Use of hydrogels for the prevention of urinary tract infections

Abstract

Use of hydrogels for the prevention of urinary tract infections. The present invention relates to a hydrogel comprising at least hydroxypropylmethylcellulose and at least carrageenan, for use in the prevention of urinary tract infections. Figure for abstract: None

Description

Title of the invention: Use of hydrogels for the prevention of urinary tract infections Technical field

[0001] The present invention relates to the field of compositions in the form of hydrogels, in particular for preventing urinary tract infections, especially in women. Prior art

[0002] Urinary tract infections are common conditions worldwide. They are one of the leading causes of bacterial infection worldwide.

[0003] Acute cystitis is a urinary tract infection located in the bladder caused by bacteria. It is the most common urinary tract infection in women. It occurs when bacteria naturally present in the digestive tract (Escherichia coli in 90% of cases) enter the urinary meatus. These bacteria travel up the urethra to reach the bladder and multiply, causing the infection.

[0004] Thus, these infections can be caused by direct inoculation of the urethra with gastrointestinal flora, particularly during sexual intercourse.

[0005] In particular, women are much more susceptible than men to urinary tract and bladder infections, or cystitis attacks. Indeed, shorter urethras, and shorter distances between the urinary meatus and the anus, would offer less protection against cystitis than longer urethras.

[0006] The urethra is often described as a "virtual" canal at rest. In adult women, the urethra is 3 to 4 cm long. It is made up of several tissue layers with, from the inside out, a urothelium, a spongy submucosal layer containing a vascular network, a thin separating layer and a longitudinally oriented muscular layer, itself surrounded by radial circular layers.

[0007] The main risk factors for acute urinary tract infections are sexual activity, a history of urinary tract infections, and menopause. The majority of simple acute urinary tract infections are related to sexual intercourse.

[0008] Sexual activity is particularly considered a major risk factor and often triggers the development of such infections, as it involves, among other things, bacteria, particularly intestinal and vaginal, which can penetrate the nearby urethra through movement and friction, colonize the urethra and bladder and cause their inflammation.

[0009] In order to prevent urinary tract infections, it is advisable to practice the Urinating after intercourse, diligent hygiene, wearing suitable, loose-fitting underwear, and drinking enough fluids. Cranberry and D-mannose products are also recommended, but their effectiveness remains very limited and controversial.

[0010] There are also preventive treatments based on antibiotics, otherwise known as antibiotic prophylaxis, for women with a high frequency of recurrences during the year. However, this type of treatment for urinary tract and bladder infections requires taking antibiotics at least as frequently, if not more frequently (weekly to daily) than the curative treatment (of the attack) without guaranteeing perfect effectiveness. In addition, stopping it generally often leads to the recurrence of attacks. In addition, antibiotic prophylaxis contributes to the development of bacterial resistance and can induce harmful side effects. However, antibiotic resistance is now a major public health problem.

[0011] Thus, despite the existence of numerous preventive solutions, cystitis can recur and impact people's daily lives. Many women already use preventive solutions. However, none of these methods have a certain, reproducible and safe effectiveness for all women. Thus, the benefit-risk balance of these means of prevention remains very limited.

[0012] The use of antibiotic therapy after each infectious episode is then often necessary, in the event of failure of preventive methods. Treatment is then generally based on the prescription of broad-spectrum antibiotics.

[0013] In addition, in a number of affected people, the infection recurs and significantly affects the quality of life. This is called recurrent cystitis. For others, it becomes complicated by a generalized infection (especially pyelonephritis), which is potentially fatal.

[0014] It therefore remains essential to effectively prevent urinary tract infections, particularly in women. Statement of the invention

[0015] It would therefore be desirable to have an effective means of preventing urinary tract infections, representing an alternative to antibiotics, and in particular having a better benefit-risk balance than current means of prevention.

[0016] There is a real need for new solutions, particularly non-drug and preferably natural, to prevent urinary tract infections, and in particular which constitute an alternative as effective or even more so and less risky than antibiotics.

[0017] The invention relates, among other things, to hydrogels for minimizing, or even preventing, urinary tract infections.

[0018] Thus, the present invention relates to hydrogels for administration to the urethra.

[0019] It has thus been surprisingly demonstrated that the use of specific hydrogels makes it possible to prevent the appearance of urinary infections. Summary of the invention

[0020] Thus, according to a first of its aspects, the present invention relates to hydrogels comprising at least hydroxypropylmethylcellulose and at least carrageenan, for their use in the prevention of urinary infections.

[0021] The hydrogels according to the invention are intended for urethral administration to prevent urinary infections, and to avoid the need for antibiotic therapy, in particular before risky situations limited in time, such as wearing specific clothing, sexual intercourse, unfavorable hygiene conditions, prolonged urine retention, for example during a trip, or even bathing in a swimming pool or at sea.

[0022] Advantageously, the hydrogels according to the invention provide a chemical and physical barrier function with respect to microorganisms, particularly potentially pathogenic bacteria, which will prevent their diffusion. Detailed description

[0023] The present invention relates to a composition in the form of a hydrogel comprising at least hydroxypropylmethylcellulose and at least carrageenan, for its use in the prevention of urinary infections.

[0024] In particular, urinary tract infection is an infection induced in particular by uropathogenic Escherichia coli bacteria.

[0025] By "urinary tract infection" we mean simple and / or recurrent cystitis.

[0026] Simple cystitis is a urinary infection that does not carry a risk of complications. This mainly concerns women without risk factors for complications in the presence of only the characteristic symptoms of cystitis such as an urgent or more frequent need to urinate, a burning sensation, or tingling, in the absence of fever.

[0027] Recurrent cystitis is a succession of infectious episodes leading to simple cystitis. For example, to be able to speak of "recurrent cystitis", the number of infectious episodes must be greater than or equal to four per year. Use of hydrogels

[0028] As indicated above, hydrogels comprising at least hydroxypropylmethylcellulose and at least carrageenan are intended to be used for preventing urinary tract infections.

[0029] Thus, they make it possible to minimize, or even prevent, infections of the airways. urinary.

[0030] For this purpose, the hydrogels are administered, for example, directly into the urethra.

[0031] Thus, according to a particular embodiment, the hydrogels according to the invention are intended for local administration, in particular for intra-urethral administration.

[0032] Indeed, the hydrogels according to the invention are intended for intra-urethral administration to prevent urinary infections, and to avoid the need for antibiotic therapy.

[0033] In particular, the hydrogels according to the invention can be deposited on all or part of the urethra.

[0034] In particular, the hydrogels according to the invention can be positioned specifically over the entire urethra.

[0035] Preferably, the hydrogels according to the invention make it possible to obtain in situ a monolithic, deformable and muco-adhesive form.

[0036] In particular, once placed in the urethra, the hydrogels form a monolithic mass in the presence of physiological liquid, which follows the contours of the urethra and remains in place for a sufficient duration, due to the development of a mucoadhesion phenomenon on the surface of the urothelium.

[0037] Thus, preferably, the hydrogels according to the invention have mucoadhesive, adhesion and detachment properties. They are in particular capable of adhering transiently to the surface of the urothelium.

[0038] The hydrogels according to the invention are easily administrable at the urethral level, and can be easily transferred from their packaging to the urethra thanks to minimal adhesion of the hydrogel to the packaging materials, and to a possible application device.

[0039] The hydrogels according to the invention are capable of adhering rapidly to the urothelial surface, namely within a few minutes after the formulation is deposited.

[0040] The hydrogels are deformable in the urethra, and allow adhesion and the barrier effect to be obtained simultaneously. Advantageously, the hydrogel adheres to the surface of the urethra under the effect of external pressure constraints.

[0041] Furthermore, the mucoadhesion of the hydrogel is such that detachment of the monolith can occur under normal conditions of post-coital urination.

[0042] The hydrogels according to the invention simultaneously have a sufficient viscous character so as to be able to quickly line the urothelium after administration, and on the other hand make it possible to confer sufficient adhesiveness to the monolith.

[0043] Thus, once in place, when the hydrogel is subjected to detachment forces, it deforms without detaching, and remains in place in the urethra.

[0044] According to a particular embodiment, the hydrogel is administered before a time-limited risk situation.

[0045] In particular, the hydrogels used according to the invention remain in place after administration at least until the next urination, and in particular for a period of less than 12 hours in the urethra. They thus make it possible to prevent infections by ascending route by repeated use.

[0046] In particular, the hydrogels may be administered for repeated use, for example at least 5 times per month, in particular at least 10 times per month.

[0047] The present invention also relates to the use of a hydrogel comprising at least hydroxypropylmethylcellulose and at least carrageenan, for preventing urinary infections.

[0048] In particular, the present invention also relates to the use of a hydrogel comprising at least hydroxypropylmethylcellulose and at least carrageenan, for targeted and local delivery of the hydrogel to the urethra, to prevent urinary infections.

[0049] The present invention also relates to a method for preventing urinary tract infections comprising the administration of a hydrogel comprising at least hydroxypropylmethylcellulose and at least carrageenan.

[0050] The present invention also relates to a method for preventing urinary infections comprising a step of administering a hydrogel comprising at least hydroxypropylmethylcellulose and at least carrageenan.

[0051] A hydrogel according to the invention is advantageously compatible with the different modes of administration usually considered in the therapeutic field.

[0052] It is in particular advantageously suitable for administration directly to the urethra.

[0053] Furthermore, unlike external patches, the location of the hydrogel after administration is advantageously discreet, or even completely invisible. Hydrogels

[0054] By "hydrogel" is meant a homogeneous water-based composition in the form of a gel consisting of a single phase. More particularly, a hydrogel is formed of a three-dimensional network of polymer chains, insoluble in water but capable of swelling in the presence of aqueous solutions.

[0055] The hydrogels used according to the invention contain water, preferably purified water.

[0056] In particular, the water content in a hydrogel used according to the invention varies from 70% to 98% by weight, in particular from 80% to 98% by weight, preferably from 90% to 97% by weight, and more preferably from 94% to 96% by weight, relative to the total weight of the hydrogel.

[0057] In particular, the hydrogels used according to the invention are viscous before administration, and swell on contact with body water after administration, in order to remain in place at the administration site level.

[0058] According to a particular embodiment, the viscosity at a shear rate of 0.01 s 1 of the hydrogels according to the invention varies from 1,000 to 30,000, in particular from 5,000 to 25,000, preferably from 10,000 to 20,000, measured using a TA Instruments™ AGR2 rheometer type viscometer.

[0059] According to a particular embodiment, the dose of hydrogel administered into the urethra varies from 5 pL to 1 mL, in particular from 50 pL to 800 pL, preferably from 80 pL to 500 pL.

[0060] Preferably, the hydrogels according to the invention contain natural or naturally occurring compounds.

[0061] Preferably, the hydrogels used according to the invention are translucent.

[0062] Preferably, the hydrogels used according to the invention are uncolored.

[0063] As indicated above, the hydrogels used according to the invention comprise at least hydroxypropylmethylcellulose and at least carrageenan. Hydroxypropylmethylcellulose

[0064] Thus, the hydrogels used according to the invention comprise at least one hydroxypropylmethylcellulose (HPMC), in particular long chain.

[0065] Hydroxypropylmethylcelluloses (hydroxypropylmethylcellulose) are water-soluble, cellulose-derived polymers with high water absorption capacity.

[0066] Preferably, the hydroxypropylmethylcellulose is chosen from Métolose 60 SH 4000 (viscosity 3000-5600 mPa.s), Mélotose 60 SH 10000 (viscosity 7500-14000 mPa.s), Mélotose 90 SH 15000 SR (particle size 20 to 160 pm; viscosity 11250-21000 mPa.s), marketed by the company Seppic, or Benecel K200 M (particle size 170-250 pm; viscosity 150000-280000 mPa.s) or Benecel K100M Pharm XR (particle size 170-250 pm; viscosity 75000-140000 mPa.s), marketed by the company IMCD.

[0067] Preferably, the hydroxypropylmethylcellulose is chosen from HPMCs with a particle size of between 20 and 160 μm, in particular Métolose 90SH 15000.

[0068] In particular, the content of hydroxypropylmethylcellulose(s) in a hydrogel used according to the invention varies from 0.1% to 10% by weight, preferably from 0.5% to 8% by weight, and more preferably from 1% to 5% by weight, relative to the total weight of the hydrogel. Carrageenan

[0069] As indicated previously, the hydrogels used according to the invention comprise at least carrageenan.

[0070] Carrageenan is a natural sulfated polysaccharide extracted from red algae.

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[0085] In particular, the carrageenan is selected from kappa carrageenan, iota carrageenan, lambda carrageenan, and mixtures thereof. Kappa carrageenan has the formula: [Chem.l] Iota carrageenan has the formula: [Chem. 2] Iota Carrageenan is marketed in particular under the name Gelcarin PH 379 (granulometry 150 pm) by the Dupont Company. Lambda carrageenan has the formula: [Chem. 3] Lambda Carrageenan is marketed in particular under the name Viscarin PH 209 (viscosity 450-750 rnPa.s) by the Dupont Company. Preferably, the carrageenan is iota carrageenan. In particular, the content of carrageenan(s) in a hydrogel used according to the invention varies from 0.1% to 5% by weight, preferably from 0.2% to 4% by weight, and more preferably from 0.4% to 2.5% by weight, relative to the total weight of the hydrogel. According to a particular embodiment, the hydroxypropylmethylcellulose(s) and the carrageenan(s) are present in a hydrogel according to the invention in a weight ratio varying from 0.5 to 10, in particular from 3 to 8, and preferably from 4 to 5. Adjuvants According to a particular embodiment, the hydrogels used according to the invention may contain one or more adjuvants, in particular pharmaceutically acceptable adjuvants, or GRAS (Generally Recognized as Safe). Preferably, the adjuvants are natural or of natural origin. In particular, the content of adjuvant(s) in a hydrogel used according to the invention varies from 0% to 28% by weight, preferably from 0.1% to 12% by weight, and more preferably 0.5% to 2% by weight, relative to the total weight of the hydrogel. Preparation of hydrogels

[0086] The hydrogels according to the invention can be prepared according to techniques well known to those skilled in the art.

[0087] Thus, a hydrogel according to the invention can be manufactured by methods known to those skilled in the art, generally used in the pharmaceutical field.

[0088] It can be manufactured for example by obtaining a homogeneous mixture of the different ingredients of the composition.

[0089] In particular, a method for preparing a hydrogel according to the invention may comprise the following steps: - providing a hydroxypropylmethylcellulose powder; - dispersing the hydroxypropylmethylcellulose powder in water to form a hydroxypropylmethylcellulose gel; - heating the hydroxypropylmethylcellulose gel formed, in particular at a temperature ranging from 75°C to 90°C; and - add and disperse the carrageenan powder.

[0090] The hydrogel obtained can then be subjected to a sterilization step. Brief description of the drawings

[0091] [Fig. la] and [Fig.lb] represent a kinetic series of fluorescence photos of formula 4 in contact with the particle suspension according to the protocol of example 3. The graphs placed to the right of the photos show the intensity of the fluorescence measured along the transverse line, from right to left, in the suspension then within the hydrogel.

[0092] Throughout the description, including the claims, the expression "comprising a" must be understood as being synonymous with "comprising at least one", unless otherwise specified.

[0093] The expressions “between ... and ...”, “includes from ... to ...”, “formed from ... to ...”, and “ranging from ... to ...” are equivalent and are intended to mean that the limits are included, unless otherwise stated.

[0094] The expression “at least one” is equivalent to “one or more”.

[0095] In the description and the examples, unless otherwise indicated, the percentages are weight percentages (i.e. mass percentages). The percentages are therefore expressed by weight relative to the total weight of the composition. The temperature is expressed in degrees Celsius unless otherwise indicated, and the pressure is atmospheric pressure, unless otherwise indicated.

[0096] The invention is illustrated in more detail by the non-limiting examples presented below. Example

[0097] Example 1: Preparation of hydrogels according to the invention

[0098] Compositions 1 to 6, according to the invention, are prepared from the weight proportions as detailed in Table 1 below.

[0099] The values ​​are expressed as a percentage by weight, relative to the total weight of the composition.

[0100] [Tableauxl] Commercially Referenced Compounds Formula 1 Formula Formula 3 Formula 4 Foumuk 5 Formula 6 Hydroxypropyl methylcellulose Métotose 90.SH 15000 SR (granulometry 20 to 160 pm; viscosity 11250-21000 mPa.sx marketed by Seppic Company 1.3 1.5 3.5 3.5 4 1.5 CaiTagh.eaaæ Iota Geicarin®'PH 379 (granulometry £50 irai) marketed by Dupont Company 0.5 0.75 0.5: 0.75 0.5 2 Purified water Qsp 100 Qsp 100 Qsp 160 Qsp 100 Qsp 100 Qsp 100

[0101] The hydrogels are formulated on 100 g.

[0102] The hydroxypropylmethylcellulose is gradually introduced into the water at room temperature, with magnetic stirring.

[0103] After dispersing the hydroxypropylmethylcellulose powder, the mixture is placed in a vacuum desiccator for 2 days to allow complete swelling of the hydroxypropylmethylcellulose by removing any air bubbles present.

[0104] Once the hydroxypropylmethylcellulose gel has swollen, the gel is heated in a water bath to 80-85°C.

[0105] After fluidification of the hydroxypropylmethylcellulose gel, the carrageenan is gradually added under magnetic stirring for 40 minutes.

[0106] Once the carrageenan is dispersed, the mixture is transferred directly into a closed vial and placed under vacuum.

[0107] The vials are left to stand for at least 24 hours before further processing.

[0108] For characterization purposes, the preparations are packaged in a 12.5 mL penicillin-type bottle with a rubber stopper and pre-crimped. The bottles are then sterilized in an autoclave (HIClave™ HV-50L, HMC Europe) and subjected to a sterilization cycle at 121°C for 20 minutes.

[0109] Example 2: Characterization of the hydrogels according to the invention 2.1 Rheology measurements

[0110] The rheological behavior of preparations 1 to 6 according to the invention was established in using commercial devices and according to conventional procedures.

[0111] The viscosity and thixotropy of the hydrogels were measured to determine their rheological behavior, using a TA Instruments™ AGR2 rotary rheometer equipped with a 20 mm parallel plane solvent trap geometry. 2.1.1 Viscosity

[0112] The flow curves of the formulations were established at 25 °C and using the test parameters listed in the table below, entered into the TRIOS software. All rheological measurements were repeated three times for each formulation.

[0113] [T ables 2] Shear Rate Range | From 100 s-1 to 0.01 s-1 Gap 1000 um Adjustment Gap 1200 pm Immersion Time 120 s Duration | 120 s Log Mode Points per Decade 10 points

[0114] The measurements were carried out at decreasing speeds in order to remove the "shear history" of each formulation sample and thus have an identical precision for each. 2.1.2 Thixotropy

[0115] The thixotropic character of the formulations was established by subjecting the sample considered to three different regimes: - a ramp with increasing speed (go): • shear speed range: from 0.01 s 1 to 100 s 1 ; • temperature: 25°C; • duration: 120 s; • mode: Log; • points per decade: 10 points, - followed by a phase consisting of maintaining the sample under shear at constant speed for a defined duration of 60 s: • applied shear rate: 100 s 1 ; • temperature: 60°C; • interval: 6 points / s; - and by a ramp at decreasing speed (return): • shear speed range: from 100 s 1 to 0.01 s 1 ; • temperature: 25°C; • duration: 120 s; • mode: Log; • points per decade: 10 points.

[0116] 2.1.3 Measurement of elastic and viscous moduli in linear regime

[0117] For the measurement of elastic and viscous moduli in linear regime, the following parameters were entered into the TRIOS software:

[0118] [Tables3] î Shear rate range From 100 S's to 0.01 s 5 Deviation 1000 pm Adjustment deviation 1200 pm î Temperature 25 °C Immersion time 120 s Duration 120 s Frequency 1 Hertz Mode Log Sweep Strain 9.01 M 1UOO% Points per decade 10 points 2.1.4 Results and conclusions

[0119] The TRIOS software gives the apparent viscosity values ​​as a function of the shear rate in the form of log-log curves which, depending on their shape, allow the rheological behavior of the formulations to be determined. These curves were linear over the entire range of experimentally accessible shear rates and did not show a viscosity plateau at low rates.

[0120] The viscosity values ​​(Pa.s) at 25°C at different shear rates for each formulation 1 to 6 according to the invention are detailed in Table 4 below:

[0121] [Tables4] Shear rate s-1 Formula 1 Formula 2 Formula 3 Formula 4 Formula 5 Formula 6 0.0 i 2559 10176 8452 S672 18897 0.1 436 1448 1651 2205 854 2536 1 96 132 430 463 511 360 10 24 40 112 98 134 54 100 7 10 29 24 33 21

[0122] The results demonstrate that formulations 1 to 6 behave like non-Newtonian fluids for which the viscosity increases when the applied shear rate increases. Formulations 1 to 6 therefore exhibit shear-thinning behavior. The formulations lose viscosity when a stress corresponding to the shear of a syringe, for example, is applied, which allows for use simpler reading.

[0123] Furthermore, the formulations exhibit thixotropic behavior.

[0124] The thixotropy of hydrogels 1 to 6 is not pronounced. Under shear, the latter restructure more quickly. Consequently, formulations 1 to 6 lose viscosity under shear, allowing for better ease of administration. After administration of formulations 1 to 6 in situ, they restructure to regain their initial viscosity.

[0125] Furthermore, the measurements of the elastic and viscous moduli measured in linear regime of the formulations demonstrate that for each formulation 1 to 6 according to the invention, the elastic modulus G' is predominant. The hydrogels according to the invention therefore have viscoelastic characteristics with an elastic predominance. 2.2 Swelling kinetics

[0126] The swelling of the formulations was characterized.

[0127] The mass variation of the formulation (swelling) was thus measured in the presence of a liquid (Dulbecco's Phosphate Buffered Saline (PBS), pH 7.4, Sigma-Aldrich) in order to establish its swelling kinetics. Each experiment is repeated three times for each time.

[0128] The filter (Merck Millipore, 2 mL, porosity 0.1 pm) for centrifuge tube alone is weighed. 0.25 g of the characterized formulation is weighed into a cup. The weighed quantity of formulation is introduced into the filter using a spatula.

[0129] A crystallizer filled with liquid is placed in an enclosure at 37°C for 20 minutes. The filters comprising the formulation are then placed on a rack in the crystallizer so that the filters are semi-emerged and the lower part is immersed in the liquid under study. A beaker filled with water is placed in the enclosure to prevent evaporation of the liquid contained in the crystallizer. The filters are left for a time between 0 and 360 minutes in order to establish the swelling kinetics. At each time, they are removed from the enclosure. Filter paper is used to remove excess liquid from the external walls of the centrifuge tube.

[0130] The tubes containing the formulations are weighed. Once weighed, the tubes are immediately put back in place and in contact with the PBS buffer.

[0131] The swelling kinetics of formulations 4 to 6 are then measured. The results are expressed as a percentage relative to the initial mass of formulation used for the measurement.

[0132] To this end, the quantity of liquid absorbed by the formulas is determined by subtracting the final mass of the filter containing the formulation from that of the filter alone, then subtracting the mass obtained from the initial mass of the formulation introduced into the tube (i.e. 0.25 g).

[0133] The results show that hydrogels 4 to 6 exhibit kinetics of slow swelling.

[0134] Thus, the hydrogels according to the invention are advantageous since they swell once administered. 2.3 Adhesion properties of hydrogels

[0135] The adhesion properties of the formulations are characterized by measuring the detachment force and the work of adhesion.

[0136] Tensile tests are carried out at 37°C on samples of the formulations, using a TA.XTplus texturometer, a 5 kg force sensor, a thermostat and Exponent software.

[0137] These tests are carried out on an artificial substrate, namely a cylindrical aluminum probe 20 mm in diameter (i.e. an adhesion surface of approximately 314 mm2).

[0138] Each experiment is repeated three times.

[0139] The adhesion measurement test parameters used are detailed below: - Substrate used: Artificial substrates, aluminum substrate and GelBond® films fixed on the aluminum probe; - Pre-test speed: 0.1 mm / s; - Test speed: from 1 to 10 mm / s; - Post test speed: 10 mm / s; - Applied force: from 0.5 to 5 Newton; - Contact time: 120 s; - Points per decade: 250.

[0140] The Exponent software makes it possible to obtain a curve for which the negative part of the curve corresponds to the applied compressive forces, while the positive part of the curve corresponds to the tensile forces. From this curve, the maximum detachment force, which is reflected by the highest peak of the tensile curve, and the work of adhesion, which corresponds to the area under the tensile curve, can be determined.

[0141] It is observed that the traction curves of the hydrogels according to the invention are large. The results are detailed in the table below:

[0142] [Tables5] FGrmtüatKms Average adhesion work (N. min) Formula 4 according to the invention 8.7 Formula 5 according to the invention 9.2 Formula 6 according to the invention 2.9

[0143] The average adhesion works of hydrogels 4 to 6 according to the invention are high.

[0144] They therefore have good adhesion to the aluminum substrate. 2.4 Syringability study

[0145] The syringability of the formulations was evaluated by means of the following test.

[0146] A syringe (body and plunger, without needle, (Terumo, 1 mL, tip diameter of 2 mm) was previously filled with the tested preparation (0.5 mL). The syringe was then placed in a suitable metal holder on the platform of a TA.XTplus texture analyzer and a 30 kg force sensor so as to impose a constant displacement speed of the plunger while measuring the force exerted to achieve this displacement.

[0147] The conditions adopted consisted of imposing a constant piston displacement speed of 0.5 mm / s, which corresponds to a flow rate of approximately 0.5 mL / min, similar to a manual injection flow rate. The force required to eject the formulation was continuously recorded. The profile of this force during ejection reflects the syringeability of the preparation. The experiment is repeated four times for each formulation.

[0148] The syringability tests were carried out on the hydrogels of formula 4, 5 and 6 according to the invention. A “control” syringability test, corresponding to a test on an empty syringe, was also carried out for comparison.

[0149] For each formulation, the average injection forces of the formulations are taken at the first level located between 4 and 10 mm, the results being repeatable. This first level corresponds to the ejection of approximately 100 qL of formulation.

[0150] The measured average injection forces of the hydrogels according to the invention were less than 0.7 N (i.e. 70 g and 60 g respectively).

[0151] Thus, for the formulas according to the invention, the injection force is relatively low, which allows simple and painless use.

[0152] Example 3: In vitro studies of the antibacterial barrier effect

[0153] In vitro studies were carried out to evaluate the antibacterial barrier effect of hydrogels according to the invention.

[0154] The barrier effect of the formulations against pathogens was estimated using a Carl Zeiss fluorescence videomicroscopy technique. This is an inverted microscope, in which the sample is illuminated from above and observed from below through a glass slide. A thermostatically controlled chamber maintains the temperature at 37°C. The device allows series of images to be acquired at predetermined time intervals. Particles containing a fluorescent tracer and of calibrated size (monodisperse) were used as model particles. The tests were carried out with microspheres of 1 qm diameter (Fluoresbrite® microsphere green).

[0155] The protocol is as follows: the preparations are inserted into devices designed for cell culture (Ibidi sticky-Slide VI 0.4 plates, equipped with six channels of diffusion of 0.4 mm in height, each connected by two wells and coverslips). The formulation was placed in the central channel observable by microscopy. A particulate suspension was deposited in one of the wells, in contact with one side of the preparation. Recordings (timelapse) were made with a x4 eyepiece continuously, in order to observe the possible progression of fluorescence within the gel.

[0156] The data were analyzed using dedicated software (Image J, Fiji).

[0157] The experiment was carried out with formula 4 according to example 1.

[0158] A 45-minute timelapse was performed with photos taken every 5 minutes. The fluorescence intensity was measured by the Fiji software, along a vertical line. The green part corresponds to the suspension of fluorescent particles and the black part corresponds to the gel. For each time, the intensity profile is given along the yellow line, from top to bottom (Figures 1a and 1b).

[0159] The recording shows that the gel immobilized in the channel swells upon contact with the liquid. An upward shift in fluorescence intensity is observed (shift to the left on the intensity analysis profiles): the gel repels the suspended fluorescent particles and the fluorescent particle front does not advance. On the contrary, diffusion of the particles within the gel would have resulted in a shift to the right on the intensity analysis curve. The observed shift is thus relative to the swelling of the hydrogel of formula 4 and not to the Brownian motion of the particles. There is therefore no penetration of the 1 μm particles through the hydrogel according to the invention.

[0160] The hydrogels according to the invention therefore have a blocking effect with respect to the particles, by constituting a physical barrier opposed to the diffusion of the particles.

Claims

Claims

1. Hydrogel comprising at least hydroxypropylmethylcellulose and at least carrageenan, for use in the prevention of urinary tract infections.

2. Hydrogel for use according to claim 1, the urinary tract infection being an infection induced by uropathogenic Escherichia coli bacteria.

3. Hydrogel for use according to any one of the preceding claims, in which the content of hydroxypropylmethylcellulose(s) varies from 0.1% to 10% by weight, preferably from 0.5% to 8% by weight, and more preferably from 1% to 5% by weight, relative to the total weight of the hydrogel.

4. Hydrogel for use according to any one of the preceding claims, wherein the carrageenan is selected from kappa carrageenan, iota carrageenan, lambda carrageenan, and mixtures thereof, and preferably the carrageenan is iota carrageenan.

5. Hydrogel for use according to any one of the preceding claims, in which the content of carrageenan(s) varies from 0.1% to 5% by weight, preferably from 0.2% to 4% by weight, and more preferably from 0.4% to 2.5% by weight, relative to the total weight of the hydrogel.

6. Hydrogel for use according to any one of the preceding claims, comprising water in a content varying from 70% to 98% by weight, in particular from 80% to 98% by weight, preferably from 90% to 97% by weight, and more preferably from 94% to 96% by weight, relative to the total weight of the hydrogel.

7. Hydrogel for use according to any one of the preceding claims, in which the hydroxypropylmethylcellulose(s) and the carrageenan(s) are present in the hydrogel in a weight ratio ranging from 0.5 to 10, in particular from 3 to 8, and preferably from 4 to 5.

8. H- d. J. Hydrogel for use according to any one of the preceding claims, further comprising at least one pharmaceutically acceptable adjuvant.

9. Hydrogel for use according to any one of the preceding claims, characterized in that it contains natural or naturally occurring compounds.

10. Hydrogel for use according to any one of the preceding claims, intended for local administration, in particular for intraurethral administration.

11. Hydrogel for its use according to the preceding claim, characterized in that its form is suitable for being administered in the urethra at a dose varying from 5 qL to 1 mL, in particular from 50 qL to 800 qL, preferably from 80 qL to 500 qL.

12. Hydrogel for use according to any one of the preceding claims, characterized in that its viscosity at a shear rate of 0.01 s 1 varies from 1,000 to 30,000, in particular from 5,000 to 25,000, preferably from 10,000 to 20,000, measured using a TA Instruments™ AGR2 rheometer type viscometer.

13. Hydrogel for use according to any one of the preceding claims, characterized in that its form is suitable for administration for repeated use, for example at least 5 times per month.

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