IMPLANTABLE DEVICE COMPRISING A TEXTILE COMPONENT COMPRISING MULTIFILAMENT YARNS AND/OR SPUN YARNS MADE OF FIBERS COMPLETELY OR PARTIALLY COATED IN CYCLODEXTRIN POLYMER

Abstract

The present invention relates to an implantable device comprising a textile component at least partially coated with a host polymer coating, said host polymer coating comprises a polymer of cyclodextrin(s) and/or derivatives of cyclodextrin(s) and/or inclusion complex(es) of cyclodextrin and/or inclusion complex(es) of cyclodextrin derivatives. Advantageously, said textile component comprises multifilament yarns and/or spun yarns made of fibers, at least a part of the filaments and/or fibers each having a diameter less than or equal to 25 micrometers.

Claims

1. An implantable device comprising a textile component at least partially coated with a host polymer coating, said host polymer coating comprising a polymer of cyclodextrin(s) and/or derivative(s) of cyclodextrin(s) and/or inclusion complex(es) of cyclodextrin and/or inclusion complex(es) of cyclodextrin derivative(s), wherein said textile component comprises multifilament yarns and/or spun yarns made of fibers and wherein at least a part of the filaments and/or fibers each have a diameter of less than or equal to 25 micrometers.

2. The implantable device as claimed in claim 1, wherein the ratio of the mass of the host coating to the total mass of the textile component coated with said host polymer coating is greater than or equal to 10%.

3. The implantable device as claimed in claim 1, wherein the textile component has a surface density of less than or equal to 120 g/m.sup.2.

4. The implantable device as claimed in claim 1, wherein the textile component comprises multifilament yarns and/or spun yarns made of fibers whose the titer of the filaments and/or the fibers is less than or equal to 10 dtex.

5. The implantable device as claimed in claim 1, wherein the textile component is a knitted component.

6. The implantable device as claimed in claim 1, wherein said device is selected from a list consisting of: a prosthesis for the treatment of a hernia in the abdominal region, a ligament, a prosthesis for the treatment of a prolapse of at least one pelvic organ, a prosthesis for the treatment of male erectile dysfunction, and a prosthesis for the treatment of the spine.

7. The implantable device as claimed in claim 1, wherein the multifilament yarns and/or the spun yarns made of fibers are made of at least one or more polymer(s) chosen from a list consisting of: polyolefins, polymers based on polyethylene oxide (PEO), block copolymers based on polypropylene oxide and ethylene oxide polyesters, and polyamides.

8. The implantable device as claimed in claim 1, wherein the host polymer coating comprises at least one guest functional agent selected from a list comprising: antibiotics, anti-inflammatory agents, anticoagulants, antithrombogenic agents, anti-mitotic agents, anti-proliferation agents, anti-adhesion agents, anti-migration agents, cell adhesion promoters, growth factors, antiparasitic molecules, hormones, antifungals, antimicrobial molecules, antiseptics, and analgesic agents.

9. The implantable device as claimed in claim 1, wherein the textile component comprises openings having at least one dimension greater than or equal to 1 mm.

10. The implantable device as claimed in claim 1, wherein the textile component is selected from a list consisting of: warp or weft knit material, fabrics, braids, twisted elements, or a combination thereof.

11. A process for manufacturing an implantable device, comprising the following steps: (i) providing a textile component comprising multifilament yarns and/or spun yarns made of fibers, at least a part of the filaments and/or fibers each having a diameter of less than 25 micrometers; (ii) applying an aqueous solution comprising: at least one cyclodextrin and/or at least one cyclodextrin derivative and/or at least one inclusion complex of cyclodextrin and/or at least one inclusion complex of cyclodextrin derivative; at least one (poly)carboxylic acid and/or its (poly)carboxylic acid anhydride, and optionally at least one catalyst, on at least a part of the multifilament yarns and/or spun yarns made of fibers; (iii) applying a heat treatment to the textile component obtained after step (ii) in order to form a host coating comprising a polymer of cyclodextrin(s) and/or derivative(s) of cyclodextrin(s) and/or inclusion complex(es) of cyclodextrin and/or inclusion complex(es) derivative(s) of cyclodextrin(s); obtaining the implantable device.

12. The manufacturing process as claimed in claim 11, comprising a step of washing (iv) of the textile component after step (iii) during which the textile component is washed with water or an aqueous solution having a temperature greater than or equal to 45 C.

13. The manufacturing process as claimed in claim 11, comprising a step of neutralizing the residual acidity of the host coating.

14. An implantable device as claimed in claim 4, wherein the textile component comprises multifilament yarns and/or spun yarns made of fibers whose the titer of the filaments and/or the fibers is less than or equal to 4 dtex.

15. An implantable device as claimed in claim 15, wherein the textile component is a warp knit component.

16. An implantable device as claimed in claim 16, wherein said device is selected from a list consisting of: a prosthesis for the treatment of a hernia in the inguinal region, a prosthesis for the treatment of a hernia in the femoral region, a prosthesis for the treatment of a hernia in the umbilical region, or a prosthesis for the treatment of a epigastric hernia, and an intervertebral prosthesis.

17. The implantable device as claimed in claim 7, wherein the multifilament yarns and/or the spun yarns made of fibers are made of at least one or more polymer(s) chosen from a list consisting of: (co)polymers of lactic acid, derived from the polymerization of at least L-lactide and/or at least D-lactide and/or at least meso-lactide, polymers derived from the polymerization of at least glycolide, copolymers derived from the polymerization of at least lactide and at least glycolide, block (co)polymers based on polylactide and polyethylene glycol, or a mixture thereof.

18. The implantable device as claimed in claim 8, wherein the host polymer coating comprises at least one guest functional agent selected from a list comprising: ciprofloxacin, ropivacaine, bupivacaine, lidocaine, and levobupivacaine.

19. The implantable device as claimed in claim 8, wherein the host polymer coating comprises at least one guest functional agent that is ropivacaine.

20. A process for manufacturing an implantable device as claimed in claim 1, comprising the following steps: (i) providing a textile component comprising multifilament yarns and/or spun yarns made of fibers, at least a part of the filaments and/or fibers each having a diameter of less than 25 micrometers; (ii) applying an aqueous solution comprising: at least one cyclodextrin and/or at least one cyclodextrin derivative and/or at least one inclusion complex of cyclodextrin and/or at least one inclusion complex of cyclodextrin derivative; at least one (poly)carboxylic acid and/or its (poly)carboxylic acid anhydride, and optionally at least one catalyst, on at least a part of the multifilament yarns and/or spun yarns made of fibers; (iii) applying a heat treatment to the textile component obtained after step (ii) in order to form a host coating comprising a polymer of cyclodextrin(s) and/or derivative(s) of cyclodextrin(s) and/or inclusion complex(es) of cyclodextrin and/or inclusion complex(es) derivative(s) of cyclodextrin(s); obtaining the implantable device.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0089] The present invention will be better understood by reading the examples of embodiments described below and cited on a non-limiting basis.

Materials Used:

[0090] Textile component A: 38 g/m.sup.2 flat warp-knitted panel consisting of multifilament yarns of polyethylene terephthalate, said yarns each having a titer of 61 dtex and each comprising 24 filaments (or about 2.54 dtex/filament, or about a diameter of 15.3 m/filament).

[0091] Textile component B: 100 g/m.sup.2 flat warp-knitted panel consisting of multifilament yarns of polyethylene terephthalate, the warp yarns (70% in number), in particular forming the warp, each having a titer of 138 dtex and each comprising 32 filaments (or about 4.31 dtex, or about a diameter of 20 m/filament); and the weft yarns (30% in number) each having a titer of 226 dtex, and each comprising 64 filaments (or about 3.53 dtex, or about a diameter of 18 m/filament). The average diameter of the filaments is thus about 19.5 m.

[0092] Hydroxypropyl--cyclodextrin (HPD), of the brand Kleptose HPB, MS=0.62; M=1387 g/mol from Roquette Freres (Lestrem, France).

[0093] Citric acid (CTR), sodium dihydrogen hypophosphite (NaH.sub.2PO.sub.4.xH.sub.2O) and ropivacaine (M=274 g/mol=from Aldrich Chemicals (Saint Quentin Fallavier, France).

[0094] Ropivacaine hydrochloride solution: Naropin 2 mg/ml and Ropivacaine KABI 10 mg/ml, respectively from AstraZeneca (London, England) and Kabi (Bad Homburg, Germany).

[0095] Textile components A and B are first washed by Soxhlet extraction with diethyl ether (24 cycles, one hour per cycle) with the goal of removing lubricants and possible residual compounds, for example sizing agents.

Adsorption/Desorption of Ropivacaine

[0096] After functionalization of the textile components by the cyclodextrin polymer, the textile components are impregnated in a ropivacaine hydrochloride solution at room temperature (of the order of 20-25 C.). In order to evaluate the amount of ropivacaine hydrochloride adsorbed by the textile components, the adsorbed ropivacaine is desorbed in 10 ml of water and then in 5 ml of 0.1M soda NaOH. The desorption solutions obtained are analyzed using a high-performance liquid chromatography method (LC 2010A-HT, Shimadzu, Noisiel, France, equipped with a visible-ultraviolet detector and a Dell integrator/recorder computer with LabSolutions software). The chromatograph was adapted with a Gemini-NX C18 column (5 m, 250*4.6 mm, Phenomenex, Le Pecq, France). The mobile phase consists of a mixture of a 72% phosphate buffer solution (pH 2.5) and 28% acetonitrile. Chromatographic separation was performed at 25 C. with a flow rate of 1 mL/min and controlled at 201 nm. The approximate retention time for ropivacaine at 20 nm is 5.5 minutes under these conditions.

[0097] The amount of ropivacaine desorbed in ultrapure water corresponds to the ropivacaine adsorbed by capillary action on the textile component itself, independently of the host polymer coating (non-specific interactions). The amount of ropivacaine desorbed in 0.1M soda NaOH corresponding to the ropivacaine loaded by the host polymer coating (specific interactions with the cyclodextrin polymer: inclusion complexes, ionic bonds hydrogen bonds).

EXAMPLE 1

[0098] Textile component A is impregnated and padded (2 m/min, 2 bar, Laboratory Padder LDP, LAB-PRO, Wikon, Switzerland) in an aqueous solution comprising HPCD, a catalyst (NaH.sub.2PO.sub.2) and CTR, in the following proportions 8/1/10 where 8, 1 and 10 are the masses (grams) of HPCD, catalyst (NaH.sub.2PO.sub.2) and CTR, respectively, dissolved in 100 mL ultrapure water. The impregnated textile component A is placed in a heat-setting chamber (Model FD, BINDER, Tuttlingen, Germany) for 5 minutes at 90 C. and then for 120 minutes at 140 C. The coated textile component A is then washed twice rapidly for 3 minutes in ultrapure water and then neutralized by passage in an aqueous solution containing sodium carbonate at 4 g/L in order to neutralize the residual acidity. The textile component is then rinsed twice quickly in ultrapure water for 3 minutes. The textile component is then washed in ultrapure water (washing step) at 80 C. (FISONS Cl, Thermo Scientific Haake, Karlsruhe, Germany) for 20 minutes and dried at 104 C. for 1 hour, and finally cooled to room temperature in a desiccator for 30 minutes. The host coating grafting rate is of the order of 13.9%. The final textile component A is flexible and wraps around itself without altering its shape or detaching from the CD polymer coating.

EXAMPLE 2

[0099] Textile component A is impregnated and padded (2 m/min, 2 bar, Laboratory Padder LDP, LAB-PRO, Wikon, Switzerland) in an aqueous solution comprising HPCD, catalyst (NaH.sub.2PO.sub.2) and CTR, in the following proportions 12/1.5/15 where 12; 1.5 and 15 are the masses (grams) of HPCD, catalyst (NaH.sub.2PO.sub.2) and CTR, respectively, dissolved in 100 mL ultrapure water. The impregnated textile component A is placed in a heat-setting chamber (Model FD, BINDER, Tuttlingen, Germany) for 5 minutes at 90 C. and then for 120 minutes at 140 C. The coated textile component A is then washed twice rapidly for 3 minutes in ultrapure water and then neutralized by passage in an aqueous solution containing sodium carbonate at 4 g/L in order to neutralize the residual acidity. The textile component is then rinsed twice quickly in ultrapure water for 3 minutes. The textile component is then washed in ultrapure water at 80 C. (FISONS Cl, Thermo Scientific Haake, Karlsruhe, Germany) for 20 minutes and dried at 104 C. for 1 hour, and finally cooled to room temperature in a desiccator for 30 minutes. The host coating grafting rate is of the order of 21%. The final textile component A is flexible and wraps around itself without altering its shape or detaching from the host polymer CD coating.

EXAMPLE 3

[0100] Textile component A is impregnated and padded (2 m/min, 2 bar, Laboratory Padder LDP, LAB-PRO, Wikon, Switzerland) in an aqueous solution comprising HPCD, a catalyst (NaH.sub.2PO.sub.2) and CTR, in the following proportions 16/2/20 where 16, 2 and 20 are the masses (grams) of HPCD, catalyst (NaH.sub.2PO.sub.2) and CTR, respectively, dissolved in 100 mL of pure water. The impregnated textile component A is placed in a heat-setting chamber (Model FD, BINDER, Tuttlingen, Germany) for 5 minutes at 90 C. and then for 120 minutes at 140 C. The coated textile component A is then washed twice rapidly for 3 minutes in ultrapure water and then neutralized by passage through an aqueous solution containing concentrated sodium carbonate at 4 g/L in order to neutralize the residual acidity. The textile component is then rinsed twice quickly in ultrapure water for 3 minutes. The textile component is then washed in ultrapure water at 80 C. (FISONS Cl, Thermo Scientific Haake, Karlsruhe, Germany) for 20 minutes and dried at 104 C. for 1 hour, and finally cooled to room temperature in a desiccator for 30 minutes. The host coating grafting rate is of the order of 29%. The final textile component A is flexible and wraps around itself without altering its shape or detaching from the host polymer CD coating.

EXAMPLE 4A

[0101] An 11 mm diameter disc cut from textile component A obtained at the end of Example 1 is immersed in a ropivacaine hydrochloride solution at 2 mg/mL for 5 minutes, and then immersed for 60 minutes in 10 ml of ultrapure water to remove unadsorbed ropivacaine. The amount (g) of desorbed ropivacaine relative to the total mass of the textile component A coated with the CD polymer is 9.02.5 mg/g.

EXAMPLE 4B

[0102] An 11 mm diameter disc cut from textile component A obtained at the end of Example 1 is immersed in a 10 mg/mL ropivacaine hydrochloride solution for 5 minutes, and then immersed for 60 minutes in 10 ml ultrapure water to remove unadsorbed ropivacaine. The amount (g) of desorbed ropivacaine relative to the total mass of the textile component A coated with the CD polymer is 60 mg/g.

EXAMPLE 5A

[0103] same protocol as for Example 4A but applied to Example 2.

EXAMPLE 5B

[0104] same protocol as for Example 4B but applied to Example 2.

EXAMPLE 6A

[0105] same protocol as for Example 4A but applied to Example 3.

EXAMPLE 6B

[0106] same protocol as for Example 4B but applied to Example 3.

[0107] For Examples 5A and 6A, desorption rates in ultrapure water are similar to the ropivacaine desorption rate in ultrapure water obtained for Example 4A. The same applies to the desorption rates in ultrapure water in Examples 5B and 6B, which are similar to the ropivacaine desorption rate in ultrapure water in Example 4B.

EXAMPLE 7A

[0108] The disc obtained at the conclusion of Example 4A is immersed in 5 ml of sodium hydroxide solution at 0.1M for 5 minutes at 37 C. to completely hydrolyze the host polymer coating formed from HPCD, thus completely releasing the adsorbed ropivacaine. The amount (g) of desorbed ropivacaine relative to the total mass of the textile component A coated with the CD polymer is 5.10.1 mg/g.

EXAMPLE 7B

[0109] The disc obtained at the conclusion of Example 4B is immersed in 5 ml of sodium hydroxide solution at 0.1M for 5 minutes at 37 C. to completely hydrolyze the host polymer coating formed from HPCD, thus completely releasing the adsorbed ropivacaine. The amount (g) of desorbed ropivacaine relative to the total mass of the textile component A coated with the CD polymer is 18.80.1 mg/g. The total amount of ropivacaine desorbed in water and soda is therefore of the order of 78.8 mg/g of support, i.e. of textile component A.

EXAMPLE 8A

[0110] same protocol as for Example 7A but applied to Example 5A. The amount (g) of desorbed ropivacaine relative to the total mass of the textile component A coated with the CD polymer is 7.20.5 mg/g.

EXAMPLE 8B

[0111] same protocol as for Example 7B but applied to Example 5B. The amount (g) of desorbed ropivacaine relative to the total mass of textile component A coated with CD polymer is 23.11.1 mg/g.

EXAMPLE 9A

[0112] same protocol as for Example 7A but applied to Example 6A. The amount (g) of desorbed ropivacaine relative to the total mass of textile component A coated with CD polymer is 9.40.8 mg/g.

EXAMPLE 9B

[0113] same protocol as for Example 7B but applied to Example 6B. The amount (g) of desorbed ropivacaine relative to the total mass of the textile component A coated with CD polymer is 33.91.1 mg/g.

EXAMPLE 10

[0114] Textile component B is impregnated and padded in an aqueous solution comprising HPCD, a catalyst (NaH.sub.2PO.sub.2) and CTR, in the following proportions 8/1/10 where 8, 1 and 10 are the masses (in grams) of HPCD, catalyst (NaH.sub.2PO.sub.2) and CTR, respectively, dissolved in 100 mL of ultrapure water. The impregnated textile component B is placed in a heat-setting chamber (Minithermo, Roaches, UK) for 60 minutes at 160 C. The coated textile component B is washed with distilled water and then treated in an aqueous solution containing sodium carbonate, then washed with distilled water at a temperature of the order of 80 C. in a Soxhlet extractor. The host coating grafting rate is of the order of 13.6%.

EXAMPLE 11

[0115] Textile component B is impregnated and padded in an aqueous solution comprising HPCD, a catalyst (NaH.sub.2PO.sub.2) and CTR, in the following proportions 12/1.5/15 where 12; 1.5 and 15 are the masses (in grams) of HPCD, catalyst (NaH.sub.2PO.sub.2) and CTR, respectively, dissolved in 100 mL of ultrapure water. The impregnated textile component B is placed in a heat-setting chamber (Minithermo, Roaches, UK) for 60 minutes at 160 C. The coated textile component B is washed with distilled water and then treated in an aqueous solution containing sodium carbonate, then washed with distilled water at a temperature of the order of 80 C. in a Soxhlet extractor. The host coating grafting rate is of the order of 17.4%.

EXAMPLE 12

[0116] Textile component B is impregnated and padded in an aqueous solution comprising HPCD, a catalyst (NaH.sub.2PO.sub.2) and CTR, in the following proportions 16/2/20 where 16, 2 and 20 are the masses (in grams) of HPCD, catalyst (NaH.sub.2PO.sub.2) and CTR, respectively, dissolved in 100 mL of ultrapure water. The impregnated textile component B is placed in a heat-setting chamber (Minithermo, Roaches, UK) for 60 minutes at 160 C. The coated textile component B is washed with distilled water and then treated in an aqueous solution containing sodium carbonate, then washed with distilled water at a temperature of the order of 80 C. in a Soxhlet extractor. The host coating grafting rate is of the order of 27.7%.

EXAMPLE 13

[0117] An 11 mm disc of textile component B of Example 11 undergoes the protocols described in Examples 4A and 7A. The rate of desorbed ropivacaine in a 0.1M soda NaOH solution is of the order of 4 mg/g.

COMPARATIVE EXAMPLE 14

[0118] An 11 mm disc of a virgin textile component B undergoes the protocols described in Examples 4A and 7A. The rate of desorbed ropivacaine in a 0.1M soda NaOH solution is of the order of 0.5 mg/g (from textile component B). It should be noted that the same behavior, i.e. very low ropivacaine absorption, is observed for the virgin textile component A.

EXAMPLE 15

[0119] An 11 mm disc of textile component B coated with CD in Example 11 undergoes the protocols described in Examples 4B and 7B (The amount of ropivacaine desorbed in a 0.1M soda NaOH solution is of the order of 9 mg/g). The total amount of ropivacaine desorbed (in water and soda) is of the order of 49.4 mg/g of textile component B.

COMPARATIVE EXAMPLE 16

[0120] An 11 mm disc of a virgin textile component B undergoes the protocols described in Examples 4B and 7B. The rate of desorbed ropivacaine in a 0.1M soda NaOH solution is of the order of 2 mg/g. It should be noted that the same behavior, i.e. very low ropivacaine absorption, is observed for the virgin textile component A.

[0121] The total amount of ropivacaine adsorbed (mg/g of support) by the functionalized textile component A (Example 7B) is increased by 60% compared with the functionalized textile component B (Example 15).

[0122] If the total amount of ropivacaine per m.sup.2 of textile component is considered, the amount of ropivacaine adsorbed (mg/m.sup.2 of textile support) for textile component B in Example 15 is of the order of 5611 mg/m.sup.2 versus 3410 mg ropivacaine per m.sup.2 of textile support A in Example 7B. Thus, although textile component A is 2.6 times lighter than textile component B, and the amount of ropivacaine adsorbed per m.sup.2 is 0.39 times less (5.28 g of grafted CD polymer versus 13.6 g of grafted CD polymer), the amount of adsorbed ropivacaine is only 0.60 times less.

[0123] This advantage results in a flexible prosthesis with improved active agent absorption capabilities. Thus, the use of a lighter textile support offers an excellent compromise between i) the amount of cyclodextrin polymer immobilized per m.sup.2 of textile component, ii) the amount of ropivacaine loaded on the textile component, and iii) the flexibility of the textile component.

[0124] The amount of analgesic loaded by the textile component A or B functionalized by the CD polymer is higher than that loaded by a virgin textile component A or B, in particular when the ropivacaine solution is concentrated at 10 mg/mL.

[0125] The presence of the CD polymer would thus improve the amount of ropivacaine physically adsorbed by the textile component.

[0126] The textile components according to the invention were tested to determine their effectiveness in the treatment of pain based on the colorectal distension model developed by Rousseaux et al. (Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat. Med. 13 (2007) 35-37) and Yang et al. (Establishment of model of visceral pain due to colorectal distension and its behavioral assessment in rats. World J. Gastroenterol. 12 (2006) 2781-2784). Textile components A, virgin and functionalized with a host polymer coating according to Example 3, not loaded with ropivacaine, were implanted in two groups of ten rats each. Pain was evaluated one day after implantation up to 8 days. No post-operative deaths were observed.

[0127] A low pain threshold of 38 mmHg (versus 46 mmHg considered as the baseline level) is observed for the virgin textile component A and the functionalized textile component A according to Example 3 not loaded with ropivacaine, one day after implantation. This low pain tolerance reveals the surgically induced visceral pain and the absence of an analgesic effect of the implanted prostheses described above. This threshold persisted until the eighth day as it is 42.7 mmHg1.7 mmHg.

[0128] Textile components A, virgin and functionalized with a host polymer coating according to Example 3, loaded with ropivacaine (10 mg/g), were implanted in two groups of 10 rats each. Pain was evaluated one day after implantation up to 8 days. No post-operative deaths were observed.

[0129] An improved pain threshold of 46 mmHg was thus observed for the virgin textile component A loaded with ropivacaine (10 mg/g) during the first two days after implantation. A significant pain relief effect was observed for Example 3, loaded with ropivacaine at the same concentration (10 mg/g), during the first four days after implantation, with a threshold of 531.71 mmHg demonstrating the contribution of the CD polymer in the release of ropivacaine. At the same amount of ropivacaine, the virgin textile component A and the textile component A of Example 3 do not have the same behavior. The implantable device according to Example 3 is more effective than the virgin textile component A in terms of duration and intensity of pain tolerance.