EP4719513A1 - Medical devices comprising antibiotics - Google Patents

Abstract

The invention relates to medical devices coated with an antibiotic, wherein the antibiotic is bound to a catechol comprising coating on the device via a pH sensitive boric acid bond, wherein the unbound antibiotic comprises a vicinal diol function.

Description

MEDICAL DEVICES COMPRISING ANTIBIOTICS

FIELD OF THE INVENTION

The invention relates to pH sensitive bound antibiotics.

BACKGROUND OF THE INVENTION

Controlled drug release offers an appealing solution in all those situations where timing and localization are crucial in achieving an effective concentration. In the case of implantable devices, contamination can occur during the operation or in a second moment from contaminated tissues (exogenous infections) or even via hematogenous infection as consequence of septicemia. Therefore, specific strategies are needed to ensure a long-term protection while allowing for a targeted release. This cannot be obtained by a diffusion dependent release of the active compound (e.g. antibiotic loaded hydrogels) as it would be cleared from the operation site in solely a few hours or, in the best case, days. Ideally, the release would occur only once biofilm formation starts and therefore exert its action at an early stage of the infection.

SUMMARY OF THE INVENTION

A valid option is to exploit a characteristic environmental variation associated to biofilm formation, i.e. the variation in pH. Biofilm formation is accompanied by acidification of the medium due to the accumulation of by-products of carbohydrate metabolism such as acetic and lactic acid. A pH gradient establishes along the biofilm thickness with the acidity increasing with the depth and reaching pH values as low as 4.5 [Xiao et al. (2017) Int J Oral Sci 9, 74-79] .

The invention regards the preparation of a pH dependant biofilm triggered release antibiotic coating for implantable devices. In particular, pH sensitive bonding of the antibiotic on the coated surface is achieved through the formation of boric esters. This strategy can be implemented with covalent, non-leaching coating with antibiofilm or biocidal compounds.

The invention has the advantage of that the released antibiotic from the device is unmodified, which ensures that the properties of the antibiotic remain preserved.

This has the additional advantage that no additional regulatory measures must be taken for these antibiotics.

The invention has the advantage that a simple chemistry is used allowing a tailored and on-site manufacturing. The invention is further summarised in the following statements:

1. A medical device coated with an antibiotic, wherein the antibiotic is bound to a catechol comprising coating on the device via a pH sensitive boric acid bond, wherein the unbound antibiotic comprises a vicinal diol function.

2. The device according to statement 1, wherein the catechol comprising coating is polydopamine.

3. The device according to statement 1 or 2, wherein the antibiotic is selected from the class of aminoglycosides, glycopeptides, tetracyclines and macrolides.

4. The device according to any one of statements 1 to 3, wherein the antibiotic is amikacin.

5. The device according to any one of statements 1 to 4, which is an implantable device.

6. A method of coupling an antibiotic comprises a vicinal diol function to a medical device comprising a coating with catechol groups, the method comprising the steps of:

-providing a device comprising a coating, the coating comprising catechol groups, -reacting the catechol groups with boric acid,

-reacting the catechol bound boric acid with the antibiotic, thereby obtaining a pH sensitive boric ester.

7. Use of a device according to any one of statements 1 to 5, in the prevention and treatment of bacterial biofilm formation on said device.

8. Use of boric acid in the preparation of a medical device comprising a pH sensitive bound antibiotic comprises a vicinal diol function.

9. A kit comprising in separate packaging:

- boric acid, and

- an antibiotic comprises a vicinal diol function.

10. The kit according to statement 9, further comprising reagents for the application of a coating comprising catechol groups.

DETAILED DESCRIPTION

Figure 1. Schematic representation of the pH dependant interaction of boric acid with the catechol and the vicinal diol containing antibiotic.

Figure 2. Results from the activity test of the amikacin-boric acid coating (effect on planktonic bacteria (top panel) and bacterial biofilm (bottom panel). PDA-BA refers to the polydopamine coating treated with the solution of boric acid only. The error bars show the standard error of the mean (SE). Statistical significance was determined by applying a two-sided ratio paired t-test using GraphPad Prism (ns, not significant; *p < 0.1; **p < 0.01, ***p < 0.001; ****p < 0.0001); structure of amikacin (right).

The pH dependant release strategy is based on the presence of a catechol rich coating layer. This can be achieved through polymerization of dopamine (polydopamine PDA), DOPA or analogue structures [Lee et al. (2007). Science (1979) 318, 426- 430; Lee et al. (2006) Proc Natl Acad. Sci 103, 12999-13003]. The primary coating layer can be prepared via dip coating, spray coating or electrochemical deposition. [Ryu et al. (2018). ACS Applied Materials & Interfaces, 10, 7523-7540]. Oxidants such as persulfates can be employed to accelerate the polymerisation and film deposition [Wei et al. (2010) Polym. Chem. 1, 1430; Hong et al. (2016) Adv. Mater. Interfaces 3, 1500857].

Apart from dopamine other catechol comprising compounds can be used such as: catechol-functionalized hydrogels, catechol-modified polymers such as modified polyethylene glycol (PEG) or modified polyurethane, and catechol-containing silanes.

"Medical device" refers to any object used for external or internal use that comes into contact with an induvial and warrants the present of an antibiotic on such objects. Examples are single use devices such as syringes or catheters;

Implants such as protheses or pacemakers;

Medical equipment such as anaesthesia machines, patient monitors, haemodialysis machines;

Personal protective equipment such as mask, gowns or gloves;

Surgical instruments.

The catechol moieties present on the coating layers can undergo reaction with boric acid, or analogue compounds, with the formation of acid liable boric ester intermediates as depicted in Figure 1. Both dip coating and spray coating can be employed. Boric acid, or other boron bifunctional compounds (i.e. tetrahydroxydiboron), can further react with the formation of a second ester with vicinal hydroxyl groups present in the active compound of choice.

In this frame several classes of antibiotic satisfy this requirement. Aminoglycosides, glycopeptides, tetracyclines and macrolides are all characterised by the presence of vicinal diols, usually in sugar residues. Examples of aminoglycosides with vicinal diol groups are kanamycin A and amikacin Examples of glycopeptides with vicinal diol groups are vancomycin, teicoplanin, bleomycin, and ristocetin.

An example of a tetracycline with vicinal diol groups is minocycline.

An example of a macrolide with vicinal diol groups is erythromycin A.

Moreover, boric acid was reported to undergo reaction also with derivatives of salicylic acid. Since quinolones present similar structure in their tautomeric form this class could also be employed in a similar fashion.

Activity studies have been performed employing the peg-in-well system of the Calgary Biofilm Device. The wells were coated with polydopamine, boric acid, and the active compound. Then filled with medium and inoculated with bacteria. Upon biofilm formation on the bottom and sides of the wells the active compound was released and affected biofilm formation also on the uncoated pegs. The planktonic phase was measured at 595nm after transferring the bacterial suspensions in a new plate. The amount of biofilm mass on the pegs is determined through crystal violet staining and measured at 570nm. This high-throughput strategy allowed the simultaneous test of several strains with sufficient statistical power.

Example 1

The activity study was performed with the aminoglycoside amikacin. The PDA coating was treated with a solution of boric acid followed by a solution of amikacin and triethylamine. After each step, the coating was washed three times with demineralized water. Finally, the coated plates were tested as described and showed exceptional activity especially against Gram- bacteria.

Studies employing a boronic acid analogue of ciprofloxacin gave insights on the relation between pH decrease and release of the active compound. The active compound did not release at neutral pH whilst burst release was observed at pH 5. Moreover, the active compound could not be detected in sterile wells and the activity was retained when a buffer was added to keep the pH of the growth medium at 7,4. These experiments confirm that bacteria were involved in the release of the compound and that it was associated to a local biofilm effect and not to medium acidification due to planktonic growth.

Claims

1. A medical device coated with an antibiotic, wherein the antibiotic is bound to a catechol comprising coating on the device via a pH sensitive boric acid bond, wherein the unbound antibiotic comprises a vicinal diol function.

2. The device according to claim 1, wherein the catechol comprising coating is polydopamine.

3. The device according to claim 1 or 2, wherein the antibiotic is selected from the class of aminoglycosides, glycopeptides, tetracyclines and macrolides.

4. The device according to any one of claims 1 to 3, wherein the antibiotic is amikacin.

5. The device according to any one of claims 1 to 4, which is an implantable device.

6. A method of coupling an antibiotic comprises a vicinal diol function to a medical device comprising a coating with catechol groups, the method comprising the steps of:

-providing a device comprising a coating, the coating comprising catechol groups,

-reacting the catechol groups with boric acid,

-reacting the catechol bound boric acid with the antibiotic, thereby obtaining a pH sensitive boric ester.

7. Use of a device according to any one of claims 1 to 5, in the prevention and treatment of bacterial biofilm formation on said device.

8. Use of boric acid in the preparation of a medical device comprising a pH sensitive bound antibiotic comprises a vicinal diol function.

9. A kit comprising in separate packaging:

- boric acid, and

- an antibiotic comprises a vicinal diol function.

10. The kit according to claim 9, further comprising reagents for the application of a coating comprising catechol groups.