WO2009131931A1 - Nitric oxide-releasing compositions, devices and methods - Google Patents
Nitric oxide-releasing compositions, devices and methods Download PDFInfo
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- WO2009131931A1 WO2009131931A1 PCT/US2009/041090 US2009041090W WO2009131931A1 WO 2009131931 A1 WO2009131931 A1 WO 2009131931A1 US 2009041090 W US2009041090 W US 2009041090W WO 2009131931 A1 WO2009131931 A1 WO 2009131931A1
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Definitions
- Nitric oxide is a short-lived, gaseous free radical signaling molecule that regulates many important physiological processes, including circulation, angiogenesis, wound healing, immune responses, neurotransmission, cell signaling, cell proliferation, and cell survival. NO deficiencies are associated with multiple pathological conditions, including hypertension, atherosclerosis, and chronic wounds.
- NO is generated in vivo by the action of nitric oxide synthases on L-arginine. Because NO degrades quickly in vivo (ty 2 ⁇ 5 sec), endogenous S-nitrosothiols serve an important role in the body to regulate NO concentrations. These nitrosothiols, which can release NO, are formed when NO is bound in vivo to thiolated molecules such as serum albumin, cysteine and glutathione.
- Certain exogenous NO donor materials which can chemically store and release NO, have been proposed for therapeutic use.
- Such materials include NO donating groups such as nitrosothiols, diazeniumdiolates, nitrosamines, NO-metal complexes, and organic nitrites and nitrates.
- NO donating groups such as nitrosothiols, diazeniumdiolates, nitrosamines, NO-metal complexes, and organic nitrites and nitrates.
- N-diazeniumdiolate NO donor materials have been given considerable attention because they are stable under ambient conditions, and can decompose in aqueous media to generate NO.
- nitrosothiol groups attached to a solid amorphous silica surface of silica nanoparticles have improved stability and can deliver NO.
- the silica nanoparticles are dispersible in an aqueous system, and for certain embodiment, the nanoparticles are distributed in a hydrogel monomer or a hydrogel.
- Such compositions can be used to release NO to a surface or to an adjacent mammalian tissue to provide a therapeutic effect, such as to promote healing in certain types of wounds, provide an antimicrobial effect, inhibit platelet adhesion and blood coagulation, stimulate angiogenesis, or to enhance blood flow to increase absorption of a drug.
- compositions for releasing nitric oxide comprising nanoparticles having an exterior surface comprising solid amorphous silica, wherein nitrosothiol-containing groups are attached to the surface, and wherein the nanoparticles are dispersible in an aqueous system.
- a medical device comprising a surface and a composition for releasing nitric oxide adjacent the surface, the composition comprising nanoparticles having an exterior surface comprising solid amorphous silica, wherein nitrosothiol-containing groups are attached to the surface, and wherein the nanoparticles are dispersible in an aqueous system.
- a product comprising the above medical device and a package impervious to water, water vapor, ultraviolet light, and visible light, wherein the composition for releasing nitric oxide is enveloped by the package.
- a method of treating a subject with nitric oxide comprising: providing a composition for releasing nitric oxide, the composition comprising nanoparticles having an exterior surface comprising solid amorphous silica, wherein nitrosothiol-containing groups are attached to the surface, and wherein the nanoparticles are dispersible in an aqueous system; contacting the subject with the composition; and releasing nitric oxide at a location where the composition or the medical device contacts the subject.
- a method of treating a subject with nitric oxide comprising: providing a medical device comprising a surface and a composition for releasing nitric oxide adjacent the surface, the composition comprising nanoparticles having an exterior surface comprising solid amorphous silica, wherein nitrosothiol-containing groups are attached to the surface, and wherein the nanoparticles are dispersible in an aqueous system; contacting the subject with the medical device; and releasing nitric oxide at a location where the medical device contacts the subject.
- kits comprising a composition for releasing nitric oxide; the composition comprising nanoparticles having an exterior surface comprising solid amorphous silica, wherein nitrosothiol-containing groups are attached to the surface, and wherein the nanoparticles are dispersible in an aqueous system; and an activating agent.
- a composition for releasing nitric oxide comprising: providing solid amorphous silica nanoparticles; bonding thiol-containing groups to an exterior surface of the solid amorphous silica nanoparticles; bonding stabilizing groups comprising hydrophilic groups to the exterior surface of the solid amorphous silica nanoparticles; and nitrosylating the thiol-containing groups to form nitrosothiol-containing groups.
- compositions for releasing nitric oxide comprising: a first part comprising nanoparticles having an exterior surface comprising solid amorphous silica, wherein thiol-containing groups are attached to the surface, and wherein the nanoparticles are dispersible in an aqueous system; and a second part comprising a nitrite source.
- a medical device comprising a surface and a composition for releasing nitric oxide adjacent the surface; the composition comprising: a first part comprising nanoparticles having an exterior surface comprising solid amorphous silica, wherein thiol-containing groups are attached to the surface, and wherein the nanoparticles are dispersible in an aqueous system; and a second part comprising a nitrite source.
- a method of treating a subject with nitric oxide comprising: providing a composition for releasing nitric oxide, the composition comprising: a first part comprising nanoparticles having an exterior surface comprising solid amorphous silica, wherein thiol-containing groups are attached to the surface, and wherein the nanoparticles are dispersible in an aqueous system; and a second part comprising a nitrite source; combining the first part of the composition with the second part of the composition to provide a composition, wherein nitrosothiol-containing groups are attached to the surface of the nanoparticles; contacting the subject with the composition for releasing nitric oxide; and releasing nitric oxide at a location where the composition contacts the subject.
- a method of treating a subject with nitric oxide comprising: providing a medical device comprising a surface and a composition for releasing nitric oxide adjacent the surface; the composition comprising: a first part comprising nanoparticles having an exterior surface comprising solid amorphous silica, wherein thiol- containing groups are attached to the surface, and wherein the nanoparticles are dispersible in an aqueous system; and a second part comprising a nitrite source; combining the first part of the composition with the second part of the composition to provide a composition, wherein nitrosothiol-containing groups are attached to the surface of the nanoparticles; contacting the subject with the medical device; and releasing nitric oxide at a location where the medical device contacts the subject.
- solid amorphous silica refers to a fully densified silica, which is typically made by condensing a silicate, for example, sodium silicate, tetraethyl orthosilicate, or tetramethyl orthosilicate, under basic conditions, for example, at a pH of about 8 to about 10. This is distinguished from a co-condensed silica, for example, co- condensation of tetraethyl orthosilicate with a di- or tri-aminoalkoxysilane, which is porous and not fully densified.
- a silicate for example, sodium silicate, tetraethyl orthosilicate, or tetramethyl orthosilicate
- solid amorphous silica nanoparticles refers to essentially spherically shaped, fully densified silica particles having a diameter of about 1 nanometer to about 100 nanometers. These nanoparticles remain substantially non-aggregated.
- the nanoparticles are relatively uniform in size.
- the nanoparticles are a mixture of two or more different sizes and are polydispersed.
- the term "dispersible in an aqueous system” indicates that the material which is dispersible, for example, the nanoparticles, can be uniformly and stably suspended in an aqueous system.
- Stably suspended means that the dispersion remains uniform with no apparent settling when held at 23 0 C for at least one week.
- Such mixtures are transparent or translucent and remain so with the nanoparticles suspended for weeks, preferably months, or even longer.
- aqueous system refers to a combination of water and at least one water dispersible compound.
- water dispersible compound refers to a compound which can be uniformly and stably suspended or dissolved in water.
- hydrogel refers to a hydrophilic polymer that absorbs water, but which is insoluble in water because of the presence of a three-dimensional network formed from crosslinks.
- the crosslinks may be covalent or ionic.
- the crosslinks may alternatively or additionally be hydrogen bonds and/or polymer chain entanglements.
- the hydrogel behaves as a solid or semisolid in that it will not flow under ambient conditions (23 0 C and atmospheric pressure).
- the absorbed water can include bound water and free water. Bound water is associated with hydrophilic groups located along the polymer chain. Additional water that is absorbed by the hydrogel is free water which fills the voids and pores of the hydrogel.
- useful hydrogels absorb at least 40% by weight based on the hydrogel's weight in an anhydrous state.
- the hydrogels are typically transparent or translucent, regardless of their degree of hydration.
- Hydrogels are generally distinguishable from hydrocolloids, which typically comprise a hydrophobic matrix that contains dispersed hydrophilic particles.
- substantially dehydrated refers to a hydrogel which contains at most about 10 percent by weight of water, preferably at most about 5 percent by weight of water.
- the term “transparent” refers to a characteristic of the composition which allows a person to sufficiently see through the composition, such that a condition of a tissue or other structure immediately behind the composition can be observed. Examples of conditions that may be observed include a degree of redness of the tissue, a degree of closure of a wound, and an amount of wound exudate.
- transparent refers to the appearance to the naked eye when viewed through a 0.5 cm, preferably a 1 cm length path cell, and includes clear and translucent, although clear is preferred.
- the term “fluid” refers to a material which is a liquid in the temperature range of room temperature to body temperature.
- aqueous composition refers to a liquid composition comprised of at least 50 percent by weight of water.
- amphiphilic compound refers to a compound which has both a hydrophilic region and a hydrophobic region.
- the present invention provides nanoparticles with a solid amorphous silica surface to which nitrosothiol groups are attached.
- the silica nanoparticles are dispersible in an aqueous system and can be dispersed in a hydrogel for use as a wound dressing or for other therapeutic applications.
- the nanoparticles can release nitric oxide (NO). Moreover, the rate of NO release has been found to be more controlled than that of small molecule nitrosothiols.
- the nitrosothiol groups on the nanoparticles have a half-life on the order of days or weeks in an aqueous system, and can have a considerably longer half-life in a dehydrated composition.
- small molecule nitrosothiols are known to have half-lives on the order of minutes to days.
- compositions for releasing nitric oxide comprising nanoparticles having an exterior surface comprising solid amorphous silica, wherein nitrosothiol-containing groups are attached to the surface, and wherein the nanoparticles are dispersible in an aqueous system.
- Two-part compositions for releasing nitric oxide may be desirable under certain circumstances, for example, where storage conditions are severe or uncontrolled.
- compositions for releasing nitric oxide comprising: a first part comprising nanoparticles having an exterior surface comprising solid amorphous silica, wherein thiol-containing groups are attached to the surface, and wherein the nanoparticles are dispersible in an aqueous system; and a second part comprising a nitrite source.
- a fluid can be used to facilitate combining the second part of the composition with the first part of the composition.
- a fluid can provide flow of the second part to the first part as well as mixing of the second part with the first part or diffusion of the second part into the first part.
- the fluid is an aqueous composition.
- the nitrite source is in an aqueous composition.
- Suitable aqueous compositions contain at least 50 percent by weight of water, preferably at least 75 or at least 90 percent by weight of water.
- the nitrite source is a nitrite salt.
- Suitable nitrite salts include, for example, sodium, potassium, and ammonium salts.
- Ammonium salts include NR 4 + where R is hydrogen, Ci_ 4 alkyl, or a combination there.
- nitrous acid or a combination of nitrous acid and a nitrite salt is used for nitrosylating the thiol-containing groups.
- the aqueous system has an acidic pH.
- the acidic pH provides favorable conditions for the nitrosylation, which consumes H + in the formation of the nitrosothiol groups.
- the pH is preferably less than or equal to about 6 or about 5.
- the pH is at least about 2 or about 3.
- the nanoparticles are solid amorphous silica nanoparticles.
- the solid amorphous silica nanoparticles are substantially spherical in shape, have a diameter of about 1 nanometer to about 100 nanometers, and, except for groups attached to the surface, are composed essentially of fully densif ⁇ ed amorphous silica. These nanoparticles are relatively uniform in size, or a mixture of sizes can be used. These nanoparticles remain substantially non- aggregated, for example, as a colloidal dispersion. Aggregation is undesirable, because it can result in precipitation, gelation, or a substantial increase in viscosity.
- Silica nanoparticles which can be used as starting materials in preparing the present compositions, can be provided as a colloidal dispersion of the nanoparticles in a liquid media.
- Such sols can be hydrosols where water is the liquid media or mixed sols where the liquid media comprises both water and an organic liquid. See, for example, the descriptions of the techniques and forms given in U.S. Patent Nos. 2,801,185 (Her) and 4,522,968 (Das et al.) as well as those given by R. K. Her in The Chemistry of Silica, John Wiley & Sons, New York (1979).
- Useful silica hydrosols are available in a variety of particle sizes and concentrations from, e.g., Nyacol Products, Inc.
- silica hydrosols can be prepared, for example, by partially neutralizing an aqueous solution of an alkali metal silicate with acid to a pH of about 8 to about 9 (such that the resulting sodium content of the solution is less than about 1 percent by weight based on sodium oxide).
- Other methods of preparing silica hydrosols such as electrodialysis, ion exchange of sodium silicate, hydrolysis of silicon compounds, and dissolution of elemental silicon, are described by Her, supra.
- the solid amorphous silica nanoparticles have a density of about 2.0 to about 2.3 grams/cm 3 .
- the density of the solid amorphous silica nanoparticles is about 2.1 to about 2.2.
- the density of the solid amorphous silica nanoparticles is about 2.2.
- the nanoparticles have an exterior surface comprising solid amorphous silica which surrounds a core, and wherein the core comprises a metal oxide selected from the group consisting of zirconium oxide, titanium oxide, aluminum oxide, zinc oxide, and cerium oxide.
- the core comprises a metal oxide selected from the group consisting of zirconium oxide, titanium oxide, aluminum oxide, zinc oxide, and cerium oxide.
- Such nanoparticles can be made by starting with colloidal particles of the metal oxide and depositing solid amorphous silica on the surface of the colloidal particles. This can be done by condensing a silicate, as described above, on the surface of the colloidal particles. Methods for depositing a silica layer on a particle are known and described, for example, in Philipse, et al, Langmuir, 10, 4451-4458 (1994).
- nitrosothiol groups include the -S-NO functional group.
- These functional groups can be covalently attached to the surface of the nanoparticles via a tether group, for example, by Si-O-Si bonds.
- Si-OH groups on the surface of the nanoparticles can be condensed with a Si-OH group bonded to a tether group to which a -S-NO group is bonded.
- H-S-Y-Si(OR. ⁇ ) is used for this purpose, wherein R 1 is Ci_ 3 alkyl, and Y is a tether group having a chain length of 2 to 10 atoms, and wherein the atoms in the chain can be carbon, oxygen, and nitrogen, at least two of the atoms in the chain being adjacent carbon atoms, and any two oxygen atoms, nitrogen atoms, or oxygen and nitrogen atoms being separated by at least two carbon atoms.
- Y is C2-6 alkylene.
- the alkoxysilyl -Si(OR 1 )3 groups can be hydrolyzed to -Si(OH) 3 , which can then condense with Si-OH groups on the surface of the nanoparticles to provide thiol groups attached to the surface of the nanoparticles.
- the thiol groups can be reacted with a source of nitrite (NO 2 " ) ions to provide nitrosthiol groups.
- NO 2 " nitrite
- Z-Y-Si(OR 1 ) 3 is used for this purpose, wherein Z is isocyanato, glycidyl, haloalkyl, or an acid anhydride group, R 1 is Ci_3 alkyl, and Y is a tether group having a chain length of 2 to 10 atoms, and wherein the atoms in the chain can be carbon, oxygen, and nitrogen, at least two of the atoms in the chain being adjacent carbon atoms, and any two oxygen atoms, nitrogen atoms, or oxygen and nitrogen atoms being separated by at least two carbon atoms.
- Y is C2-6 alkylene.
- the alkoxysilyl -Si(OR 1 ⁇ groups can be hydro lyzed to -Si(OH)3, which can then condense with Si-OH groups on the surface of the nanoparticles to provide isocyanato, glycidyl, haloalkyl, or an acid anhydride groups attached to the surface of the nanoparticles. These groups can be reacted with amine groups similar to those found on sulfhydryl containing amino acids or hydroxyl groups similar to those found on sulfhydryl containing amino acids, peptides, glycerols, and carbohydrates.
- the isocyanato-, glycidyl-, haloalkyl-, or acid anhydride-silane of the above formula may be reacted with the sulfhydryl containing molecule (with amino or hydroxyl groups) in solution and then reacted to attach to the surface of the particle.
- the sulfhydryl containing molecule with amino or hydroxyl groups
- other coupling groups may be used such as dialkoxysilyl, mono-, di, and trichlorosilyl, and the like, depending upon which other groups are present in the molecule.
- Suitable hydrophilic groups are selected from the group consisting of -OCH 2 CH 2 -, -COOH, a salt of -COOH, -CH(OH)CH 2 OH, -CH(OH)CH(OH)-, -SO 3 H, a salt of -SO 3 H, a quaternary amino group, a monosaccharide group, an oligosaccharide group, a plurality of any of the preceding groups, and a combination thereof.
- a plurality of any of these groups refers to oligomeric and polymeric groups where the repeating units include these groups.
- the stabilizing groups should stabilize the nanoparticles by preventing agglomeration of the particles and keeping the nanoparticles suspended in the aqueous system.
- the above described hydrophilic groups which are monovalent are associated with the above described stabilizing group chains as a terminal group, as at least one group attached along the chain, or as a combination of at least one group attached along the chain and a terminal group.
- the above described hydrophilic groups which are divalent are associated with the above described stabilizing group chain as part of the chain, as a repeating unit in the chain, and in certain embodiments, preferably as a terminal part of the chain.
- a divalent group is the end group of a terminal part of the chain, one of the valencies is attached to a hydrogen or Ci_4 alkyl group, preferably a hydrogen, methyl, or ethyl group.
- Terminal groups are attached to the terminal part of the chain, which is furthest from the nanoparticle surface.
- the stabilizing groups have a sufficient chain length to stabilize the nitrosothiol groups from releasing NO.
- the chain of a stabilizing group may have branches anywhere along this chain.
- the stabilizing groups have a chain length of at least about 10 in-chain atoms, wherein in-chain atoms of the hydrophilic groups, other than hydrogen, are included.
- the stabilizing groups have a chain length of not more than about 200 in-chain atoms, wherein in-chain atoms of the hydrophilic groups, other than hydrogen, are included.
- the stabilizing groups have a chain length of not more than about 150 in-chain atoms.
- the stabilizing groups have a chain length of not more than about 100 in-chain atoms, wherein in-chain atoms of the hydrophilic groups, other than hydrogen, are included.
- the stabilizing groups have a chain length of about 20 to about 150 in-chain atoms, wherein in-chain atoms of the hydrophilic groups, other than hydrogen, are included.
- the stabilizing groups have a chain length of about 20 to about 75 in-chain atoms, wherein in-chain atoms of the hydrophilic groups, other than hydrogen, are included.
- the stabilizing groups comprise a chain wherein the atoms of the chain are selected from the group consisting of carbon, oxygen, nitrogen, sulfur, and silicon.
- the chain can include at least one of C 2-14 alkylene, and optionally at least one of -O-, -S-, -SO 2 -, -SO 2 -NR 2 -, -NR 2 -SO 2 -, -NR 2 -SO 2 -NR 2 -, -NR2-C(0)-, -C(O)-NR2-, -NH-C(O)-NH-, -0-C(O)-NH-, -O-C(O)-, -C(O)-O-, -C(O)-, -CH(OH)-, or a combination thereof, wherein R 2 is H or methyl.
- the atoms of the chain are carbon, oxygen, and nitrogen.
- the atoms of the chain are carbon and oxygen.
- any of these embodiments further includes a silicon atom, preferably one silicon atom.
- the stabilizing groups comprise poly(ethylene glycol) chains.
- Poly(ethylene glycol) chains refers to oligomeric and polymeric groups of the formula (-OCH 2 CH 2 ) m O- wherein m is at least 2.
- m is not more than 100, not more than 50, or not more than 25.
- Stabilizing groups can be attached to the surface of the nanoparticles by Si-O-Si bonds.
- Si-OH groups on the surface of the nanoparticles can be condensed with Si-OH groups bonded to molecules which can be used as stabilizing groups when attached to the nanoparticles.
- a compound of the formula: R-(OCH 2 CH2) ⁇ -(OCH2CH(CH3)) y -A-X-Si(OR 1 ) 3 is used for this purpose, wherein R is hydrogen or Ci_ 4 alkyl; x is an integer from 10 to
- y is an integer from 2 to 20;
- X is C 2 - 5 alkylene;
- A is -O-, -NR'-, -NH-C(O)-NH-, -0-C(O)-NH-, -OC(O)-, -NH-C(O)-, -NH-CH 2 -CH(OH)-, or -0-CH 2 CH(OH)-;
- R is hydrogen or Ci_ 4 alkyl; and R 1 is Ci_ 3 alkyl.
- R is methyl, ethyl, or propyl
- x is an integer from 15 to 50
- y is an integer from 2 to 15
- X is -CH 2 CH 2 CH 2 -
- A is -NH-C(O)-NH-
- R 1 is methyl or ethyl.
- R-(OCH 2 CH 2 ) n O-X-Si(OR 1 )3 is used for this purpose, wherein R is hydrogen or Ci_4 alkyl, n is an integer from 5 to 20, X is C2-5 alkylene, and R 1 is Ci_3 alkyl.
- R is methyl, ethyl, or propyl, n is an integer from 7 to 15, X is -CH 2 CH 2 CH 2 -, and R 1 is methyl or ethyl.
- alkoxysilyl -Si(OR 1 ) 3 groups of the compounds of the above formulas can be hydro lyzed to -Si(OH) 3 , which can then condense with Si-OH groups on the surface of the nanoparticles to provide stabilizing groups attached to the surface of the nanoparticles.
- W-X-Si(OR ⁇ 3 is used for this purpose, wherein W is a monosaccharide or an oligosaccharide, and includes a connecting group which covalently attaches the saccharide to X; X is
- Suitable connecting groups include, for example, -C(O)N-, -C(O)O-, and the like.
- the oligosaccharide contains up to six saccharide units.
- X is -CH 2 CH 2 CH 2 -, and R 1 is methyl or ethyl.
- the alkoxysilyl -Si(OR 1 ) 3 groups can be hydrolyzed to -Si(OH) 3 , which can then condense with Si-OH groups on the surface of the nanoparticles to provide stabilizing groups attached to the surface of the nanoparticles.
- the nanoparticles are dispersed in an aqueous system.
- the aqueous system can be a combination of water and at least one water dispersible compound.
- Such water dispersible compounds include hydrophilic groups.
- the water dispersible compounds are liquid or low-melting ( ⁇ 70 0 C, preferably ⁇ 40 0 C) solid organic compounds with hydrophilic groups.
- hydrophilic groups include, for example, one or more of -OH, -C(O)OH, -C(O)-NR 3 -, -CH 2 CH 2 O-, and combinations thereof, wherein R 3 is H, methyl, or vinyl.
- the water dispersible compound is selected from the group consisting of a lower alcohol, propylene glycol, glycerol, poly(ethylene glycol), a hydrogel monomer, an amphiphilic compound, and a combination thereof.
- the water dispersible compound is a lower alcohol.
- Lower alcohols include, for example, methanol, ethanol, isopropanol, and n-propanol.
- the water dispersible compound is a hydrogel monomer.
- Suitable hydrogel monomers can be ethylenically unsaturated. Examples of those with one ethylenically unsaturated group per monomer molecule include, for example, 2- hydroxy ethyl (meth)acrylate, 2-hydroxypropyl (meth)acrylate, 3-hydroxypropyl (meth)acrylate, 4-hydroxybutyl (meth)acrylate, caprolactone (meth)acrylate, (meth)acrylic acid, ⁇ -carboxyethyl (meth)acrylate, tetrahydrofurfuryl (meth)acrylate,
- (meth)acrylonitrile (meth)acrylamide, N-(2-hydroxyethyl)(meth)acrylamide, N- methyl(meth)acrylamide, N,N-dimethyl(meth)acrylamide, diacetone acrylamide, N-vinyl- 2-pyrrolidone, N-vinylcaprolactam, poly(alkylene oxide (meth)acrylate (e.g., poly(ethylene glycol) methyl ether (meth)acrylate, poly(ethylene glycol) (meth)acrylate, poly(propylene glycol) (meth)acrylate, and poly(ethylene oxide-co-propylene oxide (meth)acrylate)).
- alkylene oxide (meth)acrylate e.g., poly(ethylene glycol) methyl ether (meth)acrylate, poly(ethylene glycol) (meth)acrylate, poly(propylene glycol) (meth)acrylate, and poly(ethylene oxide-co-propylene oxide (meth)acrylate)).
- Suitable hydrogel monomers with three ethylenically unsaturated groups per monomer molecule include, for example, alkoxylated tri(meth)acrylates.
- alkoxylated tri(meth)acrylates include, but are not limited to, alkoxylated trimethylolpropane tri(meth)acrylates such as ethoxylated trimethylolpropane tri(meth)acrylates, propoxylated trimethylolpropane tri(meth)acrylates, and ethylene oxide/propylene oxide copolymer trimethylolpropane tri(meth)acrylates; alkoxylated pentaerythritol tri(meth)acrylates such as ethoxylated pentaerythritol tri(meth)acrylates, and alkoxylated glycerol tri(meth)acrylates such as ethoxylated glycerol tri(meth)acrylates.
- Suitable hydrogel monomers with at least four ethylenically unsaturated groups per monomer include, for example, alkoxylated tetra(meth)acrylates and alkoxylated penta(meth)acrylates.
- alkoxylated tetra(meth)acrylates include alkoxylated pentaerythritol tetra(meth)acrylates such as ethoxylated pentaerythritol tetra(meth)acrylates.
- the average number of ethylenically unsaturated groups (e.g., (meth)acryloyl groups) per hydrogel monomer molecule is equal to at least 1.2. This is accomplished by including a sufficient amount of hydrogel monomer having two or more ethylenically unsaturated groups.
- the hydrogel monomers can contain at least one (meth)acrylate having two (meth)acryloyl groups per monomer molecule or can contain a mixture of at least one (meth)acrylate having two (meth)acryloyl groups per monomer molecule in combination with at least one (meth)acrylate having one (meth)acryloyl group per monomer molecule.
- the hydrogel monomers can contain at least one (meth)acrylate having three (meth)acryloyl groups per monomer molecule or can contain a mixture of at least one (meth)acrylate having three (meth)acryloyl groups per monomer molecule in combination with at least one (meth)acrylate having one (meth)acryloyl group per monomer molecule, two (meth)acryloyl groups per monomer molecule, or a mixture thereof.
- Suitable hydrogel monomers can also include hydrophilic polyols or polyamines for use in preparing polyurethane and polyurea hydrogels.
- hydrophilic polyols examples include, for example, poly(ethylene glycols), a polyether triol of a copolymer of ethylene oxide and propylene oxide, a glycerin initiated polyoxyethylene glycol triol, and the like.
- Polyamines include, for example, amine terminated analogs of these polyols, available, for example, as JEFF AMINES (Huntsman Petrochemical Corp., Salt Lake City,
- Suitable amphiphilic compounds may also be included, for example, nonionic surfactants such as poly(ethylene glycol) monolaurate, poly(ethylene glycol) monooleate, poly(ethylene glycol) myristyl tallow ether, poly(ethylene glycol) methyl ether-block- poly( ⁇ -caprolactone), poly(ethylene glycol)-block-poly(propylene glycol)-block- poly(ethylene glycol), and the like may be used.
- nonionic surfactants such as poly(ethylene glycol) monolaurate, poly(ethylene glycol) monooleate, poly(ethylene glycol) myristyl tallow ether, poly(ethylene glycol) methyl ether-block- poly( ⁇ -caprolactone), poly(ethylene glycol)-block-poly(propylene glycol)-block- poly(ethylene glycol), and the like may be used.
- the composition further comprises a hydrogel; wherein the nanoparticles are distributed in the hydrogel.
- Suitable hydrogels include natural polymers covalently or ionically crosslinked to form hydrogels.
- Suitable natural polymers for this purpose include polysaccharides such as agar, guar gum, xanthan gum, alginic acid and alginates, chitin, chitosan, cellulose and cellulose derivatives such as hydroxyethyl cellulose, hydroxypropylmethyl cellulose, carboxymethylcellulose, and the like, and pectin.
- Suitable hydrogels also include conventional synthetic hydrogels (e.g., a polymer made from at least one of the above described hydrogel monomers), silicone hydrogels (e.g., a copolymer of 2-hydroxyethyl methacrylate and methacryloyloxyethyltris(trimethoxysilyloxy)silane or the like), polyurethane hydrogels (e.g., a hydrophilic polyol reacted with a di- or polyisocyanate), and polyurea hydrogels (e.g., a hydrophilic amine terminated polyethylene glycol or polyethylene glycol/polypropylene glycol copolymer reacted with a di- or polyisocyanato functional compound).
- conventional synthetic hydrogels e.g., a polymer made from at least one of the above described hydrogel monomers
- silicone hydrogels e.g., a copolymer of 2-hydroxyethyl methacrylate and methacryl
- the hydrogel comprises the polymerization product of at least one ethylenically unsaturated compound containing hydrophilic groups.
- the at least one ethylenically unsaturated compound includes polyethylene glycol acrylate methyl ether, 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, and ethylene oxide- propylene oxide copolymer dimethacrylate (i.e., poly(ethylene oxide-ran-propylene oxide) dimethacrylate).
- the hydrogel comprises a crosslinked poly(N-vinyl lactam), such as poly(N-vinyl pyrrolidone). Hydrogels of this nature are further described in Applicant's pending application, U.S. Serial No. 61/022036.
- the hydrogel comprises the polymerization (e.g., photopolymerization) product of ethoxylated trimethylolpropane triacrylate. Hydrogels of this nature are further described in International Publication No. WO 2007/146722.
- the hydrogel comprises an ionically crosslinked alginate.
- the hydrogel comprises the reaction product of a hydrophilic polyol and a polyisocyanate.
- Hydrophilic polyols include polyethylene glycols and the like.
- Polyisocyanates include 2,4-tolylene diisocyanate, 2,6-tolylene diisocyanate, diphenylmethane diisocyanate (MDI), and the like.
- the hydrogel comprises a crosslinked guar gum.
- the hydrogels of the present invention may have a equilibrium water concentration of 5-95% water. That is, when placed in deionized water and allowed to reach an equilibrium water concentration (which is typically done by allowing it to soak submerged for 24hrs) the weight percent water in the composition will be at least 5 %, preferably at least 10%, and most preferably at least 20%.
- the equilibrium water concentration is preferably not greater than about 95% so that the gel will have sufficient integrity.
- the equilibrium water content is not more than 90% by weight and most preferably not more than 85% by weight.
- the nanoparticles described herein, having thiol-containing groups or nitrosothiol- containing groups attached to the surface of the nanoparticles, may be distributed in a hydrogel by mixing the nanoparticles in a hydrogel monomer and polymerizing the monomer.
- the resulting polymer may further be crosslinked by known radiation or chemical crosslinking methods or by ionic crosslinking.
- the hydrogel monomer may be a single monomer or a mixture of monomers, for example, as described above. Prior to polymerizing the monomer, a portion or essentially all of the water and any other volatile component, such as a lower alcohol, may be removed under reduced pressure.
- Natural hydrogel forming polymers may be added to a dispersion of the nanoparticles in an aqueous system to provide a dispersion of the nanoparticles in a natural polymer hydrogel.
- a dispersion of nanoparticles may be added to a solution or dispersion of a natural hydrogel forming polymer followed by covalent or ionic crosslinking.
- Polyanionic polymers for example, alginates, may be crosslinked with multivalent metal ions such as Ca ++ , Mg ++ , Zn ++ , Fe + , Fe +++ , Al +++ , or with polyamines.
- Polycationic polymers may be crosslinked with polyanionic compounds such as polycarboxylic, polysulfonic, polysulfate, polyphosphonate, and polyphosphate oligomers.
- polyanionic compounds such as polycarboxylic, polysulfonic, polysulfate, polyphosphonate, and polyphosphate oligomers.
- the nanoparticles are dispersed in a hydrogel monomer or a hydrophilic polyol.
- the nanoparticles comprise stabilizing groups attached to the surface of the nanoparticles which stabilize the dispersion in the monomer or polyol.
- Such dispersions can be prepared by combining a dispersion of the nanoparticles in an aqueous system with the monomer(s) or polyol(s), and removing some or all of the water and optionally any other volatile components.
- the hydrogel is a plurality of hydrogel beads. Such hydrogel beads are further described in WO 2007/146722.
- the hydrogel is substantially dehydrated. Having a reduced water content can help increase the storage stability of the present compositions by reducing premature release of NO during storage.
- the composition is transparent. As indicated above, this may be determined by viewing the composition through a path length of 1 cm or less. Because of the particle size range of the nanoparticles used in the present compositions, and because these nanoparticles are substantially not agglomerated, the nanoparticles cause minimal light scattering, thereby making it possible for the compositions to be transparent. This allows visual observation of a structure, such as a wound, which is covered by the composition.
- a medical device comprising a surface and any one of the above embodiments of a composition for releasing nitric oxide adjacent the surface.
- the composition for releasing nitric oxide can be coated onto a surface of the medical device.
- the surface can be that of a sheet, a film, a woven, knit, or nonwoven fabric, a fiber, a filament, a thread (made of multiple fibers or filaments, or a monofilament), a tube, or the like.
- the surface can be coated with one or more coatings, for example, an adhesive coating, a primer coating, or a coating containing a coupling agent, prior to coating the composition for releasing nitric oxide.
- the composition for releasing nitric oxide is any one of the compositions described supra, which comprises a first part and a second part.
- any one of the above embodiments of the first part is adjacent the surface of the medical device, for example, coated on the surface of the medical device.
- Any one of the above embodiments of the second part, which contains the nitrite source can be contained and positioned adjacent the first part for ease of combining with the first part. Such combination can be done by the clinician prior to application or it can occur without deliberate mixing, i.e., it can occur passively as the dressing hydrates. In a dressing where the nitrite source and thiol are separated until use it is preferred that the thiol be in molar excess to ensure low or no residual nitrite.
- the device is selected from the group consisting of a wound dressing, wound contact layer, a wound filler, a medical tape, a surgical thread, a vascular graft, a stent, and a catheter.
- the device is a wound dressing.
- the wound dressing comprises a backing with the composition for releasing nitric oxide adjacent a surface of the backing.
- Suitable backing materials for the backing include, for example, nonwoven fibrous webs, woven fibrous webs, knits, films, and the like.
- the backing is a translucent or transparent polymeric elastic film.
- the backing can be a high moisture vapor permeable film backing.
- U.S. Patent No. 3,645,835 (Hodgson) describes methods of making such films and methods for testing their permeability.
- preferred suitable backing materials are elastomeric polyurethane, co- polyester, or polyether block amide films, which are described in U.S. Patent Nos. 5,088,483 (Heinecke) and 5,160,315 (Heinecke et al.).
- the wound dressing comprises a hydrogel layer comprising the composition for releasing nitric oxide, a backing layer, and an adhesive layer on the backing layer facing the hydrogel layer.
- the adhesive layer and backing layer can form a perimeter around the hydrogel layer where the hydrogel layer does not cover the entire adhesive layer. The perimeter formed by the adhesive layer and backing layer can keep the hydrogel layer properly positioned, for example, with respect to a wound, and also helps maintain a sterile environment around the application surface.
- the hydrogel layer may be continuous or be coated in a pattern with areas of hydrogel and areas of no hydrogel, e.g., patterns such as dots, grids, etc.
- the adhesive layer and backing layer can be very thin, and flexible. If this adhesive layer and backing layer are not properly supported during application they may fold over and adhere to themselves, preventing proper application over a surface.
- the adhesive layer and backing layer are optionally supported by a removable carrier layer attached to the top face (side opposite the side with the adhesive and hydrogel layers) of the backing layer.
- a release liner is provided to contact the adhesive and the hydrogel layer. Both the release liner and the backing layer coated with the adhesive layer extend beyond the edges of the hydrogel layer.
- Various pressure sensitive adhesives can be used to form the adhesive layer on the backing layer to make it adhesive.
- the pressure sensitive adhesive is usually reasonably skin compatible and "hypoallergenic", such as the acrylate copolymers described in U.S. Patent No. RE 24,906 (Ulrich).
- useful adhesives are a 97:3 isooctyl acrylate: acrylamide copolymer or 70:15:15 isooctyl acrylate: ethyleneoxide acrylate: acrylic acid terpolymer described in U.S. Patent No. 4,737,410 (Kantner). Additional useful adhesives are described in U.S. Patent Nos.
- the adhesive layer can be coated on the backing layer by a variety of processes, including, direct coating, lamination, and hot lamination.
- Suitable release liners for use as described herein can be made of kraft papers, polyethylene, polypropylene, polyester or composites of any of these materials.
- the films are preferably coated with release agents such as fluorochemicals or silicones.
- release agents such as fluorochemicals or silicones.
- U.S. Pat. No. 4,472,480 describes low surface energy perfluorochemical liners.
- Fluoropolymer coated polyester films are commercially available from 3M (St. Paul, MN) under the brand "ScotchPakTM" release liners.
- Examples of commercially available silicone coated release papers are POLYSLIKTM, silicone release papers available from Rexam Release (Bedford Park, 111.) and silicone release papers supplied by LOPAREX
- Siliconized polyethylene terephthalate films are commercially available from H. P. Smith Co.
- Exemplary dressing constructions such as those described herein include Figures 1-4, described at col. 2, line 64 to col. 6, line 28, in U.S. Patent No. 6,436,432; Figures 1 and 1 A-IC, described at col. 3, line 65 to col. 4, line 43 in U.S. Patent No. 6,903,243;
- the first part and the second part of the composition for releasing nitric oxide are each separately enveloped by a barrier material, wherein preferably the barrier material is impervious to water.
- Suitable barrier materials are known and generally are multi-layer films which include at least one polymer layer, such as polyethylene, and a metal foil, metallized layer, fluorinated polymer layer, or metal oxide layer.
- the enveloped first part and the enveloped second part are separated by a breachable barrier, which when breached allows the second part to combine with the first part.
- a product comprising a medical device according to any one of the above embodiments of a medical device and a package impervious to water, water vapor, ultraviolet light, and visible light, wherein the composition for releasing nitric oxide is enveloped by the package.
- the package is hermetically sealed.
- the entire medical device is enveloped by the package.
- a limited portion of the medical device is enveloped by the package, wherein the limited portion includes the composition for releasing nitric oxide.
- Suitable package materials include, for example, a metal foil coated with a protective and/or heat sealable polymeric layer.
- the package material is a polyolefm coated aluminum foil.
- a composition for releasing nitric oxide comprising: providing a composition for releasing nitric oxide, including any one of the above embodiments of a composition for releasing nitric oxide; contacting the subject with the composition; and releasing nitric oxide at a location where the composition contacts the subject.
- a method of treating a subject with nitric oxide comprising: providing any one of the above embodiments of a medical device comprising a surface and any one of the above embodiments of a composition for releasing nitric oxide adjacent the surface; contacting the subject with the medical device; and releasing nitric oxide at a location where the medical device contacts the subject.
- the composition for releasing nitric oxide is any one of the compositions described supra, which comprises a first part and a second part.
- the method of treating the subject with nitric oxide further comprises combining the first part of the composition with the second part of the composition to provide a composition wherein nitrosothiol-containing groups are attached to the surface of the nanoparticles.
- the method further comprises activating the release of the nitric oxide from the composition.
- activating includes exposing the composition to an activating agent selected from the group consisting of an aqueous composition, a body fluid, a thiol-containing compound, an ascorbate salt, visible light, ultraviolet light, and a combination thereof.
- the release of nitric oxide from the composition can be activated or the rate of release can be substantially increased by increasing the water content of the composition, such as by exposing the composition to an aqueous composition or to a body fluid.
- the aqueous composition contains at least 50 percent by weight of water, preferably at least 75 or at least 90 percent by weight of water.
- the body fluid also contains water and can be a wound exudate, blood, an aqueous blood component, mucus, urine, or the like.
- the release of nitric oxide from the composition can also be activated or the rate of release can be substantially increased by exposing the composition to a thiol-containing compound, an ascorbate salt, visible light, ultraviolet light, or a combination thereof.
- the thiol-containing compound is preferably a small molecule, for example a thiol with molecular weight of not more than about 350, preferably not more than about 200 or not more than about 150. Such thiol-containing compounds may penetrate the stabilizing groups on the nanoparticles and reach the nitrosothiol groups, causing disulfide formation and release of NO. Suitable thiol-containing compounds include, for example, cysteine, penicillamine, glutathione, salts thereof, and the like. Thiol-containing compounds having very low molecular weights, for example, a molecular weight less than about 75, may be avoided because of excessive volatility and odor. The thiol-containing compound can be included in the above aqueous composition.
- an ascorbate salt such as sodium ascorbate
- the ascorbate salt can be included in the above described aqueous compositions. Other antioxidants also may be useful.
- the -S-NO functional group has absorption maxima at 550 to 600 and 330 to 350 nanometers. Accordingly when visible and/or ultraviolet light is used to activate or increase the rate of release of NO, the visible light preferably includes wavelengths in the range of 550 to 600 nanometers, and the ultraviolet light preferably includes wavelengths in the range of 330 to 350 nanometers.
- activating includes exposing the composition to an activating agent
- activating is carried out by exposing the composition to a body fluid, and wherein the body fluid is a wound exudate.
- the composition is in intimate contact with a body tissue to allow body fluid to easily contact the composition.
- composition for releasing nitric oxide comprises a first part and a second part
- first and second parts are combined prior to activating the release of NO.
- a kit comprising any one of the above embodiments of a composition for releasing nitric oxide and an activating agent.
- kits comprising any one of the above embodiments of a medical device comprising a surface and any one of the above embodiments of a composition for releasing nitric oxide adjacent the surface; and an activating agent.
- Suitable activating agents for use in the above kits include, for example, an aqueous composition, a thiol-containing compound, an ascorbate salt, or a combination thereof as described supra.
- the kit can include a light source which emits visible and/or ultraviolet light as described supra.
- the kit contains a device having nanoparticles with thiol- containing groups attached to the surface of the nanoparticles and a nitrite source physically separated, for example, separately contained. These may be mixed prior to use, or they may mix due to diffusion and dissolution by an aqueous composition diffusing into a coated device, for example, wherein a composition for releasing nitric oxide is coated onto a surface of the medical device as described supra.
- a method of making a composition for releasing nitric oxide comprising: providing solid amorphous silica nanoparticles; bonding thiol-containing groups to an exterior surface of the solid amorphous silica nanoparticles; bonding stabilizing groups comprising hydrophilic groups to the exterior surface of the solid amorphous silica nanoparticles; and nitrosylating the thiol-containing groups to provide solid amorphous silica nanoparticles having an exterior surface wherein nitrosothiol-containing groups are attached to the surface.
- the solid amorphous silica nanoparticles useful in the above method of making the present compositions can be provided by obtaining such nanoparticles from a commerical source as indicated supra.
- the solid amorphous silica nanoparticles for use in the above method of making a composition for releasing nitric oxide are provided by condensing a silicate under basic conditions as described supra.
- the silicate is selected from the group consisting of sodium silicate, tetraethyl orthosilicate, and tetramethyl orthosilicate.
- bonding the thiol-containing groups to an exterior surface of the solid amorphous silica nanoparticles is carried out by reacting the alkoxysilyl portion of a compound, which includes alkoxysilyl and thiol groups, with the silica nanoparticles. This can be carried out as described supra.
- bonding the stabilizing groups comprising hydrophilic groups to the exterior surface of the solid amorphous silica nanoparticles is carried out by reacting the alkoxysilyl portion of a compound, which includes alkoxysilyl and hydrophilic groups, with the silica nanoparticles. This can be carried out as described supra.
- nitrosylating the thiol-containing groups is carried out by reacting the particles with thiol-containing groups with a nitrite salt under acidic conditions.
- a molar amount of nitrite equivalent to or greater than the molar amount of thiol-containing groups present may be used.
- Suitable nitrite salts include, for example, sodium, potassium, and ammonium salts.
- nitrous acid or a combination of nitrous acid and a nitrite salt is used for nitrosylating the thiol-containing groups.
- nitrite has been found to reduce the rate of NO release, and can be used to add additional stability to the nitrosothiol-containing groups on the nanoparticles.
- a molar ratio of nitrite to thiol-containing groups of 1.5:1 or 2: 1 or more can be used.
- the composition can include such an excess of nitrite.
- 0.5 mole, 1 mole, or more of nitrite is present.
- the method further comprises dispersing the solid amorphous silica nanoparticles, having an exterior surface wherein nitrosothiol-containing groups are attached to the surface, in an aqueous system.
- aqueous systems include those described supra.
- a metal ion sequestering agent is added in order to inhibit rapid breakdown of nitrosothiols, catalyzed by metal ions such as ferric ion.
- Suitable metal ion sequestering agents include chelators such as ethylenediamine- jV,jV,jV,jV-tetraacetic acid (EDTA), l,3-diaminopropane- ⁇ /, ⁇ /,jV',JV'-tetraacetic acid, NJV- bis(2-hydroxethyl)glycine (DHEG), ethylenediamine-N,N'-bis(methylenephosphonic acid) (EDDPO), iminodiacetic acid (IDA), nitrilotriacetic acid (NTA), dipicolinic acid (DPA) as well as salts of the forgoing acids.
- immobilized chelators such as CHELEX 100 resin (Bio-Rad Laboratories, Hercules, CA) can be used. Metal ions may also be sequestered by removing them from the liquid phase by precipitation or adsorption.
- NALCO 2326 sol 50 g was combined with ethanol (50 g) and MPTMS (0.838 g) in a bottle. The resulting mixture was purged with nitrogen for 15 minutes with constant stirring. The bottle was then sealed and heated at 70 0 C in a water bath under constant stirring for 8 hours to provide nanoparticles dispersed in water and ethanol (1.2:1), with 3- mercaptopropylsilyl groups attached to the nanoparticles (sol A).
- sol A A portion of the above sol A (75 g) was combined with PEOTES (5.656 g). The resulting mixture was purged with nitrogen and heated for 8 hours at 70 0 C with constant stirring to provide nanoparticles dispersed in water and ethanol, with poly(alkylene oxide) silyl groups also attached to the nanoparticles (sol B).
- a nitrosylated sol was prepared essentially as described in Example 1 and diluted 1 :34 with water.
- the pH of the resulting dilute sol was 4.5.
- the ratio of nitrite to thiol (sulfhydryl) groups on the nanoparticles was 1.7:1.
- the absorbance of the sol was measured serially over 16 days at 336 nanometers, the UV absorbance peak wavelength of the nitrosothiol groups. Over this time period, the sol was exposed to ambient fluorescent lighting at a temperature of 20 0 C. Each of the absorbance values was normalized with respect to the initial absorbance.
- nitrosylated sols were prepared as in Example 2. Sodium ascorbate was added to one sol at a concentration of 1.2 mM. The absorbance of each of the sols was measured serially over 7 days as in Example 2. Over this time period, the sols were protected from light, and held at 20 0 C. Each of the absorbance values was normalized with respect to the initial absorbance and the percent NO released was calculated as in Example 2. The results shown in Table 2 below indicate that the ascorbate causes a significant increase in the NO release rate.
- nitrosylated sols were prepared as in Example 2.
- 1-Propanethiol was added to one sol at a concentration of 0.13 M.
- the absorbance of each of the sols was measured serially over 6 days as in Example 2. Over this time period, the sols were protected from light, and held at 5 0 C.
- Each of the absorbance values was normalized with respect to the initial absorbance and the percent NO released was calculated as in Example 2. The results shown in Table 3 below indicate that the 1-propanethiol causes a very large increase in the NO release rate.
- Nitrosylated sols were prepared as in Example 2. Absorbance values of the sols were measured serially over 21 days as in Example 2. Over this time period, the sols were protected from light, but held at 20 0 C, 5 0 C, and -20 0 C, respectively. Each of the absorbance values was normalized with respect to the initial absorbance and the percent NO released was calculated as in Example 2. The results shown in Table 4 below indicate that much less NO was released in the dark compared with the amount of NO released under light in Example 2. The results also show that NO release is greatly reduced at lower temperatures. Protection from light and reduced temperatures can, therefore, enhance storage stability. Table 4. Percent NO Released at 0 to 21 Days in the Dark at 20 0 C, 5 0 C, and -20 0 C
- nitrosylated sols were prepared as in Example 2 with the molar ratio of nitrite ion to MPTMS at 1 : 1 and 1.7:1, respectively.
- the uv absorbance of each of the sols was measured serially over 21 days and normalized with respect to the initial absorbance, and the percent NO release was calculated as in Example 2. Over this time period, the sols were protected from light and held at 5 0 C. The results shown in Table 5 below indicate that much less NO was released when an excess of nitrite was used. The presence of excess nitrite ion can, therefore, enhance storage stability.
- Nitrosylated sol prepared as in Example 1 was dialyzed in pure water using 12,000-14,000 molecular weight cutoff membrane tubing (SPECTRA/POR MOLECULARPORO, Spectrum Laboratories, Inc., Collinso Dominguez, CA) prior to the nitrosylation step and then added to M-PEG (8 grams), and at least about 90 % of the water/ethanol solvent in resulting mixture was removed under reduced pressure in a rotary evaporator. The nitrosothiol groups were still present as indicated by the red color of the resulting sol.
- This sol (1.7 g) was then combined with MAA-PEG (0.90 g), HEMA (0.22 g), CPQ (25 mg) and EDMAB (25 mg).
- the resulting mixture was placed in rectangular mold with a depth of 0.32 cm and photopolymerized for 5 minutes under a DENTAL BLUE light (available from 3M ESPE, St. Paul, MN) equipped with a 455 nanometer cutoff filter to prevent photoinitiated NO release.
- the resulting non-hydrated hydrogel retained the red color of the nitrosylated sol, indicating the presence of the nitrosothiol groups. This color was stable for weeks with the hydrogel protected from light at 5 0 C. When the hydrogel was immersed in water, the red color diminished significantly within hours.
- Nitrosylated sols were prepared essentially as in Example 1 , except that the sols were dialyzed in pure water using 12,000-14,000 molecular weight cutoff membrane tubing (SPECTRA/POR MOLECULARPORO, Spectrum Laboratories, Inc., Collinso Dominguez, CA) prior to the nitrosylation step.
- Non-nitrosylated sols were prepared as in Example 1 (sol B) and dialyzed as above.
- cysteine hydrochloride (6 mg/g sol) to facilitate release of NO from nitrosothiol groups, if present.
- Portions of each sol were diluted 10 fold, 100 fold, 1000 fold, and 10,000 fold.
- a thiolated nanoparticle sol (non-nitrosylated) was prepared as described above in Example 1 (sol B) and diluted 1 : 1 with deionized water.
- Sodium alginate (Aldrich Chemical Co.) was added to the sol at about 3 percent by weight.
- the resulting alginate/nanoparticle sol mixture was injected through a filling tab into compartment A of a two-compartment foil container equipped with filling tabs for each compartment, leaving a portion of the volume of compartment A unfilled.
- Such containers are available from 3M ESPE, St. Paul, MN.
- Hydrochloric acid (-30 mL 1 N, Malinkrodt Specialty Chemicals, Paris, KY) was then added to compartment A through the filling tab to provide an acidified alginate gel containing non-nitrosylated nanoparticles dispersed throughout the gel.
- the filling tab was folded to seal compartment A.
- a saturated solution of sodium nitrite was injected through a filling tab into compartment B of the container, and the filing tab was folded to seal compartment B.
- the contents of compartment B was emptied into compartment A by squeezing compartment B, causing the foil layers separating the compartments to separate, allowing the nitrite solution to combine with the alginate gel.
- a nitrosylated sol was prepared essentially as in Example 1 , except that the sol was dialyzed in pure water as in Example 8.
- the resulting sol was diluted 1 :29 with water.
- To each of four 1.5 mL portions of the resulting diluted sol was added 40 ⁇ L water, 40 ⁇ L 18 mM cupric bromide, 40 ⁇ L 47 mM cysteine hydrochloride, 40 ⁇ L 47 mM cysteine hydrochloride plus 40 ⁇ L 18 mM cupric bromide, respectively, to provide the following sols: control, 0.5 mM Cu ++ , 1.25 mM cysteine HCl, 1.25 mM cysteine HCl with 0.5 mM Cu + .
- Presence of Cu + is known to cause decomposition of the S-NO group where the Cu + is first reduced to Cu + , for example, in the presence of a thiol, and the Cu + then reacts with the S-NO group, releasing NO and forming a thiolate anion and Cu + (which can be reduced to Cu + by the thiolate).
- the UV absorbance (A) of the sols was measured serially over 4 days at 336 nanometers as in Example 2. Over this time period, the sols were protected from light and held at 5 0 C.
- the presence of cysteine HCl sharply increased the rate of S-NO consumption during the first 12 hours. Over the remaining time period, the rate of S-NO consumption in the presence of cysteine HCl was similar to that of the control and Cu + containing sols.
- Thiolated sols were prepared as in Example 1 (sol B). The sols were stored in the dark and at room temperature for a period of 10 months. The sols were found to maintain their optical clarity during this time. After 10 months, the thiolated nanoparticles in the sols were reacted with nitrite as in Example 1 and found to form nitrosothiol groups as well as prior to the storage period. This is surprising in view of the disulfide formation known to occur (and normally avoided with reducing agents) with small molecules and polymers containing thiol groups. The stability of the thiol groups on the nanoparticles makes the two-part compositions described above possible.
- NALCO 2326 sol (17% wt, Nalco, Naperville, IL) was charged into a 100 mL, 3 -necked round bottom flask fitted with a glass stopper, condenser, and a thermometer.
- the sol was continuously stirred using a magnetic stirrer.
- 1.25 mL of concentrated nitric acid was added drop-wise to reach a pH of 1 to 3.
- the sol temperature was increased to 70 0 C (+/- 5 0 C) and combined with 24.72 g ⁇ /-(3-triethoxysilylpropyl)gluconamide (50% wt in ethanol, Gelest Inc., Morrisville, PA).
- the resulting sol was maintained at temperature for 8 hours, and then 1.52 g of 3- mercaptopropyltrimethoxysilane (Alfa Aesar, Ward Hill, MA) was added. The resulting sol mixture was maintained at temperature with stirring for an additional 8 hours to provide a thiolated nanoparticle sol, containing nanoparticles with 3-mercaptopropylsilyl and 3-gluconamidopropylsilyl groups. Nitrosylation of thiolated nanoparticles :
- NALCO 2326 sol containing silica nanoparticles at 15% by weight in water 200 g ethanol (200 proof)
- the mixture was placed in a funnel, and the mixture exited the funnel through a 2 mm diameter orifice.
- the exiting mixture fell along the vertical axis of a 0.91 meter long, 51 mm diameter quartz tube extending through a UV exposure zone.
- This zone included a 240 Watt/inch irradiator with an "H" bulb (25 cm in length) (available from Fusion UV Systems, Gaithersburg, MD) coupled to an integrated back reflector, such that the length of the bulb was parallel to the vertical axis traveled by the mixture.
- the mixture exited the exposure zone and quartz tube as spherical hydrogel beads.
- Example 14 Preparation of Saccharide Stabilized Nanoparticles in a Crosslinked Alginate Hydrogel and Generation of Nitric Oxide from the Hydrogel Thiolated nanoparticle sol, containing nanoparticles with 3-mercaptopropylsilyl and 3-gluconamidopropylsilyl groups (0.9 ml) from Example 12 was placed in a small beaker.
- This sol which contained 0.077 mmol of thiol/g of sol was acidified to a pH of 2 by adding 40 ⁇ L of IN HCl, and then an aqueous solution of sodium nitrite (100 ⁇ L at 4.78 mg/100 ml was added to nitrosilate the nanoparticles.
- the reaction is accompanied by the appearance of a red color in the sol.
- the resulting mixture was stirred, and then a disposable pipette was used to drop this mixture (one drop at a time) in a vial containing an aqueous solution of calcium chloride (CaCl 2 , 10 mg/ml).
- CaCl 2 calcium chloride
- hydrogel beads were tested for NO release as follows. A known amount of hydrogel beads were dispensed in wells of a 12-well petri plate: Well 1 - 14 beads (0.53 g hydrogel beads) Well 2 - 7 beads (0.23 g hydrogel beads) Well 3 - 5 beads (0.1 g hydrogel beads) Phosphate -buffered saline solution (3 mL, PBS 10 mM, Sigma, St. Louis, MO, Cat. No. P3813) was added to each well, and the plate was placed in an incubator at 37 0 C. At 21.5 hours, a 1 ml sample was collected from each well and frozen at -20 0 C until analysis.
- Phosphate -buffered saline solution 3 mL, PBS 10 mM, Sigma, St. Louis, MO, Cat. No. P3813
- a 1 weight percent aqueous solution (140 ⁇ L) of sodium carbonate was then added to the mixture, followed by the addition of sodium alginate (1 g) as in Example 14.
- the resulting mixture was stirred and then a disposable pipette was used to drop this mixture (one drop at a time) in a vial containing an aqueous solution of calcium chloride (10 mg/ml) while stirring with a stir bar.
- the resulting hydrogel beads which were translucent and pink, were allowed to harden for 10 minutes.
- hydrogel beads were dispensed in wells of a 12-well petri plate to be tested for NO release: Well 1 - 14 beads (0.53 g hydrogel beads) Well 2 - 7 beads (0.23 g hydrogel beads) Well 3 - 5 beads (0.1 g hydrogel beads)
- hydrogel beads were tested for NO release as in Example 14, and the results are shown in Table 8.
- Portions of the hydrogel discs were removed using a 1.27 cm diameter hollow punch and placed in wells of 6-well petri plates to be tested for NO release.
- the small 1.27 cm diameter discs placed in the wells were about 1 mm thick.
- Ten milliliters of phosphate-buffered saline solution were added to each well.
- the plate was placed in an incubator at 37°C. At 25.5, 48, 72, and 163 hours, a 1 mL sample was collected from each well. These samples were frozen at -20 0 C until analysis. At each sampling, the remainder of the fluid in the well was removed, and a fresh 9 mL of PBS buffer was added to the well. The reason to add back 9 mL (and not 10) is that the small hydrogel discs absorb approximately 1 mL of fluid. This is absorbed after less than 2 hours of incubation and the absorbed volume remains unchanged after that.
- Example 17 The samples were analyzed for total nitrite plus nitrate as in Example 14. The results are shown in Table 9.
- Example 17
- Sol B (25 mL), prepared essentially as described in Example 1 , was placed in a beaker, and 600 ⁇ L of IN hydrochloric acid was added, bringing the pH to 2. Sodium nitrite (32 mg) was added to the sol, and the mixture was stirred.
- the hydrophilic (meth)acrylic syrup (15.28 g), described in Example 16, was placed in a IL round bottom flask.
- the above acidified sol was added to the syrup, and the flask was placed on a rotary evaporator until liquids stopped condensing (about 12 minutes).
- EDMAB 111.5 mg
- CPQ 112.0 mg
- the resulting photopolymerizable syrup was made into cured discs (about 1 mm thick by about 4.1 cm diameter), and the discs stored in a foil covered dessicator as in Example 16. Portions of these discs were removed and tested for NO release by measuring total nitrite plus nitrate as in Example 16. The results are shown in Table 9.
- Sol B (25 mL), prepared essentially as described in Example 1 , was placed in a beaker, and 600 ⁇ L of IN hydrochloric acid was added, bringing the pH to 2. Sodium nitrite (32 mg) was added to the sol, and the mixture was stirred.
- the hydrophilic (meth)acrylic syrup (15.45 g), described in Example 16, was placed in a IL round bottom flask. The above acidified sol was added to the syrup, and the flask was placed on a rotary evaporator until liquids stopped condensing (about 12 minutes). EDMAB (110.4 mg) and CPQ (112.6 mg) were added to the resulting sol and mixed in by stirring.
- the resulting photopolymerizable syrup was made into cured discs (about 1 mm thick by about 4.1 cm diameter), and the discs stored in a foil covered dessicator as in Example 16. Portions of these discs were removed and tested for total nitrite plus nitrate as in Example 16. The results are shown in Table 9.
- Benzoyl chloride (0.58 g) is blended at room temperature under an inert atmosphere with 1738 g (1 equivalent) of an approximately 5000 M. W. polyether triol (a copolymer of ethylene oxide and propylene oxide having atactic distribution). Thereafter, 191.4 g (2.2 equivalents) of an 80:20 mixture of 2,4 tolylene diisocyanate:2,6 tolylene diisocyanate is rapidly added to the resultant mixture with aggressive agitation, producing a moderate exothermic reaction. This was maintained at 80-85 0 C until the reaction is complete. The progress of the reaction is followed by titrating samples of the mixture for % NCO until the reaction is complete, whereupon the reaction is allowed to cool to room temperature. The upper portion of the reaction mixture is decanted to leave 100% solids prepolymer, designated "Prepolymer A". This is sealed in a moisture proof glass container.
- Prepolymer B Benzoyl chloride (0.415 g) is added with thorough mixing at room temperature under an inert atmosphere to 1738 g (1 equivalent) of the polyether triol as described in Prepolymer A. Thereafter, 337.5 g (2.5 equivalents) of a polymeric MDI polyisocyanate formerly sold under the trade designation "Mondur" 432 is added to the resultant mixture with constant agitation producing an exotherm. This mixture is maintained at 80-85 0 C until the reaction is complete as determined by titration for % NCO. The reactants are permitted to cool to 40 0 C or less to produce a 100% solids prepolymer, designated "Prepolymer B". This is sealed in a moisture proof glass container.
- a 4000 M.W. polyoxyethylene glycol (2000 g, 1 equivalent) is reacted with 1814 g (2.2 equivalents) of a 80:20 mixture of 2,4:2,6 tolylene diisocyanate, causing a slight exotherm which was maintained at 70-75 0 C until the reaction is complete. This is determined by titration for % NCO. After cooling to room temperature, the prepolymer reaction product is collected and sealed in a glass container, designated "Prepolymer C".
- a lO g sample of the stable dispersion of nitrosothiolated nanoparticles in water prepared according to Example 1 (nitrosylated sol C) is mixed with 4 g samples of
- Prepolymers A, B, and C are stirred vigorously and immediately poured into a mold or coated onto a substrate. Within minutes a crosslinked hydrogel is formed due to reaction of some of the terminal isocyanate groups with water to produce an amine and carbon dioxide and subsequent reaction of the amines with remaining isocyanate groups to form urea linkages.
- a 4000 M.W. polyethylene glycol) (PEG) 20.0 g. (0.01 equivalent) is mixed with 2Og of the aqueous dispersion of nitrosolated nanoparticles produced in Example 1 (nitrosylated sol C), which is approximately 6.9% SiO 2 .
- This dispersion is stable.
- the water is removed on a rotary evaporator to produce a 6.9% dispersion of SiO 2 nitrosothiolated poly(ethylene glycol) stabilized nanoparticles in PEG.
- the PEG dispersion is reacted with 1.43 g (0.01 equivalent) of Isonate 2143L (a modified MDI having an equivalent weight of 143g/equivalent available from Dow Chemical. Midland, MI). This is mixed well, poured into a Teflon mold and cured at 70-75 0 C until the reaction is complete to form a polyurethane hydrogel.
- a 3000 M. W. glycerin initiated polyoxyethylene glycol triol 15.O g. (0.01 equivalent) is mixed with 15g of the aqueous dispersion of nitrosolated nanoparticles produced in Example 1 (nitrosylated sol C), which is approximately 6.9% SiO 2 .
- This dispersion is stable.
- the water is removed on a rotary evaporator to produce a 6.9% dispersion of SiO 2 nitrosothiolated poly(ethylene glycol) stabilized nanoparticles in the glycerin initiated polyoxyethylene glycol triol.
- This dispersion is reacted with 1.43 g (0.01 equivalent) of Isonate 2143L ( a modified MDI having an equivalent with of 143g/equivalent available from Dow Chemical).
- This is mixed well, poured into a Teflon mold and cured at 70-75 0 C until the reaction is complete to form a polyurethane hydrogel.
- Example 1 (sol B).
- the volume of the resulting mixture was reduced by rapid vacuum distillation at 25 0 C, using a Buchi R-205 ROTAVAPOR, to provide a polyethylene glycol) stabilized thiolated nanoparticle sol at 39 % wt solids.
- a 2 g aliquot of this solution was nitrosylated with an excess of sodium nitrite following the nitrosylation procedure described in Example 1 (sol C).
- PES-II 3-(Triethoxysilyl)propyl isocyanate
- NALCO 2326 sol (17% wt, Nalco, Naperville, IL) (200 g) was combined with 200 g ethanol in a 500 mL, 3-necked round bottom flask fitted with a glass stopper, condenser, and a thermometer. The sol was continuously stirred using a magnetic stirrer. Using a heating mantle, the sol temperature was increased to 80 0 C (+/- 5 0 C) and combined with 3.04 g of 3-mercaptopropyltrimethoxysilane (Alfa Aesar, Ward Hill, MA). The sol was maintained at temperature for 8 hours.
- the absorbance spectra of the nitrosylated sols prepared above were measured using a Perkin Elmer Lambda 35 spectrophotometer (Perkin Elmer, Waltham, MA). The absorbance of the sol was measured serially over 16 days at 550 nanometers, the visible absorbance peak wavelength of the nitrosothiol groups. Over this time period, the sol was exposed to ambient fluorescent lighting at a temperature of 21 0 C. Each of the absorbance values was normalized with respect to the initial absorbance.
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Also Published As
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US20110151000A1 (en) | 2011-06-23 |
EP2288343A1 (en) | 2011-03-02 |
CN102065848A (en) | 2011-05-18 |
BRPI0907260A2 (en) | 2015-07-14 |
JP2011518222A (en) | 2011-06-23 |
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