CN105682640A

CN105682640A - A bioreabsorbable composition containing antibacterial agents for the treatment of lower back pain

Info

Publication number: CN105682640A
Application number: CN201480057751.5A
Authority: CN
Inventors: 达维德·科瑞玛斯蔻理; 卡洛·卢卡·罗曼诺; 恩佐·米尼; 埃德加多·科瑞玛斯蔻理
Original assignee: Novagenit Srl; Mero Srl
Current assignee: Novagenit Srl; Mero Srl
Priority date: 2013-10-21
Filing date: 2014-10-20
Publication date: 2016-06-15
Also published as: JP2016533354A; IL245164A0; ITMI20131755A1; AU2014338592A1; CA2925690A1; WO2015059623A1

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

For treating the compositions of the biological absorbable containing antibacterial of back pain

Technical field

The present invention relates to the biological absorbable compositions of the carrier as bioactive compound for treating the purposes of back pain.

Background technology

Back pain be visit motor skill with orthopaedic treatment and decline act primarily as because of, and the millions of patient of each country impact; Back pain is also referred to as english terminology " lowbackpain " or its abbreviation LBP at medical domain, and the remainder in description can adopt LBP.

Medical research shows that the population of about 80% can suffer from LBP in life. Majority being suffered to the people of LBP, pain is likely to multiple relapse, and chronic low back pain is the key constraints that age young adult below 45 years old is movable. The Epidemiological study of the U.S. has been discovered that the LBP annual loading of about 5-20%. This disease disturbs the daily life of patient, reduces their quality of life. The cost relevant with this disease is huge, and this cost not only includes direct medical expense and also includes indirectly expense, such as the work efficiency reduced; Back pain is not only health problem or society-economic problems.

Back pain is usually the result of degeneration spinal disease, and its intensity is usually by diagnostic imaging, and is estimated especially by nuclear magnetic resonance; This method can highlight the degeneration in the bone of below vertebral and cartilage.

It is typically referenced to the empirical parameter degree to this disease measure, this empirical parameter is to deliver some papers at MTModic and his office worker, particularly article " Degenerativediskdisease:assessmentofchangesinvertebralbo dymarrowwithMRimaging; " Modic et al., Radiology1988; 166 (1, Part I), 193-199 page " open after adopted. According to the method, according to the magnetic resonance signal deviation compared to three levels of normal condition, it is called MC (coming from " Modic change "), the change of vertebra is estimated. I type, also referred to as inflammation phase, is that the inflammation by fibrous tissue is determined and with the low signal intensity of T1W scanning and the high signal intensity of T2W scanning for feature. II type, is called the fat stage, is pile up for feature with adipose cell height in vertebral and region below, and its be the high signal intensity in being scanned by T1W and the equivalent signal in T2W scanning or in-Gao signal be determined. Finally, III type, also referred to as the osteosclerosis stage, is be low signal intensity for feature in T1W scanning and T2W scanning. Although but without illustrating the cause of disease completely, but MC parameter is the instrument being highly useful of the morphological change characteristics for describing intervertebral disc. Research finds, in the patient suffering from chronic back pain, the sickness rate of MC changes in different proportions relative to the asymptomatic patient of each type in the scope between 18% and 62%. Especially, it was observed that I type MC and II type MC has high incidence and relatively rare in asymptomatic volunteer in the patient suffer from chronic back pain. At article " Modicchanges; possiblecausesandrelationtolowbackpain " HBAlbert et al., Med.Hypotheses, 2008,70 (2), research described in 361-368 page finds dependency very strong between MC value (especially I type MC) and chronic LBP, it was shown that soleplate crack neutralizes the pathology results of change in inflammatory reaction subsequently.

In some nearest researchs, by the change measured by MC value owing to the rudimentary infection in local caused by anaerobic bacteria of the main (but not limited to), first time mentions that this mechanism producing LBP is reported by the paper that Albert et al. is cited. Report this LBP be likely to origin other paper for " Doesnucleartissueinfectedwithbacteriafollowingdischernia tionsleadtoModicchangesintheadjacentvertebrae? " H.B.Albert et al., Eur.SpineJ. (2013), 22,690-696 page and in May, 2013 deliver on the internet and at URLhttp://palmbeachresearch.com/2013/05/low-back-pain-linked-to-bacterial-infection/Obtainable paper " Lowbackpainlinkedtobacterialinfection ".

As such as in the above-mentioned paper two sections nearest quoted disclosed, it has already been proven that long term systemic administration antibiotic is effective in the treatment of the LBP relevant with I type MC. But this Therapeutic Method has the side effect of the known systemic antibiotics treatment worse along with the persistent period of substantially taboo.

Other of back pain is likely to the source suppurative discitis for being caused by one or more antibacterials or parasite, and these one or more antibacterials or parasite comprise gram positive bacteria, gram negative bacteria, mycobacterium, anaerobic bacteria and fungus.

Therefore need nonetheless remain for the available method having for treating back pain, the method does not have the shortcoming of known method and specifically for the possible pathogenic microorganism in treatment intervertebral disc, vertebral body, wimble structure and adjacent tissue.

Summary of the invention

According to the present invention, it is known that the problem in technology by as defined in first claim of appended claims, for treat the back pain classifying as 1 type MC or 2 type MC or for that treat the back pain that caused by suppurative discitis, to comprise the absorbed carrier (i.e. absorbable hydrogel) being loaded with antibacterial compositions overcome; Said composition is applied topically to lumbar intervertebral disc and/or contiguous vertebra (from L1 to S1), ligament, muscle and/or joint, and this application is by open surgery or by injecting or being undertaken by microsurgery or percutaneous technique.

Other key character for the compositions of the present invention of such use is open in the following detailed description.

Accompanying drawing explanation

The material that Fig. 1 is disclosed in example 4 below is used toluidine blue, acid fuchsin after implanting 12 weeks and quickly turns the histology picture that green dyeing is obtained by optical microscope under 10 x magnifications.

Detailed description of the invention

The compositions of the present invention comprises the absorbed carrier being loaded with antibacterial, and it is absorbable hydrogel. The antibacterial components that absorbable carrier means can disperse in the material and just can be degraded by organism or metabolism is fallen and do not produced to cause the residue of stimulation once enter organism.

One of preferred carrier according to the present invention be with the international patent application WO2010/086421A1 of the name of the applicant disclosed in the hydrogel of derivatives of hyaluronic acids. this hydrogel comprises water and concentration is contained between 1 weight % and 30 weight % derivatives of hyaluronic acids (HA) or its salt, this derivatives of hyaluronic acids (HA) or its salt are that the hyaluronic acid being contained between 50.000 and 3.500.000 dalton from molecular weight initiates and is attached to the polymer chain of the polyester that molecular weight is contained in the biodegradable between 3.000 and 900.000 dalton and bio-compatible and obtains, described hyaluronic acid or its salt have the amount making every 100 hyaluronic D-glucuronic acid/N-acetyl group-D-glucosamine repetitives of described derivant include 1 to 15 described polyester chain, the 7th page the 25th of patent application WO2010/086421A1 is walked to the 10th page of the 20th row and disclose in detail said composition and the method for preparing these derivants. in this application, particularly disclose polyester, particularly polylactic acid, polyglycolic acid and polycaprolactone, their mixture and copolymer preferably by make their c-terminus functional group react with dicyclohexylcarbodiimide and then with there is good leaving group (such as acid imide, preferred N-hydroxy-succinamide (NHS)) product react and activate. simultaneously HA is converted into its ammonium salt, the ammonium salt of the ammonium salt of such as cetyltrimethyl ammonium (CTA) or preferably tetrabutylammonium (TBA), then reacts with polyester-NHS under the existence as the diethylamine (DEA) of catalyst, then with the hydroxyl generation condensation of the carboxyl functional group of the polyester of NHS activation with the N-acetyl group-D-glucosamine unit of HA.

Antibacterial can have different types, and can include one of the following or multiple:

-antibiotic, such as daptomycin, tigecycline, Te Lawan star, chloromycetin, fusidic acid, bacitracin, rifampicin, ethambutol, streptomycin, isoniazid, glycopeptide class (such as teicoplanin and vancomycin), aminoglycoside is (such as, gentamycin, tobramycin, amikacin and netilmicin), cephalosporins is (such as cefazolin sodium, cefoxitin, cefotaxime, cefuroxime and latamoxef), Macrolide (such as erythromycin), (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides (such as Linezolid), quinolones and fluoroquinolones, polymyxin, sulfonamides, Tetracyclines and penicillin. these reagent are used in the compositions of the present invention with the concentration in scope between 0.01 weight % and 30 weight %,

-concentration in the composition is between 0.01 weight % and 30 weight %, selected from including those antimycotics in the family of polyene antifungal class, imidazoles and triazole antimycotic, propylamine, echinocandin class and griseofulvin;

-concentration in the composition one or more metals between 0.01 weight % and 20 weight %, in silver (can with the form of the preparation containing nanometer-level silver), zinc, copper, cobalt, titanium and nickel;

-the concentration in the composition bioactivity glass between 0.01 weight % and 50 weight %, such as S53P4 bioactivity glass;

Other antibiotic derivative of-concentration in the composition N-acetylcystein between 0.01 weight % and 20 weight % and cysteine;

-concentration ascorbic acid between 0.01 weight % and 20 weight % and its esters, such as sodium salt, potassium salt, calcium salt, magnesium salt and zinc salt.

In the present invention, all wt percent of each component is to calculate relative to the gross weight of the compositions comprising them.

Before surgery is applied, it is possible to mix the compositions preparing the present invention by its component at once being carried out, especially for can be maintained up at low temperatures and face with the antibiont in moment. For this purpose, it is possible to the disposable sterilized test kit of two kinds of components of preparation. Component carries out mixing the multiple change of the amount of the antibacterial components also allowed in compositions to be added before use, and this amount can be determined according to the degree of lumbar disc disease when application by surgeon.

Except above two solvent, compositions can comprise other component, such as radiopaque compound (such as barium sulfate), to allow position and its resorbent degree of compositions are carried out imaging evaluation.

The present invention also aims to a kind of application or endoscopic applications or treated the patient suffering from the back pain classifying as 1 type Modic change or 2 type Modic change or the back pain caused by therapeutic purulence discitis by the compositions of the present invention of percutaneous injection form of hydrogels in lumbar intervertebral disc and/or contiguous vertebra, ligament, muscle and/or joint by segment surgery.

By the compositions of the topical application present invention can be carried out for more or less invasive surgical method.

Can be applied by open surgery, in this case, patient be performed the operation really, cut skin and below portion to expose the region of set of applications compound; This technology is suitable for the compositions containing any above-mentioned biological absorbable carrier listed.

It is alternatively possible to adopt, there is microsurgery approach, as having the less invasive method of cutaneous routes or endoscopic approach; In this case it is preferable to by adopting fluent material to prepare compositions as biological absorbable carrier (hydrogel of modified hyaluronic acid as referenced before).

In both cases (open surgery or percutaneous/scope mirror approach), at the intra-operative of set of applications compound, it is also possible to tissue and bone to intervertebral disc and/or contiguous interested region carry out surgery cleaning (" debridement "); It can use Wicresoft or endoscope's curet, electric knives, radio frequency and/or carry out cyclic washing with normal saline and complete.

Such as, in typical percutaneous is applied, first pass through image amplifier or by other radiological installation, ill intervertebral disc positioned; What be subsequently introduced that diameter is gradually increased intubates and draws materials from intervertebral disc and/or contiguous bone and articulation structure, by its censorship microorganism and possible Histological assessment; Strike off focus with specific purpose tool and preferably wash with normal saline. Now prepare the hydrogel being added with antibacterial, and be introduced in the focus through cleaning in advance by cutaneous routes.

There is provided the example below in order to illustrate that the present invention is not limited.

Example 1

Preparation can absorb carrier

The hydrogel tested in the following example be hereinafter reported such as the derivatives of hyaluronic acids prepared with cryodesiccated form disclosed in 1 to 3 example of the patent application WO2010/086421 of the name with applicant and polylactic acid derivative HA-PLA_(B), and then it is translated into hydrogel as disclosed in the example 5 of same application.

1g hyaluronic acid (HA) that molecular weight is 1500kDa is dissolved in the aqueous solution of the HCl that pH is 5.0 of 100ml, then makes it react 24 hours at 37 DEG C. The product formed has the mean molecule quantity being analyzed the SEC 230kDa determined by size exclusion chromatography (SEC). TBAH (TBA-OH) is added until pH is 7 in this product; Then reactant mixture is thoroughly dialysed.

Reclaimed the salt HA-TBA formed by lyophilization and pass through¹H-NMR analyzes (D₂O) the salt HA-TBA formed being characterized, it confirms that the exchange of generation and TBA and productivity are 100%. HA-TBA's¹H-NMR(D₂O) spectrum display signals below: δ 0.97 (m, 12H, N⁺-(CH₂-CH₂-CH₂-CH₃)₄); δ 1.40 (m, 8H, N⁺-(CH₂-CH₂-CH₂-CH₃)₄); 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)。

Then according to paper " Folatereceptortargetedbiodegradablepolymericdoxorubicinm icelles ", YooH.S. et al., the synthetic route of the polylactic acid described in JournalofControlledRelease (2004) 96:273-283-common glycolic (PLGA) prepares the polyester of polylactic acid (PLA) and N-hydroxy-succinamide.

The 2.4gPLA that mean molecule quantity is 8kDa is dissolved in 30ml dichloromethane. First in this solution, add dicyclohexylcarbodiimide (DCC) condensing agent of 0.25g, be subsequently adding the NHS of 0.14g, make reaction at room temperature occur in 24 hours. After this period of time, undertaken concentrating and in ethanol and to product, product precipitation being carried out cyclic washing with identical solvent by reactant mixture by part evaporation dichloromethane. Then the solid thus obtained it is filtered under vacuo and dries. Obtaining white crystalline solid, the productivity amount relative to initial PLA is more than 80 weight %.¹H-NMR spectra there occurs the N-hydroxy-succinamide activation to the carboxyl of PLA. It is 90% that derivative degree (is expressed as the ratio between NHS molal quantity and the molal quantity of independent PLA chain connected).

Product PLA-NHS (CDCl₃)¹H-NMR spectrum display signals below: δ 1.5e δ 1.6 (d, 3H, O-CO-CH (CH₃)-OH; δ, 3H, O-CO-CH (CH₃)-O-; δ 2.80 (m, 4H, OC-CH₂-CH₂-CO-); δ 4.3e δ 5.2 (m, 1H, O-CO-CH (CH₃)-OH; M, 1H, O-CO-CH (CH₃)-O-)。

The polyester PLA-NHS making hyaluronic 4-butyl ammonium HA-TBA prepared as described above and polylactic acid and N-hydroxy-succinamide is obtained by reacting the hydrogel HA-PLA of following hyaluronic acid and polylactic acid.

Under the existence of diethylamine (DEA) catalyst of 576 μ l, the HA-TBA of 600mg is dissolved in the anhydrous DMSO of 48ml. Then pass through to be dissolved in the anhydrous DMSO of 6ml the PLA-NHS of 3.6g and prepare solution; Then this dropwise is added in first solution of HA-TBA within the time of 1 hour; Nominal ratio between the molal quantity of the molal quantity of PLA-NHS and the N-acetyl group-D-glucosamine unit of HA is 0.5.

At 40 DEG C under dry argon atmosphere after 24 hours, reactant mixture is made to pass through Dowex sodium ion exchange resin with by TBA and Na⁺Swap. Then undertaken dialysing to remove DMSO by eluent distilled water, then carry out freezing and lyophilizing. A step of being gone forward side by side by solid acetone cyclic washing is dried.

The FT-IR spectrum of the HA-PLA derivant obtained is at 3540cm^-1(the ν of HA_asOH+ν_asNH) place's display bands of a spectrum, at 1757cm^-1(the ν of PLA_asCOO), 1623cm^-1(the amide I of HA), 1456cm^-1(ν_as, the CH of PLA₃), 1382cm^-1(ν_sThe CH of PLA₃), 1189cm^-1(ν_sThe C-O-C of the ester group of PLA), 1089cm^-1And 1048cm^-1(alcohol of HA and the C-O of ether) place display bands of a spectrum.

HA-PLA derivant¹H-NMR spectrum (DMSO-d₆/D₂O90:10) display: δ 1.25e δ 1.45 (2d ,-O-CO-CH (CH₃)-O-two PLA); δ 1.85 (s, 3H ,-NH-CO-CH₃Two HA); δ 5.1ppm (m ,-O-CO-CH (CH₃)-two PLA).

By by the integration at two peaks relevant to the proton at δ 1.25 and δ 1.45 (being attributable to the methyl group of PLA chain) number of PLA chain is estimated and by be attributable to-NHCOCH₃N-acetyl group-D-glucosamine the unit being present in HA is estimated by the integration that the proton at δ 1.85 place of group is relevant; and then adopting following formula: the derivative degree (DD, %) in the PLA of DD=(molal quantity of the molal quantity/glucosamine unit of PLA) × 100 pairs of HA-PLA derivants is calculated. Calculate by prepared HA-PLA disclosed above_(B)The derivative degree of derivant is 3.5.

Example 2

By being combined carrier can be absorbed with bio-vitric and the compositions of the present invention is prepared in the change of pH that controls to combine.

For this test, have employed the bioactivity glass of BonAliveBiomaterialsLtd (S53P4). This bio-vitric is the particle form of size < 45 μm. The absorbed carrier adopted is the hydrogel according to preparation disclosed in the example 5 of WO2010/086421. The water hereinafter adopted is water for injection.

First, the pH of the suspension by being obtained by mixing by the water of the bio-vitric of 250mg Yu 1ml is measured. Forming gelatinous suspension after mixing immediately, this gelatinous suspension separates rapidly. The pH value measured immediately after bio-vitric and water are carried out mixture is 11.6.

For bio-vitric is mixed with absorbing carrier, program is as follows: the absorbed carrier of sterile cryo dried forms in the 60mg syringe prepared described in above example 1 and the water of 1ml are carried out aquation, after aquation completes, add 250mg bio-vitric S53P4. 1, after 2,4,6,24,48,72 and 96 hours, the pH of the sample mixed with bio-vitric is measured.

The outward appearance of mixture is the spawn not having to change in the observation process of 96 hours. Compositions only slightly becomes more smooth after 24 hours. The pH value measured is as follows:

The pH measured immediately after-mixing is 10.3

The pH measured after-1 hour is 9.9

The pH measured after-2 hours is 9.9

The pH measured after-4 hours is 9.6

The pH measured after-6 hours is 9.6

The pH measured after-24 hours is 9.3

The pH measured after-48 hours is 9.1

The pH measured after-72 hours is 9.1

The pH measured after-96 hours is 9.0.

Therefore observing that the pH value of the compositions of hydrogel and bioactivity glass maintains essentially in the value of more than 9, show non-specific antimicrobial activity at this value place, it is the typical feature of bio-vitric.

Example 3

Assessment antibacterial activity

The antibacterial activity of staphylococcus epidermidis and staphylococcus aureus is estimated by absorbed carrier in combination antibiotic (such as gentamycin and vancomycin) and associating N-acetylcystein (NAC) to preparation described in above example 1. By MIC (minimal inhibitory concentration) being evaluated according to the broth microdilution antifungal susceptibility test of EUCAST (European commission's drug sensitive experiment, EuropeanCommitteeonAntimicrobialSusceptibilityTesting) guide.

The standardization inoculum of each bacteria distribution thing is seeded in 96 orifice plates of the above-mentioned substance containing serial dilution. After hatching 18 hours in suitable atmosphere at 37 DEG C, the least concentration that can suppress the reagent of the visible growth of antibacterial is defined as MIC. Adopting the syringe three kinds different of absorbed carrier containing form of hydrogels, each of which contains one of three kinds of antimicrobial products testing according to the carrying out of following preparation:

Being restored by the absorbed carrier according to freeze-dried prepared in above-described embodiment 1 of 60mg with 1ml water for injection, described water for injection contains the antimicrobial product being estimated under following concentration:

-gentamycin: 256 μ g/ml

-vancomycin: 256 μ g/ml

-N-acetylcystein: 100mg/ml

The result obtained is summed up in table 1 below, wherein observe how the hydrogel restored with gentamycin, vancomycin and NAC has the MIC lower than the antibiotic substance of individually test and therefore have the high antibacterial activity to staphylococcus aureus and staphylococcus epidermidis relative to the test of individually each reagent of test, hydrogel+vancomycin in staphylococcus aureus except only, in any case it maintains the identical MIC of independent vancomycin. Based on these results, conclusion is the amplification that the interaction between the three kinds of antibiotic substance tested in the compositions of hydrogel and the present invention causes independent antibacterial activity.

Table 1

Example 4

After combining with antibiotic vancomycin, the rheological stability of the absorbed carrier of form of hydrogels is controlled

In order to check the stability of the compositions of the present invention, by room temperature (< 25 DEG C) and at the temperature of 2-8 DEG C (refrigerator) 0,4 hours, 8 hours and 24 hours places, the viscosity of compositions is measured the change to the viscosity of the absorbed carrier of the form of hydrogels after combining with antibiotic vancomycin and is estimated.

Especially, with 2ml be in aqueous 2% antibiotic vancomycin will restore according to the cryodesiccated carrier element that absorbs of 120mg prepared in above-mentioned example 1. To the identical process according to example 1, still within the different time, the aseptic carrier that absorbs in the syringe of 1 and 2 two batch of preparation is tested.

In the following time, the viscosity of batch 1 and batch 2 two batches of hydrogels obtained is tested:

The √ time is 0 (at once carrying out with after vancomycin aquation)

√ locates the time of 4 hours in room temperature with at the temperature of 2-8 DEG C respectively

√ locates the time of 8 hours in room temperature with at the temperature of 2-8 DEG C respectively

√ locates the time of 24 hours in room temperature with at the temperature of 2-8 DEG C respectively

Result is disclosed in table 2 below:

Table 2

Example 5

In vivo research in, to implant the present invention absorbed hydrogel after local effect be estimated.

By in strict accordance with at present to zooperal legislation (the 116/92nd article regulation) and UNIENISO10993-2, the regulation of 2009 carries out the assessment to the local effect implanting subject hydrogel with surgery research laboratory before the clinic of Li Zuoli (Rizzoli) the orthopaedics institute of Bologna (Italy).

Rabbit animal model is tested by compositions hydrogel+vancomycin that Srgery grafting is prepared as described above, and subsequently the local effect after implanting some times is estimated. This evaluation test it is shown that the compositions of the present invention of form of hydrogels under experimental conditions and does not cause the degenerative process to skeleton inflammatory reaction and/or osseous tissue within the time considered. In addition, to different tissue morphology parameters, particularly inject the thickness of the periosteum girth of the animal of the hydrogel of the present invention, inner cortex girth, medullary substance district, cortical areas, cortical bone, assess, be not detected by relative to by the commercial product of the hyaluroni in bone tissue restoration with the curative effect having been demonstrated (namely by FidiaFarmaceutici (A Banuo Tai Ermei, Padua, Italy) the Injectable solution form used for intraarticular that producesProduct) any significant difference of animal of processing of the hydrogel as positive control that forms.

The histology and the tissue morphology that carry out when implanting the compositions of the present invention and implanting the hydrogel 12 weeks of comparison are studied and are shown do not have structure and morphologic change in osseous tissue. Qualitative evaluation has detected that the residue of the compositions that there is the present invention and the residue of control material, and they are also present in the connective tissue with new bone formation region of implantation site and formation.

Fig. 1 illustrates to take from and implants the hydrogel tissue samples toluidine blue of animal after 12 weeks of the present invention, acid fuchsin and quickly turn green dyeing and amplify the histology picture of optical microscope of 10 times. In the image of Fig. 1, arrow shows that the initial procedure (green coloring region) along with new bone formation exists the knot hoof tissue around retained material (M).

Claims

1. a compositions, comprise the absorbed carrier being at least loaded with antibacterial, described compositions is for applying by regional surgery or endoscopic applications or treat, by compositions described in percutaneous injection in suffering from the lumbar intervertebral disc of experimenter of back pain and/or contiguous vertebra, ligament, muscle and/or joint, 1 type classified as or described back pain that 2 type Modic change or the described back pain that treatment is caused by suppurative discitis, and the wherein said carrier that absorbs is absorbable hydrogel.

2. compositions according to claim 1, wherein said absorbable hydrogel is the hydrogel including water and the concentration derivatives of hyaluronic acids between 1 weight % and 30 weight % or its salt, wherein said derivatives of hyaluronic acids is that molecular weight is contained in the hyaluronic acid between 50.000 and 3.500.000 dalton or its salt, it is connected to the chain that molecular weight is contained in the polyester of the biodegradable between 3.000 and 900.000 dalton and bio-compatible, described hyaluronic acid or its salt have the amount making every 100 hyaluronic D-glucuronic acid/N-acetyl group-D-glucosamine repetitives of described derivant include 1 to 15 described polyester chain.

3. compositions according to claim 1, including at least selected from following antibacterial:

-concentration is contained in one or more antibiotic between 0.01 weight % and 30 weight %;

-concentration is contained in one or more antimycotics between 0.01 weight % and 30 weight %;

-concentration is contained in one or more metals between 0.01 weight % and 20 weight %;

-concentration is contained in one or more bioactivity glass between 0.01 weight % and 50 weight %; With

-concentration is contained in the N-acetyl-cysteine between 0.01 weight % and 20 weight % and other antibacterial cysteine derivative; With

-concentration is contained in the ascorbic acid between 0.01 weight % and 20 weight % or its esters,

All above-mentioned percetages by weight are the total weight relative to described compositions.

4. compositions according to claim 3, wherein

-one or more antibiotic described are selected from daptomycin, tigecycline, Te Lawan star, chloromycetin, fusidic acid, bacitracin, rifampicin, ethambutol, streptomycin, isoniazid, glycopeptide class, aminoglycoside, cephalosporins, Macrolide, (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides, quinolones and fluoroquinolones, polymyxins, sulfonamides, Tetracyclines and penicillins;

-one or more antimycotics described are selected from polyene antifungal class, imidazoles and triazole antimycotic, propylamine, echinocandin class and griseofulvin;

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

-described bioactivity glass is S53P4 glass,

The salt of-described ascorbic acid is selected from sodium salt, potassium salt, calcium salt, magnesium salt and zinc salt.

5. compositions according to claim 4, wherein said glycopeptide class is selected from teicoplanin and vancomycin, described aminoglycoside is selected from gentamycin, tobramycin, amikacin and netilmicin, described cephalosporins is selected from cefazolin, cefoxitin, cefotaxime, cefuroxime and latamoxef, described macrolide is erythromycin, and described (oxazolidinon-5-yl-methyl)-2-thiophene-carboxamides is Linezolid.

6., according to compositions in any one of the preceding claims wherein, also include radiopaque compound.

7. compositions according to claim 6, wherein said radiopaque compound is barium sulfate.

8., according to compositions in any one of the preceding claims wherein, face the used time by described carrier can be absorbed carry out mixing preparing by the described antibacterial in the water being packaged individually in disposable sterilized test kit with through cryodesiccated.