LUBRICATION METHOD

Abstract

The invention relates to a method for lubricating a component consisting of a hydrophilic compound crosslinked by means of a water-soluble transition metal chelate.

Claims

1-10. (canceled)

11. A method for lubricating an element essentially consisting of hyaluronic acid crosslinked by means of a crosslinking agent which is a titanium chelate or zirconium chelate that is soluble in water, the method comprising a). bringing the element into contact with a solution of free hyaluronic acid, in order to obtain an element covered by free hyaluronic acid, which is a lubricated element.

12. The method according to claim 11, wherein the crosslinking agent is a chelate of formula 1 below: ##STR00023## where A is Ti, and where R.sub.1 is a functional group containing an oxygen or nitrogen atom, R.sub.2 represents two or three carbon atoms, and R.sub.3 and R.sub.4 represent a linear or branched or cyclic C.sub.1-C.sub.4 alkyl.

13. The method according to claim 11, wherein the crosslinking agent is selected from a group consisting of: ##STR00024##

14. The method according to claim 11, wherein the crosslinking agent is the crosslinking agent of the following formula 1a1: ##STR00025##

15. The method according to claim 11, further comprising the steps of b) crosslinking the free hyaluronic of the lubricated element by using a crosslinking agent of formula 1 in order to obtain a second layer of composition essentially consisting of crosslinked hyaluronic acid, and c) bringing the second layer of composition essentially consisting of crosslinked hyaluronic acid into contact with a solution of free hyaluronic acid, in order to obtain an element covered by a second layer of composition which is lubricated.

16. The method according to claim 15, wherein steps b) and c) are repeated at least once.

17. A lubricated element essentially consisting of at least one layer of hyaluronic acid crosslinked by a crosslinking agent which is a titanium chelate that is soluble and stable in water, the at least one layer of crosslinked hyaluronic acid being covered by a layer of non-crosslinked hyaluronic acid.

18. A method for lubricating a hydrophobic support comprising the steps of: a. covering the hydrophobic support with a first composition comprising a solvent, and a solute selected from stearylamine or stearic acid, to obtain a support covered with the first composition, the solvent being compatible with the solute and the hydrophobic surface; b. rinsing the hydrophobic support covered with the first composition with an aqueous solution in order to obtain a hydrophobic support covered with the first rinsed composition; c. bringing the hydrophobic support covered with the first rinsed composition into contact with free hyaluronic acid in order to obtain a surface having free hyaluronic acid; d. crosslinking the free hyaluronic acid present on the surface obtained in the previous step by using a crosslinking agent in order to obtain a first layer of crosslinked hyaluronic acid; and e. bringing the first layer of crosslinked hyaluronic acid into contact with a solution of free hyaluronic acid in order to obtain a lubricated hydrophobic support, wherein the crosslinking agent is a water-soluble titanium chelate or zirconium chelate.

19. The method according to claim 18, wherein the crosslinking agent is a chelate of the following formula 1: ##STR00026## where A is Ti, and where R.sub.1 is a functional group containing an oxygen or nitrogen atom, R.sub.2 represents two or three carbon atoms, and R.sub.3 and R.sub.4 represent a linear or branched or cyclic C.sub.1-C.sub.4 alkyl.

20. The method according to claim 18, wherein steps d) and e) are repeated at least once.

21. A lubricated hydrophobic support covered with a first layer of stearylamine or stearic acid, the first layer of stearylamine or stearic acid being covered by a first layer of hyaluronic acid crosslinked by a crosslinking agent which is a water-soluble titanium chelate or zirconium chelate

22. The Lubricated hydrophobic support according to claim 21, wherein the crosslinking agent is a chelate of the following formula 1: ##STR00027## where A is Ti, and where R.sub.1 is a functional group containing an oxygen or nitrogen atom, R.sub.2 represents two or three carbon atoms, and R.sub.3 and R.sub.4 represent a linear or branched or cyclic C.sub.1-C.sub.4 alkyl, the first layer of crosslinked hyaluronic acid being covered by a second layer of free hyaluronic acid.

23. A kit including: a. a first composition essentially consisting of stearylamine or stearic acid; b. a second composition comprising or essentially consisting of hyaluronic acid; and c. a crosslinking compound, the crosslinking compound being a water-soluble titanium chelate or zirconium chelate,

24. The kit according to claim 23, wherein the crosslinking compound is a chelate of the following formula 1: ##STR00028## where A is Ti, and where R.sub.1 is a functional group containing an oxygen or nitrogen atom, R.sub.2 represents two or three carbon atoms, and R.sub.3 and R.sub.4 represent a linear or branched or cyclic C.sub.1-C.sub.4 alkyl.

25. The kit according to claim 23, wherein the crosslinking compound is a chelate a compound of formula 1a1: ##STR00029## or of formula 1a2: ##STR00030##

Description

BRIEF DESCRIPTION OF THE DRAWINGS

Brief Description of the Figures

[0153] is a graph showing the force (in Newtons—N) to be applied to move the stent in the capsule as a function of the movement (in mm). A: represents a capsule covered with stearylamine and non-crosslinked hyaluronic acid; B: represents a capsule covered with stearylamine and hyaluronic acid crosslinked with Tyzor TE 200 mM; C: represents a capsule covered with stearylamine and hyaluronic acid crosslinked with 1,4-butanediol diglycidyl ether (BDDE) 200 mM, and D: represents a capsule covered with stearylamine and hyaluronic acid crosslinked with polyethylene glycol) diglycidyl ether (PEGDGE) 200 mM.

[0154] is a graph showing the force (in Newtons—N) to be applied to move the stent in the capsule as a function of the movement (in mm). A: represents the results obtained for a capsule covered with stearylamine and hyaluronic acid crosslinked with 50 mM Tyzor TE; B; represents the results obtained for a capsule covered with stearylamine and hyaluronic acid crosslinked with 100 mM Tyzor TE; [0155] C: represents the results obtained for a capsule covered with stearylamine and hyaluronic acid crosslinked with 200 mM Tyzor TE; [0156] D: represents the results obtained for a capsule covered with stearylamine and hyaluronic acid crosslinked with 400 mM Tyzor TE and [0157] D: represents the results obtained for a capsule covered with stearyla e and hyaluronic acid crosslinked with 800 mM Tyzor TE.

[0158] is a graph showing the forces (in N) for sliding (black bars) and resistance (white bars) on polyethylene probes that are covered with hyaluronic acid according to the method of the invention and subjected to passes through 50 g jaws over 8 cm of probe. 1: represents the results obtained for a probe covered with stearylamine and non-crosslinked hyaluronic acid; 2: represents the results obtained for a probe covered with stearylamine and hyaluronic acid crosslinked with 50 mM Tyzor TE; 3: represents the results obtained for a probe covered with stearylamine and hyaluronic acid crosslinked with 200 mM Tyzor TE; and 4; represents the results obtained for a capsule covered with stearylamine and hyaluronic acid crosslinked with 800 mM Tyzor TE. The results represent the mean and standard deviation of several tests.

EXAMPLES

Example 1

[0159] Hydrophobic Metal Surface Covering

[0160] Four metal capsules (nitinol) are washed beforehand by being vertically immersed in a beaker containing 95% ethanol. The beaker containing the capsules is subjected to ultrasound for 2 mins, then the beaker is left in a water bath at 60° C. for 1 hour. The capsules are removed from the washing solution and allowed to air dry. The capsules are then immersed vertically in a beaker containing 80 ml of 0.1% (mlv) stearylamine in dimethylformamide. The beaker containing the capsules is placed in a thermostatically controlled heating chamber at 27° C. on an orbital shaker for 1 hour. At the end of this time, the capsules are removed from the beaker and they are immersed in 3 successive baths of distilled water for washing. Finally, the capsules are immersed vertically in a beaker containing 80 ml of 0.2% (m/v) hyaluronic acid in distilled water. The beaker is stirred on an orbital shaker for 2 hours at room temperature. Finally, the capsules are removed and allowed to air dry for 24 hours.

[0161] Crosslinking

[0162] Four capsules are covered with hyaluronic acid according to the above method.

[0163] The hyaluronic acid layer is crosslinked by various crosslinking agents: [0164] Capsule 1 (E1): non-crosslinked, [0165] Capsule 2 (E2): crosslinked by triethanolamine titanate chelate—TYZOR TE 200 mM, [0166] Capsule 3 (E3): crosslinked by 1,4-butanediol diglycidyl ether (BDDE) 200 mM, and [0167] Capsule 4 (E4): crosslinked by polyethylene glycol) diglycidyl ether (PEGDGE) 200 mM.

[0168] The three metal capsules E2. E3, E4 are immersed vertically and in tubes containing 8 ml TYZOR TE 200 mM in distilled water, 8 ml 200 mM BDDE in 0.25N NaOH and 8 ml 200 mM PEGDGE in 0.25N NaOH, respectively, these solutions completely covering the metal capsules to be treated.

[0169] The tubes are placed on an orbital shaker for 1 hour at room temperature. At the end of this time, the capsules are removed from the solution of crosslinking agent and placed in a heating chamber at 60° C. for 60 mins for E2 and 15 mins for E3 and E4. The metal tubes are then washed with distilled water on an orbital shaker for 15 mins at room temperature. This is followed by four successive washing baths. Finally, the capsules are immersed vertically in a beaker containing 80 ml of 0.2% (m/v) hyaluronic acid in distilled water. The beaker is stirred on an orbital shaker for 2 hours at room temperature.

[0170] The crosslinking method can be repeated a second time.

[0171] The capsules are immersed in a beaker containing 80 ml of 0.3% (m/v) (hyaluronic acid in distilled water.

[0172] To evaluate the effect of the crosslinking agents, the inventors measured the stripping force. To do this, the inventors pushed a stent inside the treated capsule while measuring the force necessary to make it move forward. This is the stripping force.

[0173] The results obtained for the different instances of crosslinking are shown in FIG. 1.

[0174] The following table 1 summarizes the results in FIG. 1.

TABLE-US-00001 Capsule Stripping force (N) El - non-crosslinked HA 45.96 E2 - HA crosslinked by TYZOR TE 200 mM 26.90 E3 - HA crosslinked by BDDE 200 mM 44.64 E4 - HA crosslinked by PEGDGE 200 mM 51.58

[0175] From the data obtained, the capsule giving the best results is the E2 capsule, where only 26.9N is needed to move a stent.

[0176] The E1 and E3 capsules gave slightly lower results than an untreated capsule (no covering; not shown): an average of 45.3N for these two capsules compared with 53.7N for an untreated capsule.

[0177] The E4 capsule gives results equivalent to an untreated capsule (51.6N compared with 53.7N).

[0178] The crosslinking agents are therefore not equivalent, and TYZOR TE is the best crosslinking agent and allows good surface lubrication.

Example 2

[0179] In this example, capsules are covered as indicated in example 1, in the section “Hydrophobic surface covering.”

[0180] Crosslinking

[0181] Five capsules are covered with hyaluronic acid according to the above method.

[0182] The hyaluronic acid layer is crosslinked by TYZOR TE at different concentrations: [0183] Capsule 1 (E1a): by TYZOR TE 50 mM, [0184] Capsule 2 (E2a): by TYZOR TE 100 mM, [0185] Capsule 3 (E3a): by TYZOR TE 200 mM, [0186] Capsule 4 (E4a): by TYZOR TE 400 mM, and [0187] Capsule 5 (E5a): by TYZOR TE 800 mM.

[0188] The five metal capsules E1a, Eta, E3a, E4a and E5a are immersed vertically in tubes containing 8 ml TYZOR TE 50, 100, 200, 400 and 800 mM, respectively, in distilled water, these solutions completely covering the metal capsules to be treated. The tubes are placed on an orbital shaker for 1 hour at room temperature. At the end of this time, the capsules are removed from the solution of crosslinking agent and placed in a heating chamber at 60° C. for 60 mins. The metal tubes are then washed with distilled water on an orbital shaker for 15 mins at room temperature. This is followed by four successive washing baths. Finally, the capsules are immersed vertically in a beaker containing 80 ml of 0.2% (m/s′) hyaluronic acid in distilled water. The beaker is stirred on an orbital shaker for 2 hours at room temperature.

[0189] The crosslinking method can be repeated a second time. In this case, the capsules are immersed in a beaker containing 80 ml of 0.3% (m/v) hyaluronic acid in distilled water.

[0190] Results

[0191] To evaluate the effect of the crosslinking agents, the inventors measured the stripping force. To do this, the inventors pushed a stent inside the treated capsule while measuring the force necessary to make it move forward. This is the stripping force.

[0192] The results obtained for the different instances of crosslinking are shown in FIG. 2.

[0193] The following table 2 summarizes the results in said figure.

TABLE-US-00002 Capsule Stripping force (N) El a - HA crosslinked by TYZOR TE 50 mM 41.3 E2a - HA crosslinked by TYZOR TE 100 mM 33.0 E3a - HA crosslinked by TYZOR TE 200 mM 26.0 E4a - HA crosslinked by TYZOR TE 400 mM 24.5 E5a - HA crosslinked by TYZOR TE 800 mM 23.6

[0194] The efficiency of the sliding is dose-dependent on the concentration of the crosslinking agent (TYZOR TE). The more crosslinking agent is present, the more the sliding makes it possible to retain the layer of non-crosslinked hyaluronic acid.

Example 3

[0195] Hydrophobic Polymer Surface Covering

[0196] Polyethylene probes are washed beforehand by being vertically immersed in a beaker containing 95% ethanol. The beaker containing the probes is subjected to ultrasound for 2 min, then the beaker is left in a water bath at 60° C. for 1 hour. The probes are removed from the washing solution and allowed to air dry. The probes are then immersed vertically in a beaker containing a solution of 0.1% (m/v) stearylamine in dimethylformamide. The beaker containing the probes is placed in a thermostatically controlled heating chamber at 27° C. on an orbital shaker for 1 hour. At the end of this time, the probes are removed from the beaker and they are immersed in 3 successive baths of distilled water for washing. Finally, the probes are immersed vertically in a beaker containing a solution of 0.2% (m/v) hyaluronic acid in distilled water. The beaker is stirred on an orbital shaker for 2 hours at room temperature.

[0197] Finally, the probes are removed and allowed to air dry for 24 hours.

[0198] The probes are covered with hyaluronic acid according to the method described above. The probes are divided into 4 batches.

[0199] The hyaluronic acid layer is crosslinked by TYZOR TE at different concentrations: [0200] Batch 1: non-crosslinked, [0201] Batch 2: crosslinked by TYZOR TE 50 mM, [0202] Batch 3: crosslinked by TYZOR TE 200 mM, and [0203] Batch 4: crosslinked by TYZOR TE 800 mM.

[0204] The probes of batches 2, 3 and 4 are immersed vertically in tubes containing a solution of TYZOR TE 50 mM, 200 mM, and 800 mM, respectively, in distilled water; these solutions completely cover the polyethylene probes to be treated.

[0205] The tubes are placed on an orbital shaker for 1 hour at room temperature. At the end of this time, the probes are removed from the solution of crosslinking agent and placed in a heating chamber at 60° C. for 60 mins. The probes are then washed with distilled water on an orbital shaker for 15 mins at room temperature. This is followed by four successive washing baths. Finally, the probes are immersed vertically in a beaker containing a solution of 0.2% (mlv) hyaluronic acid in distilled water. The beaker is stirred on an orbital shaker for 2 hours at room temperature.

[0206] The crosslinking method is repeated a second time.

[0207] Finally, the probes of batch 1 (non-crosslinked), and batch 2, 3 and 4 (crosslinked) are immersed in a beaker containing a solution of 0.3% (m/v) hyaluronic acid in distilled water.

[0208] To evaluate the effect of the crosslinking agents, the inventors carried out sliding and/or resistance tests with a pass through 50 g jaws over 8 cm of probes hydrated by immersion in distilled water just before the measurement.

[0209] The sliding coefficients of friction (sliding CoF) are estimated by a mean of the coefficients of the first pass through the jaws.

[0210] The resistance coefficients of friction (resistance CoF) correspond to the mean of 5 passes of the same probe.

[0211] The results are shown in FIG. 3, and in the following table:

TABLE-US-00003 Standard Standard Sliding CoF deviation Resistance CoF deviation Batch 1 0.0946 II 0.2577 0.1418 Batch 2 0.0363 II 0.0401 0.0037 Batch 3 0.0307 II 0.0309 0.0021 Batch 4 0.0281 II 0.0304 0.0017

[0212] The results show that the crosslinking of the layer of hyaluronic acid significantly improves the sliding and very significantly improves the resistance of the covering even after several friction passes, compared with the control probe.

[0213] The invention is not limited to the embodiments presented here and other embodiments will become clearly apparent to a person skilled in the art.