WO2015059623A1

WO2015059623A1 - A bioreabsorbable composition containing antibacterial agents for the treatment of lower back pain

Info

Publication number: WO2015059623A1
Application number: PCT/IB2014/065471
Authority: WO
Inventors: Davide Cremascoli; Carlo Luca Romano'; Enzo Meani; Edgardo Cremascoli
Original assignee: Novagenit S.R.L.; Mero S.R.L.
Priority date: 2013-10-21
Filing date: 2014-10-20
Publication date: 2015-04-30
Also published as: CN105682640A; AU2014338592A1; ITMI20131755A1; CA2925690A1; IL245164A0; JP2016533354A

Abstract

The invention relates to compositions comprising a resorbable carrier and at least an antibacterial agent for use in the treatment of lower back pain, by local surgical application of the composition.

Description

A BIOREABSORBABLE COMPOSITION CONTAINING ANTIBACTERIAL AGENTS FOR THE TREATMENT OF LOWER BACK PAIN

DESCRIPTION

Field of the invention

The present invention refers to the use of a bio-reabsorbable composition as the carrier for bioactive compounds for the treatment of lower back pain.

State of the art

Lower back pain is the main cause of visits and orthopaedic treatments and of reduced motor skills, and affects millions of patients in every country; the lower back pain is also known in the medical field with the English term "low back pain" or its acronym LBP, which will be adopted in the rest of the description.

Medical research shows that about 80% of the population suffer from LBP during life. For a lot of people with LBP, it is likely that the pain reappears on several occasions, and chronic lower back pain is a major limiting factor of activities in young adults under the age of 45 years. Epidemiological investigations in the US have revealed about 5-20% of annual prevalence of LBP. This disease interferes with the daily life of patients, decreasing their quality of life. The costs associated with this condition are enormous, and include both direct medical costs and indirect costs, such as reduced productivity at work; lower back pain is not only a health problem but also a socio-economic problem.

Lower back pain is generally a consequence of degenerative spinal disorder, whose magnitude is commonly evaluated by diagnostic imaging, and in particular by magnetic resonance imaging; this method is able to highlight degenerative changes in the vertebral end plate and in the bones under the cartilage.

The degree of this disorder is generally measured with reference to an empirical scale, adopted after the publication of some papers of MT Modic and his staff; see in this regard, in particular, the article "Degenerative disk disease: assessment of changes in vertebral body marrow with MR imaging," Modic et al., Radiology 1988; 166 (1 , Part 1 ), pages 193-199. According to this method, the vertebral alterations are evaluated according to three levels of deviation of the magnetic resonance signal compared to the normal situation, known as MCs (from "Modic Changes"). The Type I, also known as inflammatory phase, is identified by inflammation of the fibrous tissue, and is characterized by low signal intensity on T1W scans and by high signal intensity on T2W scans. The Type II, known as the fat phase, is characterized by a high degree of deposition of fat cells in the vertebral endplate and in the area below, and it is identified by high signal intensity in T1W scans and an equivalent signal or a medium- high signal on T2W scans. Finally, the type III, also known as phase of bone sclerosis, is characterized Dy low signal intensity in both T1W and T2W scans. Although the aetiology has not been fully elucidated, the MCs scale is a useful tool to characterize morphological changes of the intervertebral disc. From the studies it has emerged that the prevalence of MC varies in the range between 18% and 62% in patients with chronic back pain, with different ratios with respect to asymptomatic patients for each type. In particular, it was observed that MCs Type I and II have a high prevalence in patients with chronic back pain and are infrequent in asymptomatic volunteers. In the study described in the article "Modic changes, possible causes and relation to low back pain" HB Albert et al., Med. Hypotheses, 2008, 70 (2), pages 361-368, was found a strong correlation between MCs values, especially of Type I, and chronic LBP, reflecting the pathologic results of changes in the fissure of the end plate and the subsequent inflammatory response.

In some very recent studies, the changes measured by MCs values have been attributed to a local low-grade infection, due mainly (but not only) to anaerobic bacteria. A first reference to this mechanism of generation of LBP is reported by the cited paper of Albert et al.. Further papers reporting of this possible origin of LBP, are "Does nuclear tissue infected with bacteria following disc herniations lead to Modic changes in the adjacent vertebrae?", H.B. Albert et al., Eur. Spine J. (2013), 22, pages 690-696 and the paper "Low back pain linked to bacterial infection", published in Internet in May 2013 and available at the URL http://palmbeachresearch.com/2013/05/low-back-pain- linked-to-bacterial-infection/.

The prolonged systemic administration of antibiotics has proved to be efficacious in the treatment of LBP associated to MCs of Type 1 , as disclosed for instance in the two latest papers cited above. This method of treatment has though the obvious contraindication of the known side effects of the antibiotic treatments on the whole body, made even worse by its duration in time.

A further possible source of lower back pain is the septic spondylodiscitis caused by one or more bacteria or parasites, including Gram-positive bacteria, Gram-negative bacteria, mycobacteria, anaerobic bacteria and fungi.

It is therefore still felt the need to have available a method for the treatment of lower back pain that does not have the defects of the known methods and is specifically directed to the treatment of possible pathogenic microorganisms in the intervertebral disc, vertebral bodies and structures and adjacent tissues.

Summary of the invention

According to the present invention the problems in the known art are overcome by a composition comprising a reabsorbable carrier, that is a reabsorbable hydrogel, loaded with an antibacterial agent for the use in the treatment of low back pain classified as MCs of Type 1 or 2 or for the treatment of low back pain due to septic spondylodiscitis, as defined in the first of the claims attached here; the composition is locally applied in the lumbar intervertebral disc and / or the adjacent vertebrae (from L1 to S1 ), ligaments, muscles and joints, and the application is carried out by open surgery or by injection or by means of a microsurgical or percutaneous technique.

Further important features of the present composition for the use said above are disclosed in the following detailed description.

Brief description of the drawings

The figure 1 is a histological image obtained by an optical microscope with toluidine blue staining, Acid Fuchsin and Fast-green and 10x magnification, of the material disclosed in the Following Example 4, 12 weeks after implantation.

Detailed description of the invention

The composition of the invention comprises a reabsorbable carrier, which is a reabsorbable hydrogel, loaded with an antibacterial agent. By reabsorbable carrier a material is meant wherein an antibacterial component can be dispersed, and that once entered in the organism can be then degraded or metabolized by it without giving residues that may cause irritations.

One of the preferred carriers according to the present invention is the hydrogel of hyaluronic acid derivatives disclosed in the International patent application N. WO 2010/086421 A1 in the name of the present Applicants. This hydrogel comprises water and a hyaluronic acid derivative (HA) or a salt thereof, in concentration comprised between 1 % and 30% by weight, obtained starting from hyaluronic acid of molecular weight comprised between 50.000 and 3.500.000 Da and binding on this polymer chains of a biodegradable and biocompatible polyester of molecular weight comprised between 3.000 and 900.000 Da, in such an amount that said derivative comprises between 1 and 15 of said chains of polyester per 100 repeating unit of D-glucuronic acid/N-acetyl-D-glucosamine of hyaluronic acid; the composition and the method for the preparation of these derivatives are disclosed in detail from page 7, line 25, to page 10, line 20, of the patent application WO 2010/086421 A1. In this application is disclosed in particular as the polyester, in particular polylactic acid, polyglycolic acid and polycaprolactone, their mixtures and copolymers, are preferably activated by reacting their carboxyl end function with dicycloexylcarbodiimide and then with a product bearing a good leaving group, for instance an imide, preferably N- hydroxysuccinimide (NHS). At the same time HA is converted in an ammonium salt thereof, for instance of cetyltrimethylammonium (CTA) or preferably of tetrabutylammonium (TBA), which is then reacted with the polyester-NHS in the presence of dietylamine (DEA) as catalyst; so the condensation occurs of the carboxyl function of the polyester activated with NHS with the hydroxyl group of the N-acetyl-D- glucosamine units of HA.

The antibacterial agent can be of different type, and can comprise one or more amongst the following:

- antibiotics, as daptomycin, tigecycline, telavancin, chloramphenicol, fusidic acid, bacitracin, rifampicin, ethambutol, streptomycin, isoniazid, glycopeptides (such as teicoplanin and vancomycin), aminoglycosides (such as gentamicin, tobramycin, amikacin and netilmicin), cephalosporins (such as cefazolin, cefoxitin, cefotaxime, cefuroxime and moxalactam), macrolides (such as erythromycin), oxazolidinones (such as linezolid), quinolones and fluoroquinolones, polymyxins, sulphonamides, tetracyclines and penicillins. These agents are used in the compositions of the invention at a concentration ranging between 0.01% and 30% by weight;

- antifungals, selected among those comprised in the families of polyene antifungals, imidazole and triazole antifungals, allylamines, echinocandins and griseofulvine, at a concentration in the composition comprised between 0.01 % and 30% by weight;

- one or more metals selected among silver, possibly in form of formulations containing nanometric silver, zinc, copper, cobalt, titanium and nickel at a concentration in the composition comprised between 0.01 % and 20% by weight;

- bioactive glasses, such as the bioactive glass S53P4, at a concentration in the composition comprised between 0.01 % and 50% by weight;

- N-acetylcysteine and other antibacterial derivatives of cysteine at a concentration in the composition comprised between 0.01% and 20% by weight;

- ascorbic acid and salts thereof, such as sodium, potassium, calcium, magnesium, and zinc, in concentration comprised between 0.01% and 20% by weight.

In the present invention all the weight percentages of individual components are calculated with respect to the total weight of the composition that comprises them.

The composition of the invention can be prepared by mixing its components immediately before surgical application, in particular for antibiotics that can be so maintained at low temperatures until the moment of use. To this aim it is possible to prepare disposable sterile kits of the two components. The mixture of the components just before use also allows a great versatility in the amount of antibacterial component to be added in the composition; this amount can be determined by the surgeon at the time of application in accordance with the degree of the lumbar disorder.

Besides the two base components described above, the composition can comprise further components, for instance a radiopaque compound (such as barium sulphate), in order to allow the radiographic evaluation of the position of the composition and its grade of reabsorption.

It is also subject of the present invention a method of treatment of a patient suffering from lower back pain classified as Modic Changes of Type 1 or 2, or of lower back pain from septic spondylodiscitis, by local surgical or endoscopic application, or by percutaneous injection of the present composition in the form of hydrogel in a lumbar intervertebral disc and / or on adjacent vertebrae, in the ligaments, in the muscles and / or in joints. The composition of the invention is locally applied by surgical methods that can be more or less invasive.

It is possible the application by open surgery, in this case the patient is subjected to a real operation with incision of the skin and of the underlying parts so as to expose the area of application of the composition; this technique is suitable for compositions containing anyone of the above listed bio-reabsorbable carriers.

In the alternative, less invasive methods can be used, with a microsurgical approach, such as with a percutaneous or endoscopic approach; in this case, the composition is preferably prepared by using a fluid material as the bio-resorbable carrier, such as the hydrogel of modified hyaluronic acid previously cited.

In both cases (open surgery or percutaneous/endoscopic approach), during the operations for the application of the composition it is also possible to carry out a surgical cleaning ("debridement") of the intervertebral disc and/or of the tissues and bones adjacent to the area of interest; this can be done using minimally invasive or endoscopic curette, motorized cutter, radiofrequencies and/or repeated washings with a saline solution.

For instance, in a typical percutaneous application, the vertebral disc with the disease is first localized by image intensifier or by other radiological equipment; subsequently cannulas of progressively increasing diameter are introduced and material is taken from the disc and/or from the adjacent bone or joint structures, which is sent for microbiological and possibly histological evaluation; with special tools the curettage of the lesion and the washing of the same is then performed, preferably with saline solution. At this moment the hydrogel added with the antibacterial agent is prepared, and it is introduced by percutaneous route in the previously cleaned lesion.

The following examples are provided to illustrate the present invention without limiting it.

Example 1

Preparation of the resorbable carrier

The hydrogel tested in the following examples is the derivative of hyaluronic acid and of polylactic acid HA-PLA_(B) prepared in freeze-dried form as disclosed in the examples from 1 to 3 of the patent application No. WO 2010/086421 in the name of the Applicants, herein below reported, and then it is converted in hydrogel as disclosed in the example 5 of the same application.

1 g of hyaluronic acid (HA) having molecular weight of 1500 kDa is dissolved in 100 ml of an aqueous solution of HCI having pH of 0.5, and it is left to react for 24 hours at 37°C. The resulting product has an average molecular weight of 230 kDa, determined by size exclusion chromatographic analysis SEC. To this product tetrabutylammonium hydroxide (TBA-OH) is added until a pH of 7 is obtained; the reaction mixture is then subjected to exhaustive dialysis.

The resulting salt HA-TBA is recovered by freeze-drying and characterised by ¹H- NMR analysis (D₂0), which confirms that the exchange with TBA occurred with a yield of 100%. The spectrum ¹H-NMR (D₂0) of HA-TBA shows signals at: δ 0.97 (m,12H, N⁺- (CH₂-CH₂-CH₂-CH₃)4); δ 1.40 (m, 8H, N⁺-(CH₂-CH₂-CH₂-CH₃) ); δ 1.64 (m, 8H, N⁺-(CH₂- CH₂-CH₂-CH₃)4); δ 2.04 (s, 3H, -NH-CO-CH₃); δ 3.82 (m, 8H, N⁺-(CH₂-CH₂-CH₂-CH₃)₄).

A polyester of polylactic acid (PLA) with N-hydroxysuccinimide (NHS) is then prepared by following the synthetic route of the polylactic-coglycolic acid (PLGA) described in the paper "Folate receptor targeted biodegradable polymeric doxorubicin micelles", Yoo H.S. et al., Journal of Controlled Release (2004) 96: 273-283.

2.4 g of PLA having an average molecular weight of 8 kDa are dissolved in 30 ml of dichloromethane. To this solution are first added 0.25 g of the condensation agent dicyclohexylcarbodiimide (DCC), and then 0.14 g of NHS, allowing the reaction to occur at room temperature in 24 hours. After this period of time, the reaction mixture is concentrated by partial evaporation of dichloromethane and the product is precipitated in ethanol and repeatedly washed in the same solvent. The so obtained solid is then filtered and dried under vacuum. A white crystalline solid is obtained, with a yield higher than 80% by weight with respect to the amount of starting PLA. The ¹H-NMR spectrum confirms that the activation of the carboxyl group of PLA with N-hydroxysuccinimide occurred. The derivatization degree, expressed as the ratio between the moles linked of NHS and the moles in a single chain of PLA, is of 90%.

The ¹H-NMR spectrum of the product PLA-NHS (CDCI₃) shows signals at: δ 1.5 e δ 1.6 (d, 3H, 0-CO-CH(CH₃)-OH; δ, 3H, 0-CO-CH(CH₃)-0-; δ 2.80 (m, 4H, OC-CH₂- CH₂-CO-); δ 4.3 e δ 5.2 (m, 1 H, 0-CO-CH(CH₃)-OH; m, 1 H, 0-CO-CH(CH₃)-0-). The tetrabutylammonium salt of hyaluronic acid HA-TBA and the polyester of polylactic acid with N-hydroxysuccinimide PLA-NHS, prepared as described above, were made to react to obtain a hydrogel of hyaluronic acid and polylactic acid HA-PLA as follows.

600 mg of HA-TBA were dissolved in 48 ml of anhydrous DMSO in the presence of 576 μΙ of the catalyst diethylamine (DEA). Then a solution was prepared by dissolving 3.6 g of PLA-NHS in 6 ml of anhydrous DMSO; this solution was then added drop by drop to the first solution of HA-TBA during a period of time of 1 hour; the nominal ratio between the moles of PLA-NHS and the moles of N-acetyl-D- glucosamine units of HA was of 0.5.

After 24 hours under anhydrous atmosphere of Argon at 40°C, the reaction mixture was passed through a Dowex sodium exchange resin for the exchange of TBA with Na⁺. The eluate was then dialyzed against distilled water to remove the DMSO, then frozen and lyophilized. The solid is repeatedly washed with acetone and dried further.

The FT-IR spectrum of the derivative HA-PLA obtained shows a band at 3540 cm^"1 (v_as OH + v_as NH of HA), bands at 1757 cm^"1 (v_as COO of PLA), 1623 cm^"1 (amide I of HA), 1456 cm^"1 (v_as, CH₃ of PLA), 1382 cm^"1 (v_s CH₃ of PLA), 1189 cm^"1 (v_s C-O-C of the ester groups of PLA), 1089 cm^"1 and 1048 cm^'1 (valcohol and ether C-0 of HA).

The ¹H-NMR spectrum of the derivative HA-PLA (DMSO-d₆/D₂0 90:10) shows: δ

1.25 e δ 1.45 (2d, -0-CO-CH(CH₃)-0- di PLA); δ 1.85 (s, 3H, - NH-CO-CH₃ di HA) δ 5.1 ppm (m, -0-CO-CH(CH₃)- di PLA).

The derivatization degree (DD, %) in PLA of the HA-PLA derivative is calculated by evaluating the number of PLA chains from the integrals of the two peaks related to the protons at δ 1.25 and δ 1.45 (attributable to the methyl groups of the PLA chain) and the number of N-acetyl-D-glucosamine units present in the HA from the integral related to the protons at δ 1.85 attributable to the group -NHCOCH₃, and then applying the formula: DD = (N. moles PLA/N. moles glucosamine unit) x 100. The degree of derivatization calculated for the HA-PLA_(B) derivative prepared as disclosed above, was 3.5.

Example 2 Preparation of the composition of the invention by association of the reabsorbable carrier with bioglass, and control of the variation of the pH of the association

For this test a bioactive glass of BonAlive Biomaterials Ltd (S53P4) is used. This bioglass is the form of granules with size < 45 μιτι. The reabsorbable carrier used is the hydrogel prepared as disclosed in Example 5 of WO 2010/086421. The water used in the following is water for injection.

At the beginning it is measured the pH of the suspension, which is obtained by mixing 250 mg of bioglass, with 1 ml of water. Immediately after the mixing a gelatinous suspension is formed that rapidly separates. The pH value measured immediately after the mixing of bioglass with water is of 11.6.

For the mixing of the bioglass with the absorbable carrier the procedure is as follows: 60 mg of resorbable carrier in sterile freeze-dried form in a syringe, prepared as described above in Example 1 , is hydrated with 1 ml of water. Once hydration is complete, 250 mg of bioglass S53P4 are added. The pH value of the sample mixed with the bioglass is measured after 1 , 2, 4, 6, 24, 48, 72 and 96 hours.

The appearance of the mixture is as a gelatinous mass that does not change during the 96 hours of observation. The composition just becomes slightly more fluid after 24 hours. The pH values measured are the following:

- pH measured immediately after mixing is of 10.3

- pH measured after 1 hour is of 9.9

- pH measured after 2 hours is of 9.9

- pH measured after 4 hours is of 9.6

- pH measured after 6 hours is of 9.6

- pH measured after 24 hours is of 9.3

- pH measured after 48 hours is of 9.1

- pH measured after 72 hours is of 9.1

- pH measured after 96 hours is of 9.0.

It is therefore observed a substantial maintenance of the pH value of the composition of the hydrogel with bioactive glass at values above 9, at which a nonspecific antibacterial activity is expressed, that is typical of the bio-glass. Example 3

Evaluation of the antibacterial activity

It was evaluated the antibacterial activity of the reabsorbable carrier prepared as described above in Example 1 , in association with antibiotics as the gentamicin and the vancomycin, and with the N-acetylcysteine (NAC) against Staphylococcus epidermidis and Staphylococcus aureus. The MIC (Minimal Inhibitory Concentration) was evaluated by means of a method of broth microdilution according to EUCAST guidelines (European Committee on Antimicrobial Susceptibility Testing).

A standardized inoculum of each bacterial isolate was inoculated in a 96-well plate containing serial dilutions of the aforementioned substances. After incubation for 18 hours at 37°C in a suitable atmosphere, the lowest concentration of agents capable of inhibiting the visible growth of the bacteria was defined as MIC. Three different syringes containing the reabsorbable carrier in the form of hydrogel were used, each of them contained one of the three antibacterial products tested, prepared as follows:

60 mg of reabsorbable carrier in freeze-dried form prepared as described above in Example 1 , have been reconstituted with 1 ml of water for injections containing the antibacterial product under evaluation at the following concentrations:

- Gentamicin: 256 pg / ml

- Vancomycin: 256 pg / ml

- N-acetylcysteine: 100 mg / ml

The obtained results are summarized in the Table 1 below, where it can be observed how the hydrogel reconstituted with gentamicin, vancomycin and NAC has a MIC lower than the antibacterial substances tested alone and, accordingly, a higher antibacterial activity against S. aureus and S. epidermidis with respect to the test of each agent tested alone, with the only exception of hydrogel + vancomycin in S. aureus, which maintains anyway the same MIC of the vancomycin alone. Based on these results, the conclusion is that the interaction between the hydrogel and the three antibacterial substances tested in the compositions of the invention brings to an amplification of the single antibacterial activity. Table 1

Example 4

Control of the rheological stability of the reabsorbable carrier in the form of hydrogel after association with the antibiotic vancomycin

In order to check the stability of the compositions of the invention it was evaluated the variability in the viscosity of the reabsorbable carrier in the form of hydrogel after association with an antibiotic, the vancomycin, by carrying out measurements of viscosity of the composition at the time 0, 4 hours, 8 hours and 24 hours, both at room temperature (<25°C) and at temperature of 2-8°C (refrigerator).

In particular 120 mg of the freeze-dried reabsorbable carrier prepared as described above in Example 1 have been reconstituted with 2 ml of the antibiotic vancomycin at 2% in aqueous solution. The test has been carried out on two batches 1 and 2 of sterile reabsorbable carrier in syringe, prepared according to the same procedure of Example 1 but in different times.

The viscosity of the two hydrogels obtained as batch 1 and batch 2 is tested at the following times: Time 0 (immediately after hydration with vancomycin)

Time 4 hours respectively at room temperature and at temperature of 2-

Time 8 hours respectively at room temperature and at temperature of 2-

Time 24 hours respectively at room temperature and at temperature of

The results are disclosed in the following Table 2:

Table 2

Example 5

Evaluation of the local effects after implantation of the resorbable hydrogel of the invention in an in vivo study

The evaluation of the local effects to the implantation of the present hydrogel was performed by strictly following the current legislation on animal experimentation (Leg. No. 1 16/92) and the rules of UNI EN ISO 10993-2, 2009, at the laboratory of Preclinical and Surgical Studies of the Rizzoli Orthopaedic Institute in Bologna (Italy).

The test was carried out in a rabbit animal model by surgical implant of the composition hydrogel + vancomycin prepared as described above, and subsequent evaluation of the local effects after some time from the implantation. The results of this evaluation test have shown that the compositions of the invention in the form of hydrogel do not cause, under the experimental conditions and during the time considered, any inflammatory reactions to the bones and/or degenerative processes of the bone tissue. Furthermore, different histomorphometric parameters were evaluated, in particular Periosteal Perimeter, Endocortical Perimeter, Medullary Area, Cortical Area, Thickness of the cortical bone, in the animals injected with the hydrogel of the invention, without detecting any significant differences with respect to the animals treated with an hydrogel acting as positive control, consisting of a commercial product of hyaluronic acid sodium salt having proved efficacy in the reparation of the bone tissue, i.e. the product HYALGAN^® manufactured by Fidia Farmaceutici (Abano Terme, Padua, Italy) in the form of injectable solution for intra-articular use.

The histological and histomorphometric investigations performed at 12 weeks from the implantation of the composition of the invention and of the control hydrogel have demonstrated the absence of structural and morphometric alterations in the bone tissue. The qualitative assessment has detected the presence of residues of both the composition of the invention and of the control material that are still present at the implant site and the formation of connective tissue with areas of new bone formation.

Figure 1 shows an histological image of the optical microscope with toluidine blue, fuchsin acid and Fast-green staining, and a 10x magnification, for a sample of tissue taken from the animal 12 weeks after the implantation of the hydrogel of the invention. In the image of Figure 1 , the arrow indicates the presence of connective tissue surrounding the residual material (M) with initial processes of new bone formation (areas coloured in green).

Claims

1. A composition comprising a resorbable carrier loaded with at least an antibacterial agent for the use in the treatment of lower back pain classified as Modic Changes of Type 1 or 2, or in the treatment of lower back pain from septic spondylodiscitis, by local surgical or endoscopic application, or by percutaneous injection, of said composition in a lumbar intervertebral disc and / or on adjacent vertebrae, in ligaments, in muscles and / or in joints of a subject suffering from said lower back pain, wherein said resorbable carrier is a resorbable hydrogel.

2. The composition according to claim 1 , wherein said resorbable hydrogel is an hydrogel comprising water and a hyaluronic acid derivative or a salt thereof in concentration comprised between 1% and 30% by weight, wherein said hyaluronic acid derivative is hyaluronic acid or a salt thereof having molecular weight comprised between 50.000 and 3.500.000 Da on which chains of a biodegradable and biocompatible polyester having molecular weight comprised between 3.000 and 900.000 Da are linked, in an amount such that said derivative comprises between 1 and 5 of said polyester chains per 100 repeating units of D-glucuronic acid/N-acetyl- D-glucosamine of the hyaluronic acid.

3. The composition according to claim 1 , comprising at least an antibacterial agent selected among:

- one or more antibiotics in concentration comprised between 0.01% and 30% by weight;

- one or more antifungals in concentration comprised between 0.01 % and 30% by weight;

- one or more metals in concentration comprised between 0.01 % and 20% by weight;

- one or more bioactive glasses in concentration comprised between 0.01 % and 50% by weight; and

- N-acetyl-cysteine and further antibacterial cysteine derivatives in concentration comprised between 0.01% and 20% by weight; and

ascorbic acid or salts thereof in concentration comprised between 0.01 % and

20% by weight, all the above said weight percentages being calculated with respect to the total weight of the composition.

4. The composition according to claim 3, wherein:

- said one or more antibiotics are selected from daptomycin, tigecycline, telavancin, chloramphenicol, fusidic acid, bacitracin, rifampicin, ethambutol, streptomycin, isoniazid, glycopeptides, aminoglycosides, cephalosporins, macrolides, oxazolidinones, quinolones and fluoroquinolones, polymyxins, sulphonamides, tetracyclines and penicillins;

- said one or more antifungals are selected from polyene antifungals, imidazole and triazole antifungals, allylamines, echinocandins and griseofulvine;

- said one or more metals are selected from silver, zinc, copper, cobalt, titanium and nickel;

- said bioactive glass is the glass S53P4,

- said salts of ascorbic acid are selected from the salts of sodium, potassium, calcium, magnesium and zinc.

5. The composition according to claim 4, wherein said glycopeptides are selected from teicoplanin and vancomycin, said aminoglycosides are selected from gentamicin, tobramycin, amikacin and netilmicin, said cephalosporins are selected from cefazolin, cefoxitin, cefotaxime, cefuroxime and moxaiactam, said macrolide is erythromycin and said oxazolidinone is linezolid.

6. The composition according to any of the preceding claims, further comprising a radiopaque compound.

7. The composition according to claim 6, wherein said radiopaque compound is barium sulphate.

8. The composition according to any of the preceding claims, which is prepared by mixing said antibacterial agent in water and said resorbable carrier freeze-dried, separately packed in a disposable sterile kit until use.