, than the corresponding amount of and / or rate of growth of the microorganism in the absence of the preservative, such as at 1, 7 or 14 days from exposure to the preservative.

[0082] Alternatively, the amount of the microorganism in the presence of the preservative is at least 1 -log, at least 2-log, at least 3-log or at least 4-log, lower than the amount of the microorganism in the absence of the preservative, such as at 1 , 7 or 14 days from exposure to the preservative.

[0083] Alternatively, the preservative reduces the amount of microorganism according to European Pharmacopoeia 9th. Edition, 5.1.3 Efficacy of Antimicrobial Preservation, as described at Example 9 herein below.

[0084] In a particular embodiment, the formulation of the invention does not comprise a preservative selected from a paraben, such as an alkyl paraben, e.g. methyl, ethyl, propyl or butyl paraben, preferably it does not comprise methyl paraben.

[0085] In another particular embodiment, the formulation of the invention does not comprise a preservative selected from a benzoate and benzoic acid, such as sodium benzoate or methyl and propyl parahydroxybenzoates. In another more particular embodiment, the formulation does not comprise neither a preservative selected from a paraben nor a preservative selected from a benzoate and benzoic acid, such as those defined immediately above. Most particularly, it does not comprise neither methyl paraben nor sodium benzoate.

[0086] In a particular embodiment, the liquid formulation, preferably suspension, of the invention further comprises a sweetening agent and / or a flavouring agent.

[0087] In a particular embodiment, the formulation, preferably suspension, does not comprise a sweetening agent, such as sucralose, maltitol and / or saccharin. Preferably, the formulation, preferably suspension, does not comprise sucralose, maltitol and / or saccharin as sweetening agent, this is, in an amount of 5% w / v or less.

[0088] The liquid formulation, preferably suspension, of the invention may comprise an anti-foaming agent such as simethicone emulsion. However, it has been found that excellent properties can be achieved in the formulations of the present invention even in the absence of the anti-foaming agent. Thus, in a particularly preferred embodiment, the liquid formulation, preferably suspension, of the invention does not comprise an anti-foaming agent such as an anti-foaming agent selected from the aforementioned list, preferably it does not comprise a simethicone emulsion.

[0089] The liquid formulation, preferably suspension, of the invention may comprise a buffering system. However, contrary to expectation, it has been found that excellent appearance and physicochemical stability can be achieved in the formulations of the present invention even in the absence of the buffering system. Thus, in a particularly preferred embodiment, the formulation, preferably suspension, does not comprise a buffering system such as a buffering system selected from the aforementioned list, preferably it does not comprise a citratephosphate buffering system, more particularly it does not comprise a citric acid monohydrate - disodium hydrogen phosphate dihydrate (also known as sodium phosphate dibasic, chemical formula Na2HPC>4 ■ 2H2O) buffering system.

[0090] The liquid formulation, preferably suspension, of the invention may comprise an acidifying agent. However, it has been found that excellent stability can be achieved in the formulations of the present invention even in the absence of an acidifying agent. Thus, in a particularly preferred embodiment, the formulation, preferably suspension, of the present invention does not comprise an acidifying agent such as an acidifying agent selected from the aforementioned list, preferably it does not comprise a sodium hydrogen phosphate such as disodium hydrogen phosphate (also known as sodium phosphate dibasic, chemical formula Na2HPO4), disodium dihydrogen phosphate (chemical formula (NaH2PC>4)2) or sodium dihydrogen phosphate (also known as sodium phosphate monobasic, chemical formula NaH2PO4), and their hydrated forms, e.g. Na2HPC>4 ■ 2H2O, (NaH2PO4)2■ 2H2O or NaH2PO4■ 2H2O.

[0091] Surprisingly, there is no need to add neither a buffering system nor an acidifying agent to stabilize the liquid formulation of the present invention, contrary to what is observed with prior art quetiapine suspensions.

[0092] In a preferred embodiment, the suspension of the present invention comprises: i) quetiapine or a pharmaceutically acceptable salt thereof, preferably in an amount between 1 and 4% w / v; ii) the suspending agent, preferably tragacanth gum, preferably in an amount between 0.1 % and 2.5%, more preferably between 0.2 and 1.5% w / v; iii) the thickener, preferably sorbitol, preferably in an amount between 30 and 60%, preferably between 35 and 55% w / v, and iv) the humectant, preferably glycerine, polyethyleneglycol and / or propylene glycol, preferably any of them in an amount between 1 and 5%, more preferably between 2 and 4% w / v.

[0093] In a preferred embodiment, the formulation further comprises:

[0094] - a surfactant, preferably polysorbate and / or sodium lauryl sulphate.

[0095] In a preferred embodiment, the suspension of the present invention comprises: i) quetiapine or a pharmaceutically acceptable salt thereof, preferably quetiapine fumarate, in an amount between 1 and 4%, preferably between 2 and 3% w / v, ii) the suspending agent, preferably tragacanth gum in an amount between 0.1 and 2.5%, preferably between 0.2 and 1.5% w / v, iii) the thickener, preferably sorbitol, in an amount between 30 and 60%, preferably between 35 and 55% w / v, iv) the humectant, preferably glycerine, polyethyleneglycol and / or propylenglycol, preferably any of them in an amount between 1 and 5%, preferably between 2 and 4% w / v, v) optionally a surfactant, preferably polysorbate and / or sodium lauryl sulphate, in an amount between 0.005 and 0.5%, preferably between 0.01 and 0.3% w / v.

[0096] In a preferred embodiment, the suspension of the present invention comprises: i) quetiapine fumarate in an amount between 2 and 3% w / v ii) tragacanth gum in an amount between 0.2 and 1.5% w / v, preferably 0.3 and 1.0% w / v, iii) sorbitol in an amount between 35 and 55% w / v, preferably between 42 and 53% w / v, iv) glycerine, polyethylene glycol and / or propylene glycol, preferably glycerine, any of them in an amount between 2 and 4% w / v, and v) a polysorbate and / or sodium lauryl sulphate, preferably polysorbate 20, any of them in an amount between 0.01 and 0.3% w / v, preferably between 0.01 and 0.05% w / v.

[0097] The formulations of the invention as defined above are preferably suitable for oral use, i.e. they exert the pharmaceutical action described elsewhere herein after administration to a patent by the oral route.

[0098] The formulations of the invention have a viscosity between 30 and 1100 cP, preferably between 100 and 1000 cP, more preferably between 150 and 900 cP, even more preferably between 150 and 750 cP, yet more preferably between 400 and 800 cP, measured at 25°C. The measurement can be carried out according to European Pharmacopoeia (Ph Eur) 7.0. - 2.2.10. Viscosity - rotating viscometer method, with a rotating viscometer, preferably a rotating spindle viscometer such as an Anton Paar ViscoQC 300-L equipped with an SC4-31 spindle, which rotates at a speed of 30 r.p.m., and ensuring a torque value of >10%. The formulations of the invention have a density measured at room temperature (between 15 and 25°C according to the Ph Eur, preferably 21 °C) higher than 1 g / mL, preferably between 1.01 and 1.30, more preferably between 1.02 and 1.25, even more preferably between 1.03 and 1.25, even more preferably between 1.03 and 1.20, yet more preferably between 1.05 and 1.20, yet more preferably between 1.10 and 1.20, most preferably between 1.14 to 1.20 g / mL. Density may be measured according to Ph Eur 7.0 - 2.2.5, with a densimeter or a pycnometer.

[0099] Preferably, the formulations of the invention have a pH between 4.5 and 6. pH may be measured according to Ph Eur 7.0 - 2.2.3, with an automatic pHmeter.

[0100] Preferably, at least 75% of the quetiapine or quetiapine salt of the formulations of the invention is fully dissolved in 45 minutes in water at 37 ± 0.5°C. More preferably, at least 80% is fully dissolved in 30 minutes in water at 37 ± 0.5°C. Thus, the formulations of the invention are suitable for administering quetiapine to a human being. The dissolution test may be performed according to Ph Eur 7.0 - 2.9.3. Dissolution test for solid dosage forms.

[0101] Methods

[0102] The formulations of the invention can be prepared following any known process of the prior art.

[0103] A second aspect of the present invention is directed to a method for preparing the liquid formulation of the invention, wherein said method comprises the following steps: a) Mixing water and the thickener; b) Adding the suspending agent and the humectant, previously mixed with each other, to the mixture obtained in step a) and mixing; c) Adding quetiapine or the salt thereof to the mixture obtained in step b) and mixing.

[0104] In a preferred embodiment, the mixing in step a) is performed until a homogeneous solution is obtained. Homogeneity can be determined by any manner known to the skilled person, such as by visual inspection, e.g. by verifying that no solid is visible to the naked eye. This step is preferably performed in a suitable tank equipped with a stirrer.

[0105] In a particular embodiment, the thickener is sorbitol and is added as an aqueous solution, preferably as a non-crystallising aqueous solution, of sorbitol at 65 to 75%, such as at 70 %, w / w (weight sorbitol over weight of solution).

[0106] In a preferred embodiment, step b) comprises dispersing the suspending agent in the humectant. The dispersion is performed in a suitable container independent from the tank of step a), and then added to the mixture obtained in step a). Preferably, the mixing in step b) is performed until a homogeneous dispersion is obtained. Homogeneity can be determined by any manner known to the skilled person, such as by visual inspection, e.g. by verifying that no solid lumps are visible to the naked eye.

[0107] In a preferred embodiment, step c) comprises dispersing quetiapine or the salt thereof in the surfactant. The dispersion is performed in a suitable container independent from the tank of step a) and the container used for the dispersing of step b). This dispersion is then added to the mixture obtained in step b). Preferably, the mixing in step c) is performed until a homogeneous dispersion is obtained. Homogeneity can be determined by any manner known to the skilled person, such as by visual inspection, e.g. by verifying that no solid lumps are visible to the naked eye.

[0108] Optionally, the method comprises adding the sweetening agent and / or the flavouring agent and / or the preservative in any of the above steps.

[0109] In a preferred embodiment, the method comprises a step d) of adding water (q.s. to final volume) and mixing.

[0110] The water used in the formulations of the invention is preferably purified water.

[0111] In a preferred embodiment, the method comprises a final step of homogenising the obtained mixture. The mixture is considered homogeneous when samples of the formulation from various areas in the formulation container, such as from the top, middle, and bottom, reveal a concentration of quetiapine or the salt thereof differing in at most 10%.

[0112] Embodiments, particularities and preferences for each component of the formulation are those described for the formulation in the first aspect of the invention.

[0113] In a particular embodiment, the method comprises: a) Mixing water and the thickener, which is preferably sorbitol, and optionally the sweetening agent and / or the flavouring agent and / or the preservative, to obtain a solution; b) Preparing a dispersion of the suspending agent, which is preferably tragacanth gum, in the humectant, which is preferably glycerine, propylene glycol and / or polyethyleneglycol; then adding this dispersion to the solution obtained in step a), and mixing to obtain a new dispersion; c) Preparing a dispersion of quetiapine or the salt thereof in the surfactant, which is preferably a polysorbate and / or sodium lauryl sulphate, adding this dispersion to the dispersion obtained in step b) and mixing to obtain a new dispersion.

[0114] In a more particular embodiment, the method comprises: a) Mixing water and the thickener, which is preferably sorbitol, and optionally the sweetening agent and / or the flavouring agent and / or the preservative, to obtain a solution; b) Preparing a dispersion of the suspending agent, which is preferably tragacanth gum, in the humectant, which is preferably glycerine; then adding this dispersion to the solution obtained in step a), and mixing to obtain a new dispersion; c) Preparing a dispersion of quetiapine or the salt thereof in the surfactant, which is preferably Tween 20, and adding this dispersion to the dispersion obtained in step b) and mixing to obtain a new dispersion.

[0115] In another particular embodiment, the method is as described above, however the sweetening agent and / or the flavouring agent and / or the preservative is added to the new dispersion obtained in step b), prior to the adding of step c). In another particular embodiment, the method is as described above, however the sweetening agent and / or the flavouring agent and / or the preservative is added to the new dispersion obtained in step c) and the resulting dispersion is mixed, preferably until obtaining a homogeneous dispersion.

[0116] In another particular embodiment, the method is as described above, and may further include a step d) of adding water (q.s to final volume) to the dispersion obtained in c) and mixing until obtaining an homogeneous suspension.

[0117] The manufacturing process may require mixing by vigorous stirring, such as up to 1800 - 2500 rpm, to ensure efficient dispersion of the active and the excipients. This in turn aerates the product and can produce excessive foam on the surface of the product. Surprisingly, it was determined that the use of an antifoaming agent is not necessary in the formulation of the present invention.

[0118] In a different aspect, the invention refers to a formulation obtainable by any of the methods described herein.

[0119] Uses

[0120] In a further aspect, the present invention relates to a liquid formulation of the invention, preferably a suspension, as defined in any of the embodiments described above, for use as a medicament.

[0121] Another aspect of the invention is directed to a liquid formulation of the invention, preferably a suspension, as defined in any of the embodiments described above, for use in the prevention and / or treatment of a mental, behavioural and / or mood condition.

[0122] The above aspect can be formulated as the use of a liquid formulation of the invention, preferably a suspension, as defined in any of the embodiments described above, in the manufacture of a medicament for the prevention or treatment of a mental, behavioural and / or mood condition.

[0123] The above aspect can be formulated as the use of a liquid formulation of the invention, preferably a suspension, as defined in any of the embodiments described above, for the prevention or treatment of a mental, behavioural and / or mood condition.

[0124] The above aspect can be formulated as a method of treating or preventing a mental, behavioural and / or mood condition, the method comprising administering to a patient in need of such treatment a liquid formulation of the invention, preferably a suspension, as defined in any of the embodiments described above.

[0125] In a particular embodiment, the mental, behavioural and / or mood condition is selected from schizophrenia; bipolar disorder, in particular treatment of moderate to severe manic episodes and / or major depressive episodes, prevention of recurrence of manic or depressive episodes in patients with bipolar disorder; major depressive disorder, in particular treatment of major depressive episodes in patients who have not had an optimal response to treatment with antidepressants in monotherapy; anxiety; and agitation.

[0126] The following examples are merely illustrative of certain embodiments of the invention and cannot be considered as restricting it in any way.

[0127] EXAMPLES

[0128] EXAMPLE 1 : Method of preparation

[0129] Formulations according to the invention can be prepared as follows:

[0130] Add 100 liters of purified water to a main tank. Incorporate 334,620 kg of sorbitol 70% (non-crystalisable) under stirring until complete dissolution. In a suitable stainless steel reactor, add 14,625 kg of glycerin and stir. Incorporate, little by little and under stirring, 2,210 kg of tragacanth gum. Add the dispersion of tragacanth gum in glycerin (predispersion 1) to the main tank and stir the resulting mixture. Incorporate to the main tank 0,585 kg of strawberry aroma and stir, and then incorporate 0,500 kg of sodium benzoate and stir. Visually verify that sodium benzoate is completely dissolved before adding the following components. If not, continue stirring. In another suitable stainless steel reactor, add 40 liters of purified water and 0,115 kg of polysorbate 20 (or 0,585 kg of sodium lauryl sulphate) and stir. Incorporate 14,390 kg of quetiapine fumarate, little by little and under stirring. Add the quetiapine dispersion in water (predispersion 2) to the main tank under stirring. Bring up to 500 liters with purified water and stir. Homogenize the suspension by passing it through a suitable mill. Recirculate for approximately 30 minutes.

[0131] EXAMPLE 2: Quetiapine Oral Suspension 25 mg / mL

[0132] Ingredient Quantity (g / 100 mL-% w / v)

[0133] Quetiapine fumarate 2.878

[0134] Sorbitol 70% (non-crystallisable) 66.924 (~ 46.85 g sorbitol)

[0135] Glycerin 2.925

[0136] Tragacanth gum (anhydrous) 0.442

[0137] Polyoxyethylene (20) sorbitan monolaurate 0.023

[0138] Sodium benzoate 0.100

[0139] Strawberry flavour 0.117

[0140] Purified water q.s. to 100

[0141] This formulation was stored under different conditions and proved to be physically and chemically stable for at least 2 years at 5°C, 25°C / 60% HR, 30°C 165% HR, 30°C 175% HR and 40°C 175% HR.

[0142] This demonstrates the superior stability of the formulation according to the present invention over commercial products such as Quetiapine Rosemont 20mg / ml Oral Suspension, which lacks sorbitol in its composition and which requires a buffering system and strict refrigeration between 2° and 8 °C in order to achieve 2-year stability.

[0143] EXAMPLE 3: Quetiapine Oral Suspension 25 mg / mL

[0144] Ingredient Quantity (g / 100 mL)

[0145] Quetiapine fumarate 2.878

[0146] Sorbitol 70% (non-crystallisable) 66.924

[0147] Glycerin 2.925

[0148] Tragacanth gum (anhydrous) 0.442

[0149] Sodium lauryl sulphate 0.117

[0150] Sodium benzoate 0.100

[0151] Strawberry flavour 0.117

[0152] Purified water q.s. to 100

[0153] EXAMPLE 4: Quetiapine Oral Suspension 25 mg / mL Ingredient Quantity (g / 100 mL-% w / v)

[0154] Quetiapine fumarate 2.878

[0155] Sorbitol 70% (non-crystallisable) 66.924

[0156] Glycerin 2.925

[0157] Tragacanth gum (anhydrous) 0.469

[0158] Polyoxyethylene (20) sorbitan monolaurate 0.023

[0159] Sodium benzoate 0.100

[0160] Strawberry flavour 0.117

[0161] Purified water q.s. to 100

[0162] EXAMPLE 5: Quetiapine Oral Suspension 25 mg / mL

[0163] Ingredient Quantity (g / 100 mL)

[0164] Quetiapine fumarate 2.878

[0165] Sorbitol 70% (non-crystallisable) 66.924

[0166] Glycerin 2.925

[0167] Tragacanth gum (anhydrous) 0.469

[0168] Sodium lauryl sulphate 0.117

[0169] Sodium benzoate 0.100

[0170] Strawberry flavour 0.117

[0171] Purified water q.s. to 100

[0172] EXAMPLE 6:

[0173] Ingredient Quantity (g / 100 ml)

[0174] Quetiapine fumarate 2.500

[0175] Sorbitol 70% (non-crystallisable) 66.924

[0176] Glycerin 2.925

[0177] Tragacanth gum (anhydrous substance) 0.468

[0178] Polyoxyethylene (20) sorbitan monolaurate 0.023

[0179] Strawberry flavour 0.117

[0180] Water q.s. to 100

[0181] EXAMPLE 7: Phase separation analysis

[0182] A phase separation analysis of quetiapine formulations with different excipients (Table I) was conducted, storing the formulations below at different conditions during six months. Table I: Formulations tested

[0183] The suspensions were prepared as reported above. The physical stability of the suspensions at three different temperatures (5°C, 25°C and 50°C), in particular their phase separation behaviour, was verified by checking the appearance by visual inspection.

[0184] The formulation L19 / 11 corresponds to Example 4 and L19 / 14 to Example 5. In the formulation L19 / 12 propylene glycol is used instead of sorbitol (in a smaller amount) while in L19 / 13 neither propylene glycol nor sorbitol are used.

[0185] Samples have been stored at 5°C, 25°C / 60% RH and 50°C. Once a month, during all the months of the study, a visual analysis was carried out in the container without resuspending. The results at 6 months are summarized in Table II.

[0186] Table II. Phase separation analysis at 6 months

[0187] Formulations L19 / 12 and L19 / 13, which do not comprise sorbitol, show more compact lower phases at sixth month, exhibiting the tendency of these formulations to caking (the particles settle to a more dense sediment) and then to be less stable under storage.

[0188] EXAMPLE 8: Stability test

[0189] For the purposes of the present invention, the stability of quetiapine suspensions comprising different excipients was tested, using formulation of Example 2 as reference.

[0190] The alternative formulations are prepared by substituting an excipient of the reference formula with an excipient of similar properties or removing it.

[0191] Table III: Composition of reference formula

[0192] (*) 2.878 mg of quetiapine fumarate are equivalent to 2.5 mg of quetiapine base

[0193] The composition of the different formulations (in comparison with the reference formulation) is detailed in the Tables V - VIII below.

[0194] Each formulation (50 ml) is packaged in multi-dose translucent High Density Polyethylene (HDPE) bottles (60 ml) with childhood shutter cup and stored in chambers at different conditions (25±2°C / 60±5%RH, 30±2°C / 65±5%RH, for at least 12 months; and 40±2°C / 75%RH for at least 6 months) and various parameters are analysed. The samples were analysed at the beginning of the study (t=0) and every three months (t=3M, t=6M).

[0195] At every sampling time, one bottle of each formulation is withdrawn from every chamber to analyse the parameters described in Table IV, which also indicates the sample quantity needed to perform each analysis:

[0196] Table IV: Parameters to be analysed

[0197] (1) The same sample used for these analyses will be used to measure the pH.

[0198] 8.1 METHODS OF ANALYSIS AND SPECIFICATIONS

[0199] Redispersion (Resuspendibility)

[0200] Before taking the sample for analysis, manually shake the bottle for 30 seconds through 180° rotations. The particles should be suspended homogeneously.

[0201] Appearance

[0202] Immediately after redispersing the sample, carry out a visual inspection. The sample should be a white colour, homogenous suspension. pH

[0203] Measure the pH of the samples with an automatic pHmeter keeping the suspension in continuous stirring. (Procedure according to 2.2.3 of Ph Eur)

[0204] Density

[0205] Determine the density of the sample with a densimeter or a pycnometer at room temperature. (Procedure according to 2.2.5 of Ph Eur at room temperature)

[0206] 8.2 FORMULATIONS TESTED AND RESULTS The formulations of Tables V-VIII were analysed in order to determine the parameters detailed below.

[0207] A formulation was considered compliant when:

[0208] - It showed a white colour and a homogeneous suspension of quetiapine particles following redispersion.

[0209] - pH was between 4.5 - 6.0.

[0210] - Density was between 1.03 and 1.20 g / mL.

[0211] - Sodium benzoate content is between 0.90 - 1.10 mg / mL (90 - 110%) for a density 1.14 - 1.20 g / mL. Sodium benzoate amount considered compliant was proportionally shifted when resulting density of the suspension was outwith stated range but still acceptable (i.e.: benzoate content could be between 0.81 - 0.99 g / mL for a density between 1.03 and 1.09 g / mL, or between 0.86 - 1.05 g / mL for a density between 1.08 and 1.14 g / mL).

[0212] - Quetiapine content is between 23.75 - 26.25 mg / mL (95 - 105%) for a density 1.14 - 1.20 g / mL. Sodium benzoate assay amount considered compliant was proportionally shifted when resulting density of the suspension was outwith stated range but still acceptable (i.e.: quetiapine content could be between 21.38 - 23.63 g / mL for a density between 1.03 and 1.09 g / mL, or between 22.56 - 24.94 g / mL for a density between 1.08 and 1.14 g / mL).

[0213] Table V: Composition of the formulas with replacement or elimination of polysorbate 20 (surfactant) Water q.s. _ 50ml | 500 ml | 500 ml | 500 ml |

[0214] L23 / 04 - Quetiapine suspension with Sodium lauryl sulfate instead of Polysorbate 20: all tested parameters comply.

[0215] L23 / 12 - Quetiapine suspension without surfactant: all tested parameters comply.

[0216] L23 / 13 - Quetiapine suspension with Polysorbate 80 instead of Polysorbate 20: all tested parameters comply.

[0217] Conclusion: The absence or substitution of the reference surfactant does not impair the stability of the alternative formulations.

[0218] Table VI: Composition of the formulas with replacement or elimination of glycerin (humectant)

[0219] Note: The formula L23 / 07 could not been manufactured due to the gum could not been dispersed in water without an humectant.

[0220] L23 / 05 - Suspension with PEG 400 instead of Glycerin: all tested parameters comply.

[0221] L23 / 06 - Suspension with Propylenglycol instead of Glycerin: all tested parameters comply.

[0222] Conclusions: The humectant would be an essential ingredient for the preparation of the suspensions, particularly for the dispersion of the suspending agent in water. The substitution of the reference humectant seems not to impair the stability of the alternative formulations.

[0223] Table VII: Composition of the formulas with replacement of sorbitol (thickener)

[0224] L23 / 11 - Suspension with PG instead of Sorbitol: all tested parameters are considered acceptable. L23 / 14 - Suspension with PEG 400 instead of Sorbitol: all tested parameters are considered acceptable.

[0225] Conclusion: The substitution of the reference thickner does not seem to be detrimental to the stability of the alternative formulations (even though it could be prejudicial to the taste of the suspension due to PEG and PPG lack the sweet taste of sorbitol).

[0226] Table VIII: Composition of the formulas with replacement of tragacanth gum (suspending agent)

[0227] L23 / 08 - Suspension with Xantan gum instead of Tragacanth gum: all tested parameters comply.

[0228] Conclusion: The substitution of the reference gum is not detrimental to the stability of the alternative formulation.

[0229] Table IX: Composition of the formulas with replacement or elimination of sodium benzoate (preservative)

[0230] L23 / 30 - Quetiapine suspension without preservative: all tested parameters comply.

[0231] L23 / 31 - Quetiapine suspension with sodium methylparaben instead of sodium benzoate: all tested parameters comply. Conclusion: The absence or substitution of the reference preservative does not impair the stability of the alternative formulations.

[0232] EXAMPLE 9: Microbial challenge test For the purposes of the present invention, the capability of quetiapine suspensions of withstanding a low level of microbial contamination during manufacturing, storage and use was tested.

[0233] Through the forced inoculation of the product with microorganisms representative of the main groups (gram-negative bacteria, gram-positive bacteria, yeasts and molds), the contamination of the product under study is recreated.

[0234] By sampling and microbiological seeding of the tested formulation at different times, from the initial contamination (inoculation) and up to a maximum of 28 days, its ability to eliminate or reduce contamination is verified.

[0235] 9.1 METHOD OF ANALYSISAND SPECIFICATIONS

[0236] The samples were tested according to European Pharmacopoeia 9th. Edition, 5.1.3 Efficacy of Antimicrobial Preservation.

[0237] A formulation is considered compliant when a 3 log reduction in the inoculated dose of bacteria and 1 log reduction in the inoculated dose of fungi after 14 days and no increase as compared to the previous reading at 28 days are verified.

[0238] 9.2 FORMULATION TESTED AND RESULTS

[0239] Table X: Composition without sodium benzoate (preservative)

[0240] Table XI: Results

[0241] 9.3 CONCLUSION

[0242] The tested formulation meets the criteria of the European Pharmacopeia Edition for oral preparations. The ability of the formulations of the present invention to eliminate or reduce contamination is verified even though they do not contain a preservative.

Claims

CLAIMS1. A liquid formulation comprising: i) quetiapine or a pharmaceutically acceptable salt thereof; ii) a suspending agent in an amount between 0.05% and 5.0% w / v; iii) a thickener in an amount of at least 25% w / v; and iv) a humectant in an amount between 0.5% and 10% w / v.

2. The formulation according to claim 1 , wherein the formulation is in the form of a suspension.

3. The formulation according to claim 2, wherein the formulation is in the form of an aqueous suspension comprising at least 20% w / v of water.

4. The formulation according to any one of the preceding claims, wherein the concentration of quetiapine of pharmaceutically acceptable salt thereof is between land 4% w / v, preferably between 1.5and 3.5% w / v, more preferably between 2and 3% w / v, even more preferably from 2 to 2.5% w / v.

5. The formulation according to any one of the preceding claims, wherein the quetiapine or a pharmaceutically acceptable salt thereof is quetiapine fumarate.

6. The formulation according to any of the preceding claims, wherein the thickener is selected from sugars, sugar alcohols, propyleneglycol, polyethyleneglycol and their mixtures, preferably it is sorbitol.

7. The formulation according to any one of the preceding claims, wherein the thickener is in an amount of at least 35% w / v, preferably at least 40% w / v, more preferably at least 42%.

8. The formulation according to any one of the preceding claims, wherein the humectant is selected from glycerol, polyethylene glycol, propylene glycol and their mixtures.

9. The formulation according to any one of the preceding claims, further comprising a surfactant selected from the group of polyoxyethylene sorbitan fattyacid esters, polyoxyethylene fatty acids, polyoxyethylene alkyl ethers and poloxamers, preferably is a polysorbate selected from Polysorbate 20, Polysorbate 40, Polysorbate 80; and / or sodium lauryl sulfate.

10. The formulation according to any one of the preceding claims, which is a suspension comprising: i) quetiapine fumarate in an amount between 1 and 4% w / v, ii) tragacanth gum in an amount between 0.2 and 1.5% w / v, iii) sorbitol in an amount between 35 and 55% w / v, iv) glycerine, polyethyleneglycol and / or propylenglycol, in an amount between 1 and 5% w / v, and v) a polysorbate and / or sodium lauryl sulphate in an amount between 0.01 and 0.3% w / v.

11. The formulation according to any one of the preceding claims, not comprising a buffering system.

12. Method for preparing a formulation as defined in claims 1-11 , said method comprising the following steps: a) Mixing water and the thickener; b) Adding the suspending agent and the humectant, previously mixed with each other, to the mixture obtained in step a) and mixing; c) Adding quetiapine or the salt thereof to the mixture obtained in step b) and mixing.

13. Method according to claim 12, said method comprising the following steps: a) Mixing water and the thickener to obtain a solution; b) Preparing a dispersion of tragacanth gum in the humectant, and adding this dispersion to the solution obtained in step a), and mixing to obtain a second dispersion; c) Preparing a dispersion of quetiapine or the salt thereof in the surfactant and adding this dispersion to the second dispersion obtained in step b) and mixing to obtain a final dispersion. d) Optionally, adding water (q.s. to final volume) and mixing until obtaining an homogeneous suspension.

14. A formulation as defined in any of claims 1-11 for use as a medicament.

15. A formulation as defined in any of claims 1-11 , for use in the prevention and / or treatment of mental, behavioural and / or mood conditions.