Medical devices

Abstract

The present invention relates to medical devices, such as catheters, made from a composition comprising at least one (per) fluoropolyether polymer; methods for the manufacture thereof; and their uses and applications in medicine.

Claims

1. A composition (C) comprising: (I) at least one melt-processable polymer selected from the group consisting of poly(vinyl chloride) (PVC), polyolefins, polyolefin-based elastomer (POBE) and silicones, and (II) at least one F-TPU polymer, wherein the F-TPU polymer is at least one fluorinated polyurethane polymer having a weight average molecular weight of from 30,000 to about 150,000 Da, determined by means of gel permeation chromatography (GPC) technique and comprising recurring units derived from: at least one monomer (b), wherein monomer (b) is at least one hydroxy-terminated (per)fluoropolyether polymer [PFPE polymer] comprising a (per)fluoropolyoxyalkylene chain (R.sub.pf) having two chain ends, wherein one or more chain ends terminates with at least one —OH group, wherein R.sub.pf has the formula:
—O-D-(CFX.sup.#).sub.z1—O(R.sub.f)(CFX*).sub.z2-D*-O— wherein z1 and z2, equal or different from each other, are equal to or higher than 1, X.sup.# and X*, equal or different from each other, are —F or —CF.sub.3, provided that when z1 and/or z2 are higher than 1, X.sup.# and X* are —F, D and D*, equal or different from each other, are an alkylene chain comprising from 1 to 6 carbon atom, said alkylene chain being optionally substituted with at least one perfluoroalkyl group comprising form 1 to 3 carbon atoms, (Rf) comprises repeating units R.sup.o, said repeating units being independently selected from the group consisting of: (i) —CFXO—, wherein X is F or CF.sub.3, (ii) —CFXCFXO— wherein X, equal or different at each occurrence, is F or CF.sub.3, with the proviso that at least one X is F, (iii) —CF.sub.2CF.sub.2CW.sub.2O—, wherein each of W, equal or different from each other, are F, Cl, or H, (iv) —CF.sub.2CF.sub.2CF.sub.2CF.sub.2O—, (v) —(CF.sub.2).sub.j—CFZ-O—, wherein j is an integer from 0 to 3 and Z is a group of general formula —O—R(.sub.f-a)-T, wherein R.sub.(f-a) is a fluoroalkylene chain comprising a number of repeating units from 0 to 10, said repeating units selected from the group consisting of —CFXO—, —CF.sub.2CFXO, —CF.sub.2CF.sub.2CF.sub.2O—, —CF.sub.2CF.sub.2CF.sub.2CF.sub.2O—, with each of X being independently F or CF.sub.3 and T being a C1-C3 perfluoroalkyl group; at least one monomer (c), wherein monomer (c) is at least one aromatic, aliphatic or cycloaliphatic diisocyanate; and at least one monomer (d), wherein monomer (d) is at least one aliphatic, cycloaliphatic or aromatic diol having from 1 to 14 carbon atoms; said melt-processable polymer being different from said F-TPU polymer.

2. The composition according to claim 1, wherein said composition (C) comprises said melt-processable polymer in an amount of at least 60 wt. % and of at most 99.99 wt. % based on the total weight of said composition (C).

3. The composition according to claim 1, wherein: said at least one monomer (b) is a PFPE polymer, wherein the PFPE polymer is the hydroxy-terminated (per)fluoropolyether polymer as defined in claim 1; said at least one monomer (c) is selected from the group consisting of, 4,4′-methylene diphenylene-di-isocyanate (MDI), 1,6-hexane-diisocyanate (HDI), 2,4-toluene-diisocyanate, 2,6-toluene-diisocyanate, xylylene-diisocyanate, naphthalene-diisocyanate, paraphenylene-diisocyanate, hexamethylene-diisocyanate, isophorone-diisocyanate, 4,4′-dicyclohexyl-methane-diisocyanate and cyclohexyl-1,4-diisocyanate; and said at least one monomer (d) is selected from the group consisting of ethylene-glycol, 1,4-butanediol (BDO), 1,6-hexane diol (HDO), N,N-diethanolamine and N,N-diisopropanolaniline.

4. The composition according to claim 1, wherein said F-TPU polymer further comprises recurring units derived from at least one monomer (a), wherein monomer (a) is at least one diol selected from the group consisting of poly-ether type diol, poly-ester type diol, polybutadien-diol and polycarbonate-diol.

5. The composition according to claim 1, wherein said composition (C) comprises said F-TPU polymer in an amount of at least 0.01 wt. % and of at most 40 wt. % based on the total weight of said composition (C).

6. The composition according to claim 1, wherein said composition (C) comprises at least one further ingredient selected from the group consisting of: plasticizers; radiopaque materials; pigments; and dyes.

7. The composition according to claim 6, wherein each further ingredient is used in an amount from about 0.01 wt. % and up to 5 wt. %, based on 100 wt. % of said composition (C).

8. An article obtained from a composition (C) as defined in claim 1.

9. The article according to claim 8, wherein said article is a medical tubing.

10. The article of claim 9, wherein said medical tubing is selected from in the group consisting of catheters for blood transport and delivery, dialysis tubing, enteral feeding systems, oxygen tubing, drainage tubing, peristaltic pump tubing, central venous catheters (CVCs), peripherally inserted central catheters (PICCs or PIC lines), arterial lines, ports, renal infusion systems, drainage catheters and haemodialysis catheters.

11. A method for administering a medical substance to at least one cavity, duct or vessel of the human or animal body, said method comprising the use of the medical tubing as defined in claim 9.

12. A method for performing a surgical procedure in at least one cavity, duct or vessel of the human or animal body, said method comprising the use of a medical tubing as defined in claim 9.

13. A method for the extracorporeal treatment of a patient's body fluid, said method comprising the use of a medical tubing obtained from composition (C) as defined in claim 9.

14. The composition according to claim 6, wherein said plasticizer is selected from di-2-ethyl-hexyl-phthalate (DEHP), bis(2-ethyl-hexyl) adipate (DEHA), di-octyl adipate (DOA), butyryl-trihexyl-citrate (BTHC), acetyl-tributyl-citrate (ATBC), cyclohexane-1,2-dicarboxylic acid, dibutyl-sebacate (DBS), di-isononyl-ester (DINCH), di-isononyl-phthalate(DINP), di(2-ethyl-hexyl)-terephthalate (DEHT), tris(2-ethyl-hexyl) trimellitate (TOTM), or mixtures thereof; and wherein said radiopaque material is selected from bismuth subcarbonate, bismuth oxychloride, bismuth trioxide, tungsten or barium sulphate, or mixtures thereof.

15. The article according to claim 9, wherein said medical tubing comprises at least one elongated tubular structure having an internal surface and an external surface; a proximal end; a distal end; and at least one lumen.

Description

EXPERIMENTAL SECTION

(1) Materials and Methods:

(2) Monomer (a):

(3) PTMG 1000 Poly(tetramethylene ether)glycol-linear polyether glycol with hydroxyl groups on both ends having molecular weight (Mw) of about 1,000 and hydroxyl value of about 107˜118 mg KOH/g.

(4) Monomer (b) having formula:
H(OCH.sub.2CH.sub.2).sub.pOCH.sub.2CF.sub.2O(CF.sub.2CF.sub.2O).sub.m(CF.sub.2O).sub.nCF.sub.2CH.sub.2O(CH.sub.2CH.sub.2O).sub.pH

(5) with p=1.6, ratio m/n>1 and Mw of about 1,700.

(6) Monomer (c): diphenylen-4,4′-diisocyanate (MDI)

(7) Monomer (d): 1,4-butanediol (BDO)

(8) Catalyst: zinc neodecanoate

(9) Solvents (such as tetrahydro furan) and additives were obtained from Sigma-Aldrich.

(10) PVC medical grade for catheters in form of pellets (having Shore A=74) was obtained from TPV Compound S.r.l. (Italy).

(11) Commercially available PVC bloodline (hereinafter referred to as “catheter”) was purchased and used as such.

(12) Weight average molecular weight of the F-TPU polymers was determined by means of gel permeation chromatography (GPC) technique according to the following technique: a solution of the F-TPU polymer was prepared in tetrahydrofuran (THF) at 0.5% wt./vol. concentration; the solution was then centrifuged at 20,000 rpm for 60 minutes at room temperature using a Sorvall RC-6 Plus centrifuge and the supernatant was injected in the GPC apparatus; to correlate retention time and molecular weights, a calibration curve was calculated from narrow standards of polystyrene having molecular weights from 1,700 to 4,000,000 Da.

(13) Preparation of F-TPU Polymers

(14) F-TPU polymer specimen 1 and comparative H-TPU 1 were prepared starting from the abovementioned monomers following the same procedure detailed in Example 15 of U.S. Pat. No. 5,332,798 (AUSIMONT S.P.A.) cited above.

(15) The monomers were used in the molar ratios reported in the following

(16) Table 1.

(17) TABLE-US-00001 TABLE 1 Monomers (molar ratio) Sample a b c d F-TPU 1 0.75 0.25 3.0 2.0 H-TPU 1(*) 1.0 — 3.0 2.0 (*)comparative

(18) Preparation of the Mixtures

(19) 9 g of PVC in the form of pellets and 1 g of F-TPU 1 prepared as disclosed above were added to 40 g of THF under magnetic stirring.

(20) After 1.5 hours at 60° C., an homogenous solution was obtained (herein after referred to as ‘Mixture 1’).

(21) Using the same procedure, 10 g of PVC pellets were dissolved in 40 g of THF, thus obtaining comparative Mixture 2.

(22) Preparation of Films

(23) Flat homogenous films (having a thickness of about 35 microns) were prepared by filming each of Mixture 1 and Mixture 2 obtained as disclosed above, over a suitable smooth glass support by means of an automatized casting knife. After casting, the solvent was left to evaporate in an oven at 40° C. for 1 hour.

(24) Film 1 was obtained from Mixture 1 according to the present invention.

(25) Comparative Film 2C was obtained from comparative Mixture 2 (pure PVC).

(26) Preparation of a Coated Catheter

(27) A PVC catheter was coated by dipping it in a mixture at 10% by weight of F-TPU 1 in THF and drying it in an oven at 40° C. for 1 hour (Catheter 1).

(28) As comparison, PVC catheter 2C was used as obtained, without the coating.

Example 1

Measurement of Contact Angle (SCA)

(29) The contact angle towards water (H.sub.2O) and hexadecane (C16) was evaluated on the films and on the catheters obtained as described above at 25° C. by using the DSA10 instrument (from Krüss GmbH, Germany) according to ASTM D5725-99.

(30) The results are reported in the following Table 2.

(31) TABLE-US-00002 TABLE 2 SCA vs. SCA vs. Sample Ingredient(s) Amount (wt. %) H.sub.2O (°) C16 (°) Film 1 PVC 90 107 63 F-TPU 1 10 Film 2C(*) PVC 100 93 43 Catheter 1 PVC coated — 109 65 with FTPU 1 Catheter 2C(*) PVC — 96 44 (*)comparison

(32) The above results show that Film 1 and Catheter 1 according to the present invention are both more hydrophobic and more oleophobic than Film 2C(*) and Catheter 2C(*), manufactured with pure PVC.

Example 2

Evaluation of the Mechanical Properties

(33) The mechanical properties on Film 1 and Film 2C(*) were assessed at room temperature (23° C.) following ASTM D 638 standard procedure (type V, grip distance=25.4 mm, initial length Lo=21.5 mm). Velocity was set between 1 and 50 mm/min.

(34) The average results obtained for Film 1 and Film 2C prepared as disclosed above are summarized in the following Table 3.

(35) TABLE-US-00003 TABLE 3 Film No. Stress at break (MPa) Strain at break (%) 1 19.2 347 2C(*) 14.5 302 (*)comparison

(36) The above results show that Film 1 according to the present invention has improved mechanical properties than Film 2C(*) manufactured with pure PVC.

Example 3

Measurement of Coefficient of Friction (COF)

(37) By using LF Plus Lloyd Dinamometer, the coefficient of friction (COF) test according to ASTM D1894 was carried out on the Films, prepared as described above starting from each of Mixture 1 and Mixture 2.

(38) Three different measurements were performed, and the average value for each Film was evaluated.

(39) The results of static and dynamic COF are reported in following Table 4.

(40) TABLE-US-00004 TABLE 4 Film No. Static COF Dynamic COF 1 1.57 0.76 2C(*) 2.28 0.99 (*)comparison

(41) The above results showed that Film 1 according to the present invention had values of COF strongly reduced compared to Film 2C(*).

Example 4

Biocompatibility Tests

(42) The biocompatibility of F-TPU 1 obtained as described above was evaluated using human plasma as follows:

(43) cytotoxicity, by elution test according to ISO 10993-5:2009 (qualitative and quantitative evaluation);

(44) haemolysis, according to ASTM F756-13 (both direct and indirect contact);

(45) thrombogenicity according to EN ISO10993-4:20017, evaluating PT (Prothrombin time), uPTT (Partial thromboplastin time) and fibrinogen.

(46) The results demonstrated that F-TPU 1 must be considered not cytotoxic, not haemolytic and does not cause alteration in the human plasma.