Pharmaceutical composition of the gel type for the treatment / prevention of infection

Description

[0001] The present invention relates to novel pharmaceutical compositions, suitable for localized and controlled administration in terms of duration, of active ingredients such as antibiotics, as well as corresponding medical devices. It further relates to their therapeutic uses for treating or preventing an infection, in particular a bacterial infection and in particular osteoarticular bacterial infections.

[0002] Antibiotics remain the most widely used active ingredients for treating bacterial infections today. However, in some cases, their implementation is not yet entirely satisfactory, particularly in terms of efficacy, spectrum of action, and bioavailability.

[0003] In addition, antibiotics are generally administered to the patient orally or parenterally. However, in the case of specifically localized bacterial infections, this method of administration may be insufficiently effective due to a lack of optimal diffusion at the site of infection. This difficulty particularly affects infections affecting bones, joints, or infections developing at the site of an implanted medical device, such as an implant or prosthesis, and for which it is often necessary to implement additional surgical treatment in order to resolve the infection.

[0004] Consequently, the development of galenic formulations dedicated to the administration of active ingredients to treat infections, particularly bacterial ones, which are more effective in terms of pharmacokinetic and pharmacodynamic properties and targeting is of great interest.

[0005] It is already known from FR3017294 to transport antibiotics such as daptomycin, vancomycin and rifampicin in lipid nanocapsules. This galenic form is particularly interesting in terms of bioavailability and therefore allows the use of lower doses of antibiotics for an efficacy at least equivalent to that of other forms. However, these lipid nanocapsules only tolerate a low antibiotic loading rate, namely a rate lower than 50 mg / ml of suspension. Indeed, beyond a certain antibiotic concentration, the surfactant properties of the latter disrupt the formation of particles. Furthermore, these nanocapsules do not allow the release profile of the active ingredient to be modulated over time. Most often, the release is rapid and / or non-linear.

[0006] Finally, the administration of these nanocapsules is mainly recommended by parenteral route. Consequently, the difficulty of locally targeting a bacterial infection such as those of the osteoarticular type remains.

[0007] However, osteoarticular infections are serious pathologies that affect a bone and / or a joint. They can occur spontaneously following septicemia, after a deep wound or an open fracture for example, or constitute a complication of a surgical procedure, such as the placement of an implant, prosthesis, plate or screw, what is commonly called infections on foreign material (or implanted medical device). These osteoarticular infections therefore remain difficult to treat today, especially when it comes to infections on joint prostheses, because the bacteria also attach themselves to the materials of the implants, making antibiotics ineffective and requiring surgical treatment in order to control or resolve the infection.

[0008] It should also be noted that the treatment of osteoarticular infections can be particularly difficult for the patient due to the severity and duration of the antibiotic therapy and all too often the need to resort to appropriate prior surgery in order to control or resolve the infection, most often followed by a post-operative period of rehabilitation.

[0009] The present invention aims precisely to propose a new galenic form for antibiotics making it possible to overcome the aforementioned shortcomings.

[0010] In particular, the present invention provides an effective pharmaceutical composition for locally delivering an effective amount of at least one therapeutic active ingredient, in particular an antibiotic, and in particular directly to the site of bacterial infection.

[0011] The present invention aims in particular to provide a pharmaceutical composition suitable for targeted administration of at least one therapeutic active ingredient, in particular an antibiotic for treating a bacterial infection affecting the bones, the joints, or developing at the level of an implanted medical device, such as an implant or a prosthesis.

[0012] In particular, the present invention provides a pharmaceutical composition effective for locally treating an osteoarticular bacterial infection.

[0013] The present invention further aims to provide an effective pharmaceutical composition for delivering in a controlled manner and in particular over a prolonged period of time the active ingredient that it contains so that the drug is as effective as possible and has a prolonged duration of action.

[0014] The invention is defined in the appended claims.

[0015] Thus, the present invention relates primarily to a pharmaceutical composition stabilized in a gelled state at at least one temperature varying from 15°C to 40°C, comprising at least: a gelled aqueous phase with at least one polymeric hydrophilic gelling agent, said polymeric hydrophilic gelling agent(s) being present in an amount of between 2% and 25% by weight, relative to the weight of the gelled aqueous phase; said polymeric hydrophilic gelling agent(s) being at least chosen from C1-C2 carboxymethylcelluloses having a viscosity of between 1500 mPa.s and 4500 mPa.s, and / or triblock copolymers consisting of poly(ethylene oxide) and poly(propylene oxide) having a lower critical solubility temperature (LCST) of between 15°C and 40°C; said gelled aqueous phase further comprising at least one polyol; said polyol being sorbitol; said polyol(s) being present in an amount of between 2% and 20% by weight, relative to the total weight of the composition;lipid nanocapsules comprising a lipid core that is liquid or semi-liquid at room temperature and enveloped by a lipid shell that is solid at room temperature, said nanocapsules being present in a content varying from 10% to 80% by weight, relative to the total weight of the composition; said gelled aqueous phase and nanocapsules containing at least one antibiotic, the antibiotic in said aqueous phase being present therein in the solute state; said antibiotic(s) being released constantly over a period of at least 14 days; the core of the nanocapsules and the gelled aqueous phase both containing at least daptomycin.;

[0016] Also described but not claimed as polymeric hydrophilic gelling agents are triblock copolymers of poly(ethylene glycol) and poly(lactic-co-glycolic acid), which may be thermosensitive and have a lower critical solubility temperature (LCST) of between 15°C and 40°C.

[0017] Surprisingly, the inventors have thus observed that the formulation of specific lipid nanocapsules containing at least one antibiotic, within a gelled aqueous phase in accordance with the invention and itself loaded with antibiotic, proves to be particularly advantageous.

[0018] Against all expectations, the packaging of the nanocapsules loaded with antibiotic, in a gelled aqueous phase is not detrimental on the one hand to the integrity of the nanocapsules during storage of the pharmaceutical composition nor to the release in vivo of the antibiotic contained in said nanocapsules.

[0019] A pharmaceutical composition in accordance with the invention also proves to be suitable for localized administration and therefore close to or even in contact with an organ or implant. in vivo. This is particularly interesting for preventing and / or treating osteoarticular infections.

[0020] Due to its viscosity, it can be easily taken and applied to infectious or potentially infected sites or to the implant intended to be in contact or already in contact with this site.

[0021] A pharmaceutical composition in accordance with the invention is suitable for the formulation of a high quantity of antibiotic not accessible with only conventional lipid nanocapsules.

[0022] It also allows controlled and in particular prolonged release of antibiotics insofar as it transports the antibiotic(s) in two distinct modes, one directly in the gelled aqueous phase and the other in a form encapsulated in the gelled aqueous phase. This is particularly advantageous for the treatment and / or prevention of internal infections such as osteoarticular infections. It is not necessary to carry out repeated administrations within a short period of time to guarantee the effectiveness of the antibiotics. In particular, the compositions according to the invention allow the active ingredient to be released constantly over a period of at least 14 days. At the end of a period of 14 days, the concentrations of antibiotic still present remain very high, exceeding by 50 to 100 times the Minimum Inhibitory Concentrations (MIC) of the bacteria generally responsible for these infections.

[0023] The present invention further relates to an internal medical device dedicated to being manipulated in vivo and / or implanted in vivo and loaded with at least one pharmaceutical composition as defined according to the invention for its use in treating or preventing an infection, in particular bacterial, in particular osteoarticular and affecting a joint, a bone, or developing at the level of an implanted medical device.

[0024] This medical device considered can be directly an implant-type device dedicated to being implanted, permanently or not, in vivo but also a dressing, compress or gauze intended to be placed in temporary contact with an internal organ or implant for the purpose of treating or preventing a bacterial infection.

[0025] The present invention also relates to a pharmaceutical composition as defined according to the present invention, or an internal medical device as defined according to the invention, for their use in targeted, local and prolonged delivery of the antibiotic(s) at the level of an infection, in particular bacterial, preferably osteoarticular, affecting a joint, a bone, or developing at the level of an implanted medical device or at the level of a site potentially subject to such an infection, in particular bacterial, preferably osteoarticular.

[0026] The present invention also relates to the use of a pharmaceutical composition as defined according to the present invention, or of an internal medical device as defined according to the invention, for targeted, local and prolonged delivery of the antibiotic(s) at the level of an infection, in particular bacterial, preferably osteoarticular, affecting a joint, a bone, or developing at the level of an implanted medical device or at the level of a site potentially subject to such an infection, in particular bacterial, preferably osteoarticular. FIGURES

[0027] There figure 1 represents the daptomycin concentrations measured 4 days after treatment with a single dose of 200 mg of the composition according to the invention in a rabbit osteomyelitis model Staphylococcus aureus Methicillin Resistant (MRSA). The figure 2represents the determination of the bacterial load (Δlog 10 CFU / g of tissue) at the bone level 4 days after treatment with a single dose of 200 mg of the composition according to the invention in comparison with other antibiotics administered intravenously (IV) for 4 days in an experimental osteoarticular infection model of the rabbit with SAMR (*p<0.05 versus control and other groups of antibiotics: LZD = Linezolid, DPT = Daptomycin, VAN = Vancomycin, CPT = Ceftaroline). figure 3represents the determination of the bacterial load (Δlog 10 CFU / g of tissue) at the bone marrow level 4 days after treatment with a single dose of 200 mg of the composition according to the invention in comparison with other antibiotics administered intravenously (IV) for 4 days in an experimental osteoarticular infection model of the rabbit with SAMR (*p<0.05 versus control and other groups of antibiotics: LZD = Linezolid, DPT = Daptomycin, VAN = Vancomycin, CPT = Ceftaroline). figure 4 represents the determination of the bacterial load (Δlog 10 CFU / g of tissue) at the bone marrow level 14 days after treatment with a single dose of 200 mg of the composition according to the invention in comparison with an untreated group in an experimental osteoarticular infection model of the rabbit with SAMR (*p<0.05) versus control. The Figure 5represents the determination of the bacterial load (Δlog 10 CFU / g of tissue) at the bone marrow level 4 days after treatment with a single dose of 200 mg of the composition according to the invention combined with rifampicin (RIF) administered intramuscularly (IM, 20 mg / kg every 12 hours, for 4 days), in an experimental osteoarticular infection model of the rabbit with MRSA. COMPOSITION

[0028] As stated previously, a composition according to the invention is in the form of a gel at at least one temperature varying from 15°C to 40°C. Thus, a composition according to the invention is stabilized in a gelled state at a temperature varying at least from room temperature to body temperature.

[0029] In particular, a composition according to the invention has a viscosity between 15°C and 40°C greater than 10 Pa.s, preferably varying from 10 Pa.s to 10000 Pa.s, more preferably from 50 to 1000 Pa.s.

[0030] This viscosity can be characterized at 25°C with a shear rate of 0.01 s -1< , for example using a rheometer such as that marketed by the Malvern Company under the name KINEXUS pro+.

[0031] This gelled appearance is mainly adjusted via the choice of the associated polymeric gelling agent.

[0032] However, it is clear that the concentration of the nanocapsules and the active ingredient, in this case the antibiotic in its non-encapsulated form, will also contribute to the adjustment of this viscosity.

[0033] The gelled aqueous phase represents, for example, from 40% to 90% by weight, preferably from 45% to 85% by weight, relative to the total weight of the composition.

[0034] This gelled aqueous phase comprises at least one aqueous medium, a polymeric hydrophilic gelling agent, an active ingredient, preferably an antibiotic, and where appropriate a polyol distinct from said polymeric hydrophilic gelling agent. a) Polymeric hydrophilic gelling agent

[0035] As previously indicated, the aqueous phase is gelled with at least one polymeric hydrophilic gelling agent.

[0036] Polymeric hydrophilic gelling agents are of course chosen for their compatibility with use in vivo and their inertia with respect to the associated active ingredient but also to the nanocapsules.

[0037] The polymeric hydrophilic gelling agents are at least chosen from C 1 -C 2 carboxyalkylcelluloses having a viscosity of between 1500 mPa.s and 4500 mPa.s, triblock copolymers consisting of poly(ethylene oxide) and poly(propylene oxide), triblock copolymers consisting of poly(ethylene glycol) and poly(lactic-co-glycolic acid), described but not claimed, and mixtures thereof.

[0038] More particularly, triblock copolymers comprised of poly(ethylene oxide) and poly(propylene oxide) may be thermosensitive and have a lower critical solubility temperature (LCST) of between 15°C and 40°C, and triblock copolymers comprised of poly(ethylene glycol) and poly(lactic-co-glycolic acid), described but not claimed, may be thermosensitive and have a lower critical solubility temperature (LCST) of between 15°C and 40°C.

[0039] The carboxyalkylcelluloses suitable for the invention are water-soluble carboxymethylcelluloses, in particular carboxymethylcelluloses and their sodium salts.

[0040] High viscosity carboxymethylcelluloses (also called CMC HV), i.e. with a viscosity of at least 1500 mPa.s, and in particular those marketed by the company Sigma-Aldrich or under the trade name Calbiochem ®< by the company Merck Millipore, and ultra high viscosity carboxymethylcelluloses (also called CMC Ultra high viscosity) marketed by the company Sigma-Aldrich, are particularly suitable for implementing the invention.

[0041] The triblock copolymers consisting of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) suitable for the invention may be the copolymers of formula (PEO)x (PPO)y (PEO)z where x is between 5 and 200, y is between 5 and 100 and z is between 5 and 200.

[0042] Preferably, the values ​​of x and z are the same.

[0043] Compounds in which x = 106, y = 69 and z = 106 are very advantageously used.

[0044] Triblock copolymers particularly suitable for implementing the invention are liquid at 4°C and gelled at 37°C. They are thus water-soluble and heat-sensitive. They preferably have a molecular weight of between 9500 and 15000 g / mol, in particular between 9800 and 14600 g / mol and more particularly between 9840 and 14600 g / mol and an ethylene oxide content of between 70.0% and 80.0%, in particular between 71.0% and 75.0%, and more particularly between 71.5% and 74.9%.

[0045] Triblock polymers consisting of commercial poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) known as Pluronic ®< F127 (marketed by the company Sigma Aldrich, CAS number 9003-11-6), Polaxamer ®< 407 or P407 (marketed by the company BASF) or Pluronic ®< P123 marketed by BASF are particularly suitable for implementing the invention.

[0046] Described but not claimed, the triblock copolymers consisting of poly(ethylene glycol) and poly(lactic-co-glycolic acid) suitable for the invention are advantageously triblock polymers of the PEG-PLGA-PEG type, soluble in aqueous media and having a heat-sensitive character.

[0047] The polymeric hydrophilic gelling agents included in the gelled aqueous phase suitable for the present invention are chosen from C 1 -C 2 carboxymethylcelluloses having a viscosity of between 1500 mPa.s and 4500 mPa.s and / or poly(ethylene oxide) and poly(propylene oxide) triblock copolymers having a lower critical solubility temperature (LCST) of between 15°C and 40°C.

[0048] Of course, the quantity of polymeric gelling agent is adjusted to provide the expected viscosity to the composition according to the invention.

[0049] This adjustment clearly falls within the skills of a person skilled in the art.

[0050] A composition according to the invention comprises from 2% to 25% by weight of polymeric hydrophilic gelling agent(s), relative to the weight of the gelled aqueous phase.

[0051] According to a preferred variant, a composition according to the invention further contains a polyol. b) Polyols

[0052] The term “polyol” refers to organic molecules comprising at least two hydroxyl functions (-OH).

[0053] This polyol is distinct from the hydroxylated polymers that can be used as gelling agents.

[0054] The presence of this polyol is particularly advantageous for adjusting the pH of the composition and / or solubilizing the different constituents.

[0055] The polyol of the composition according to the invention has a saturated, branched or unbranched linear hydrocarbon chain.

[0056] The polyol comprises a number of carbon atoms ranging from 2 to 20, preferably from 2 to 12, even better from 5 to 12, and comprises from 2 to 12, even better from 2 to 8, and even better from 2 to 6 hydroxyl functions.

[0057] The polyols of the composition according to the invention may be chosen from sorbitol (also called glucitol), are also described but not claimed, mannitol, dulcitol, maltitol, isomaltitol (also called isomalt), xylitol, arabitol (also called lyxitol or arabinitol), ribitol (also called adonitol), volemitol, and mixtures thereof.

[0058] The polyol is sorbitol.

[0059] A composition according to the invention comprises from 2% to 20% by weight of polyol(s) relative to its total weight. c) Aqueous medium

[0060] As regards the aqueous medium, it is formed of water, where appropriate mixed with one or more additional water-soluble solvents.

[0061] According to an alternative embodiment, this solvent medium consists solely of water. d) Lipid nanocapsules

[0062] As specified above, a composition according to the invention further contains nanocapsules.

[0063] These nanocapsules are advantageously present within the gelled aqueous phase.

[0064] These nanocapsules are present in a content varying from 10% to 80% by weight, or even from 10% to 70% by weight, relative to the total weight of the composition.

[0065] In particular, they can be implemented in a nanocapsules / gelled aqueous phase weight ratio varying from 10 / 90 to 50 / 50.

[0066] For the purposes of the present invention, the lipid nanocapsules suitable for the invention have an architecture distinct from micelles, reverse micelles or particles with liposome architecture.

[0067] More specifically, the lipid nanocapsules in accordance with the invention comprise a lipid core (or heart) which is liquid or semi-liquid at room temperature, in which at least one lipophilic or hydrophilic antibiotic is incorporated, this core being surrounded (or enveloped) by a lipid envelope which is solid (therefore rigid) at room temperature.

[0068] The expression "at room temperature" means, in the context of the present invention, at a temperature between 15°C and 25°C.

[0069] The expression "body temperature" means, in the context of the present invention, at a temperature between 35°C and 38°C.

[0070] A "semi-liquid" medium should be understood as a medium having a higher viscosity than a liquid medium. The "semi-liquid" medium is obtained by any suitable means, for example from the medium in liquid form, preferably by the addition of gelling agents. However, the semi-liquid medium may also consist of a compound or combination of compounds having a suitable viscosity in order to behave like a gel.

[0071] Preferably, the lipid nanocapsules suitable for the invention have a size of less than 100 nm, preferably a size of between 10 nm and 50 nm, advantageously of between 17 nm and 25 nm. These sizes can be determined by dynamic light scattering, photon correlation spectroscopy, scanning electron microscopy, transmission electron microscopy in cryoscopic mode.

[0072] Preferably, the nanocapsules suitable for the invention are those described and obtained according to the methods detailed in documents WO2001064328, WO2009004214, WO2009001019, WO2010067037 and WO2015118496.

[0073] According to a first variant, the lipid nanocapsules suitable for the present invention are nanocapsules known under the trade name “Soludots” from the company CARLINA Technologies. They comprise a lipid core based on medium-chain triglycerides, caprylic and / or capric acids, for example Labrafac ®< WL 1349 from the company Gattefossé and / or Captex ®< 8000 from the company Abitec, which is a glycerol tricaprylate.The core is stabilized by a solid shell consisting of phospholipids, for example lecithin (or soy lecithin known as Lipoid S75-3, from Lipoid GmbH, comprising about 69% phosphatidylcholine and about 9% phosphatidyl ethanolamine or Lipoid S-100, from Lipoid GmbH) and a non-ionic hydrophilic surfactant, such as polyethylene glycol stearate (polyethylene glycol 2-hydroxystearate-660 marketed as Solutol ®< HS 15 (also called Kolliphor ®< HS15) by BASF).

[0074] Preferably, the solid shell surrounding the core of the lipid nanocapsules comprises, or consists essentially of, a lipophilic surfactant which is a phosphatidylcholine.

[0075] According to a second variant, the lipid nanocapsules suitable for the present invention are also “Soludots” as described previously, but whose lipid core further comprises an additive, a non-ionic excipient dispersible in water, for example Labrasol ®< from the company Gattefossé, based on PEG ester compounds and a glyceride fraction.

[0076] Preferably, for a lipophilic active ingredient and in particular a lipophilic antibiotic, the liquid or semi-liquid lipid core comprises, or is essentially composed of, a fatty substance which is liquid or semi-liquid at room temperature, for example a triglyceride or a fatty acid ester or one of their mixtures.

[0077] More preferably, the liquid or semi-liquid lipid core of the lipid nanocapsules comprises, or is essentially composed of, one or more triglycerides, one or more fatty acid esters, or a mixture thereof.

[0078] On the other hand, for a hydrophilic active ingredient and in particular a hydrophilic antibiotic, the active ingredient must be stabilized, at the lipid core, in the form of a reverse micellar system. Consequently, the liquid or semi-liquid lipid core comprises an oily phase comprising at least one fatty substance that is liquid or semi-liquid at room temperature, advantageously at least one triglyceride, a fatty acid ester, or one of their mixtures, and at least one surfactant.

[0079] Preferably, the encapsulated antibiotic(s) may represent up to 30% by weight of the lipid nanocapsules suitable for the invention, relative to the total weight of said lipid nanocapsules.

[0080] According to a preferred variant, lipid nanocapsules suitable for the invention comprise at least: polyethylene glycol stearate, preferably polyethylene glycol-660 2-hydroxystearate; glycerol tricaprylate; sodium chloride; a phospholipid chosen from lecithin, soy lecithin and mixtures thereof, preferably from lecithin and soy lecithin; an antibiotic, and in particular at least daptomycin.

[0081] The antibiotic included in the core of the lipid nanocapsules suitable for the invention is at least one daptomycin.

[0082] The lipid nanocapsules suitable for the invention may further comprise one or more other active ingredients distinct from the antibiotic(s) required according to the invention, for example a vitamin, an analgesic, an anti-inflammatory, a growth hormone, an antiseptic, a hemostatic, and mixtures thereof. e) Antibiotics

[0083] When the term "antibiotic" is used in this description without any further specification, this means that it can refer to both the antibiotic incorporated in the core of the nanocapsules and that included in the gelled aqueous phase.

[0084] A composition according to the invention may also be defined as comprising at least one free antibiotic and at least one encapsulated antibiotic.

[0085] We understand by: “free antibiotic”, the antibiotic not encapsulated in the nanocapsules and therefore transported directly into the gelled aqueous phase; “encapsulated antibiotic”, the antibiotic only present in the core of the lipid nanocapsules.

[0086] A composition may comprise from 5% to 50% by weight of antibiotic(s), and preferably from 10% to 40% by weight of antibiotic(s), relative to its total weight.

[0087] The quantity of antibiotic(s) contained directly in the gelled aqueous phase (i.e. without taking into account that contained in the nanocapsules present in this same gelled aqueous phase) may in particular be at least 50 mg / ml, preferably between 50 and 500 mg / ml, more preferably between 75 and 400 mg / ml, even more preferably between 100 and 300 mg / ml, or even better between 125 and 250 mg / ml relative to the total weight of the gelled aqueous phase.

[0088] The amount of antibiotic(s) contained in the core of the nanocapsules may represent from 1% to 20% by weight, and preferably from 2% to 10% by weight, of the total weight of the nanocapsules.

[0089] In addition to daptomycin, an additional antibiotic suitable for the present invention may be selected from: lipopeptides, glyco- or lipo-glycopeptides, such as for example vancomycin, telavancin, teicoplanin, polypeptides, such as for example colistin, rifamycins, such as for example rifampicin, rifabutin, penicillins, such as for example penicillin G, penicillin V, amoxicillin, oxacillin, cephalosporins, such as for example ceflacor, cefalexin, cefuroxime, cefixime, penems, such as for example imipenem, meropenem, doripenem, macrolides and related agents, such as for example erythromycin A, spiramycin, clarithromycin, roxithromycin, azithromycin, midecamycin, telithromycin, virginiamycin, pristinamycin, ansamycin, aminoglycosides, such as for example amikacin, gentamicin, tobramycin, quinolones and their fluorinated derivatives, such as for example ofloxacin, moxifloxacin, ciprofloxacin, levofloxacin,sulfonamides or sulfonamides, such as for example trimethoprim, sulfamethoxazole, fusidanines, such as fusidic acid, fosfomycin, oxazolidinones, such as linezolid, tedizolid, tetracyclines, such as for example doxycycline, lymecycline, methacycline, minocycline, and mixtures thereof.

[0090] More particularly, said additional antibiotic(s) are chosen from rifampicin, vancomycin, colistin and mixtures thereof.

[0091] According to an alternative embodiment, said additional antibiotic(s) included in the core of said lipid nanocapsules and in said gelled aqueous phase are identical.

[0092] The core of said lipid nanocapsules on the one hand and said gelled aqueous phase on the other hand, both contain at least daptomycin.

[0093] According to another embodiment variant, said additional antibiotic(s) included in the core of said lipid nanocapsules and in said gelled aqueous phase are distinct.

[0094] A pharmaceutical composition according to the invention may also simultaneously comprise lipid nanocapsules according to the invention comprising daptomycin as the sole antibiotic and other lipid nanocapsules comprising at least one antibiotic other than daptomycin, in particular chosen from lipopeptides, lipoglycopeptides, polypeptides, rifamycins, penicillins, cephalosporins, carbapenems, macrolides, aminoglycosides, quinolones and their fluorinated derivatives, sulfonamides (or sulfonamides), oxazolidinones, fosfomycin, fusidic acid, tetracyclines, and mixtures thereof. f) Other components of the composition

[0095] Of course, a pharmaceutical composition according to the invention may further comprise at least one active ingredient distinct from said antibiotic(s) required according to the invention.

[0096] This active ingredient may be present directly in the gelled aqueous phase and / or be present in the composition in a form encapsulated in nanocapsules distinct from those carrying said antibiotic.

[0097] For example, the additional active ingredient(s) may be chosen from vitamins, healing agents, minerals, analgesics, anti-inflammatories, growth hormones, antiseptics, hemostatics, and mixtures thereof.

[0098] The pharmaceutical composition according to the invention may also further comprise at least one pharmaceutically acceptable excipient and / or additive and / or solvent.

[0099] The pharmaceutically acceptable excipient(s) and / or additive(s) may in particular be chosen according to the method of administration of the pharmaceutical composition. PROCESS FOR PREPARING THE COMPOSITION ACCORDING TO THE INVENTION

[0100] A composition according to the invention may in particular be obtained by simply mixing the nanocapsules in accordance with the invention with the other components required in the composition according to the invention. The order of introduction of the different components is not decisive.

[0101] Another variant may be to first form the aqueous phase by mixing the liquid components in the aqueous medium and then introducing the nanocapsules.

[0102] Advantageously, the preparation of the composition can be carried out at a temperature between 2°C and 25°C.

[0103] As regards the nanocapsules, they can be prepared according to the protocols described in the examples and detailed in documents WO2001064328, WO2009004214, WO2009001019, WO2010067037 and WO2015118496. USES OF A COMPOSITION ACCORDING TO THE INVENTION

[0104] A pharmaceutical composition according to the invention is advantageously compatible with the different modes of administration usually considered in the therapeutic field.

[0105] It is particularly advantageously suited to administration directly to the joint, bone, or implanted medical device. For example, its administration can be carried out by injection in particular via a syringe but also by applying a deposit of composition to the surface of the targeted organ or a device, implant or other, dedicated to being placed in contact with the organ.

[0106] Thus, the composition according to the invention is suitable for use in treating or preventing an osteoarticular bacterial infection affecting a joint, a bone, or developing at the level of an implanted medical device.

[0107] The present invention also relates to internal medical devices comprising at least one pharmaceutical composition according to the invention.

[0108] By "medical device", for the purposes of the present invention, is meant the generic term designating any instrument, apparatus, equipment, material or other article, used alone or in combination, for therapeutic purposes, for the control, treatment or alleviation of a disease.

[0109] By "internal medical device" is meant a medical device suitable for direct application to the joint, bone, or implanted medical device.

[0110] The present invention also relates to an internal medical device according to the invention, for its use in treating or preventing an infection, in particular bacterial, preferably osteoarticular affecting a joint, a bone or developing at the level of an implanted medical device, preferably said internal medical device then being represented by a dressing, a compress or a gauze.

[0111] An internal medical device according to the invention may in particular be an implant, a prosthesis, a screw, a plate, a dressing, a compress or a gauze.

[0112] The term "implant" or "prosthesis" can refer to an element intended to be introduced and remain in an organism for a more or less long period of time. This may be, for example, an active implant (whose operation requires a source of electrical energy), an electronic chip, a bone segment, a bone, a prosthesis, including a visual prosthesis or a bone prosthesis, in particular of the hip or knee, a catheter, an implantable chamber.

[0113] As regards dressings, compresses or gauzes, they can in particular be dedicated to being placed in contact with a bone or a joint for the purposes of preventing or treating an osteoarticular bacterial infection, but also in contact with an implanted internal device (i.e. prosthesis, implant, plate or screw).

[0114] For example, the pharmaceutical composition according to the invention may be applied to at least part of the surface of the dressing, compress or gauze, intended to come into contact with the site of the infection. However, it may also be incorporated within the dressing, compress or gauze, by any suitable means for diffusion to the site of the infection.

[0115] The association of a pharmaceutical composition according to the invention with the constituent material of an internal medical device according to the invention can be carried out before and / or simultaneously with the use or implantation in the body of said internal medical device.

[0116] The following examples and figures are presented for illustrative purposes and do not limit the scope of the invention.

[0117] Expressions "between ... And ... », "variant of ... à ... " And "going from... to ... » must be understood inclusive of limits, unless otherwise specified. EXAMPLES EXAMPLE 1: PREPARATION OF NANOCAPSULES LOADED WITH DAPTOMYCIN

[0118] 2.548 g of an emulsion containing 56 mg of Lipoïd ®< S75-3 (soy lecithin marketed as Lipoïd ®< S75-3 from Lipoid GmbH), 678 mg of lipophilic Captex ®< 8000 (glycerol tricaprylate marketed as Captex ®< 8000 from Abitec), 1.547 g of Kolliphor ®< HS15 (also called Solutol ®< HS15) from BASF), 71 mg of sodium chloride, 196 mg of daptomycin and 1.64 g of a 30% sorbitol solution in milli-Q water are prepared.

[0119] All of the above components are combined in a single beaker under magnetic stirring. Heating is applied until a temperature of 85°C is reached. Still under magnetic stirring, the system is allowed to cool to a temperature of 60°C. This cycle (between 85°C and 60°C) is carried out until the cancellation of the conductivity as a function of temperature is observed. Phase inversion occurs after three cycles. At the last cooling, a quench is carried out by throwing 12.5 ml of distilled water at 2°C + / - 1°C onto the mixture at 70°C. The system is then kept under magnetic stirring for 5 min.

[0120] The particles obtained under the conditions described above, after three temperature cycles, have an average size of 43 + / - 7 nm. Their size polydispersity is 0.071. The particle size is measured by quasi-elastic light scattering (Dynamic Light Scattering or DLS). An average particle size of around 50 nm is measured. Furthermore, an observation made by atomic force microscopy in contact mode (Park Scientific Instruments, Geneva, Switzerland) shows that the nanocapsules are indeed solid at a temperature of 25 °C. EXAMPLE 2: PREPARATION OF A COMPOSITION ACCORDING TO THE INVENTION

[0121] The polymeric gelling agent selected for these tests is of the triblock copolymer type consisting of poly(ethylene oxide) and poly(propylene oxide).

[0122] The nanocapsules of Example 1 are mixed under mechanical stirring at 50 rpm at 4 °C, with 5.541 g of daptomycin, 1.64 g of a 0.3 mg / ml sorbitol solution, 1.62 g of a 0.3 mg / ml sorbitol solution in quenching water and 490 mg of Pluronic ®< F127 (from BASF).

[0123] The viscosity of the composition of Example 2 was further evaluated at different shear rates, at room temperature (25°C).

[0124] These characteristics are summarized in Table 1 below. Table 1 Example 2 Value (Pa.s) Viscosity of the composition (at a shear rate of 0.00 s -1< ) 4700 Viscosity of the composition (at a shear rate of 0.01 s -1< ) 2500 Viscosity of the composition (at a shear rate of 0.10 s -1< ) 950 Viscosity of the composition (at a shear rate of 10.00 s -1< ) 400 Viscosity of the composition (at a shear rate of 100.00 s -1< ) 70

[0125] The nanocapsules of Example 2 were further characterized in size (average diameter, polydispersity) by dynamic light scattering and their zeta potential was measured by electrokinetic methods. For the measurements, the nanocapsule suspensions were prepared by diluting the prepared formulas with ultrapure water.

[0126] Table 2 shows their specificities. Table 2 Hydrodynamic size of nanocapsules (nm) 22,3 Zeta potential of nanocapsules (mV) -16,3

[0127] The determination of the charge rate of the composition obtained is carried out by HPLC-UV assay of daptomycin. To do this, 50 mg of the composition was mixed with 9.46 ml of isopropanol, 4.151 ml of THF, 2.795 ml of 0.2 M PBS pH 5.5 and 3.225 ml of Milli-Q water. Then, the extract was filtered through a filter with a porosity of 0.22 µm and diluted with 0.2 M PBS pH 5.5 before injection into the HPLC-UV system. Table 3 below summarizes the results obtained. Table 3 Appearance Daptomycin concentration (mg / ml of composition) Example 2 Yellow viscous solution 192,00 + / - 4,55 EXAMPLE 3: PREPARATION OF A COMPOSITION ACCORDING TO THE INVENTION

[0128] The polymeric gelling agent chosen for these tests is of the carboxymethylcellulose polymer type.

[0129] The nanocapsules of Example 1 are mixed under mechanical stirring using a U-shaped paddle at 200 rpm with 20.50 g of a 0.3 mg / ml sorbitol solution, and 48.49 g of a 0.3 mg / ml sorbitol dilution solution are added. Ultra-high viscosity carboxymethylcellulose, marketed by Sigma-Aldrich, and daptomycin are introduced. The percentage of polymers relative to the mass of the aqueous phase is 3%. Subsequently, heating is interrupted and mechanical stirring is maintained for 2 hours. The samples are stored at 4 °C.

[0130] The composition thus obtained is opaque and yellow in appearance and has a daptomycin concentration of 187.55 mg / ml + / - 2.76. EXAMPLE 4: EFFECTIVENESS TESTS IN VIVO OF A COMPOSITION ACCORDING TO THE INVENTION

[0131] A dose of the composition according to Example 2 was injected into a model of MRSA Rabbit Osteomyelitis by injectable route. in situ. Tissue assays were performed using HPLC, in situ(bone and bone marrow) and in plasma, spleen, liver, kidneys and muscles 1 day, 4 days and 14 days after injection, allowing to obtain the pharmacokinetics of daptomycin. The summary of the results (plasma, bone and BM) is presented in figure 1 .

[0132] Daptomycin concentrations are very high 4 days after a single administration, particularly in bone and bone marrow. Moreover, this concentration remains high even 14 days after injection.

[0133] In order to determine the bacterial load of the tissues, 1 ml of the composition according to Example 2 was injected in situ in an experimental rabbit model of MRSA osteoarticular infection (OAI) ( Staphylococcus aureus Methicillin Resistant) for a dose of 200 mg / ml in daptomycin ( figures 2 , 3 and 4 ).

[0134] Bacterial loads in both compartments (bone and bone marrow) were significantly reduced by injection of the composition according to the invention, 4 days and 14 days after injection, in comparison with other reference antibiotics at humanized doses (Linezolid (LZD, 10 mg / kg / 12h), Daptomycin (DPT, 6 mg / kg / d), Vancomycin (VAN, 100 mg / kg / d in continuous infusion) and Ceftaroline (CPT, 10 mg / kg / 12h) (p < 0.001 versus controls, VAN, LZD, CPT and DPT).

[0135] Finally, the composition according to example 2 was administered by local injection in combination with an antibiotic, rifampicin by IM route at a dose of 20 mg / kg / 12h.

[0136] A significant decrease (p < 0.001 versus control) of the bacterial load in both bone compartments (bone and bone marrow) is observed ( Figure 5 ).

Claims

1. Pharmaceutical composition stabilized in a gelled state at at least one temperature ranging from 15°C to 40°C, comprising at least: - an aqueous phase gelled with at least one polymeric hydrophilic gelling agent, said polymeric hydrophilic gelling agent(s) being present in an amount of between 2% and 25% by weight, relative to the weight of the gelled aqueous phase; said polymeric hydrophilic gelling agent(s) being at least selected from C1-C2 carboxymethylcelluloses having a viscosity of between 1500 mPa.s and 4500 mPa.s, and / or triblock copolymers consisting of poly(ethylene oxide) and poly(propylene oxide) having a lower critical solubility temperature (LCST) of between 15°C and 40°C; said gelled aqueous phase further comprising at least one polyol; said polyol being sorbitol; said polyol(s) being present in an amount of between 2% and 20% by weight, relative to the total weight of the composition; - lipid nanocapsules comprising a lipid core which is liquid or semi-liquid at ambient temperature, enveloped by a lipid shell which is solid at ambient temperature, said nanocapsules being present in a content ranging from 10% to 80% by weight, relative to the total weight of the composition; - said gelled aqueous phase and nanocapsules containing at least one antibiotic, the antibiotic in said aqueous phase being present therein in the form of a solute; said antibiotic (s) being constantly released over a period of at least 14 days; - the core of the nanocapsules and the gelled aqueous phase both containing at least daptomycin.

2. Pharmaceutical composition according to Claim 1, characterized in that the viscosity of the composition is greater than 10 Pa.s, preferably between 10 Pa.s and 10 000 Pa.s, and more preferentially between 50 Pa.s and 1000 Pa.s, at a temperature ranging from 15°C to 40°C.

3. Composition according to either one of the preceding claims, in which the liquid or semi-liquid lipid core of the lipid nanocapsules comprises, or consists essentially of, one or more triglycerides, one or more fatty acid esters, or a mixture thereof.

4. Composition according to any one of the preceding claims, in which the solid shell enveloping the core of the lipid nanocapsules comprises, or consists essentially of, a lipophilic surfactant which is a phosphatidylcholine.

5. Composition according to any one of the preceding claims, in which said lipid nanocapsules have a size of less than 100 nm, preferably between 10 nm and 50 nm, and better still between 17 nm and 25 nm.

6. Composition according to any one of the preceding claims, in which the nanocapsules are present in a content ranging from 10% to 70% by weight, relative to the total weight of the composition.

7. Composition according to any one of the preceding claims, said composition being suitable for administration directly to the joint, bone, or implanted medical device.

8. Composition according to any one of the preceding claims, for use thereof in treating or preventing an osteoarticular bacterial infection affecting a joint or a bone, or developing at an implanted medical device.

9. Internal medical device comprising a pharmaceutical composition according to any one of Claims 1 to 8.

10. Internal medical device according to the preceding claim, said device being selected from an implant, a prosthesis, a screw, a plate, a dressing, a compress or a gauze.

11. Internal medical device according to Claim 9 or 10, for use thereof in treating or preventing an infection, in particular a bacterial infection, preferably an osteoarticular bacterial infection, affecting a joint or a bone, or developing at an implanted medical device, said internal medical device preferably then being represented by a dressing, a compress or a gauze.

12. Pharmaceutical composition according to any one of Claims 1 to 8, or internal medical device according to Claims 9 to 11, for use thereof for targeted, local and sustained delivery of the antibiotic(s) at an infection, in particular a bacterial infection, preferably an osteoarticular bacterial infection, affecting a joint or a bone, or developing at an implanted medical device or at a site potentially prone to such an infection.