Quetiapine long-acting injection

Abstract

The present invention provides an injectable pharmaceutical composition for subcutaneous or intramuscular administration comprising quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 50% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, or a pharmaceutically acceptable salt of any of them, and any mixture thereof; and a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 70:1 to 1.5:1; and the composition is a suspension. It also relates to such compositions for use in the treatment of schizophrenia and / or bipolar disorder, wherein the treatment comprises subcutaneous or intramuscular administration of the composition to a subject in need thereof. It also relates to a kit for the preparation of the injectable pharmaceutical composition.

Description

[0001] Quetiapine long-acting injection

[0002] This application claims the benefit of European Patent Application EP24383040.3 filed on 27 September 2024.

[0003] Technical Field

[0004] The present invention belongs to the field of antipsychotic pharmaceutical compositions. In particular, the invention relates to injectable pharmaceutical compositions comprising quetiapine or a pharmaceutically acceptable salt thereof, as well as these pharmaceutical compositions for use in the treatment of schizophrenia and / or bipolar disorder.

[0005] Background Art

[0006] Schizophrenia is a chronic and severe mental disorder that affects a person's thinking, feeling, and behavior. Patients with schizophrenia often struggle with symptoms such as hallucinations, delusions, and cognitive impairments, which can significantly decrease their ability to adhere to daily medication regimens. Bipolar disorder is a mental health condition characterized by alternating periods of depression and abnormally elevated mood, with each episode persisting for durations ranging from several days to weeks. The etiology of this disorder remains incompletely understood; however, it is believed to result from a combination of genetic predispositions and environmental influences.

[0007] Quetiapine, an atypical antipsychotic, is widely used in the management of both disorders due to its efficacy in controlling both positive and negative symptoms. However, the necessity for daily oral administration of quetiapine presents significant challenges for these patients.

[0008] Non-adherence to medication is a critical issue in the management of both disorders mentioned above, often leading to relapse, hospitalization, and overall poor prognosis. Patients may forget to take their medication, may deliberately avoid taking it due to side effects, or may be unable to maintain the medication schedule due to the nature of their illness. In addition, the daily oral administration of quetiapine leads to fluctuations in plasma drug levels, which can negatively impact the patient's mood. Consequently, there is a significant clinical need for long-acting (i.e. , extended-release) formulations that can ensure consistent therapeutic levels of the drug in the patient's system while reducing the frequency of administration and improving patient adherence.

[0009] Quetiapine, in its conventional oral dosage form, exhibits poor water solubility and low bioavailability, thereby presenting significant challenges in the development of injectable dosage forms. These challenges include ensuring good injectability, achieving an extended and sustained release of quetiapine, administering the required high daily drug dose and maintaining therapeutic plasma levels within acceptable and pharmaceutically active limits.

[0010] Intramuscular and subcutaneous injectable dosage forms, when adequately formulated, may have the potential to allow for the prolonged release of the active pharmaceutical ingredients into the bloodstream, thereby providing a therapeutic effect over an extended period. Quetiapine injectable formulations designed to achieve extended and sustained release could offer considerable benefits over daily oral administration.

[0011] CN105147700A relates to a quetiapine fumarate composition for use in preparing a medicine for treating glioma. It discloses an injectable composition comprising quetiapine fumarate which is administered daily to mice for increasing the sensitivity of the glioma cells to the chemotherapeutic drug temozolomide and delaying the growth of recurrent glioma.

[0012] WQ2023201390A1 discloses an aqueous solution comprising a quetiapine salt, together with one or both of a benzoic acid salt and a citric acid salt. The concentration of the quetiapine salt in the aqueous solutions ranges from 0.1 mg / ml to 5 mg / ml. Among the advantages of the aqueous solution according to this document are an increased solubility and rapid solubilization of quetiapine.

[0013] CN102552128A discloses a quetiapine fumarate injection for intravenous administration and a preparation method thereof. The quetiapine fumarate injection further comprises a solubilizer, a stabilizing agent and water for injection. The concentration of quetiapine fumarate in the solution for injection accounts for 1-5% w / w of the total weight of the injection and the solubility of quetiapine is increased by thermal treatment and the use of a solubilizing agent.

[0014] Based on current knowledge in the field, there remains a need for developing injectable quetiapine compositions that are capable of delivering therapeutic effective doses of quetiapine over an extended period of time, to overcome the technical challenges of the known treatments. Overcoming these challenges would provide a much-needed therapeutic option for patients with schizophrenia or bipolar disorder, potentially improving their adherence to treatment, reducing risk of relapse, and improving their quality of life. Summary of Invention

[0015] The inventors have developed new injectable pharmaceutical compositions comprising quetiapine or a pharmaceutically acceptable salt thereof, and a biocompatible polymer in certain ratios, which are highly concentrated long-acting quetiapine suspensions for subcutaneous or intramuscular injection.

[0016] The inventors have surprisingly found that the compositions according to the invention provide an extended release of quetiapine, or a pharmaceutically salt thereof, into the bloodstream, as well as showing acceptable bioavailability. It has been found that the highly concentrated suspensions according to the invention can deliver amounts of quetiapine into the bloodstream over at least 7 days and can ensure adequate therapeutic levels of the drug, which leads to reducing the frequency of administration and improving patient adherence. In fact, the compositions according to the invention can in some embodiments even provide a sustained release of quetiapine into the bloodstream until at least 14, 21 or 28 days from administration.

[0017] The pharmaceutical compositions according to the invention can also provide almost uniform levels of quetiapine in the bloodstream of the patient during at least 7 days after administration, which provides a therapeutic benefit versus fluctuations in drug plasma levels obtained by daily administration. These compositions thus avoid negatively affecting the patient's mood by avoiding large fluctuations in quetiapine bloodstream levels. Furthermore, the injectable pharmaceutical compositions according to the invention avoid lag times after administration by providing therapeutic plasma levels already in the first two hours.

[0018] In spite of the high concentration, the quetiapine suspensions according to the invention have good injectability for being administered intramuscularly or subcutaneously for instance, using a 21-gauge (21G) needle. Administering a high drug dose using the quetiapine solutions disclosed in the prior art would necessitate a significantly larger volume than the compositions provided by the present invention, rendering such volume unsuitable for intramuscular or subcutaneous administration.

[0019] Accordingly, a first aspect of the invention relates to an injectable pharmaceutical composition for subcutaneous or intramuscular administration comprising quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 50% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; and a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 70:1 to 1.5:1 ; and the composition is a suspension.

[0020] A second aspect of the invention relates to an injectable pharmaceutical composition as defined above for use in the treatment of schizophrenia and / or bipolar disorder, wherein the treatment comprises subcutaneous or intramuscular administration of the composition to a subject in need thereof.

[0021] A third aspect relates to a kit for preparing the injectable pharmaceutical composition for subcutaneous or intramuscular administration as defined above which comprises a first receptacle comprising the quetiapine or the pharmaceutically acceptable salt thereof and the biocompatible polymer, and a second receptacle comprising the polar solvent; optionally, an injectable device; and optionally, instructions for preparing and for injecting the pharmaceutical composition, wherein optionally one of the first or second receptacles is the injectable device.

[0022] As explained above, the injectable pharmaceutical compositions described herein provide an extended and sustained release of quetiapine into the bloodstream. The administration of these long-acting quetiapine compositions therefore results in good patient adherence, reduced risk of relapse, and an acceptable management of schizophrenia.

[0023] Brief Description of Drawings

[0024] FIG. 1 shows the quetiapine plasma level in Sprague-Dawley (SD) rats injected subcutaneously according to Example 2 with the injectable pharmaceutical compositions MED-1 to MED-3 of Example 1. Results are expressed as the concentration ([C]) in ng / ml of quetiapine in plasma as a function of time (t) in days (d). The circle-shaped markers represent the values for MED-1 ; the square-shaped markers represent the values for MED-2; and the triangle-shaped markers represent the values for MED-3.

[0025] FIG. 2 shows the quetiapine plasma level in Sprague-Dawley (SD) rats injected subcutaneously according to Example 2 with the injectable pharmaceutical compositions MED-4 to MED-6 of Example 1. Results are expressed as the concentration ([C]) in ng / ml of quetiapine in plasma as a function of time (t) in days (d). The circle-shaped markers represent the values for MED-4; the triangle-shaped markers represent the values for MED-5; and the square-shaped markers represent the values for MED-6. Detailed description of the invention

[0026] All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly through-out the specification and claims unless an otherwise expressly set out definition provides a broader definition.

[0027] For the purposes of the invention, any ranges given include both the lower and the upper endpoints of the range. Ranges given, such as temperatures, quantities, times, sizes, and the like, should be considered approximate, unless specifically stated.

[0028] The terms “long acting” and “extended release” are considered herein interchangeable and refer to a composition which releases an active ingredient over a prolonged period after a therapeutically effective amount of the composition has been administered. The term “prolonged period” as used herein refers to a time of at least 7 days, particularly at least 14 days, more particularly at least 21 days, and even more particularly at least 28 days.

[0029] The term "effective amount” when used for therapeutic purposes, refers to the amount of a compound or composition that, when administered, is sufficient to provide a therapeutic benefit in relation to a disease condition and the symptoms caused by the said disease.

[0030] The term “sustained release” and “controlled release” are considered herein interchangeable and refer to a composition which releases an active ingredient at approximately a constant rate.

[0031] The term “bioavailability” refers to the proportion of an active ingredient which enters the bloodstream when administered to a subject.

[0032] The term “injectability” when used for a composition refers to the ability of the composition to be discharged through a needle of a syringe or a needle of an injection device. Needles come in various gauges. The gauge (abbreviated as “G”) of a needle refers to the size of the hole in the needle. For example, a 21 -gauge (21 G) needle has an inner diameter of about 0.51 mm.

[0033] The term “biocompatible” refers to the condition of being compatible with living tissue or a living system by not being toxic or injurious and not causing immunological rejection. The term “aliphatic polyester” refers to linear polymers containing linked ester repeating units which do not contain aromatic rings. Suitable examples of aliphatic polyesters are polycaprolactone (PCL), poly(glycolic acid) (PGA), poly(lactic acid) (PLA), and poly(lactic- co-glycolic) acid (PLGA), or mixtures thereof.

[0034] The term “glycosaminoglycan” refers to linear polysaccharides consisting of repeating disaccharide units consisting of a uronic sugar and an amino sugar, except in the case of the keratan sulfate, where, in place of the uronic sugar there is a galactose unit. Suitable examples of glycosaminoglycans are chondroitin, hyaluronic acid or mixtures thereof. Suitable examples of pharmaceutically acceptable salts of glycosaminoglycans are chondroitin sulfate, dermatan sulfate, keratan sulfate, sodium hyaluronate, or mixtures thereof.

[0035] The term “cellulose derivative” refers to a chemically modified form of cellulose, particularly O-substituted cellulose derivatives, more particularly O-substituted esters or ethers of cellulose. The term “O-substituted cellulose derivative” refers to a chemically modified form of cellulose having a substitution at the oxygen atom of the hydroxyl groups in cellulose. Examples of O-substitution are alkylation, etherification, esterification, nitration, carbamoylation, or combinations thereof, of the hydroxyl groups of cellulose. Suitable examples of cellulose derivatives are methyl cellulose, ethyl cellulose, aminoethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, nitrocellulose or mixtures thereof. Suitable examples of pharmaceutically acceptable salts of cellulose derivatives are cellulose acetate, cellulose acetate phthalate, sodium carboxymethyl cellulose, or mixtures thereof.

[0036] The term “weight ratio” refers to the relation of weights of the compounds indicated. For instance, a weight ratio (weight / weight) of 70:1 between quetiapine or the pharmaceutically acceptable salt thereof and the biocompatible polymer refers to 70 units of quetiapine or the pharmaceutically acceptable salt thereof per 1 unit of biocompatible polymer. As used herein, "% by weight" or “% w / w” of a component refers to the amount of the single component relative to the total weight of the composition or, if specifically mentioned, of another component.

[0037] The term “polar solvents” as used herein refers to solvents that have a dipole moment of 1.40 D or more. Suitable solvents are non-toxic, biocompatible and appropriate for intramuscular or subcutaneous injection. Solvents susceptible of causing toxicity should not be used for the injection of any material into any living body. Preferably, solvents are biocompatible in order not to cause severe tissue irritation or necrosis at the injection site. Therefore, examples of appropriate solvents for the pharmaceutically composition of the present invention are solvents classified as class III, according to ICH Guidelines. Suitable examples of polar solvents are water, dimethyl sulfoxide, ethanol, N-methyl-2pyrrolidone, polyethylene glycol, triacetin or mixtures thereof.

[0038] As mentioned above, the first aspect of the invention provides an injectable pharmaceutical composition for subcutaneous or intramuscular administration comprising quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 50% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; and a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 70:1 to 1.5:1 ; and the composition is a suspension.

[0039] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the polar solvent is either water for injection or dimethyl sulfoxide.

[0040] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the biocompatible polymer is selected from the group consisting of poly(lactic acid), poly(lactic-co-glycolic) acid, sodium hyaluronate, hyaluronic acid, carboxymethyl cellulose, and any mixture thereof.

[0041] The inventors surprisingly found that injectable pharmaceutical compositions comprising carboxymethyl cellulose in the amounts according to the invention were able to provide a sustained release of quetiapine up to at least 7 days after administration of the composition, and also to provide good quetiapine bioavailability. These compositions are able to reduce the frequency of administration versus existing quetiapine treatments and may thus improve patient adherence by providing therapeutically effective amounts of quetiapine over an extended period. Therefore, in a particular embodiment, optionally in combination with any of the embodiments provided above or below, the biocompatible polymer is carboxymethyl cellulose.

[0042] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition for subcutaneous or intramuscular administration comprising quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 50% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 70:1 to 1.5:1, the composition is a suspension; the biocompatible polymer is carboxymethyl cellulose; and the polar solvent is water for injection.

[0043] Advantageously, a more extended and sustained release can be obtained when the compositions according to the invention comprise sodium hyaluronate or hyaluronic acid. The inventors realized that injectable pharmaceutical compositions comprising sodium hyaluronate or hyaluronic acid resulted in an extended release of quetiapine into the bloodstream of animals subcutaneously injected with the composition of the invention up to at least 14 days after administration. Therefore, in a particular embodiment, optionally in combination with any of the embodiments provided above or below, the biocompatible polymer is sodium hyaluronate or hyaluronic acid.

[0044] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition for subcutaneous or intramuscular administration comprising quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 50% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 70:1 to 1.5:1 ; the composition is a suspension; the biocompatible polymer is sodium hyaluronate; and the polar solvent is water for injection.

[0045] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition for subcutaneous or intramuscular administration comprising quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 50% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 70:1 to 1.5:1 ; the composition is a suspension; the biocompatible polymer is hyaluronic acid; and the polar solvent is water for injection.

[0046] In the preclinical assays carried out to assess the pharmacokinetic profile of the compositions according to the invention, the inventors surprisingly observed that quetiapine was consistently released up to at least 28 days after administration, while having a more sustained and uniform release profile, in compositions comprising poly(lactic acid) or poly(lactic-co-glycolic) acid. Therefore, in a particular embodiment, optionally in combination with any of the embodiments provided above or below, the biocompatible polymer is poly(lactic acid) or poly(lactic-co-glycolic) acid.

[0047] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition for subcutaneous or intramuscular administration comprising quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 50% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 70:1 to 1.5:1 ; the composition is a suspension; the biocompatible polymer is poly(lactic-co-glycolic) acid; and the polar solvent is dimethyl sulfoxide.

[0048] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition for subcutaneous or intramuscular administration comprising quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 50% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 70:1 to 1.5:1 ; the composition is a suspension; the biocompatible polymer is poly(lactic acid); and the polar solvent is dimethyl sulfoxide.

[0049] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the weigh average molecular weight (Mw) of the biocompatible polymer ranges from 10000 to 20000 g / mol, preferably from 12000 to 18000 g / mol, as measured by size exclusion chromatography (SEC). A Waters set of equipment (pump 590, universal injector U6K and differential refractometer 410 (Milford, MA) has been used for SEC experiments. A sets of columns (each one of 7.8- x 300- mm i.d.) based on a polystyrene (PS)-divinylbenzene (DVB) copolymer from Tosohaas, Tosoh Corp. (Tokyo, Japan) has been employed consisting of three TSK Gel HHR columns (particle size 5 pm; effective Mw separation range between 200-4 million g / mol) with total exclusion volume (Vo)=16.4 mL and pore volume (Vp)=16.8 mL; Vo and Vp were determined with a PS standard of high molar mass (Mw = 3,800,000) and with small molecules such as THF, toluene or benzene. All solvents used as eluents were previously degassed and filtered by passing them under vacuum through a 0.45-pm regenerated cellulose filter from Micro Filtration Systems (Dublin, CA). All chromatographic experiments were performed at 25°C in a thermostated heater, and the columns were equilibrated overnight prior to starting any experiment. Chromatograms were obtained at a flow rate of 1.0 mL / min by injection of 100 pL of sample solution.

[0050] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition is an in-situ forming implant. The term “in-situ forming implant” refers to a liquid or semi-liquid composition that generates solid or semisolid depots following administration. In other words, an in situ forming implant is a liquid or semi-liquid dosage form that solidifies into a gel or solid or semisolid depots upon injection into the body. This transformation typically occurs due to changes in environmental conditions like temperature, pH, or the presence of bodily fluids. The changes in environmental conditions comprise the diffusion of the solvent in the body fluids (solvent may be substituted by body fluids), causing the precipitation of solid contents from the composition.

[0051] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the quetiapine or the pharmaceutically acceptable salt thereof is in an amount ranging from 15 to 50% w / w, from 20 to 50% w / w, from 25 to 50% w / w, from 30 to 50% w / w, from 35 to 50% w / w, from 40 to 50% w / w, from 10 to 45% w / w, from 10 to 40% w / w, from 10 to 30% w / w, from 10 to 25% w / w, from 10 to 20% w / w, from 10 to 15% w / w, from 10 to 46% w / w, from 20 to 46% w / w, from 30 to 46% w / w, from 35 to 46% w / w, from 40 to 46% w / w, from 45 to 50% w / w, or from 10 to 35% w / w of the total weight of the composition.

[0052] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 60:1 to 1.5:1 , from 50:1 to 1.5:1, from 45:1 to 1.5:1, from 40:1 to 1.5:1 , from 35:1 to 1.5:1, from 30:1 to 1.5:1, from 25:1 to 1.5:1, from 20:1 to 1.5:1, from 15:1 to 1.5:1, from 10:1 to 1.5:1, from 5:1 to 1.5:1 , from 3:1 to 1.5:1 , from 3:1 to 1.8:1, from 70:1 to 3:1 , from 70:1 to 5:1, from 70:1 to 10:1 , from 70: 1 to 20: 1 , from 70: 1 to 30: 1 , from 70: 1 to 40: 1 , from 70: 1 to 50: 1 , from 70: 1 to 60: 1 , from 60: 1 to 5: 1 , from 60: 1 to 10: 1 , from 50: 1 to 20: 1 , from 40: 1 to 30: 1 , from 5: 1 to 2.5:1, from 3:1 to 2:1, from 2:1 to 1.5:1 , from 50:1 to 3:1, from 50:1 to 5:1, from 50:1 to 10:1, from 50: 1 to 20: 1 , from 50: 1 to 30: 1 , from 50: 1 to 40: 1 , from 60: 1 to 3: 1 , from 66: 1 to 1.8:1, from 49: 1 to 1.8: 1 , from 66: 1 to 3: 1 , from 66: 1 to 49: 1 , from 66: 1 to 35: 1 , from 49: 1 to 3:1 , from 40:1 to 10:1, from 30:1 to 10:1, or from 20:1 to 10:1. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition for subcutaneous or intramuscular administration comprises quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 46% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 3:1 to 1.8:1; the composition is a suspension; the biocompatible polymer is poly(lactic-co-glycolic) acid; and the polar solvent is dimethyl sulfoxide.

[0053] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition for subcutaneous or intramuscular administration comprises quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 35 to 46% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 3:1 to 1.8:1; the composition is a suspension; the biocompatible polymer is poly(lactic-co-glycolic) acid; and the polar solvent is dimethyl sulfoxide.

[0054] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition for subcutaneous or intramuscular administration comprises quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 46% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 3:1 to 1.8:1; the composition is a suspension; the biocompatible polymer is poly(lactic acid); and the polar solvent is dimethyl sulfoxide.

[0055] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition for subcutaneous or intramuscular administration comprises quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 35 to 46% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 3:1 to 1.8:1; the composition is a suspension; the biocompatible polymer is poly(lactic acid); and the polar solvent is dimethyl sulfoxide.

[0056] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition for subcutaneous or intramuscular administration comprises quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 46% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 66:1 to 49:1 ; the composition is a suspension; the biocompatible polymer is sodium hyaluronate; and the polar solvent is water for injection.

[0057] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition for subcutaneous or intramuscular administration comprises quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 35 to 46% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 66:1 to 49:1 ; the composition is a suspension; the biocompatible polymer is sodium hyaluronate; and the polar solvent is water for injection.

[0058] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition for subcutaneous or intramuscular administration comprises quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 46% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 66:1 to 49:1 ; the composition is a suspension; the biocompatible polymer is hyaluronic acid; and the polar solvent is water for injection. In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition for subcutaneous or intramuscular administration comprises quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 35 to 46% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 66:1 to 49:1 ; the composition is a suspension; the biocompatible polymer is hyaluronic acid; and the polar solvent is water for injection.

[0059] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition for subcutaneous or intramuscular administration comprises quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 46% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 66:1 to 35:1 ; the composition is a suspension; the biocompatible polymer is carboxymethyl cellulose; and the polar solvent is water for injection.

[0060] In another particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition for subcutaneous or intramuscular administration comprises quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 35 to 46% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 66:1 to 35:1 ; the composition is a suspension; the biocompatible polymer is carboxymethyl cellulose; and the polar solvent is water for injection.

[0061] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the hyaluronic acid is not cross-linked hyaluronic acid or the sodium hyaluronate is not cross-linked sodium hyaluronate. The term “cross-linked” refers to a chemical modification by which linear chains are covalently linked to each other. Therefore, in other words, the hyaluronic acid or sodium hyaluronate according to this particular embodiment may consist essentially of linear chains. In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the hyaluronic acid is cross-linked hyaluronic acid or the sodium hyaluronate is cross-linked sodium hyaluronate.

[0062] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition for subcutaneous or intramuscular administration comprises quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 50% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative selected from the group consisting of methyl cellulose, ethyl cellulose, aminoethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, and carboxymethyl cellulose, a pharmaceutically acceptable salt of any of them, and any mixture thereof; and a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 70:1 to 1.5:1 , and the composition is a suspension.

[0063] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the O-substituted cellulose derivative is selected from the group consisting of (Ci-Cs)alkyl-O-substituted cellulose, OH-(Ci-Cs)alkyl-O-substituted cellulose, HOOC-(Ci-Cs)alkyl-O-substituted cellulose, a pharmaceutically acceptable salt of any of them, and any mixture thereof.

[0064] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the O-substituted cellulose derivative is selected from the group consisting of methyl cellulose, ethyl cellulose, aminoethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and mixtures thereof.

[0065] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the O-substituted cellulose derivative is selected from the group consisting of nitrocellulose cellulose acetate, cellulose acetate phthalate, sodium carboxymethyl cellulose, and mixtures thereof.

[0066] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the composition comprises a pharmaceutically acceptable salt of quetiapine, the salt being selected from the group consisting of quetiapine fumarate, quetiapine hemifumarate, quetiapine succinate, quetiapine tartrate, quetiapine hydrochloride and quetiapine phosphate. In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the composition comprises a pharmaceutically acceptable salt of quetiapine, the salt being quetiapine fumarate.

[0067] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the biocompatible polymer is in a form other than nanoparticles. The highly concentrated suspensions according to the invention may maintain an acceptable stability without the need of using nanoparticles or delivery systems, such as nanoliposomes or nanocapsules. The term “nanoparticles” refers to structured particulate matter having a diameter of less than 1 micrometer.

[0068] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the composition comprises the polar solvent in an amount ranging from 35 to 65% w / w, from 40 to 65% w / w, from 45 to 65% w / w, from 50 to 65% w / w, from 55 to 65% w / w, from 35 to 55% w / w, from 35 to 50% w / w, from 35 to 45% w / w, from 35 to 40% w / w, from 40 to 55% w / w, or from 45 to 50% w / w of the total weight of the composition.

[0069] An injectable pharmaceutical composition as defined above for use in the treatment of schizophrenia and / or bipolar disorder, wherein the treatment comprises subcutaneous or intramuscular administration of the composition to a subject in need thereof is also part of the invention.

[0070] This aspect can also be formulated as use of quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 50% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 70:1 to 1.5:1 , for the preparation of an injectable pharmaceutical composition in the form of a suspension for the treatment of schizophrenia and / or bipolar disorder, wherein the treatment comprises subcutaneous or intramuscular administration of the composition to a subject in need thereof. Alternatively, this aspect can also be formulated as a method for the treatment of schizophrenia and / or bipolar disorder, the method comprising administering subcutaneously or intramuscularly an amount of injectable pharmaceutical composition as defined above to a subject in need thereof. In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the composition is administered either once a week, every two weeks, every three weeks or once a month. In an embodiment, optionally in combination with any of the embodiments provided above or below, the composition is administered either every 7 days, every 14 days, every 21 days or every 28 days. This frequency of administration may be achieved while maintaining therapeutic levels of quetiapine in the bloodstream of the patients because the subcutaneous or intramuscular administration of a single therapeutically effective dose of the composition provides quetiapine in the bloodstream of the patient during at least 7 days after administration, preferably at least 14 days after administration, more preferably 21 days after administration, even more preferably at least 28 days after administration.

[0071] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the amount of quetiapine or pharmaceutically acceptable salt thereof administered is from 50 mg to 3000 mg.

[0072] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the amount of quetiapine or pharmaceutically acceptable salt thereof administered is from 100 to 3000 mg, from 125 to 3000 mg, from 150 to 3000 mg, from 175 to 3000 mg, from 200 to 3000 mg, from 300 to 3000 mg, from 400 to 3000 mg, from 500 to 3000 mg, from 600 to 3000 mg, from 700 to 3000 mg, from 800 to 3000 mg, from 900 to 3000 mg, from 1000 to 3000 mg, from 1250 to 3000 mg, from 1500 to 3000 mg, from 1750 to 3000 mg, from 2000 to 3000 mg, from 2250 to 3000 mg, from 2500 to 3000 mg, from 2750 to 3000 mg, from 100 to 2750 mg, from 100 to 2500 mg, from 100 to 2250 mg, from 100 to 2000 mg, from 100 to 1750 mg, from 100 to 1500 mg, from 100 to 1250 mg, from 100 to 1000 mg, from 100 to 900 mg, from 100 to 800 mg, from 100 to 700 mg, from 100 to 600 mg, from 100 to 500 mg, from 100 to 400 mg, from 100 to 300 mg, from 100 to 200 mg, from 125 to 2750 mg, from 175 to 2500 mg, from 200 to 2250 mg, from 300 to 2000 mg, from 400 to 1750 mg, from 500 to 1500 mg, from 600 to 1250 mg, from 700 to 1000 mg, from 800 to 1000 mg, from 260 to 1300 mg, from 520 to 2600 mg, from 260 to 2600 mg, from 260 to 520, or from 1300 to 2600 mg.

[0073] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the amount of injectable composition comprises a dose of quetiapine or pharmaceutically acceptable salt thereof sufficient to continuously provide therapeutically effective plasma levels of quetiapine or pharmaceutically acceptable salt thereof in the subject throughout a dosing period of at least 7 days, at least 14 days, at least 21 days, or at least 28 days beginning from the day of administration. As used herein, the term “dosing period” refers to the period of days, weeks or months between the administration of the required doses to maintain therapeutically effective plasma levels of the drug in a patient, which according to the present invention may be 7, 14, 21 or 28 days.

[0074] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the dosing period can exceed four weeks (28 days), two months, three months, four months, five months or six months. In a particular embodiment, the method comprises one or more dosing periods as part of an overall treatment period.

[0075] As used herein, a “treatment period” refers to the weeks, months or years during which the composition of the invention is administered to a subject. A treatment period generally comprises plural dosing periods. Dosing periods can occur sequentially or in an overlapping manner during a treatment period.

[0076] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the dosing period can end after expiration of a predetermined number of days or after the plasma level of quetiapine drops below therapeutic levels.

[0077] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable pharmaceutical composition may be administered to a subject in one or more injection sites on the same day and still be considered as being part of the same dosing period.

[0078] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the amount of injectable composition to be administered is that which comprises a dose of quetiapine or pharmaceutically acceptable salt thereof sufficient to continuously provide therapeutically effective plasma levels of quetiapine or pharmaceutically acceptable salt thereof in the subject throughout a dosing period of at least 7 days, or at least 14 days, or at least 21 days, or at least 28 days beginning from the day of administration.

[0079] A kit for preparing the injectable pharmaceutical composition for subcutaneous or intramuscular administration as defined above which comprises a first receptacle comprising the quetiapine or the pharmaceutically acceptable salt thereof and the biocompatible polymer, and a second receptacle comprising the polar solvent; optionally, an injectable device; and optionally, instructions for preparing and for injecting the pharmaceutical composition, wherein optionally one of the first or second receptacles is the injectable device.

[0080] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the injectable device is a syringe.

[0081] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the first and / or second receptacle is a vial.

[0082] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the first and second receptacle form part of a single injectable device.

[0083] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the first and second receptacle are attached or connected to each other.

[0084] In a particular embodiment, optionally in combination with any of the embodiments provided above or below, the first and second receptacle are configured in such a way that, when the injectable device is activated, the injectable pharmaceutical composition is prepared. In other words, when the injectable device is activated, the quetiapine or a pharmaceutically acceptable salt thereof, the biocompatible polymer and the polar solvent are mixed to form a suspension.

[0085] Throughout the description and claims the word "comprise" and variations of the word, are not intended to exclude other technical features, additives, components, or steps. Furthermore, the word “comprise” encompasses the case of “consisting of”. Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples and drawings are provided by way of illustration, and they are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular embodiments described herein.

[0086] For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:

[0087] Clause 1. An injectable pharmaceutical composition for subcutaneous or intramuscular administration comprising quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 50% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; and a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 70:1 to 1.5:1 , and the composition is a suspension.

[0088] Clause 2. The composition according to clause 1 , wherein the polar solvent is either water for injection or dimethyl sulfoxide.

[0089] Clause 3. The composition according to any of the clauses 1-2, wherein the biocompatible polymer is selected from the group consisting of poly(lactic acid), poly(lactic-co-glycolic) acid, hyaluronic acid, sodium hyaluronate, carboxymethyl cellulose and any mixture thereof.

[0090] Clause 4. The composition according to any of the clauses 1-3, wherein the biocompatible polymer is poly(lactic acid) or poly(lactic-co-glycolic) acid.

[0091] Clause 5. The composition according to any of the clauses 1-3, wherein the biocompatible polymer is hyaluronic acid or sodium hyaluronate.

[0092] Clause 6. The composition according to clause 5, wherein the hyaluronic acid is not crosslinked hyaluronic acid and the sodium hyaluronate is not cross-linked sodium hyaluronate.

[0093] Clause 7. The composition according to any of the clauses 1-6, wherein the composition comprises a pharmaceutically acceptable salt of quetiapine, the salt being quetiapine fumarate.

[0094] Clause 8. The composition according to any of the clauses 1-7, wherein the biocompatible polymer is in a form other than nanoparticles.

[0095] Clause 9. The composition according to any of the clauses 1-8, wherein the quetiapine or the pharmaceutically acceptable salt thereof are in an amount ranging from 30 to 50% w / w of the total weight of the composition.

[0096] Clause 10. The composition according to any of the clauses 1-9, wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 3:1 to 1.8:1.

[0097] Clause 11. The composition according to any of the clauses 1-10, wherein the composition comprises the polar solvent in an amount ranging from 35 to 65% w / w of the total weight of the composition. Clause 12. An injectable pharmaceutical composition according to any of the clauses 1-11 , for use in the treatment of schizophrenia and / or bipolar disorder, wherein the treatment comprises subcutaneous or intramuscular administration of the composition to a subject in need thereof.

[0098] Clause 13. The composition for use according to clause 12, wherein the composition is administered either once a week, every two weeks, every three weeks or once a month.

[0099] Clause 14. The composition for use according to any of the clauses 12-13, wherein the amount of quetiapine or pharmaceutically acceptable salt thereof administered is from 50 mg to 3000 mg.

[0100] Clause 15. A kit for preparing the injectable pharmaceutical composition for subcutaneous or intramuscular administration according to any of the clauses 1-11 , which comprises; a) a first receptacle comprising the quetiapine or the pharmaceutically acceptable salt thereof and the biocompatible polymer, and b) a second receptacle comprising the polar solvent; c) optionally, an injectable device; and d) optionally, instructions for preparing and for injecting the pharmaceutical composition, wherein optionally one of the first or second receptacles is the injectable device.

[0101] Clause 16. The composition according to clause 1 , wherein the composition comprises the biocompatible polymer is a cellulose derivative.

[0102] Clause 17. The composition according to clause 16, wherein the cellulose derivative is selected from the group consisting of methyl cellulose, ethyl cellulose, aminoethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, nitrocellulose, a pharmaceutically acceptable salt of any of them, and any mixture thereof.

[0103] Examples

[0104] Examples 1. Preparation of the pharmaceutical compositions

[0105] The following compositions according to the first aspect of the invention (MED-1 to MED- 6) were prepared by mixing the indicated substances (quetiapine fumarate (QF), sodium hyaluronate (HNa), water for injection (WFI), dimethyl sulfoxide (DMSO), poly(lactic acid) (PLA), poly(lactic-co-glycolic) acid (PLGA), and carboxymethyl cellulose (CMC)):

[0106] The compositions were prepared by dissolving the biocompatible polymer in the polar solvent, thereby forming a polymeric solution, and subsequently adding quetiapine to the polymeric solution to form a suspension. All prepared pharmaceutical compositions were visually inspected and remained as stable suspensions and no particle settlement was observed.

[0107] Example 2. Preclinical data: In vivo pharmacokinetic study in Sprague-Dawley (SD) rats

[0108] The compositions of Example 1 were subcutaneously injected into Sprague-Dawley (SD) rats. Each of the compositions of Example 1 was tested in a group of six animals. After administration of a single dose of the composition to each animal, with a total dose of 50 mg of quetiapine per composition and animal, blood aliquots (0.3 ml) were extracted from the end of its tail at different times (0, 1, 2, 6, 12 and 24 hours; and 2, 4, 7, 14, 21 , and 28 days) over a period of 28 days and processed to end with plasma samples.

[0109] On day 0, all the animals were sedated with isoflurane and, after shaving the interscapular region, were administered by subcutaneous injection in this region using a 0.5 mL syringe and a 21 G x 16 mm needle in a single dose.

[0110] For plasma preparation from blood aliquots, a centrifugation (16000xg, 10 min) was carried out at 2-8 °C. Following centrifugation, plasma was transferred into plastic 1.5-mL polypropylene Eppendorf tubes. All plasma samples were stored frozen at -25 ± 10 °C until shipment.

[0111] The body weight of the rats was measured on arrival, on the administration day and on days 2, 4, 7, 14, 21 and 28. After dosing, no weight loss was observed for any of the groups. All the groups increased body weight until the end of the experimental phase. No animal showed adverse clinical signs during the study. The health status of the animals was good during the entire experiment. No mortality was reported. For the quantification of the plasmatic level of quetiapine, a LC-MS / MS method for rat plasma was developed. Liquid chromatography-tandem mass spectrometry (LC-MS / MS) was performed using an Agilent series 1100 / 1200 system coupled to Sciex API 4000 Triple Quadrupole mass spectrometer. Chromatographic separation was achieved on a ZORBAX SB-C18 column (50 mm x 4.6 mm, 5 pm) maintained at room temperature and a filter Supelco 0.5 pm. The separation was made in reverse phase using an isocratic mode and mobile phase consisting of ammonium formate 4.7 mM, pH 2.5 / Methanol (42.5 / 57.5). The flow rate was set at 1 mL / min, column pressure 1700 psi approximately and the injection volume was 10 pL.The mass spectrometer was operated in positive electrospray ionization (ESI) mode with a TurboIon Spray ionization probe. Ion source parameters were set as follows: CAD, 8; CUR, 45; GS1 , 50; GS2, 50, IS, 2000; temperature, 600°C; lhe, ON; Dwell time 500 msec. Data acquisition and analysis were conducted using Sciex Analyst version 1.6.2 software. The limit of quantification of the developed LC-MS / MS method for the quantification of quetiapine was 0.5 ng / ml.

[0112] Plasma sample treatment for analysis

[0113] 1 . The samples were thawed at room temperature.

[0114] 2. The samples were shaken and centrifuged at 1900 g for 5 minutes at 4 °C.

[0115] 3. 50 pL of the sample was transferred to polypropylene tubes, and 750 pL of internal standard solution (quetiapine-d4) at 4 ng / mL was added.

[0116] 4. The samples were shaken and centrifuged at 1900 g for 5 minutes at 4 °C.

[0117] 5. 10 mg reverse phase, strong cation exchange plates (Oasis MCX or Strata X-C) were used. After activating the plates, 600 pL of each sample was seeded in the corresponding well, and vacuum / pressure was applied until the samples were completely filtered.

[0118] 6. The wells were washed, and the contents of the plate were eluted by adding 400 pL of elution solution (Ammonium Hydroxide / Methanol 5:95) under vacuum / pressure and collected in a collecting plate.

[0119] 7. The samples were evaporated to dryness, and the plate was reconstituted by adding 200 pL of mobile phase (Ammonium formate 4.7 mM, pH 2.5 / Methanol 42.5:57.5).

[0120] 8. The plates were shaken and centrifuged at 2900 g for 2 minutes at 4 °C.

[0121] 9. The plate was stored at room temperature until analysis.

[0122] Concentration of quetiapine in plasma

[0123] The concentrations of quetiapine in plasma-treated samples are presented in the table below. These results are expressed in ng / ml and are recorded as a function of time in days.

[0124] The pharmacokinetic profiles of the drug plasma levels corresponding to each formulation were assessed, with the results presented in the table above and in FIG. 1. As demonstrated, quetiapine was quantified in plasma samples from animals administered with compositions MED-1 through MED-3 up to 28 days following subcutaneous administration. Notably, the quetiapine plasma levels were more sustained over time in animals receiving compositions MED-2 and MED-3 compared to those receiving MED-1 , which however exhibited higher circulating levels within the first 7 days postadministration. No significant safety concerns were reported across these formulations, and overall, good tolerability was observed.

[0125] With respect to FIG. 2, elevated concentrations of quetiapine were measured in plasma samples from animals treated with composition MED-4 up to 7 days post-administration. For composition MED-5, significant quetiapine levels persisted for up to 28 days postadministration. In animals receiving composition MED-6, high quetiapine plasma levels were maintained until 14 days after administration. In general, a less sustained quetiapine release over time correlated with higher quetiapine concentrations during the initial hours following injection.

[0126] Compositions MED-2, MED-3, and MED-5 demonstrated a prolonged release of quetiapine into the bloodstream, with quantifiable levels persisting for at least 28 days post-administration. Accordingly, certain embodiments of the compositions disclosed herein exhibit a more sustained release profile compared to others. However, all compositions in accordance with the present invention maintained measurable quetiapine plasma concentrations for at least 7 days following administration.

Claims

1. Claims1. An injectable pharmaceutical composition for subcutaneous or intramuscular administration comprising quetiapine or a pharmaceutically acceptable salt thereof in an amount ranging from 10 to 50% w / w of the total weight of the composition; a biocompatible polymer selected from the group consisting of an aliphatic polyester, a glycosaminoglycan, a O-substituted cellulose derivative, a pharmaceutically acceptable salt of any of them, and any mixture thereof; and a polar solvent; wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 70: 1 to 1 .5: 1 , and the composition is a suspension.

2. The composition according to claim 1 , wherein the polar solvent is either water for injection or dimethyl sulfoxide.

3. The composition according to any of the claims 1 -2, wherein the biocompatible polymer is selected from the group consisting of poly(lactic acid), poly(lactic-co-glycolic) acid, hyaluronic acid, sodium hyaluronate, carboxymethyl cellulose and any mixture thereof.

4. The composition according to any of the claims 1 -3, wherein the biocompatible polymer is poly(lactic acid) or poly(lactic-co-glycolic) acid.

5. The composition according to any of the claims 1 -3, wherein the biocompatible polymer is hyaluronic acid or sodium hyaluronate.

6. The composition according to claim 5, wherein the hyaluronic acid is not cross-linked hyaluronic acid and the sodium hyaluronate is not cross-linked sodium hyaluronate.

7. The composition according to any of the claims 1-6, wherein the composition comprises a pharmaceutically acceptable salt of quetiapine, the salt being quetiapine fumarate.

8. The composition according to any of the claims 1 -7, wherein the biocompatible polymer is in a form other than nanoparticles.

9. The composition according to any of the claims 1-8, wherein the quetiapine or the pharmaceutically acceptable salt thereof are in an amount ranging from 30 to 50% w / w of the total weight of the composition.

10. The composition according to any of the claims 1-9, wherein the weight ratio of quetiapine or the pharmaceutically acceptable salt thereof to the biocompatible polymer is from 3:1 to 1.8:1.

11. The composition according to any of the claims 1-10, wherein the composition comprises the polar solvent in an amount ranging from 35 to 65% w / w of the total weight of the composition.

12. An injectable pharmaceutical composition according to any of the claims 1-11 , for use in the treatment of schizophrenia and / or bipolar disorder, wherein the treatment comprises subcutaneous or intramuscular administration of the composition to a subject in need thereof.

13. The composition for use according to claim 12, wherein the composition is administered either once a week, every two weeks, every three weeks or once a month.

14. The composition for use according to any of the claims 12-13, wherein the amount of quetiapine or pharmaceutically acceptable salt thereof administered is from 50 mg to 3000 mg.

15. A kit for preparing the injectable pharmaceutical composition for subcutaneous or intramuscular administration according to any of the claims 1-11 , which comprises; a) a first receptacle comprising the quetiapine or the pharmaceutically acceptable salt thereof and the biocompatible polymer, and b) a second receptacle comprising the polar solvent; c) optionally, an injectable device; and d) optionally, instructions for preparing and for injecting the pharmaceutical composition, e) wherein optionally one of the first or second receptacles is the injectable device.

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