阅读说明：本技术 碳酸酯连接的表面改性大分子 (Carbonate-linked surface-modified macromolecules ) 是由 J·P·桑特雷 S·木里克 于 2019-03-07 设计创作，主要内容包括：本发明涉及碳酸酯连接的表面改性大分子及其掺混物。所述大分子包含表面活性的多氟有机基基团、聚环氧烷基团和软链段。所述基团和链段通过碳酸酯键连接。所述掺混物可用于其中需要增强的表面性能(例如,降低或防止生物结垢、生物分子的固定或某些生物分子的变性的表面性能)的工业和医学应用。(The present invention relates to carbonate-linked surface-modified macromolecules and blends thereof. The macromolecule comprises surface active polyfluoro organic groups, poly (alkylene oxide) groups and soft segments. The groups and segments are linked by carbonate linkages. The blends are useful in industrial and medical applications where enhanced surface properties are desired (e.g., surface properties that reduce or prevent biofouling, immobilization of biomolecules, or denaturation of certain biomolecules).)

1. A compound of formula (I):

F_T–OC(O)O–B–OC(O)O–[A–OC(O)O–B]_n–OC(O)O–F_T(I)

wherein

(i) A comprises a soft segment and is covalently bonded to B via a carbonate bond;

(ii) b comprises a polyalkylene oxide or a moiety described by the formula:

and covalently bonded to a via a carbonate bond; and

(iii)F_Tis a surface-active radical comprising a polyfluoro organic radical, in which F_TCovalently bonded to via a carbonate bondB; and

(iv) n is an integer of 1 to 10.

2. The compound of claim 1, wherein B comprises polypropylene oxide, polyethylene oxide, or polytetrahydrofuran.

3. The compound of claim 1, wherein B is formed from triethylene glycol, tetraethylene glycol or bisphenol a.

4. The compound of any one of claims 1-3, wherein A comprises hydrogenated polybutadiene (HLBH), hydrogenated polyisoprene (HHTPI), poly ((2, 2-dimethyl) -1, 3-trimethylene carbonate), polybutadiene, poly (diethylene glycol) adipate (PEGA), poly (hexamethylene carbonate) (PHCN), poly (ethylene-co-butene), (diethylene glycol-phthalic anhydride) polyester, (1, 6-hexanediol-phthalic anhydride) polyester, (neopentyl glycol-phthalic anhydride) polyester (PDP), polysiloxane, bisphenol a ethoxylate, poly (ethylene oxide) -b-poly (propylene oxide) -b-poly (ethylene oxide) (PLN), polyethylene oxide (PEO), polypropylene oxide (PPO) or Polytetrahydrofuran (PTMO).

5. The compound of claim 1, wherein the compound of formula (I) is further described by formula (II):

F_T–OC(O)O–(CH₂CH₂O)_m–OC(O)O–[A–OC(O)O–(CH₂CH₂O)_m]_n–OC(O)O–F_T(II)

wherein

(i) A comprises a soft segment;

(ii)F_Tis a surface active group comprising a polyfluoro organic group;

(iii) m is an integer from 2 to 4; and

(iv) n is an integer of 1 to 10.

6. The compound of claim 5, wherein A comprises hydrogenated polybutadiene (HLBH), hydrogenated polyisoprene (HHTPI), poly ((2, 2-dimethyl) -1, 3-trimethylene carbonate), polybutadiene, poly (diethylene glycol) adipate (PEGA), poly (hexamethylene carbonate) (PHCN), poly (ethylene-co-butylene), (diethylene glycol-phthalic anhydride) polyester (PDP), (1, 6-hexanediol-phthalic anhydride) polyester, (neopentyl glycol-phthalic anhydride) polyester, polysiloxane, bisphenol a ethoxylate, poly (ethylene oxide) -b-poly (propylene oxide) -b-poly (ethylene oxide) (PLN), polyethylene oxide (PEO), polypropylene oxide (PPO) or Polytetrahydrofuran (PTMO).

7. The compound of claim 6, wherein a comprises the triblock copolymer PPO-b-PEO-b- (polysiloxane) -b-PEO-b-PPO (plnsi).

8. The compound of claim 6, wherein a comprises hydrogenated polyisoprene (HHTPI) or hydrogenated polybutadiene (HLBH).

9. The compound of claim 6, wherein A comprises polypropylene oxide (PPO) or Polytetrahydrofuran (PTMO).

10. The compound of claim 6, wherein A comprises polyethylene oxide-polydimethylsiloxane-polyethylene oxide (C10 MW)_PEO2,500Da), polyethylene oxide-polydimethylsiloxane-polyethylene oxide (C15 MW)_PEO1,000Da) or polyethylene oxide-polydimethylsiloxane-polyethylene oxide (C22 MW)_PEO＝2,500Da)。

11. The compound of claim 6, wherein A comprises a propylene oxide-polydimethylsiloxane-propylene oxide block copolymer (C22 MW)_PPO＝2,500Da)。

12. The compound of claim 6, wherein A comprises polyethylene oxide (PEO).

13. The compound of claim 6, wherein A comprises diethylene glycol-phthalic anhydride.

14. The compound of claim 6, wherein A comprises poly (ethylene oxide) -b-poly (propylene oxide) -b-poly (ethylene oxide) (PLN).

15. The compound of any one of claims 1-5, wherein A has no ester linkage.

16. The compound of claim 5, wherein A comprises hydrogenated polybutadiene (HLBH), hydrogenated polyisoprene (HHTPI), poly ((2, 2-dimethyl) -1, 3-propylene carbonate), polybutadiene, poly (ethylene-co-butylene), polysiloxane, bisphenol A ethoxylate, poly (ethylene oxide) -b-poly (propylene oxide) -b-poly (ethylene oxide) (PLN), polyethylene oxide (PEO), polypropylene oxide (PPO), or Polytetrahydrofuran (PTMO).

17. A compound of formula (III):

wherein:

(i)F_Tis a polyfluoro organic radical;

(ii)X₁and X₂Is independently H, CH₃Or CH₂CH₃；

(iii) B comprises a polyalkylene oxide; and

(v) n is an integer of 5 to 100.

18. The compound of claim 17, wherein B comprises polypropylene oxide, polyethylene oxide, or polytetrahydrofuran.

19. The compound of claim 18, wherein B is formed from triethylene glycol or tetraethylene glycol.

20. The compound of claim 17 wherein B is polyethylene oxide and X₁Is ethyl, and X₂Is H (YMEROH-1226-PCT-PC).

21. The compound of claim 17, wherein B is polyethylene oxide,X₁is ethyl, and X₂Is methyl (YMer-1226-PCT-PC).

22. A compound of formula (IV):

wherein:

(i) each F_TIs a polyfluoro organic radical;

(ii)X₁and X₂Is independently H, CH₃Or CH₂CH₃；

(iii) B comprises a polyalkylene oxide; and

(iv) each of n1 and n2 is independently an integer from 5 to 50.

23. The compound of claim 22, wherein B comprises polypropylene oxide, polyethylene oxide, or polytetrahydrofuran.

24. The compound of claim 23, wherein B is formed from triethylene glycol or tetraethylene glycol.

25. The compound of claim 22, wherein B is polyethylene oxide and X₁Is H, and X₂Is H (XMer-1226-PCT-PC).

Technical Field

The present invention relates to surface-modifying macromolecules (SMM) and blends thereof with base polymers. The blends may be used in applications where enhanced surface properties (e.g., surface properties that reduce or prevent biofouling, immobilization of biomolecules, or denaturation of certain biomolecules) are desired, for example, in industrial and medical applications.

Background

Wetted surfaces may be susceptible to interaction with biological agents such as proteins, nucleic acids, and living organisms. These interactions can lead to degradation of the adsorption of biological agents (e.g., proteins or nucleic acids). These interactions may also lead to surface fouling by water components such as biomolecules, living organisms (e.g. bacteria), dissolved inorganic or organic compounds, colloids and suspended solids. Biofouling can be attributed to the accumulation of extracellular material, such as soluble microbial products and extracellular polymeric substances, such as polysaccharides and proteins (see, e.g., Asatekin et al, Journal of Membrane Science, 285:81-89, 2006). For example, membranes used in industrial water filtration or in medical applications (e.g. in dialysis) may be subject to fouling due to e.g. adsorption of proteins, attachment of suspended particles or precipitated salts to the membrane. Other examples of fouling in biomedical applications may often be caused by, for example, cell and pathogen attachment to the surface of a medical device (e.g., a catheter or other implantable medical device), and such fouling may have potentially adverse consequences. Fouling may also be evident on marine vessel hulls, which may be covered by marine organisms or their secretions.

Thus, compositions and blends having surface properties that reduce or prevent biofouling, immobilization of biomolecules, or denaturation of certain biomolecules are useful in a variety of industrial and medical applications.

Disclosure of Invention

Drawings

FIG. 1 shows the structure of Compound (1).

FIG. 2 shows the structure of Compound (2).

FIG. 3 shows the structure of Compound (3).

FIG. 4 shows the structure of Compound (4).

FIG. 5 shows the structure of Compound (5).

FIG. 6 shows the structure of Compound (6).

FIG. 7 shows the structure of Compound (7).

FIG. 8 shows the structure of Compound (8).

Fig. 9 shows the structure of compound (9).

Detailed Description

In general, the present invention provides surface-modifying macromolecules (SMM) whose structure is based on the linking of an oligo-segment to a surface-active group via a linker having at least one carbonate bond. The surface-modifying macromolecule of the present invention can have a structure of any of formulae (I) - (IV) described herein (e.g., the surface-modifying macromolecule of the present invention can be any of compounds (1) - (9)).

The present invention provides carbonate linkages that can introduce hydrophilic surface energy in the base polymer that, despite migration of the highly hydrophobic fluoroalkyl end groups to the surface, undergo rearrangement to expose hydrophilic ethylene oxide groups present in the carbonate linkages.

Typically, urethanes are hydrogen donors that tend to aggregate together due to self-hydrogen bonding. As a result, such carbamates can have high contact angles, are primarily hydrophobic, and present challenges in interacting with water, which is an important criterion for imparting anti-biofouling properties to surfaces using SMM. In contrast, the present disclosure describes hydrophilic compounds that include polyethylene oxide units in combination with carbonate linkages (e.g., fig. 1). The hydrophilic character of carbonate-linked SMMs may be important compared to traditional polyurethanes because they attract water and provide anti-biofouling properties.

The compounds of the invention may be hydrolytically stable compared to the corresponding compounds in which the carbonate bond is replaced by an ester bond.

In particular, the present invention provides blends of base polymers and surface-modifying macromolecules and articles made therefrom. In some embodiments, more than one SMM comprising carbonate is used in a blend with a base polymer. The articles of the present invention may exhibit advantageous surface properties relative to articles lacking the surface modifying macromolecule. For example, the surface properties may be modified to render such surfaces resistant to biofouling, immobilization of biomolecules, or mediation of biomolecule denaturation. Biofouling can be attributed to the accumulation of extracellular material, such as soluble microbial products and extracellular polymeric materials, such as polysaccharides and proteins (e.g., Asatekin et al, Journal of Membrane Science, 285:81-89, 2006). In particular, the surfaces of the present invention may be resistant to fouling (e.g., biofouling). The surfaces of the invention can also reduce degradation (e.g., by adsorption or denaturation) of a biological agent (e.g., a polypeptide (e.g., a monoclonal antibody or antigen-binding fragment thereof), a polynucleotide (e.g., an siRNA or antisense compound), or a vaccine); the degradation may be due to interaction between the biological agent and the surface lacking the surface-modifying macromolecule. Without being bound by theory, the inclusion of the surface modifying macromolecule may alter the wettability (with water) of the surface, thereby reducing contact between a biological agent (e.g., a protein, nucleic acid, or bacteria) and the surface. The surface of the invention may be capable of sustaining prolonged contact with a biological product without causing substantial denaturation or immobilization, for example, the biological product may be abeucapt (abatacept), interferon beta-1 a or insulin. In particular, these and other biologics may benefit from the surface properties of the present invention that reduce or prevent undesirable interactions between the surface and the biologics (e.g., immobilization and/or denaturation of the biologics). Alternatively, the inclusion of the surface modifying macromolecule may increase surface wettability (with water). Such materials are useful in applications requiring a hydrophilic surface.

It is believed that the desirable surface properties in the articles of the present invention are provided by the surface-modifying macromolecule of the present invention, which migrates to the surface of the article during manufacture, thereby exposing the surface-active groups at the surface of the article. The surface active groups may be responsible, in part, for carrying the surface modifying macromolecule to the surface of the blend where the surface active groups are exposed on the surface. The migration of the surface modifying macromolecule to the surface is a dynamic process and depends on the surface environment. The process of migration is driven by the tendency to build up low surface energy at the surface of the mixture. When equilibrium is reached between anchoring and surface migration, the surface-modified macromolecule remains stable at the polymer surface while at the same time changing the surface properties. Anchoring within the base polymer may be provided by oligomeric segments.

Aggregation of multiple oligomer molecules can increase their effective molecular radius, thereby reducing the permeability of the oligomer molecules through the base polymer. The effectiveness of surface property modification can be improved by the surface modifying macromolecules of the present invention. By excluding the combination of hydrogen bond donors and acceptors within the same molecule, the ability of the surface-modifying macromolecule of the invention to migrate to the surface of the article may be enhanced due to the potential for reduced aggregation. Furthermore, SMMs comprising carbonate linkages may exhibit increased stability compared to SMMs having ester linkages due to greater stability against hydrolytic degradation of the carbonate linkages. The surface-modified macromolecules of the invention may exhibit enhanced ability to migrate to the surface of the article without compromising their anchoring in the base polymer. Thus, certain surface-modifying macromolecules of the invention do not contain hydrogen bond donors (e.g., O-H, N-H or S-H moieties). In particular, the surface-modifying macromolecule may be free of urethane moieties.

The choice of a particular SMM and a particular base polymer combination may be determined by a number of factors. First, the type and amount of SMM to be added to the base polymer depends in part on whether the blend forms a single stable phase in which the SMM is soluble (e.g., separating the blend to form two or more distinct phases would indicate an unstable solution). The compatibility of the blend can then be tested by various known analytical methods. The surface as a film or as a blend of fibers can be analyzed by any available spectroscopic method, such as X-ray photoelectron spectroscopy (XPS) with Elemental Analysis (EA). The data from XPS may indicate the extent to which the surface is modified by the migrating SMM, and the data from EA may indicate the extent to which the bulk material is modified. The stable blends can then be tested to determine the surface's anti-fouling performance under various conditions.

In particular embodiments, the surface modification can maintain transparency relative to the neat base polymer. Inclusion of blends in the base polymer can often result in compromised optical properties (e.g., lower transparency), thereby limiting the utility of such materials in applications where transparency of the material is desired. In contrast, an article of the present invention comprising a surface-modified macromolecule and a base polymer can have the same or slightly lower transparency as the neat base polymer.

The articles of the present invention can be prepared, at least in part, from the base polymer using processes that require high temperature processing (e.g., extrusion or molding). For example, COC and COP often require processing temperatures greater than 200 ℃ (e.g., greater than or equal to 250 ℃, or greater than or equal to 300 ℃). Some of the compounds of the invention, for example PDP-1226PCT (Tg 314 ℃), are suitable for high temperature processing. The surface-modifying macromolecule described herein can be thermally stable (e.g., can have a thermal degradation temperature of greater than or equal to 200 ℃ (e.g., greater than or equal to 250 ℃ or greater than or equal to 300 ℃). Thus, the articles of the present invention can be formed from a blend of a base polymer and a surface-modifying macromolecule at a temperature greater than 200 ℃ (e.g., greater than or equal to 250 ℃ or greater than or equal to 300 ℃). Articles of the invention can be made from blends of base polymers and surface-modifying macromolecules (e.g., by high temperature processing, such as melt processing). The surface modifying macromolecule may be added prior to melt processing of the base polymer to make the article of the present invention. To form a blend by melt processing, the surface-modifying macromolecule may, for example, be mixed with a granulated or powdered polymer and then melt processed by known methods (e.g., molding or melt extrusion). The surface modifying macromolecule may be mixed directly with the polymer under melt conditions, or may be premixed with the polymer first in a brabender mixer as a masterbatch of surface modifying macromolecule/polymer blend. If desired, the organic solution of the surface-modifying macromolecule can be mixed with the powdered or granulated base polymer, followed by evaporation of the solvent, and then melt processing. Alternatively, the surface modifying macromolecule may be injected into a molten polymer stream to form a blend immediately prior to extrusion into the desired shape.

After melt processing, an annealing step may be performed to enhance the development of the beneficial properties described herein in the base polymer. In addition to or instead of the annealing step, the melt processed combination may also be embossed between two heated rollers, one or both of which may be patterned. The annealing step is typically performed below the melting temperature of the polymer (e.g., at about 50 ℃ to about 220 ℃).

The surface modifying macromolecule is added to the base polymer in an amount sufficient to achieve the surface properties required for a particular application. Typically, the amount of surface modifying macromolecule used is in the range of 0.05 to 15% (weight/weight) of the blend. The amount can be determined empirically and can be adjusted as needed or desired to achieve the desired surface properties without compromising other physical properties of the base polymer.

Surface-modified macromolecules

The surface-modifying macromolecule of the present invention may be a compound of any of formulas (I), (II), (III), and (IV).

The surface-modified macromolecule of the invention may be a compound of formula (I):

F_T–OC(O)O–B–OC(O)O–[A–OC(O)O–B]_n–OC(O)O–F_T(I)，

wherein

A comprises a soft segment and is covalently bonded to B via a carbonate bond;

b comprises a polyalkylene oxide or a moiety described by the formula:

and covalently bonded to a via a carbonate bond; and

F_Tis a surface-active radical comprising a polyfluoro organic radical, in which F_TCovalent bonding to B via a carbonate bond; and

n is an integer of 1 to 10.

In particular, the compound of formula (I) may be a compound of formula (II):

F_T–OC(O)O–(CH₂CH₂O)_m–OC(O)O–[A–OC(O)O–(CH₂CH₂O)_m]_n–OC(O)O–F_T(II)，

wherein

A comprises a soft segment;

F_Tis a surface active group comprising a polyfluoro organic group;

m is an integer from 2 to 4; and

n is an integer of 1 to 10.

The surface-modified macromolecule of the invention may be a compound of formula (III):

wherein

F_TIs a polyfluoro organic radical;

X₁and X₂Is independently H, CH₃Or CH₂CH₃；

B comprises a polyalkylene oxide; and

n is an integer of 5 to 100.

The surface-modified macromolecule of the invention may be a compound of formula (IV):

wherein

Each F_TIs a polyfluoro organic radical;

X₁and X₂Is independently H, CH₃Or CH₂CH₃；

B comprises a polyalkylene oxide; and

each of n1 and n2 is independently an integer from 5 to 50.

Oligomeric chain segments

The surface-modified macromolecules of the invention may be prepared from oligo-segmented diols, triols or tetrols. Because the reactions are sensitive to moisture, they are usually in an inert N₂Under atmosphere and under anhydrous conditions. The resulting surface-modified macromolecule may be isolated and purified where appropriate. The surface-modified macromolecule of formula (III) or (IV) can be terminated, for example, by a commercially available mono-dihydroxy substituted alkyl or alkoxyalkyl PEG (e.g., Ymer)^TMN120, a difunctional polyethylene glycol monomethyl ether from Perstorp). Exemplary oligo-segment diols, triols, and tetrols are shown below.

Scheme 1 shows a non-limiting example of a structure of an oligo-segmented triol that can be used to prepare a surface-modified macromolecule of formula (III):

scheme 1

Polyol 3165(Perstorp)

Trimethylolpropane ethoxylate

MW＝1,000Da

Scheme 2 shows some of the oligo-segmented diols that can be used to prepare compounds of formula (I) or (II):

scheme 2

PLN ═ Pluronics (Pluronics)

PDP diols

Scheme 3 shows some of the oligomeric segmented diols that can be used to prepare compounds of formula (II):

scheme 3

C15 siloxane diol

MW＝1,000Da

Hydroxy-terminated polydimethylsiloxane (EtO-PDMS-OEt) block copolymer (m ═ 1, n is an integer)

C22 siloxane diol

MW＝2,500-3,000Da

Hydroxy-terminated polydimethylsiloxane (PrO-PDMS-OPr) block copolymer (m ═

12-16, n is an integer)

C25 siloxane diol

MW＝3,500Da

Hydroxy-terminated polydimethylsiloxane (EtO-PDMS-OEt) block copolymer (m ═ 25, n is an integer)

Diols known in the art can be used to prepare compounds of formula (I) or (II). For example, the diol of the oligomeric segment may be selected from the group consisting of polyureas, polyurethanes, polyamides, polyalkylene oxides, polycarbonates, polyesters, polylactones, silicone polymers, polyethersulfones, polyalkylenes, polyvinyls, polypolysaccharides, or ether-linked or amine-linked segments thereof (e.g., the segments may in this case refer to the repeat units in the listed oligomers).

Synthesis of

The compounds of the present invention can be prepared using methods similar to those described in the examples starting from appropriately selected reagents (e.g., dicarboxylic acid derivatives, diols, and fluorinated alcohols) to form a wide range of carbonate-based surface-modifying macromolecules.

Article of manufacture

The present invention also provides articles formed from the blends of the present invention. Articles that can be formed using the blends of the present invention include, but are not limited to, surgical caps, surgical drapes, masks, gloves, surgical drapes, filters (e.g., portions of respirators, water filters, air filters, or masks), cables, films, panels, pipes, fibers, sheets, and implantable medical devices (e.g., heart assist devices, catheters, stents, prosthetic implants, artificial sphincters, or drug delivery devices).

The surface modifiers and blends of the present invention are useful in film and nonwoven applications, for example, surgical drapes, gowns, masks, wraps, bandages, and other protective wear garments for medical technicians (e.g., coveralls, lab coats) that require high temperature processing often in excess of 200 ℃ in the form of extruded articles (e.g., thermoplastic films, thermoplastic fibers, fibrous nonwovens, thermoplastic foams, etc.) where processing temperatures can reach the range of 250 ℃ to 300 ℃. In a particular embodiment, the surface modifying agent used in the nonwoven application is formed from bisphenol a. The surface modifiers and blends of the present invention may also be used in implantable medical devices (e.g., central venous catheters to impart reduced occlusive properties and enhanced hemocompatibility). The surface modifiers and blends of the present invention may also be used in hollow fiber membrane filtration made from polyethylene, polypropylene or polysiloxane base polymers for fluid or gas separation.

The surface modifying agents and blends of the present invention may have the desired high temperature stability during processing in the manufacture of nonwoven fabrics or compatibility with the polymers used in the manufacture of catheters. The blends of the present invention may have desirable high temperature stability during processing. In a particular embodiment, the surface modifying agent suitable for high temperature processing is formed from bisphenol a. Thus, the blends can provide the desired resistance to degradation at high temperatures while providing the desired biocompatible properties, such as resistance to biofouling, resistance to immobilization of anti-biomolecules on a surface, and resistance to mediated denaturation of biomolecules. The technique may include incorporating SMM into the base polymer, which then re-bloom to the surface, thus modifying the surface of the polymer, but leaving bulk properties intact. The fluorinated surface of the base polymer is now highly hydrophobic. Articles that can be formed from the blends of the present invention include implanted medical devices that can be transdermal or percutaneous.

Implanted device

Devices that may be formed from the blends of the present invention include implanted devices. Implanted devices include, but are not limited to, prostheses such as pacemakers, electrical leads such as pacing leads, defibrillators, artificial hearts, ventricular assist devices, anatomical reconstruction prostheses such as breast implants, artificial heart valves, heart valve stents, pericardial patches, surgical patches, coronary stents, vascular grafts, vascular and structural stents, vascular or cardiovascular shunts, biological conduits, gauzes (pledges), sutures, annuloplasty rings, stents, staples (staples), valve grafts, dermal grafts for wound healing, orthopedic spinal implants, orthopedic needles, intrauterine devices, urinary system stents, maxifacial reconstruction plates, dental implants, intraocular lenses, clips, sternum wires, bones, skin, ligaments, tendons, and combinations thereof. Transdermal devices include, but are not limited to, various types of catheters, cannulas, drains, such as chest tubes, surgical instruments, such as forceps, retractors, needles and gloves, and catheter sheaths. Skin devices include, but are not limited to, burn dressings, wound dressings, and dental hardware, such as dental bridge braces and support assemblies.

Exemplary uses of medical devices modified with SMM, as described herein, include uses as biosensors, catheters, heart valves, orthopedic implants, ureteral stents, ventilation tubes, and drug delivery devices. In a particular embodiment, a blend is used in the manufacture of a catheter that includes a surface modifier that includes a polysiloxane as a soft segment.

Detailed Description