This application is a National Stage application of International Application No. PCT/FR2019/050345, filed Feb. 15, 2019, wherein the above-mentioned International Application claims the benefit under 35 U.S.C. § 119(a) of the filing date of Feb. 16, 2018 of French Patent Application No. 1851353, the entire contents of each of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION

Technical Field

The present invention relates to an aqueous composition including torasemide and at least one organic solvent, to a bottle or container including the composition and to a kit including the bottle or container and a system for administering the composition (for example a syringe).

The present invention also s to a use of at least one organic solvent for increasing the stability and/or the antimicrobial properties of a composition including torasemide.

Finally, the present invention also relates to a method for preparing a composition according to the invention.

PRIOR ART

Torasemide or torsemide (1-isopropyl-3-[(4-m-toluidino-3-pyridyl)sulfonyl]urea) is a known active ingredient, which possesses strong diuretic action. It is used in the treatment of edemas associated with heart failure, kidney diseases and in the treatment of hypertension, in human and veterinary therapeutics.

Torasemide (C16H20N4S, M=348.4 g·mol−1, CAS: 56211-40-6) has the following structural formula I:



It is marketed notably under the trademarks Demadex®, Diuver®, Dytor®, Examide® and Upcard®.

The diseases for which treatment including torasemide is recommended are chronic diseases that generally require daily treatment.

Recent studies presented in Peddle et al. (J. Vet. Cardiolog 2012) have recommended favoring torasemide for a better diuretic effect. Thus, there is growing interest in torasemide for treating heart disorders in particular. Despite these encouraging results, torasemide has a small (or narrow) therapeutic margin, meaning that any variation of its concentration in the organism, even slight or moderate, may possibly lead to undesirable, potentially serious effects. It is therefore important to be able to distribute the required dose.

An ion imbalance in humans or animals being treated is observed in chronic treatment. This imbalance leads to other undesirable effects such as a drop in pressure or increase of aldosterone and creatinine.

To date, furosemide (CAS: 54-31-9) constitutes the reference treatment. It is generally administered by the oral or intravenous route. Recently, scored tablets based on torasemide have been marketed in response to the problem of a narrow therapeutic margin and adjustment of the dose as a function of the weight of the person or animal.

However, this solution does not allow adjustment of the dose taking into account the entire range of available weights.

Moreover, the solubility of torasemide depends on the pH of the solution. The stability of torasemide in solution is, moreover, a function of the additives and excipients used in the composition. Thus, torasemide is insoluble at a pH between about 2 and 7 (FIG. 1).

Thus, torasemide is known to have low stability in an aqueous medium. Single-use injectable alkaline solutions based on torasemide are known in the prior art. U.S. Pat. No. 4,861,786 in particular describes an injectable alkaline torasemide composition including a physiologically compatible buffer with a pH between 9.3 and 9.9 and from 5 to 20% of an organic solvent, the organic solvent being selected from the group including polyethylene glycols (having a molecular weight between 100 and 1500 g·mol−1), polypropylene glycols (having a molecular weight between 50 and 1000 g·mol−1), glycerol, propylene glycol, ethanol and propanol. These compositions include from 2 to 40 mg·ml−1of torasemide. For reasons of stability, and in particular the appearance of crystals, the pH must be between 9.3 and 9.9, and the percentage of solvents must be below 20%.

Thus, the injectable alkaline torasemide compositions of the prior art have neither sufficient stability, nor an antimicrobial effect guaranteeing good preservation. Furthermore, their properties do not allow multiple usage (or multi-use), that is, repeated use of the same composition over a period of time ranging from several hours to several days.

The known compositions also do not offer a composition which in addition to increased stability and an antimicrobial effect, offers greater freedom for modulating the doses at the time of administration.

There is therefore a real need for a multi-use aqueous composition, which may be administered by the oral route or the parenteral route, and that overcomes these faults, drawbacks and obstacles of the prior art. There is also a need for a bottle or container including such compositions allowing extremely precise control of dosage in humans or animals, reduction of costs and thus overall improvement of the treatment.

DISCLOSURE OF THE INVENTION

The applicant has developed torasemide compositions including at least one organic solvent at a percentage by weight greater than or equal to 30%. Not only is the physical, chemical and/or antimicrobial stability of the composition improved, but it is so over wider ranges of pH, namely between 7.5 and 10, preferably between 8 and 9.9 and even more preferably between 9 and 9.9. Thus, the compositions according to the present invention are stable for a time of at least 24 months, preferably 36 months at a storage temperature between 25 and 30° C. The improvement of these properties makes the composition suitable for multiple usage (or multi-use), namely repeated use of the same composition over a period of time ranging from several hours to several days.

Furthermore, the compositions according to the invention have an antimicrobial preservation efficacy that complies with the American and European pharmacopeias.

Thus, not only is the stability improved, but it is so over an extended range of pH and in addition the composition has the benefit of an antimicrobial effect. The latter makes it possible for example to save on an antimicrobial preservative in the torasemide composition.

The present invention thus relates to an aqueous composition including torasemide and at least one organic solvent, wherein the concentration of organic solvent by weight may be greater than or equal to 30% relative to the total weight of the composition, preferably greater than or equal to 35% and even more preferably greater than or equal to 40%. Preferably, the concentration of organic solvent may be less than or equal to 70%.

“Aqueous composition” means a composition including water. In the context of the present invention, an aqueous composition includes at least water, an organic solvent and torasemide.

Advantageously, the concentration of torasemide by weight may be between 0.01% and 5% relative to the total weight of the composition, preferably between 0.1 and 3% and even more preferably between 0.1 and 2%. The concentration of torasemide by weight expressed in mg·ml−1may be between 0.1 and 50 mg·ml−1, preferably between 1 and 30 mg·ml−1and even more preferably between 1 and 20 mg·ml−1. The concentration of torasemide by weight may be for example 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 15 or 20 mg·ml−1. Advantageously, the compositions according to the invention are free from impurities. In the context of the invention, “impurities” means particles resulting from degradation of torasemide, or from precipitation of torasemide in the form of crystals, of molecules of the aldehyde or ketone type. Preferably, the total concentration of unknown or known impurities, such as impurities A and B (European Pharmacopeia) or impurities A and E (according to the USP) may be below 5%. The compositions according to the invention may be in the form of clear solutions. In the context of the invention, “clear” means a solution that does not comprise visible particles according to the monograph of the European Pharmacopeia.

Advantageously, the at least one organic solvent may be selected from the group including alcohols derived from propane. For example, the organic solvent may be selected from the group including propylene glycol (also called propane-1,2-diol or PG), glycerol (also called 1,2,3-propanetriol), propane-1,3-diol (also called PDO), propanol (also called propan-1-ol), isopropanol (also called propan-2-ol) and mixtures thereof. Preferably, the organic solvent may be selected from the group including glycerol and propylene glycol.

Advantageously, the compositions according to the present invention may further include a physiologically compatible buffer or an alkalizing agent. The buffer or alkalizing agent may be selected for example from the group including tromethamine (TRIS), triethanolamine, diethanolamine, monoethanolamine, sodium hydroxide, potassium hydroxide, ammonium hydroxide and meglumine. The concentration of buffer or alkalizing agent by weight may be between 1 and 5% relative to the total weight of the composition, preferably between 1 and 2%.

Advantageously, the composition according to the present invention may further include a rheology modifier (or thickener). The rheology modifier may be for example a hydrophilic synthetic polymer of acrylic acid (carbomer), a polysaccharide (cellulose derivatives, chitosans, starches or alginates), a gum, polyvinyl povidone, a poloxamer (Pluronic), hydrophilic silica, or a poly(meth)acrylate. The carbomer may be selected from the group including the homopolymer of 2-propenoic acid such as for example Carbopol971NF,974,934P or941. The polysaccharide may be selected from the group including starch and derivatives thereof, cellulose derivatives such as for example hydroxy ethylcellulose (HEC), ethylcellulose (EC), carboxymethylcellulose (CMC) and hydroxypropyl cellulose (HPC), derivatives of chitosan such as for example deacetylated chitin, copolymers of glucosamine and N-acetylglucosamine with different degrees of acetylation and having a molecular weight from 10 000 to 1 000 000. The gums may be selected from the group including xanthan gum and guar gum (galactomannan). “Derivative” means a conjugated base, a salt, ether, ester or, more generally, a compound that is derived from a similar compound by a chemical reaction. The concentration of rheology modifier by weight may be between 0.01 and 10% relative to the total weight of the composition, preferably between 0.1 and 5% and even more preferably between 0.1 and 2%.

Advantageously, the viscosity of the compositions according to the present invention may be between 0.001 and 5 Pa·s. The viscosity makes it possible to obtain optimal distribution of the active ingredient at the time of administration of the composition.

Advantageously, the composition according to the present invention may further include an agent for adjusting the osmolarity of the composition. The agent may be selected for example from sugar (glucoses), NaCl or KCl.

Advantageously, the composition according to the present invention may further include a sweetener. The sweetener may be selected from the group including saccharin (saccharin sodium), potassium acesulfame, advantame, aspartame, erythritol and isomalt. The concentration of sweetener by weight may be between 0.01 and 2% relative to the total weight of the composition. “Sweetener” or “sweetening agent” means, in the sense of the present invention, a compound or mixture of compounds having a sweet taste. Addition of this type of compound to the composition increases the palatability of the latter, when it is intended to be administered by the oral route, and thus makes it more easily accepted b the subject, especially when the drug is intended for an animal.

Advantageously, the composition according to the present invention may further include any pharmaceutically acceptable excipient. The composition may thus include one or more surfactant(s), inorganic compound(s) or isotonic agent(s).

Advantageously, the compositions according to the invention may have a pH between 7.5 and 10, preferably between 8.0 and 9.9 and even more preferably between 9 and 9.9 or else 9.3 and 9.9. The pH of the compositions may easily be adapted by a person skilled in the art as a function of the solubility and the amount of components in the composition, and in particular as a function of the solubility and the amount of torasemide. The pH of the compositions according to the invention may be adjusted by means of any pharmaceutically acceptable acid or base. The pH may for example be adjusted by means of NaOH, HCl, meglumine (N-methylglucamine), or tromethamine.

The improved stability of the compositions according to the invention also has the advantage of allowing greater modulation of the treatments, by reducing the constraints usually associated with torasemide. The compositions according to the invention supply a solution that is more adapted to each patient, notably owing to the possibility of more easily adjusting the dose distributed to all the potential body masses. For the first time in treatments based on torasemide, a composition addresses the problem of adjustment of dose to weight, for this substance, which has a narrow therapeutic margin.

Also for the first time, a torasemide composition is suitable for multiple use (or multi-use) and does away with the constraints associated with single-use compositions. This is reflected for example in a decrease of the amount of packaging, more flexible constraints on usage or ease of storage of a composition that has already been opened, which would be intended to be reused.

The compositions according to the invention are thus suitable both for chronic treatment (for example in the form of an oral composition) and for emergency treatment (for example in the form of an injectable composition). The volume of liquid administered to the person or to the animal may be adjusted as a function of the therapeutic dose required and the subject's body weight.

Advantageously, the compositions according to the invention may be administered by the oral, subcutaneous (SC), intramuscular (IM) or intravenous (IV) route.

According to another aspect, the invention relates to a composition according to the invention for use as a drug, in particular in the treatment of the clinical signs, including edema and fluid collection, associated with congestive heart failure, and treatment of kidney diseases and hypertension.

The invention thus also relates to:the use of a composition according to the invention for treating the clinical signs, including edema and fluid collection, associated with congestive heart failure, and for treating kidney diseases and hypertension,a method for treating the clinical signs, including edema and fluid collection, associated with congestive heart failure, method for treating kidney diseases and hypertension, comprising administration of a composition according to the invention.

The present invention also relates to the use of at least one organic solvent, at a concentration by weight greater than or equal to 30%, preferably greater than or equal to 35% and even more preferably greater than or equal to 40%, in an aqueous composition comprising torasemide. Preferably, the concentration by weight of at least one organic solvent may be less than or equal to 70%. The present invention also includes the use of at least one organic solvent, at a concentration by weight greater than or equal to 30%, preferably greater than or equal to 35% and even more preferably greater than or equal to 40% for increasing the stability of an aqueous composition including torasemide and/or imparting antimicrobial properties to the composition; that is, the composition is stable for a period of at least 24 months, preferably 36 months, at a temperature between 25° C. and 40° C., preferably 30° C. For example, the composition is stable for at least 24 months at a temperature of 30° C. or at least 36 months at a temperature of 25° C. Furthermore, the composition may, after opening, owing to its physical; chemical and microbiological stability, be stored for up to 28 days.

The invention also relates to a method for preparing the compositions according to the invention comprising the steps:(a) adding the buffer or the alkalizing agent to water at room temperature and stirring to obtain mixture1,(b) adding torasemide to mixture1and stirring to obtain mixture2,(c) gradually adding the rheology modifier with stirring to obtain mixture3,(d) optionally adding one or more pharmaceutically acceptable excipient(s) and stirring until a clear solution is obtained (mixture4),(e) adding at least one organic solvent and stirring until a clear solution is obtained (mixture5),(f) optionally adjusting the volume while stirring,(g) optionally adjusting the pH,and obtaining the composition according to the invention.
Stirring may be mechanical (magnetic stirrer) and/or carried out using a turbine.

According to another aspect, the present invention also relates to a bottle or container including a composition according to the present invention.

Advantageously, the bottle may be provided with a cap, a reducer or any other opening system facilitating delivery of the composition. The device, which houses a syringe or other system for administering the composition makes it possible, as a function of the graduation, to administer just the dose that is required, effective and adapted to each treatment. The device makes it possible to limit microbial contamination during use of the composition according to the present invention, as the system for administration (i.e. the syringe) does not come into contact with the composition. For example, during accidental contact, the antimicrobial properties of the composition protect it from possible contamination.

Finally, the present invention also relates to a kit including:a bottle or container including a composition according to the present invention; anda system for administering the composition.

“System for administering the composition” means any system for taking the composition from the bottle or container and then administering it by the oral, SC, IM or IV route, such as for example a dropper, a dosing cap or a syringe. Other advantages will become apparent to a person skilled in the art on reading the examples given hereunder.

