Polymer formulations for nasolacrimal stimulation

ES 2 812 752 T3

DESCRIPTION

Polymer formulations for nasolacrimal stimulation

Countryside

Described herein are polymer formulations that provide electrical contact between an electrode and nasal or sinus tissue. Specifically, hydrogel formulations are disclosed that are crosslinked using UV radiation. Methods of making hydrogels and methods of treating dry eye with nasal stimulation devices including hydrogels are also described.

Background

Dry eye disease is a major eye condition throughout the world for which there is currently no permanent cure. For example, the current average annual cost of treating dry eye disease has been estimated to be $ 850 per person (Yu, J., Andre, CV and Fairchild, CJ “The economic burden of dry eye disease in the United States : a decision tree analysis. ”Cornea 30 4 (2011): 379-387). Epidemiological estimates of the incidence frequency of dry eye disease vary widely, depending on the symptoms being monitored. For example, Friedman reports that the incidence of dry eye disease ranges from 5% to 35% globally (Friedman, N. “Impact of dry eye disease and impact on quality of life.” Current Opinion in Ophthalmology 21 (2010): 310-316).

Current treatments include the use of lubricants (eg, hydroxymethylcellulose and sodium carboxypropylcellulose, generally known as artificial tears), anti-inflammatory therapies (eg, corticosteroids and immunomodulators such as cyclosporine), tear retention therapies (eg, ear plugs). tear points) and treatment of underlying causes such as meibomian gland dysfunction, eyelid abnormalities, etc. These treatments have been shown to have a mild to moderate improvement in the quality of life of the patient. For example, McDonald et al. demonstrated that the Lacrisert® ophthalmic insert (Aton Phama, Lawrenceville, NJ), a hydroxypropylcellulose ophthalmic insert placed in the cul-de-sac of the lower eyelid, has a 21% improvement in Ocular Surface Disease Index scores (McDonald's , MB, D'Aversa, Perry HD, et al. "Hydroxypropyl cellulose ophthalmic inserts (Lacrisert) reduce the signs and symptoms of dry eye syndrome." Trans Am Ophthalmol Soc 107 (2009): 214-222). However, these treatments often require multiple administrations per day and typically do not prevent long-term damage to the ocular surface, often caused by the chemical being administered. For example, some preservatives (eg benzalkonium chloride) are known to damage the surface of the eye and cause irritation.

CN 103467652 discloses a hydrogel contact lens and a method of preparing the same. The hydrogel contact lens comprises a reaction product of a polymerizable composition, wherein the polymerizable composition contains a hydroxysulfonated zwitterionic monomer, at least one or more polymerizable monomers, a cross-linking agent of at least one or more monomers, and at least a radical initiator.

US 6,020,445 discloses a reaction mixture comprising one or more olefinic monomers containing silicone, one or more hydrophilic monomers and a diluent comprising a secondary or tertiary alcohol.

Therefore, the development of alternative treatments for dry eye syndrome would be useful. In particular, treatments that do not involve long-term administration of drug therapy would be beneficial. Furthermore, treatments with simplified administration regimens would be desirable.

Summary

Polymer formulations to facilitate electrical stimulation of nasal or sinus tissue are described herein. Polymer formulations can form hydrogels that are prepared by a crosslinking process using UV or visible light. In some applications, hydrogels may be included as a component of devices (referred to in this case and throughout the document as nasal stimulation devices or nasostimulation devices) that electrically stimulate the lacrimal gland through a nasal afferent nerve. or sinus in patients with dry eye to improve tear production. Nasal stimulators can be used to treat dry eye of varying etiology. For example, they can be used to treat dry eye due to age, hormonal imbalances, side effects of medications, and medical conditions such as Sjogren's syndrome, lupus, scleroderma, thyroid disorders, etc.

Generally, polymer formulations can form electroconductive hydrogels composed of various monomers. The present invention discloses a formulation for electrical stimulation of nasal or sinus tissue, comprising: a first monomer, a second monomer, a photoinitiator; and a diluent selected from the group consisting of glycerin, methanol, polyethylene glycol, and combinations thereof, wherein the first monomer is an acrylate monomer selected from a monofunctional monomer, a difunctional monomer, and a trifunctional monomer, and the second monomer is selected from the group consisting of dimethylacrylamide, glycidyl methacrylate,

ES 2 812 752 T3

N-vinylpyrrolidone and 1,4-butanediol diacrylate. As used herein and throughout the document, the terms "formulation", "polymer formulation", "hydrogel formulation", "electroconductive hydrogel formulation", "hydrogel" and "electroconductive hydrogel" may refer to formulations comprising monomers and monomer mixtures, before or after they have been cured, depending on the context in which the term is used. Cured or uncured formulations are understood to comprise monomers or a mixture of monomers.

Methods for producing electroconductive hydrogels are also described herein. The procedures may generally include the steps of mixing a first monomer, a second monomer, and a photoinitiator to prepare a formulation, in which the first monomer is an acrylate monomer; and irradiating the formulation with UV radiation to cross-link the formulation. The formulation can be cross-linked by covalent bonds or ionic bonds to form the hydrogel.

Also described herein are methods for fabricating the nasal stimulation devices, including shaping the conductive hydrogel, for example, to form a bulge that can enhance contact of the hydrogel with the nasal mucosa, and bond the tip assembly with or without the hydrogel conforming to a base unit of nasal stimulation devices. Methods for shaping the hydrogel are further described below, and may comprise dipping the tip assembly into the hydrogel, using the tip assembly to collect the hydrogel therein, molding or pouring the hydrogel, or dispensing the hydrogel into the tip assembly through a window disposed therethrough. The tip assemblies comprising the shaped hydrogel can be stored in a dispensing cassette for subsequent attachment to a base unit of the nasal stimulation device, as further described below.

In addition, methods for stimulating the nasal cavity or lacrimal gland are described herein, which comprise placing an arm of a nasal stimulation device against a nasal or sinus tissue, the arm having a distal end and an electroconductive hydrogel disposed therein. distal end; and activating the nasal stimulation device to provide electrical stimulation to the nasal or sinus tissue. Electroconductive hydrogel is typically used to facilitate an electrical connection between the nasal stimulation device and the nasal or sinus tissue. These methods can be used to treat dry eye.

Brief description of the drawings

Figure 1 depicts an exemplary nasal stimulation device having a pair of adjustable stimulator electrodes.

Figure 2 depicts a top view of the disposable component of another exemplary nasal stimulation device that includes a pair of spring-shaped electrodes substantially enclosed by an opaque sleeve.

Figures 3A-3C depict exemplary configurations of the electroconductive polymer provided in the disposable component of a nasal stimulation device. Figure 3A shows a perspective view of the stimulator electrode surrounded by an opaque polymeric sleeve. Figure 3B is a cross-sectional view of the stimulator electrode of Figure 3A showing an electroconductive polymer disposed within the tip portion. Figure 3B depicts a stylized view of the stimulator electrode of Figure 3A in which the conductive polymer forms a cover around the distal end of the polymeric sleeve.

Figure 4 depicts an exemplary disposable mold for use in forming the hydrogel component of a nasal stimulation device.

Figure 5 illustrates an exemplary assembly procedure for the disposable component.

Figure 6 depicts the chemical structure of exemplary acrylic-terminated silane and siloxane monomers.

Figure 7 depicts the proposed morphology of the SB5 hydrogel formulation cured to form electrical contact at the tip of a nasal stimulation device.

Figures 8A-8C depict exemplary methods for shaping the hydrogel embedded in the tip of the nasal stimulation device. Figure 8A depicts a dipping method for forming a hydrogel. Figure 8B illustrates a collection method for forming a hydrogel. Figure 8C shows a hydrogel tip in which portion of the tip has been masked during spraying of an insulator to provide a conductive portion.

Figures 9A-9I depict exemplary methods for forming the hydrogel by molding and then cutting.

Figures 10A-10C depict dispensing methods and exemplary dispensing devices for shaping the hydrogel.

ES 2 812 752 T3

Figures 11A-11C depict exemplary structures and methods that can be used to help control hydrogel delivery.

Figures 12A-12D depict an exemplary mold and casting method for forming the hydrogel.

Figure 13 shows an exemplary thin-walled tip capable of holding larger volumes of hydrogel.

Figures 14A-14D show an exemplary tip assembly structure and a method of attaching the structure to an eyeglass of a nasal stimulation device.

Figures 15A-15C show an exemplary method in which a hydrogel preform is included in the tip assembly and then hydrated.

Figures 16A-16D depict exemplary tip assembly structures and methods of use that include a hinge.

Figures 17A-17E depict an exemplary dispensing cassette and a method for manufacturing the tip assemblies.

Figures 18A-18D illustrate an exemplary method of attaching tip assemblies to a base unit using the dispensing cassette of Figures 17A-17E.

Figures 19A-19C show an exemplary tool and method for removing base unit tip assemblies.

Figures 20A-20B show additional exemplary tip assembly structures and assembly methods thereof.

Figures 21A-21B show the DMA and NVP monomer extraction rates for the SB1 hydrogel.

Figures 22A-22B show the NVP and methanol monomer extraction rates for the SB2 hydrogel.

Figures 23A-23B provide data related to hydration of hydrogels SB1 and SB2 as a function of electrical resistance.

Figures 24A-24B provide data related to hydration of hydrogels SB2 and SB3 as a function of electrical resistance.

Figure 25 provides data related to hydration of hydrogels SB4A and SB4B as a function of electrical resistance.

Figures 26A-26B provide data related to the expansion of hydrogels SB2 and SB3 due to hydration.

Figures 27A-27B provide data related to the expansion of hydrogels SB4A and SB4B due to hydration.

Figures 28A-28C show the extraction rates of DMA and NVP monomers, and of methanol for the SB5 hydrogel.

Figure 29 provides data related to the hydration of the hydrogel SB5 as a function of electrical resistance.

Figures 30A-30C provide data related to the expansion of the hydrogel SB5 due to hydration.

Detailed description

The polymer formulations described herein are generally hydrogels that can be used to facilitate an electrical connection between an electrode of a nasal stimulation device and nasal or sinus tissue, as mentioned above. Therefore, hydrogels are biocompatible and are formed to be non-irritating or abrasive to nasal and sinus tissue. Hydrogels are also generally formed so that they will not break or break during insertion or use, and have moderate adhesion to nasal or sinus tissue in order to minimize resistance to contact, heating, and heat damage to the tissue with which it comes into contact. Hydrogels can be prepared by crosslinking various monomers using UV or visible light. The nasal stimulation device can include a disposable component and a reusable component. The disposable component can generally include a pair of stimulating electrodes and the hydrogel

ES 2 812 752 T3 electrically conductive, and the reusable component a source of electrical energy for the stimulating electrodes. However, in some cases, the nasal stimulation device can be made to be completely disposable.

Electroconductive Hydrogel Formulations

Electroconductive hydrogels ("conductive hydrogels") may comprise any monomer that is capable of providing a formulation suitable for use with nasal or sinus tissue, and suitable for facilitating an electrical connection between a nasal stimulation device, eg, a device. hand-held nasal stimulation, and nasal or sinus tissue. The formulation is typically prepared by UV light crosslinking of the monomers, as further described below. In some variations, the formulations provide electrically conductive acrylate / methacrylate / vinyl hydrogels. In other variations, the formulations provide electroconductive silicone acrylate hydrogels.

In a variation, the conducting hydrogel formulation can include a first monomer; a second monomer; and a photoinitiator, in which the first monomer is an acrylate monomer. In this case, the acrylate monomer can be a monofunctional monomer, a difunctional monomer, a trifunctional monomer, or a precursor or derivative thereof.

Examples of monofunctional monomers that can be included in the formulations include, without limitation, acrylic acid, butyl acrylate, butyl methacrylate, 2-chloroethyl vinyl ether, ethyl acrylate, 2-ethylhexyl acrylate, furfuryl acrylate, glycerol monomethacrylate. , hydroxyethyl methacrylate, methacrylic acid, methoxypolyethylene glycol dimethacrylate, methoxypolyethylene glycol monoacrylate and aminoethyl methacrylate.

Difunctional monomers that can be used in the formulations include, but are not limited to, diethylene glycol diacrylate, ethylene glycol dimethacrylate, neopentyl glycol diacrylate, polyethylene glycol diacrylate, polyethylene glycol dimethacrylate, triethylene glycol dimethacrylate, N.

With respect to the trifunctional monomer, examples include, without limitation, pentaerythritol triacrylate, propoxylated glycol triacrylate, trimethylpropane triacrylate, and trimethylolpropane trimethacrylate.

The first monomer and the second monomer are not the same type of monomer. The second monomers are selected from the group consisting of dimethylacrylamide, glycidyl methacrylate, N-vinylpyrrolidone, and 1,4-butanediol diacrylate.

Silane or siloxane monomers can also be used to form an electroconductive hydrogel. Suitable siloxane monomers normally comprise one group. In a variation, silane methacrylate monomers are included in conducting hydrogel formulations as the first and / or second monomer. For example, monomers of methacryloxypropyltris (trimethylsiloxy) silane, methacryloxymethyltris (trimethylsiloxy) silane, methacryloxypropylbis (trimethylsiloxy) silanol, 3-methoxypropylbis (trimethylsiloxy) methylsilane, methacryloxypropyl methacryloxypropyl silane, and methacryloyloxypropyl silanoxy In further variations, acrylic terminated silane and siloxane monomers can be used, for example, as shown in Figure 6. These acrylic terminated silane and siloxane monomers include, but are not limited to, trimethylsilyl methacrylate, 2- (trimethylsilyloxy) ethyl methacrylate, 3- (trimethyloxysilyl) propyl methacrylate, and (3-methacryloyloxypropyl) tris (trimethylsiloxy) siloxy. In some cases, it may be beneficial to include 3-methacryloxypropyltris (trimethylsiloxy) silane in the hydrogels. Vinyl substituted silane monomers can also be used in hydrogel formulations. In this case, the silane monomer can be one comprising a -SiR group, where R can be hydrogen, or a methyl or alkyl group.

Hydrogels containing siloxane monomers can retain the water they absorb during longer exposure to air and thus retain their electrical conductivity for a longer period of time. The mole fraction of siloxane groups in silicone hydrogels can range from about 5% to about 20%. When a silane group is employed, the mole fraction of silane groups in hydrogels can range from about 5% to about 20%.

Conductive hydrogels can be formed by a UV light crosslinking process. In this case, a photoinitiator is generally included in the formulation. Photoinitiators can be any chemical compound that decomposes into free radicals when exposed to light, for example UV radiation, which has a wavelength in the range of about 350 nm to about 450 nm. Free radicals initiate polymerization to form cross-linked hydrogels. In a variation, the photoinitiator initiates ring-opening polymerization. In another variation, the photoinitiator initiates cationic polymerization. In a further variation, the photoinitiator initiates polymerization via a thiol-ene reaction.

Any suitable photoinitiator can be employed in the formulations described herein. For example, the photoinitiator may be selected from the group consisting of acylphosphine oxides (APO), oxides of

ES 2 812 752 T3 bisacylphosphine (BAPO), 2,2-dimethoxy-1,2-diphenylethane-1-one (Igracure® photoinitiator), benzoin ethers, benzyl ketals, alpha-dialkoxyacetophenones, alpha-hydroxyalkylphenones, alpha-aminoalkylphenones, benzophenones, thioxanthones and combinations and derivatives thereof. In some cases, it may be useful to include an acylphosphine oxide or bisacylphosphine oxide photoinitiator in the formulation.

Acylphosphine oxide photoinitiators that can be used include, without limitation, 2,4,6-trimethylbenzoyldiphenylphosphine oxide (TMDPO); benzoyl diphenylphosphine oxide (BDPO); 2,4,6-trimethylbenzoyl-methoxy-phenylphosphine oxide (TMMPO); phthaloyl-bis (diphenylphosphine oxide) (PBDPO); tetrafluoroterephthanoyl-bis (diphenylphosphine oxide) (TFBDPO); 2,6-Difluoro-benzoyl-diphenylphosphine oxide (DFDPO); (1-Naphthoyl) diphenylphosphine oxide (NDPO); and combinations thereof. In one variation, 2,4,6-trimethylbenzoyl-diphenylphosphine oxide (TMDPO) is a useful photoinitiator.

Bisacylphosphine oxide photoinitiators that can be used include, without limitation, bis (2,4,6-trimethylbenzoyl) -phenylphosphine oxide (BTMPO); bis (2,6-dimethoxybenzoyl) -2,4,4-trimethyl-pentylphosphine oxide; 1-hydroxycyclohexyl phenyl ketone; and combinations thereof.

The conductive hydrogels described herein may further include a suitable diluent. Suitable diluents can be glycerin, isopropanol, polyethylene glycol, water, methanol, and combinations thereof. Table 1 shows an exemplary list of monomers, photoinitiators (eg, UV initiators), and diluents that can be used to prepare the conductive hydrogels.

Table 1: Example list of UV monomers, diluents and initiators in the formulation.

<td>Monofunctional monomers</td><td>Diffunctional monomers</td><td>Trifunctional monomers</td><td>Silane and siloxane monomers</td><td>UV initiators</td><td>Thinners</td>

<td>Acrylic acid</td><td>Dimethacrylate or ethylene glycol</td><td>Pentaerythritol Triacrylate</td><td>Trimethylsilyl methacrylate</td><td>Irgacure 189 (Ciba / BAS F)</td><td>Water</td>

<td>Methacrylic acid</td><td>Polyethylene glycol diacrylate (200- 1500)</td><td>Trimethylpropane triacrylate</td><td>2- (trimethylsilyloxy) ethyl methacrylate</td><td>Irgacure 819 (Ciba / BAS F)</td><td>Isopropanol</td>

<td>Monoacrylate methoxypolyethylene glycol (300-550)</td><td>Neopentylglyc ol diacrylate</td><td>Propoxylated Glycol Triacrylate</td><td>3- (trimethoxysilyl) propyl methacrylate</td><td>Irgacure 1173 (Ciba / BAS F)</td><td>Polyethylene glycol</td>

<td>Dimethacylate methoxypolyethylenengli cabbage</td><td>Diethylene glycol diacrylate</td><td>Trimethylolpropa trimethacrylate no</td><td>3- (methacryloyloxypropyl) tris (trimethylsiloxy) si lano</td><td>Lucirin TPO (BASF)</td><td>Glycerin</td>

<td>Methacrylate hydroxyethyl</td><td>Triethylene glycol diacrylate</td><td></td><td></td><td></td><td>Methanol</td>

<td>Furfuryl acrylate</td><td>N, N'dimethylenebisacrylamide a</td><td></td><td></td><td></td><td></td>

<td>Glyceryl monomethacrylate</td><td>Dimethacrylate or polyethylene glycol</td><td></td><td></td><td></td><td></td>

In some variations, monofunctional monomers are selected from Table 1 and comprise no more than 80% and no less than 30% mole / mole of the formulation prior to the addition of diluents. In other variations, the difunctional monomers are selected from Table 1 and comprise no more than 25% and no less than 5% mole / mole of the formulation prior to the addition of diluents. In further variations, the trifunctional monomers are selected from Table 1 and comprise from about 0.0 to about 5.0 moles / 100 moles of the formulation prior to the addition of diluents.

Conductive hydrogels will generally be formed to have one or more characteristics that adapt it for use with a nasal stimulation device. For example, characteristics such as electrical resistivity, level

ES 2 812 752 T3 maximum hydration, tensile strength (elongation break), Young's modulus, glass transition temperature, and crosslinking density can be adjusted to tailor the conductive hydrogel for use with a nasal stimulation device.

The electrical resistivity of the conductive hydrogel can range from about 50 to about 2000 Ω · ατ or from about 150 to about 800 t&gt; cm. In one variation, the electrical resistivity ranges from about 400 to about 800 t&gt; cm. In another variation, the electrical resistivity ranges from about 200 to about 600 t&gt; cm. In a further variation, the electrical resistivity ranges from about 150 to about 500 t&gt; cm. Alternatively, the electrical resistivity can range from about 550 to about 600 Q ^ cm.

With respect to other characteristics of the conductive hydrogel, the maximum level of hydration can range from about 35% to about 80% by weight, and the tensile strength (elongation at break) can range from about 35% to 150%. % or from about 35% to about 100%, at 30% relative humidity. In this case, the hydration level is defined as (W hydrated polymer - W eco polymer) / W hydrated polymer. The Young's modulus ranges of the conducting hydrogel can range from about 0.1 to about 1.5 MPa or from about 0.1 to about 1.0 MPa. The glass transition temperature of the conductive hydrogel can range from about 5 to about 65 ° C in the dry state. In addition, the crosslink density can range from about 0.01 to about 0.10 mole / mole.

Conductive hydrogel formulations can contain fillers to improve one or more of the following: mechanical properties, cosmetic appearance, electrical properties, and cost. Suitable fillers can include, without limitation, silica, alumina, titanium dioxide, polyethylene microspheres, carbon black, nanofibers, nanoparticles, and combinations thereof.

Conductive hydrogel formulations can be a homogeneous material or can comprise a multiphasic mixture or a block copolymer with relatively hydrophobic and relatively hydrophilic domains that have undergone microphase separation.

In addition, conductive hydrogel formulations may contain additives that are either soluble or present in dispersed form in the polymeric material. These additives can include hydrophilic molecules, cage-shaped molecular structures, surface modifying agents, or amphiphilic molecules. Exemplary amphiphilic molecules include, without limitation, cellulose, dextran, hydroxypropyl cellulose, hydroxymethyl cellulose, hyaluronic acid, sodium hyaluronate, chitin, chitosan, crown ether derivatives, and combinations thereof.

Conductive hydrogel formulations that have the following characteristics may be useful in facilitating electrical communication between a nasal stimulation device and nasal or sinus tissue:

• electrical resistivity ranging from 200 to 800 Q ^ cm, elongation at break greater than 50% in traction mode and hydration level in the range of 25 to 80% (the hydration level is expressed as the swelling ratio at equilibrium , Wh / Wc x 100, where Wh is the mass of water in equilibrium at a particular temperature, and Wg is the weight of the hydrated gel measured under the same conditions);

• electrical resistivity in the fully hydrated state ranging from 300 to 500 Q ^ cm;

• equilibrium swelling ratio ranging from 35 to 65%;

• hydration level that does not change by more than approximately 10% (or 5.0 to 30 g when comparing the weight of the hydrogel before and after hydration), over 15 hours of continuous exposure to indoor air at 25 ° C, with a relative humidity of not less than 30%;

• Young's modulus ranging from 0.10 to 10 MPa in the fully hydrated state, and a glass transition temperature of the dry gel ranging from 5 to 65 ° C; or • crosslink density ranging from 0.01 to 0.10 mole / mole.

Some variations of conductive materials may comprise carbon black filled polyethylene or polypropylene polymers or metallic particles. Other variations can include conductive polymers such as polyphenylene sulfide, polyaniline, or polypyrrole. Ion conduction variations such as hydrophilic cross-linked polymeric networks are also contemplated. However, in some cases, the conductive hydrogel may be neutral and comprise hydrophobic segments or domains in a hydrophilic network. In still further variations, the conductive hydrogel may comprise pendant ionic groups, some of which provide ionic or electrostatic crosslinking. A conductive hydrogel which is a cross-linked, hydrophilic and biocompatible network comprising hydrophobic segments, and which has a glass transition temperature in the range of 5 to 65 ° C and an elongation at break in

ES 2 812 752 T3 the range from 50% to 150% may be useful.

In still further variations, it may be beneficial for conductive hydrogels to have a high water content, for example, a water content of 60% or more, as calculated by the following formula:% water = (Wgel hydrated - Wgel dry) / (Wgel hydrated) x 100, where W is the weight. In some variations, the water content can range from about 60% to about 99%, from about 60% to about 95%, from about 60% to about 90%, from about 60% to about 85%, from about 60% to about 80%, from about 60% to about 75%, from about 60% to about 70% or from about 60% to about 70%. In general, the lower limit is the amount of water that needs to be absorbed for the hydrogel to maintain a high water content after several hours of exposure to air at room temperature and moderate levels of relative humidity. The value of the upper limit of the water content can be influenced by the need for mechanical robustness, including a tensile modulus greater than about 0.1 MPa and an elongation failure greater than 50%.

Exemplary conductive hydrogels having a high water content may comprise crosslinked networks that include monomers such as acrylamide, methacrylamide, dimethylacrylamide, or combinations thereof. In a variation, the high water content hydrogel includes potassium persulfate cross-linked polydimethylacrylamide.

In another variation, the high water content hydrogel may comprise an ionic comonomer including, but not limited to, sodium acrylate, zinc acrylate, calcium acrylate, or combinations thereof. The ionic comonomer can be used at a concentration ranging from zero to about 20 mole percent. Hydrogels using an ionic comonomer can have a percent water content of 99% or more.

Hydrogels that have a high water content generally have an elastic modulus that ranges from about 0.001 to 0.01 MPa. When used with the nasal stimulation devices referred to herein, hydrogels may require a higher level of crosslinking so that the minimum elastic modulus is about 0.1 MPa. Additional crosslinking can be provided by adding N, N'-diethylbis-acrylamide comonomer to the hydrogel formulation. The N, N'-diethylbisacrylamide comonomer can be added in an amount ranging from about 0.5% to about 2.0% or from about 0.5% to about 1.0% by weight of the formulation. . In Table 2 below, exemplary conductive hydrogel formulations with high conductivity in water are provided.

Table 2: Exemplary High Water Content Conductive Hydrogel Formulations

<td>MONOMER</td><td>CONCENTRATION</td><td>Function</td>

<td>N, N'-dimethyl-acrylamide</td><td> 50-90%</td><td>Monomer and crosslinker</td>

<td>N, N'-dimethyl-bisacrylamide</td><td> 0,5-2,0%</td><td>Crosslinking</td>

<td>Sodium acrylate</td><td> 0-10%</td><td>Monomer</td>

<td>Zinc acrylate</td><td> 0-10%</td><td>Monomer</td>

<td>Polyethylene glycol diacrylate</td><td> 0-10%</td><td>Crosslinking</td>

<td>Cumyl hydroperoxide</td><td> 0-1%</td><td>Initiator</td>

<td>Potassium persulfate</td><td> 0-1%</td><td>Initiator</td>

In some variations, it may be useful to include hydrophilic groups in conducting hydrogels so that the hydrogels form a relatively strong complex with water molecules, thus increasing the activation energy of the dehydration process in the molecular structure of the hydrogel network and reducing the rate of drying (or drying) of the hydrogels. For example, polysaccharides can be included in hydrogels as a hydrophilic additive, since they are biocompatible, strongly bind to water, and can be chemically immobilized in the hydrogel network. Polysaccharides that can be used include, but are not limited to, dextran sulfate, hyaluronic acid, sodium hyaluronate, hydroxymethylcellulose, chitosan, sodium alginate, and combinations thereof. When a polysaccharide additive is used, it can be included in the hydrogels in an amount ranging from about 0.5% to about 20%, from about 0.5% to about 15%, from about 0.5%. % to about 10% or from about 0.5% to about 5%, by weight of the formulation. The polysaccharide additive can be added to the monomer formulation or can be incorporated into the network during hydration.

The drying rate of the hydrogel can also be substantially reduced by including a hydrating agent or hydration medium in the hydrogel formulation. For example, propylene glycol and polymers thereof can be included as a hydrating agent. In addition, mixtures of propylene glycol and water can be used as the medium of

ES 2 812 752 T3 hydration. Including a mixture of propylene glycol and water in the hydrogel formulation can result in less water being present on the surface of the hydrogel and thus evaporating from the surface of the hydrogel.

Propylene glycol and water can combine in various amounts or ratios in the hydration medium. In some variations, the hydration mixtures may comprise propylene glycol in an amount between about 5 and about 85 percent by volume, between about 5 and about 80 percent by volume, between about 5 and about 75 percent. by volume, between about 5 and about 70 percent by volume, between about 5 and about 65 percent by volume, between about 5 and about 60 percent by volume, between about 5 and about 55 percent by volume, between about 5 and about 50 percent by volume, between about 5 and about 45 percent by volume, between about 5 and about 40 percent by volume, between about 5 and about 35 percent by volume, between about 5 and about 30 percent by volume, between about 5 and about 25 percent by volume, between about 5 and about 20 percent by volume, between about 5 and about 15 percent by volume or between about 5 and about 10 percent by volume. In other variations, the hydration mixtures may comprise propylene glycol in an amount between about 20 and about 50 percent by volume or between about 20 and about 35 percent by volume. In further variations, the hydration mixtures may comprise propylene glycol in an amount of about 5 percent by volume, about 10 percent by volume, about 15 percent by volume, about 20 percent by volume, about 25 percent. volume percent, about 30 volume percent, about 35 volume percent, about 40 volume percent, about 45 percent by volume, about 50 percent by volume, about 55 percent by volume, about 60 percent by volume, about 65 percent by volume, about 70 percent by volume, about 75 percent by volume, about 80 percent by volume, or about 85 percent by volume.

Water may constitute the remainder of the hydration mixtures or, in some cases, other components may be included. The hydration mixtures can comprise water in an amount of between about 15 and about 95 percent by volume. For example, hydration mixtures may comprise water in an amount of about 15 percent by volume, about 20 percent by volume, about 25 percent by volume, about 30 percent by volume, about 35 percent by volume. volume percent, about 40 volume percent, about 45 volume percent, about 50 volume percent, about 55 volume percent, about 60 percent by volume, about 65 percent by volume, about 70 percent by volume, about 75 percent by volume, about 80 percent by volume, about 85 percent by volume, about 90 percent by volume or about 95 percent by volume. Instead of water, you can also use saline solution, and include it in the same amounts described as for water.

Exemplary hydration mixtures may include propylene glycol and water (or saline) in the following amounts: about 5 percent by volume propylene glycol and about 95 percent by volume water; about 10 volume percent propylene glycol and about 90 volume percent water; about 15 percent by volume propylene glycol and about 85 percent by volume water; about 20 volume percent propylene glycol and about 80 volume percent water; about 25 volume percent propylene glycol and about 75 volume percent water; about 30 volume percent propylene glycol and about 70 volume percent water; about 35 volume percent propylene glycol and about 65 volume percent water; about 40 volume percent propylene glycol and about 60 volume percent water; about 45 volume percent propylene glycol and about 55 volume percent water; about 50 volume percent propylene glycol and about 50 volume percent water; about 55 volume percent propylene glycol and about 45 volume percent water; about 60 volume percent propylene glycol and about 40 volume percent water; about 65 volume percent propylene glycol and about 35 volume percent water; about 70 percent by volume propylene glycol and about 30 percent by volume water; about 75 volume percent propylene glycol and about 25 volume percent water; about 80 volume percent propylene glycol and about 20 volume percent water; or about 85 volume percent propylene glycol and about 15 volume percent water. The exemplary hydration media provided below in Table 3 may be useful in hydrogels that are used as electrical contacts in nasal stimulation devices.

Table 3: Example hydration media

ES 2 812 752 T3

<td>Component / quantity</td><td>Source of hydration 1</td><td>Source of hydration 2</td><td>Source of hydration 3</td><td>Source of hydration 4</td>

<td>Propylene glycol (% by volume)</td><td> 35</td><td> 40</td><td> 45</td><td> 50</td>

<td>Water (% by volume)</td><td> 65</td><td> 60</td><td> 55</td><td> 50</td>

The hydrogels described herein generally have a functional time period and a drying time period. The functional time period is normally the period of time during which the hydrogels can be used without any substantial loss of function (eg, the impedance of the hydrogel does not rise above about 2500 Ω). The drying time period is normally the maximum time period of use of the hydrogel, in which at the end of the period, the function, eg, the stimulating function, of the hydrogel has decreased substantially. It would be beneficial to maximize both the functional time period and the drying time period for the hydrogel tips of the nasal stimulation devices described herein to increase, for example, their useful life. Table 4 provides the functional time periods, drying time periods and impedances for four hydrogel tips by way of example. All four hydrogels included the SB5 formulation described in Example 15, but further included a propylene glycol hydration medium that had amounts of propylene glycol ranging from about 35 percent by volume to about 50 percent by volume.

Table 4: Exemplary functional time periods, drying time periods and impedances

<td rowspan="2"></td><td colspan="4">Hydrogels with Propylene Glycol (PG) Hydration Medium</td>

<td>35% PG by volume</td><td>PG 40% by volume</td><td>45% PG by volume</td><td>50% PG by volume</td>

<td>Time frame functional (hours)</td><td> 14</td><td> 17,1</td><td> 22</td><td> 24,4</td>

<td>Drying time period (hours)</td><td> 17,8</td><td> 22,1</td><td> 27,1</td><td> 31,0</td>

<td>Impedance (Ω)</td><td> 1150</td><td> 1300</td><td> 1670</td><td> 1600</td>

By varying the amount or ratio of propylene glycol in the hydration medium, Table 4 shows that the useful life of the hydrogel tip can be adapted to the desired indication. For example, if a nasal stimulation device is intended for daily use, it may be helpful to include 35 volume percent (volume%) of propylene glycol hydration medium to form the hydrogel tip. Hydrogels, whether they include a hydration agent or a hydration medium, or do not include any hydration agent or any hydration medium, can be sized, shaped, molded, etc., suitably to form an electrical contact of a nasal stimulation device. For example, hydrogels can be included as part of a goggle of a nasal stimulation device, generally at the tip of the goggle. Although the use of hydration media in hydrogel tips for nasal or sinus stimulation has been described, it should be understood that they can be used in hydrogels for other applications.

As noted above, conductive hydrogels can be included in the goggles or tips of nasal stimulation devices and used to facilitate an electrical connection between a nasal stimulation device and nasal or sinus tissue. Some examples of such goggles or nasal stimulation device tips are provided in US Application Serial No. 14 / 256,915 (US Publication No. 2014/0316485), entitled "NASAL STIMULATION DEVICES AND METHODS," filed 18 April 2014. The nasal stimulation device can be configured to include a disposable component that removably attaches to a reusable housing or component. An exemplary disposable component is shown in Figure 1. In that figure, the disposable unit (100) consists of a pair of arms or glasses (102, 106) that house the electrodes (not shown), that are adjustable in a lateral direction, and that can also be rotated or rotated to vary the angle between them. Each electrode is provided in the form of a metal rod that is encased in a polymeric sleeve (104). Each sleeve (104) terminates in a slot (108, 110), which is filled with an electroconductive polymer (eg, hydrogel) that forms an electrical contact between the electrode and the nasal or sinus tissue.

Alternatively, and as illustrated in Figure 2, the disposable unit (200) has a pair of arms or glasses (202, 204) comprising an opaque polymeric sleeve (206) that encloses the electrodes (not shown). The opaque polymeric sleeve can be configured to completely cover the electrodes or to partially cover the electrodes. In this variation, the sleeve 206 and the electrodes are made flexible and spring-shaped. Its flexibility is designed to accommodate variations in the width of the nose and the angular orientation preferred by an individual user. Similar to Figure 1, an electroconductive hydrogel may be provided at the tip of the goggles (202, 204) to function as an electrical contact between the electrode and the nasal or sinus tissue.

ES 2 812 752 T3

Figures 3A-3C provide exemplary configurations of the conductive hydrogel when used with a nasal stimulation device. Figure 3 shows the polymeric sleeve (300) as an opaque tube, surrounding the interior of the support electrode. In this variation, the sleeve (300) terminates in a groove that is filled with a conductive polymer that provides an electrical connection between the electrode and the nasal or sinus tissue. As depicted in the cross-sectional view of Figure 3B, polymer 302 fills slot 304 and forms a slightly protruding cylindrical surface for optimal contact with nasal tissue. It may be beneficial if this polymer is compressible so that it can conform to the contours of the nasal cavity, which is lined with a mucous membrane of squamous epithelium, the tissue of which then becomes columnar respiratory epithelium. The cavity provides drainage for the paranasal sinuses and the nasolacrimal duct and therefore presents a very moist and hydrated environment (Anatomy of the human nose, Wikipedia). In the variation shown in Figure 3B, the conductive polymer forms a cover (306) around the end of the sleeve (300), filling the slot and extending down the sleeve to contact the electrode.

Procedure for the manufacture of electroconductive hydrogels

The process for producing the electroconductive hydrogels described herein generally comprises the steps of: mixing a first monomer, a second monomer, and a photoinitiator to prepare a formulation, wherein the first monomer is an acrylate monomer; and irradiating the formulation with UV radiation to cross-link the formulation. The monomers can be those provided above, for example, as listed in Table 1. In some variations, the conductive hydrogel is crosslinked by covalent bonds. In other variations, the hydrogel is cross-linked by ionic bonds. In hydrogels with hydrophilic and hydrophobic domains, the hydrophobic domains can form a shell around a hydrophilic core, forming a core-shell structure. A hydrogel with a high water content (e.g. 50-70%) with a hydrophobic layer can dry more slowly than a hydrogel without any hydrophobic layer and therefore can retain its electrical conductivity for a longer period when drying. Leave exposed to air between uses.

In some variations, the hydrogel can be surface modified to develop a relatively more hydrophilic surface in order to further reduce the resistance of the skin upon contact with the nasal tissue. Surface modification may be desired for hydrogels that have developed a hydrophobic coating, causing their surface to become hydrophobic. In this application, a surface is generally considered to be hydrophobic if its contact angle with water (sessile drop) exceeds 80 degrees, whereas it is generally considered to be hydrophilic if the contact angle is less than 30 degrees. Modifying the surface can be accomplished in a number of ways. One method is to treat the formed hydrogel with a low pressure plasma, produced by RF discharge or microwave discharge. Suitable plasma materials include air, oxygen, and water vapor. This method is believed to cause a chemical modification of the molecules on the surface, forming hydroxyl groups that make the surface hydrophobic. Another method is to deposit a hydrophilic polymer through plasma polymerization, including plasma assisted chemical vapor deposition (PACVD) or plasma initiated vapor phase chemical deposition (PICVD). Suitable materials to be deposited using the plasma polymerization method include HEMA or GMA. Still another method of surface modification, applicable to hydrogels with siloxane groups on the surface (for example, the SB5 hydrogel described in examples 1519 below), includes chemical activation of the surface, for example, treating the surface with hydroxide aqueous sodium (1-10% w / w), washing to remove unreacted alkali, then reacting with a hydroxyl- or amino-terminated molecule, such as polyethylene glycol. In yet another method, the surface modification may consist of the addition of a surfactant to the hydrogel formulation that migrates to the surface after polymerization. A surfactant is an amphiphilic molecule that exposes a hydrophilic end on the surface of the hydrogel. Exemplary surfactants include sodium dodecyl sulfate, polyuronic acid salts, Triton X-80, etc. Alternatively, the surface of the hydrogel can be modified, for example, to make it more hydrophilic, by including a hydration medium in the formulation. Exemplary hydration media are described above.

Conductive hydrogel formulations can be prepared to cure to a zero or low expansion solid that is formulated with diluents in the same weight fraction as the equilibrium swelling ratio of the hydrogel when fully cured. The weight ratio of diluents to the monomer and photoinitiator mixture can be from about 35% to about 70%. Exemplary diluents that may be employed are listed in Table 1. These diluents are water soluble, biocompatible and have a viscosity of less than 100 CST at 25 ° C.

The curing procedure can be triggered by any suitable wavelength of light. In some variations, the curing process is triggered by irradiation with UV light in the wavelength range of about 350 nm to about 450 nm, and is catalyzed by one or more photoinitiators selected from Table 1. Other photoinitiators can be used, as also described above. For example, acylphosphine oxides and bisacylphosphine oxides which are biocompatible and which absorb long wavelength ultraviolet radiation can be used.

Table 5 provides an exemplary list of conductive hydrogel formulations that were cured by irradiation with UV light in a wavelength range of 300 nm to 480 nm, eg, 350 nm to 450 nm, at

ES 2 812 752 T3 a temperature ranging from 10 to 65 ° C, preferably from 25 to 45 ° C, and for a period of time from 10 seconds to 30 minutes, for example, from 1 minute to 15 minutes, and using oxide of 2,4,6-trimethylbenzoyldiphenylphosphine (TMDPO) as a photoinitiator.

Table 5: Exemplary Conductive Hydrogel Formulations.

<td colspan="2">Formulation*</td><td>Water content (%) **</td>

<td> 1</td><td>HEMA / DMA 700CL</td><td> 34</td>

<td> 2</td><td>GMA / DMA 700CL</td><td>NM</td>

<td> 3</td><td>100% MAA / DMA 700CL</td><td> 44</td>

<td> 4</td><td>HEMA / GMA / DMA 700 CL</td><td> 42</td>

<td> 5</td><td>HEMA / HEMA10 / DMA 700 CL</td><td> 44</td>

<td> 6</td><td>Crosslinking agent HEMA / DMAC / DMA (700)</td><td> 50</td>

<td> 7</td><td>HEMA / GMA / BDDA CL</td><td> 41</td>

<td> 8</td><td>HEMA10 / HEMA / BDDA CL</td><td> 39</td>

<td> 9</td><td>Crosslinking agent HEMA / DMAC / DMA (700)</td><td> 57</td>

<td> 10</td><td>NVP / DMAC / HEMA</td><td> 50</td>

<td> 11</td><td>NVP / DMAC / HEMA</td><td> 69</td>

<td> 12</td><td>NVP / DMAC / HEMA</td><td> 78</td>

<td> 13</td><td>NVP / DMAC / HEMA</td><td> 77</td>

<td> 14</td><td>NVP / DMAC / HEMA with glycerol diluent</td><td> 77</td>

<td> 15</td><td>NVP / DMAC / HEMA</td><td> 70</td>

<td> 16</td><td>NVP / DMAC / HEMA with glycerol diluent</td><td> 78</td>

<td> 17</td><td>HEMA / MEMA / PEG thinner</td><td> 34</td>

<td> 18</td><td>HEMA / MAA / DMA 700 / water / PEG400</td><td>NM</td>

<td> 19</td><td>HEMA / MAA / DMA 700 / water / PEG400</td><td> 20</td>

* HEMA = hydroxyethyl methacrylate; DMA = dimethylacrylamide; GMA = glycerol monomethacrylate; MAA = methacrylic acid; DMAC = dimethylacetamide; BDDA = 1,4-butanediol diacrylate; NVP = N-vinylpyrrolidone; MEMA = methoxyethyl methacrylate; HEMA10 = polyethoxy (10) ethyl methacrylate.

** NM = not measured.

Other examples of conductive hydrogel formulations are provided in Examples 1-7 and 15. Based on data from experiments performed with these hydrogel formulations, a hydrogel exhibiting high hydration with minimal increase in mass and height (i.e. , swelling / expansion) may be helpful. Expansion due to swelling of the hydrogel generally produces effects that may require balancing. For example, swelling improves electrical conductivity, makes the hydrogel more hydrophilic and therefore more comfortable when in contact with the skin, and reduces resistance to contact. However, higher swelling also makes the hydrogel stickier and less robust, and thus more prone to breaking during current application, and increases the drying rate (although the amount of water remaining after a Specific drying period depends on both drying speed and initial water content). With these effects in mind, exemplary formulations (for example, SB4A and SB4B formulations) may incorporate a diluent that is an inert solvent that forms a hydrogel that has a substantial but no swelling (or water uptake) ratio. it expands after hydration as the incoming water replaces the diluent leaving a minor volume change after hydration and swelling in water. For example, the hydrogel formulations provided in Example 6 (SB4A hydrogel formulation) and Example 7 (SB4B hydrogel formulation) that include acrylic terminated siloxane monomers may be useful. The hydrogel formulations SB4A and SB4B demonstrated a high level of hydration with minimal expansion, as shown in the data provided in Example 14. The silicone hydrogel formulation provided in Example 15 (SB5 hydrogel formulation), which showed increased crosslinking due to the inclusion of trimethylolpropane trimethacrylate, demonstrated zero expansion, as shown in the data provided in Example 18. In In general, the data provided in Examples 16-19 provide that formulation SB5 (SB5) may be useful when formed as a hydrogel tip of a nasal stimulation device. The expansion of the SB5 formulation upon hydration was shown to be significantly less than previous formulations (eg SB1 and SB2) and to extend less than 0.5mm beyond the tip boundary when the hydrogel was fully hydrated.

ES 2 812 752 T3

Furthermore, the resistance was less than 600 Ω, well within the requirements, and did not increase beyond 1000 Ω after drying for up to 8 hours. The results also showed that the SB5 formulation was extracted and hydrated enough to be ready for use after 12-24 hours of extraction in saline at 55 ° C. However, the hydrophobic nature of its surface caused an increase in resistance to contact, especially in contact with parts of the nasal tissue that are especially hydrated. It is likely that this problem can be solved by a modification of the hydrophilic surface or the addition of a hydration medium, as previously described herein. A hydrogel that is capable of picking up high levels of water (ie high hydration) will normally be more electrically conductive. Parameters such as monomer extraction rate and electrical resistance can be measured, and the resulting values ​​can be used to indicate the level of hydration of the hydrogels, as indicated in Examples 8-12, 16 and 17. The addition of a diluent, as shown in Example 9, does not appear to affect the hydration of the hydrogel, but may affect the rate of cure.

Manufacturing methods

Various manufacturing methods are also described herein. These procedures can include various ways of curing hydrogel formulations, various ways of obtaining a suitable hydrogel conformation, and various ways of assembling the hydrogel at the tip of a nasal stimulator. Fabrication methods may be useful in forming the hydrogel contact of the disposable eyeglass portion of the nasal stimulator provided in Figure 2, or hydrogel contacts of the nasal stimulator glasses / tips that have alternative configurations, such as the glasses / Nasal Stimulator Tips described in US Application Serial No. 14 / 256,915 (US Publication No. 2014/0316485), entitled "NASAL STIMULATION DEVICES AND METHODS", filed April 18, 2014. In general, fabrication methods that help with scalability and storage of the shaped hydrogel can be helpful. Additionally, manufacturing methods that increase the volume of hydrogel at the electrode tip of a nasal stimulator may be beneficial, as this would lead to less drying of the hydrogel. Fabrication methods adapted for the hydrogel to bulge at the distal end of the electrode of a nasal stimulator may also be useful.

In a variation of the curing of the hydrogel formulation, disposable molds are used, for example, as shown in Figure 4. The disposable molds form a continuous covering of the conductive hydrogel formulation around the sleeve, while filling the space within. of the groove and the sleeve right next to the electrode. As indicated in the figure, the tube can be made of inexpensive biocompatible processable material that is transparent to UV radiation, for example, polyethylene, polyvinylidene fluoride (PVDF), polypropylene (non-UV absorbing grades), polystyrene , ABS and the like. The tube is normally open at one end and closed at the other, and can have an internal diameter of about 6.0mm, a length of about 14mm, and a wall thickness ranging from about 0.20 to about 1.0 mm. Other variations of the tube may have an internal diameter ranging from about 3.0 to about 10mm and a length ranging from about 5.0mm to about 20mm.

Disposable molds can be injection molded just in time for use in the curing procedure. An exemplary assembly and curing procedure, as shown in Figure 5, can be traced to transport parts and subassemblies, and a robot to place them. In this process, the electrodes, shaped as rods, springs or sheets, are assembled in the sleeves that are injection molded separately. The pre-assembled sleeve and electrode assembly may be inventoried and provided to the final assembly procedure depicted in Figure 5, or it may be assembled in-line, as shown in Figure 5.

Conductive hydrogel formulations can be contained in sealed containers that are opaque and isolated from air. The formulations can also be deaerated before being loaded into the container. In some variations, disposable molds are injection molded online and stored in the ongoing process inventory. Preferably, long-term storage of disposable molds is avoided, since long-term storage would introduce dust particles into the molds, and would then require the disposable molds to be washed or cleaned before use. The electrode subassembly is then placed into the disposable mold and a specific volume of hydrogel formulation is discharged into the disposable mold. The disposable mold is then moved to a station where radiation sources are placed in order to provide uniform radiation on all sides of the disposable mold. Temperature is controlled by flowing nitrogen through the station, which also keeps the cure mix in an oxygen-free environment. In this case, the curing temperature range is 30 to 45 ° C and the curing times range from about 1 to about 15 minutes. The subassembly is then removed from the disposable mold and the disposable mold is discarded once curing is complete.

In some variations, mold release can be achieved by applying a rapid cooling pulse, for example by a brief immersion in water at 0 ° C. The electrode subassembly comprising a hydrogel shell can then be immersed in deionized water for a period of 2 to 24 hours in order to remove unreacted monomers and diluent. The temperature of the deionized water can range from about 35 to about 50 ° C or from about 10 to about 40 ° C. Then the

ES 2 812 752 T3 electrode subassembly, also called disposable unit, is removed from the water, briefly dried to remove excess water, and then packaged in a sealed bag to be ready for sterilization.

Alternative manufacturing methods for forming the hydrogel into a shape suitable for use with a nasal stimulation device are also described herein. Some variations of the method include a dip and spray coating technique. For example, the tip of a goggle (s) (800) of a nasal stimulator can be dipped up and down (in the direction of the arrows) into the hydrogel (802) repeatedly, as shown in Fig. Figure 8A, or the goggle (s) used to pick up the hydrogel (802) at an angle, as shown in Figure 8B. In this case, the viscosity of the hydrogel can be adjusted so that the cavity (804) within the goggle (800) is filled with the hydrogel after immersion or collection. Additionally, a primer can be included in the hydrogel formulation to help adhere the hydrogel to the eyeglass when dipped or scooped up. The thickness of the hydrogel can be controlled by factors such as the rate of rise / fall of the goggle during immersion or collection, the temperature and / or the viscosity of the hydrogel. The viscosity of the hydrogel can be adjusted to be high enough to allow shape memory prior to final cure. After dip coating either by dipping or by collecting, curing of the hydrogel at the tip of the goggle can be accomplished using UV light (as described above) or by thermal methods. It is understood that multiple dip / cure cycles can be implemented. One or more portions of the hydrogel tip can then be masked so that an insulating layer (806) can be applied, for example, by spraying or adhesion, to the hydrogel tip (800) to cover and isolate those portions of tip 800 which is not intended to be conductive, as shown in FIG. 8C. The insulation layer can comprise any suitable insulator, for example a non-conductive polymer. After applying the insulator, for example, by spraying or adhesion, the masked portion (808) of the tip (800) would be conductive. Alternatively, when a mask is not worn, the orientation of the hydrogel tip can be controlled so that only isolated areas are sprayed or exposed.

The hydrogel can also be shaped first and then attached to the end of a conductor, for example the tip of a nasal stimulator goggle. Using such methods, the shaped hydrogel portion can be prepared in advance and then hydrated in bulk and / or excess diluent and / or excess unreacted monomer removed in bulk, stored as a hydrogel / conductor subassembly prior to hydration , or stored during hydration (i.e., stored by leaving it in a saline solution).

Shaping of the hydrogel can be done in any suitable way. In a variation, the hydrogel formulation is poured into a tray and then conductors are placed in the formulation. The formulation is then cured to form a hydrogel sheet and the sheet is shaped by cutting it using a laser cutter, die cutter, knife, etc. The cut hydrogel can be referred to as a hydrogel preform. If desired, the cured hydrogel can also be shaped to include a bulge. Alternatively, the hydrogel formulation can be poured into a tray that includes individual molds or cavities having the desired shape, eg, a bulge. The hydrogel shape formed by the individual molds or cavities can also be referred to as a hydrogel preform. In some cases, cutting and molding can be used in combination in a manner in which the hydrogel is cut to give a molded preform.

More specifically, and as shown in Figures 9A-9I, the hydrogel mixture (1) is first poured into a tray (2). As shown in Figure 9B, the tray (2) can be configured to include individual molds or cavities (3) into which the hydrogel (1) is poured. The conductors (4) can be placed inside the hydrogel (1) before curing. The conductors can be of any suitable shape and made of any suitable conductive material. For example, and as shown in Figure 9C, the conductors can be configured as a metal strip (5) with holes (7), a helical spring (6) or a cable that is bent / shaped, for example, in a loop (8), etc. These conductor configurations can be useful in creating a mechanical lock between the hydrogel and the conductor. In some cases, the metal strip (5) is configured without holes.

The placement of the conductors in the hydrogel formulation may include the use of localization or capture functions. The locate and capture functions can also assist with the insertion of the conductors to the desired depth in the hydrogel. For example, as shown in Figure 9D, one end of the conductor (4) can be placed in the tray with the help of a locating function configured as a pin (9) or a well (10). The end of the conductor (4) can also be positioned with the help of a capture function such as the plate (11), which is provided on top of the tray (2), as shown in figure 9E. In such cases, the plate (11) may be configured to capture conductors based on their geometry, for example, the conductor may have a larger section (12) at one of its ends, have a bent / deformed section (13) or have an interference or pinch fit (14) with the plate (11). After the conductors have been placed on the hydrogel, the hydrogel is cured according to any of the methods described herein. When the hydrogel has been molded / cured into a sheet, the hydrogel can be subsequently formed into the desired shape, for example, by a laser cutter, a die cutter, a blade, etc. The component created by shaping (item 16 in Figure 9G), either by cutting or by molding, may be referred to as a conductor-hydrogel subassembly (item 17 in Figure 9G).

As shown in Figure 9G, the conductor-hydrogel subassembly (17) can be subsequently hydrated and

ES 2 812 752 T3 can be stored in an aqueous environment until used for further assembly of the tip of a nasal stimulation device, or can be stored dry for further processing. According to a variation, as shown in Figure 9H, assembling the conductor-hydrogel subassembly (17) in a molded part (20) to create the desired end tip assembly may include dropping the subassembly (17) into a hollow shaft (21) of the molded part (20), such that the hydrogel (16) rests on a stepped section (22) within the shaft (21). In this case, the conductor (4) can be bent / deformed at the location where it exits the shaft (21), for example, to create a mechanical lock between the subassembly (17) and the molded part (20). Referring to Figure 9I, a cover (24) may also be included as part of the molded part (20) by, for example, a hinge-type mechanism (23).

The hydrogel can also be incorporated into the tip of the nasal stimulation device by controlled dispensing of the hydrogel formulation, for example, by computer numerical control (CNC) or robotics, or by hand, directly into a cavity of the tip assembly. Controlled dispensing can be accomplished by, but is not limited to, tilting mechanisms to ensure vertical window alignment, or the use of guides. It is understood that other suitable controlled dispensing procedures may be employed. A controlled dispensing method may be helpful in controlling the size of the bulge on the hydrogel tip.

In a variation, the inclination during the dispensing procedure can be useful to control the introduction of hydrogel at the tip of the device. For example, as shown in FIG. 10A, the tip portion (25) may be tilted during dispensing of the hydrogel formulation (26) from a dispensing device (28). The amount of tilt can vary, and can range from about 5 to about 45 degrees. The amount of tilt can be determined by the geometry of the window being filled. In general, the nasal stimulation device will be tilted so that the walls of the window are equidistant about a vertical center line of the opening, thus allowing gravity to disperse the liquid hydrogel formulation evenly. For example, if the center line of the window being filled is 45 degrees from the center line, the nasal stimulation device is tilted (rotated) 45 degrees. Tilting can generally be achieved using tilting mechanisms such as pins, rollers and / or plates, etc. Figure 10B illustrates how a scroll roller (27) can be used to tilt the tip portion (25) after the hydrogel formulation has been dispensed and cured. After dispensing the hydrogel formulation at a tip of the tip portion (25), the formulation is cured and the shift roller (27) is moved to tilt the tip portion (25) in the opposite direction. Tilt mechanisms generally tilt the fixtures (e.g. flat surfaces such as plates) on which the tip portions have been placed to expose each cavity to the dispenser, as the cavity faces inward in the normal orientation (when the tip portion is placed on the fixed element), and to dispense the opening in the tip portions you need to face up. In some cases, the fixture may also have alignment pins that complement the holes provided in the base portion of the nasal stimulator.

One or more of the tip portions may be tilted during the dispensing procedure. For example, as shown in Figure 10C, the hydrogel dispenser (28) includes multiple dispensing tips (29) and multiple tip portions (25) disposed on the plate (30). Sliders (not shown) coupled to multiple rollers (31) are used to tilt the multiple portions (25) of the tip. The plate (30) can also be moved back and forth in the direction of the arrows to achieve a rocking / tilting movement.

In another variation, one or more guides arranged in or on a portion of the tip portion may function to control the dispensing of the hydrogel by allowing the tip portion to tilt or flex so that the cavity is substantially perpendicular to the dispenser. hydrogel. The guides may be rails and / or grooves / grooves that are in contact with a corresponding structure or geometry in a fixed element to reversibly join the tip portion to the fixed element and tilt or flex the tip portion so that the tip can be filled. cavity. For example, as shown in Figures 11A-11C, an interior slot (32) may be provided in the tip portion (33) (Figure 11A), a rail or slit (34) may be provided within an opening (35) of the tip portion (33) or on the outer surface (36) of the tip portion (33) (Figure 11B), or a slot (37) may be provided in the tip (38) of the tip portion (33) similar to a combination lock and key (Figure 11C).

In still a further variation, the hydrogel in the tip portion can be shaped using a casting process. In this case, the hydrogel formulation is poured into a mold containing a hollow cavity of the desired shape and then allowed to solidify. Some variations of the mold may be configured as shown in Figure 12A. Referring to the figure, the mold (39) includes a base block (44), rocker plates (42), screws (43) and compression springs (45). The base block (44) includes one or more casting surfaces (41) configured to form a protrusion on the hydrogel tip (ie, a protruding casting surface). The raised casting surface will normally have the same radius as a distal end of the tip portion (see item 48 in Figure 12B) and includes a recess such as recess (40) to create a protrusion during casting. The rocker plates (42) compress and secure the tip portions (see FIG. 12C) to the base block (44) using compression screws (43) and springs (45). The tilting plates can be made from a material that transmits UV light, for example an acrylic material. The height of the screws (43) can be adjusted to control the amount of compression imparted by the plate (42). More

Specifically, as shown in Figures 12B-12D, the fabrication of a cast hydrogel tip may include providing a disposable tip (46) with windowed glasses (47) and orienting the ends (48) distal so that the windows (47) face the casting surface (41) of the base block (44) of the mold (39) (Figure 12B). The distal ends (48) of the goggle tip (46) are then secured to the base block (44) by tightening the screws (43) so that the rocker plates (42) are compressed against the base block (44) ( Figure 12C). Again, the tips (46) are loaded into the mold with the windows facing the casting surface. A UV curable hydrogel formulation as described herein can then be injected through a channel (49) in the disposable tip (46) that is fluidly connected to the distal ends (48) of a a way that supplies hydrogel to the windows and the casting surface (Figure 12C). As noted above, the casting surface includes a recess to form a bulge in the hydrogel. After the hydrogel formulation is injected into the tip portion (46), UV light can be applied to cure the hydrogel. Either the tilting plates or the base block can be made from a material that transmits UV light. An exemplary UV transmitting material comprises glass. In this case, UV light can be transmitted through the base block (44) and the distal end (48). The toggle plates (42) are then released so that the distal ends (48) can be removed from the base block (44). As shown in Figure 12D, the resulting hydrogel formed by the casting process has a bulge (50) protruding from the window (47). Although a single mold is shown in Figures 12A-12D, it is understood that a series of grouped molds could be configured and employed for large-scale production.

Some manufacturing methods include decreasing the wall thickness at the end of the tip portions so that the hydrogel volume can be increased at the tip portions. In a variation, this is accomplished by molding the tip from a single component and using a micro-molding process and material. Using this procedure, for example, the wall thickness of the tip portion can be reduced from thickness A (shown between arrows on the left) to thickness B (shown between arrows on the right) in Figure 13 thus increasing the volume within the tip end. Other methods may include steps that create a high volume to surface area ratio to maintain the desired level of hydration of the hydrogel.

Tip assembly methods

Methods for assembling the tip portion of a nasal stimulation device are further described herein. These assembly methods can be mixed and matched with the various ways of shaping the hydrogel, as described above. The methods can also be used to assemble the portion of the disposable tip shown in Figure 2, or portions of the tip having other configurations. Some variations of the tip portion may require only partial assembly before adding the hydrogel. In general, assembly methods include steps that fix the hydrogel within the tip portion, or mechanically (eg, hydrating after placing the hydrogel on the tip, interference fit, thread fit, etc. ) or chemistry (for example, by epoxies, bioadhesives, ultrasounds, etc.).

In variations where the hydrogel formulation is dispensed into the window of the tip portion, the tip may include an electrode (51) having a distal end (59) that is insert molded into a cap (52). and a flexible, frangible or spring-type proximal end (60) comprising arms (61), as shown in FIG. 14A. The electrode (51) may include a slot (53) that functions to provide mechanical retention of the hydrogel within the cavity (item 54 in Figure 14B) of a tip assembly (item 55 in Figure 14B). In its partially assembled state, as provided in Figure 14b, the hydrogel can be injected, using a delivery system and method as described above, into cavity (54) through window (56). In this case, the formation of the hydrogel bulge can be controlled by the surface tension and / or the viscosity of the uncured hydrogel.

After curing the hydrogel, the tip assembly can be attached to a nasal stimulation device as shown in Figure 14C. Referring to Figure 14C, the tip assembly (55) is attached to the remaining portion of the disposable tip portion through a retaining block (57) at the distal end of a flexible tube (58) ( within the goggle of a stimulation device) having a tip retainer (62b) with a ramping surface (62). The electrode (51) of the tip assembly (55) is pushed in the direction of the arrow so that it is forced to follow the ramping surface (62). The flexible / frangible nature of the electrode arms (61) allows them to return to their original configuration when fully inserted to substantially surround the tip retainer (62b). The electrode arms (61) are configured to permanently deform when pulled up in the direction of the arrow and separated from the tip retainer (62b), so that the tip assembly cannot be reused, as shown. shown in Figure 14D.

In variations where the hydrogel is preformed using, for example, any of the methods described above, the hydrogel can be preformed as a cylinder (63) having a slot (64) to accept an electrode (65), as shown in Figure 15A. In this case, the hydrogel is a non-hydrated preform that hydrates after the tip assembly is fully assembled. It is understood that the hydrogel preform may or may not be washed of excess unreacted monomer prior to integration into the tip assembly. During the hydration procedure, the hydrogel preform (63) will generally swell in the direction of the arrows, fill the open spaces, and expand through the window (66) to create a surface (67) (of

ES 2 812 752 T3 contact) stimulation. Furthermore, since the free space between the electrode (65) and the groove (64) is small, the electrode is normally in full contact with the hydrogel in the initial hydration phase (eg after 20% hydration). This is a beneficial safety feature, as it ensures that when a patient uses the nasal stimulation device, the entire surface of the electrode carries the electrical current. An angled groove (68) on the outside of the tip assembly opposite the window (66) may be used to align and couple the tip assembly to a corresponding frame on a dispensing cassette during the manufacturing process, as shown. described below.

In other variations, a hydrogel preform can be placed in a tip assembly that includes a hinge, eg, a live hinge. For example, as shown in Figure 16A, the tip assembly (69) may be configured to include a first side (70) having a cavity (77a) for placement of the hydrogel preform (not shown). , a window (71) that allows the hydrogel preform to expand, a channel (72) for sliding engagement of an electrode (not shown), and a hole (73). The first side (70) is coupled to a second side (74) through a live hinge (75). The second side (74) includes a cavity (77b), a tapered projection (76) that is accepted by the hole (73) when the second side (74) is folded upon contact with the first side (70) at the hinge (75) alive. The tapered protrusion (76) and hole (73) have an interference fit and can be welded together prior to hydration of the hydrogel preform. In another example, the tip assembly may include a deflectable electrode (78) capable of being deflected in the direction of the arrow to allow a hydrogel preform (79) to be installed in the tip assembly, as shown. in Figure 16B. In this case, the electrode includes a hole (73) for accepting the tapered projection (76) when the first (70) and second (74) sides are rotated on the live hinge (75) to close the sides together. Instead of a tapered shoulder and hole, the sides can also be attached to each other using a tongue and groove configuration. For example, as shown in Figure 16C, a female tapered slot (80) can be configured to have an interference fit with a male tapered tab (81). Other variations of the tip assembly are shown in Figure 16D, and include a hydrogel retention bar (82) to help secure the hydrogel within the tip and / or a live hinge (84) recessed within a slot ( 83) provided on the surface of the tip to help prevent abrasion of the nasal tissue.

Manufacturing methods may also employ the use of a dispensing cassette to assemble the bulk tip assemblies. Bulk packaging can reduce the amount of packaging materials and volume, which is convenient for the end user. An exemplary dispensing cassette is provided in Figures 17A-17B. Referring to FIG. 17A, the dispensing cassette (90) may include a cassette housing (85) having a proximal end (86) and a distal end (87), and an alignment block (88) coupled to the end. (86) proximal and a spring (89) of constant force. A plurality of tip assemblies (91) can be stored in the cassette housing (85) and held in place by the constant force spring (89), which biases the tips (91) against the alignment block (88). . A plurality of holes (93) are provided in the constant force spring (89), which are spaced a distance equal to the length of a tip assembly (91). When the dispensing cassette (90) is at rest, a pin (92) of the alignment block (88) is not engaged with a hole (93) in the constant force spring (89). As provided in more detail in Figure 17B, when the dispensing cassette is at rest, a spring (94) in its untensioned state pushes the pin (92) out of the hole (93) in the spring (89) of constant force, and the constant force spring (89) biases the tips (91) (see FIG. 17A) back toward the surface (95) of the alignment block (88). When the user activates the dispensing cassette for attachment of the tips (91) to the remaining portion of the nasal stimulation device (not shown) as depicted in Figure 17C, the alignment block (88) is depressed to compress the spring (94) and allow engagement of the pin (92) with the hole (93) of the constant force spring to release the load provided by the constant force spring (89) against the tips (91) while attaching a tip . A wick (96) may also be provided to maintain a supply of moisture in the dispensing cassette so that the hydrogel at the tips (91) does not dry out prematurely. The wick (96) can be saturated with a liquid such as saline. As described above, the tip assemblies may include a slot (97) (as shown in Figure 17D) configured to engage a complementary structure of the cassette housing (99) so that angular alignment can be controlled. of the electrodes. For example, as shown in Figure 17E, the grooves (97) in the tips (91) engage the ribs (98) of the cassette housing (99).

Some variations of the manufacturing method combine the electrode and tip retainer shown in Figure 14C with the dispensing cassette described in Figures 17A-17C, as illustrated in Figures 18A-18D. First, the alignment block (88) is pressed in the direction of the arrow (Figure 18A) to expose a new tip assembly (91) that can be accessed by the spectacle portion (101) of the device (103 ) of nasal stimulation (Figure 18B). Electrode (105) is aligned to engage a connector (not shown) on goggle (101). The device (103) and goggles (101) are then advanced through the access holes (107) in the alignment block (88) until a tip (not shown) is attached as described in Figure 14C. After fixation, the device (103) can be removed from the alignment block (88) and the compressive force on the alignment block (88) can be released in the direction of the arrow, as shown in FIG. 18D.

If it is desired to separate the tip, a tip removal tool can be used, as shown in Figures 19A-19C. Referring to Figure 19A, the tip assemblies (91) can be inserted into a cavity

ES 2 812 752 T3 (111) of the tip extraction tool (113) that resembles a buckle. The extraction tool (113) can be squeezed to compress the tip assemblies (91) within the extraction tool (113), as shown in FIG. 19B. While maintaining the compression force, the device (103) can be removed from the tip removal tool (113) to separate the device (103) from the tip assemblies (91), as shown in the figure. 19C.

In still further variations, the manufacturing methods include steps that attach a flexible base unit to a rigid tip assembly. For example, as shown in Figure 20A, caps 115 may be provided on hydrogel preforms 117. The elongated and rigid electrodes (119) may extend from the caps (115) to advance through a flexible base (121). Segments 123 including windows 125 are attached to flexible base 121. As shown in the figure, the segments 123 have an open upper part 127 so that the hydrogel preforms 117 can be loaded therein. After the electrodes (119) have been inserted into the flexible base (121), the caps (115) can be attached to the flexible base, for example, by welding. In another example, as shown in Figure 20B, the flexible base 121 is configured to include tapered ends 129 that accept complementary structures 131 near the distal end 133 of the elongated electrodes 119.

Methods of use

Methods for stimulating the nasal or sinus tissue (and the lacrimal gland) are also described herein. In a variation, the method includes placing an arm of a nasal stimulation device against nasal or sinus tissue, the arm having a distal end and an electroconductive hydrogel disposed at the distal end; and activating the nasal stimulation device to provide electrical stimulation to the nasal or sinus tissue, wherein the electroconductive hydrogel is used to facilitate an electrical connection between the nasal stimulation device and the nasal or sinus tissue. As indicated above, the conductive hydrogel can comprise a first monomer; a second monomer; and a photoinitiator, in which the first monomer is an acrylate monomer and the electroconductive hydrogel has one or more characteristics that make it suitable for use with a nasal stimulation device. The conductive hydrogel can include monomers, diluents, photoinitiators, and other components as described herein, for example, the components provided in Table 1 and Table 3. Again, the formulations are subjected to UV radiation to form a cross-linked conductive hydrogel. Conductive hydrogels used in these methods may include those listed in Tables 2 and 5.

In general, when one or more sinus or nasal afferents are stimulated (trigeminal afferents as opposed to olfactory afferents), a tearing response is activated through a nasolacrimal reflex. This stimulation can be used to treat various forms of dry eye, including (but not limited to) chronic dry eye, episodic dry eye, seasonal dry eye. To provide continuous relief from dry eye symptoms, nasolacrimal stimulation may be necessary one to five times a day. In some cases, stimulation can be used as a prophylactic measure to treat users who may be at increased risk of developing dry eye, such as patients who have undergone eye surgery, such as laser vision correction and surgery. cataracts. In other cases, stimulation can be used to treat eye allergies. For example, an increase in tear production can remove allergens and other inflammatory mediators from the eyes. In some cases, the stimulation can be configured to cause habitability of the neural pathways that are activated during an allergic response (for example, by delivering a stimulation signal continuously over a prolonged period of time). This can result in reflex livability that can suppress the response a user would normally have to allergens.

Examples

The following examples further illustrate conductive hydrogel formulations as disclosed herein, and should not be construed as limiting their scope in any way.

Example 1: method of manufacturing an electroconductive hydrogel for use with a nasal stimulation device

In a round bottom flask wrapped in aluminum foil and fitted with a magnetic stirrer, introduce a first monomer, a second monomer and a photoinitiator. Additional monomers (eg a third or fourth type of monomer, etc.) and / or a diluent can also be added. Clamp the flask to the top of a magnetic stirrer / heater that is equipped with a nitrogen purge line. After turning on the magnetic stirrer and nitrogen purge, mix the contents of the flask for five minutes to form a monomer mixture. While the monomers are mixed, insert the cuffs of a nasal device (for example, the cuff (300) shown in Figures 3A-3C) into disposable molds (for example, as shown in Figure 4) that have windows or louvers that open to let in UV light. The sleeves should be oriented vertically within the molds. Next, extract the monomer mixture from the flask into a syringe and cover the syringe with aluminum foil. Attach a needle, for example a 30 gauge blunt needle, to the syringe. Insert the needle into the cuff and fill it with the monomer mixture. Next, open the racks and irradiate the molds for approximately three minutes with UV light. After that, turn the molds horizontally with the racks facing up and irradiate the molds for approximately seven minutes with UV light. Cool the molds before

ES 2 812 752 T3 to remove the sleeves.

Example 2: Preparation of a silicone hydrogel including methacryloxypropyl-tris- (trimethoxysiloxy) silane and methanol diluent

In a round bottom flask wrapped in aluminum foil and fitted with a magnetic stirrer, the following was added:

EGMDA (ethylene glycol dimethacrylate) (0.081 g)

NVP (N-vinylpyrrolidone) (2,179 g)

GMA (glyceryl monomethacrylate) (1,112 g)

DMA (dimethylacrylamide) (3.917 g)

Methacryloxypropyl-tris (trimethyloxysiloxy) silane (2.712 g)

Lucirin (TPO) (0.081 g)

Methanol (2.88 g)

The flask was clamped on top of a magnetic stirrer / heater that was fitted with a nitrogen purge line. The contents of the flask were then mixed for five minutes to form a monomer mixture. While the monomers were mixed, the nasal device cuffs and disposable molds were prepared as described in Example 1. The monomer mixture was then drawn into a syringe, injected into the sleeves and irradiated as described in Example 1. The molds were cooled before removing the sleeves.

Example 3: SB1 silicone hydrogel

The silicone hydrogel formulation SB1 was prepared and molded into sleeves as described in Example 1. The components of the hydrogel SB1 are provided below. No diluent was included in the SB1 hydrogel formulation.

<td rowspan="3">Monomers</td><td colspan="7">SB1</td>

<td colspan="7">14020 (for kinetic study (formulated 03/13/14))</td>

<td>molecular weight (g / mol)</td><td>moles</td><td>mass (g)</td><td>Molar fraction</td><td>10 gram batch (g)</td><td>molar ratio to main monomer</td><td>% in weigh</td>

<td>HEMA</td><td> 130,14</td><td> 0,0768</td><td> 10,0000</td><td> 0,0964</td><td> 0,9606</td><td> 0,2152</td><td> 9,5299</td>

<td>EGDMA</td><td> 198,00</td><td> 0,0018</td><td> 0,3500</td><td> 0,0022</td><td> 0,0336</td><td> 0,0049</td><td> 0,3335</td>

<td>NVP</td><td> 111,14</td><td> 0,2969</td><td> 33,0000</td><td> 0,3726</td><td> 3,1700</td><td> 0,8315</td><td> 31,4487</td>

<td>DMA</td><td> 99,13</td><td> 0,3571</td><td> 35,4000</td><td> 0,4481</td><td> 3,4006</td><td> 1,0000</td><td> 33,7359</td>

<td>allyl methacrylate</td><td> 126,16</td><td> 0,0028</td><td> 0,3500</td><td> 0,0035</td><td> 0,0336</td><td> 0,0078</td><td> 0,3335</td>

<td>(3-methacryloyloxypropyl) tris- (trimethylsiloxy) silane</td><td> 422,82</td><td> 0,0591</td><td> 25,0000</td><td> 0,0742</td><td> 2,4015</td><td> 0,1656</td><td> 23,8248</td>

<td>Lucirin</td><td> 348,00</td><td> 0,0024</td><td> 0,8320</td><td> 0,0030</td><td> 0,0800</td><td> 0,0067</td><td> 0,7937</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Total</td><td></td><td> 0,7969</td><td> 104,9320</td><td> 1,0000</td><td> 10,0800</td><td></td><td> 100,0000</td>

Example 4: SB2 silicone hydrogel

The silicone hydrogel SB2 was prepared as in Example 1. The components of the hydrogel SB2 are provided below. A methanol diluent was included in the SB2 hydrogel formulation.

<td>Monomers</td><td>SB2</td>

ES 2 812 752 T3

<td rowspan="2"></td><td colspan="7">14021 (for kinetic study (formulated 03/13/14))</td>

<td>molecular weight (g / mol)</td><td>moles</td><td>mass (g)</td><td>Molar fraction</td><td>10 gram batch (g)</td><td>molar ratio to main monomer</td><td>% in weigh</td>

<td>HEMA</td><td> 130,14</td><td> 0,0768</td><td> 10,0000</td><td> 0,0443</td><td> 0,9606</td><td> 0,2152</td><td> 7,4582</td>

<td>EGDMA</td><td> 198,00</td><td> 0,0018</td><td> 0,3500</td><td> 0,0010</td><td> 0,0336</td><td> 0,0049</td><td> 0,2610</td>

<td>NVP</td><td> 111,14</td><td> 0,2969</td><td> 33,0000</td><td> 0,1714</td><td> 3,1700</td><td> 0,8315</td><td> 24,6120</td>

<td>DMA</td><td> 99,13</td><td> 0,3571</td><td> 35,4000</td><td> 0,2061</td><td> 3,4006</td><td> 1,0000</td><td> 26,4020</td>

<td>allyl methacrylate</td><td> 126,16</td><td> 0,0028</td><td> 0,3500</td><td> 0,0016</td><td> 0,0336</td><td> 0,0078</td><td> 0,2610</td>

<td>(3-methacryloyloxypropyl) tris- (trimethylsiloxy) silane</td><td> 422,82</td><td> 0,0591</td><td> 25,0000</td><td> 0,0341</td><td> 2,4015</td><td> 0,1656</td><td> 18,6455</td>

<td>Lucirin</td><td> 348,00</td><td> 0,0024</td><td> 0,8320</td><td> 0,0014</td><td> 0,0800</td><td> 0,0067</td><td> 0,6211</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>thinner</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>methanol</td><td> 32,04</td><td> 0,9357</td><td> 29,9808</td><td> 0,5401</td><td> 2,88</td><td> 2,6203</td><td> 22,3602</td>

<td>Diluent + total hydrogel</td><td></td><td> 1,7327</td><td> 134,9128</td><td> 1,0000</td><td> 12,88</td><td></td><td> 100,0000</td>

Example 5: SB3 silicone hydrogel

The silicone hydrogel SB3 was prepared and molded into sleeves as in Example 1. The components of the hydrogel SB3 are provided below. The SB3 hydrogel formulation included a methanol diluent and the HEMA monomers were replaced by EGDMA monomers, which are more hydrophilic than HEMA monomers.

<td></td><td colspan="5">SB3 (kinetic study 3)</td>

<td>Monomers</td><td>molecular weight (g / mol)</td><td>Molar fraction</td><td>10 gram hydrogel batch (g)</td><td>molar ratio to main monomer</td><td>weight fraction</td>

<td>EGDMA</td><td> 198,00</td><td> 0,0025</td><td> 0,081</td><td> 0,0103</td><td> 0,0062</td>

<td>NVP</td><td> 111,14</td><td> 0,1203</td><td> 2,179</td><td> 0,4963</td><td> 0,1681</td>

<td>GMA</td><td> 160,00</td><td> 0,0426</td><td> 1,112</td><td> 0,1759</td><td> 0,0858</td>

<td>DMA</td><td> 99,13</td><td> 0,2424</td><td> 3,917</td><td> 1,0000</td><td> 0,3022</td>

<td>(3-methacryloyloxypropyl) tris- (trimethylsiloxy) silane</td><td> 422,82</td><td> 0,0393</td><td> 2,712</td><td> 0,1623</td><td> 0,2092</td>

<td>Lucirin</td><td> 348,00</td><td> 0,0014</td><td> 0,080</td><td> 0,0058</td><td> 0,0062</td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td>Thinner</td><td></td><td></td><td></td><td></td><td></td>

<td>methanol</td><td> 32,04</td><td> 0,5514</td><td> 2,88</td><td> 2,2751</td><td> 0,2222</td>

<td>Total</td><td></td><td> 1,0000</td><td> 12,9600</td><td></td><td> 1,0000</td>

Example 6: SB4A silicone hydrogel

The silicone hydrogel SB4A was prepared and molded into sleeves as in Example 1. The components of the hydrogel SB4A are provided below. The SB4A hydrogel formulation included a methanol diluent and two different acrylic-terminated siloxane monomers.

<td></td><td colspan="5">SB4A (kinetic study 3)</td>

<td rowspan="2">Monomers</td><td>weight</td><td>fraction</td><td>batch of</td><td>molar ratio with</td><td>fraction</td>

<td>molecular</td><td>cool</td><td>hydrogel</td><td>With respect to</td><td>in weigh</td>

ES 2 812 752 T3

<td></td><td>(g / mol)</td><td></td><td>10 grams (g)</td><td>main monomer</td><td></td>

<td>Trimethacrylate trimethylolpropane</td><td> 338,00</td><td> 0,0019</td><td> 0,131</td><td> 0,0103</td><td> 0,0091</td>

<td>NVP</td><td> 111,14</td><td> 0,0908</td><td> 2,074</td><td> 0,4963</td><td> 0,1440</td>

<td>GMA</td><td> 160,00</td><td> 0,0322</td><td> 1,058</td><td> 0,1759</td><td> 0,0735</td>

<td>DMA</td><td> 99,13</td><td> 0,1830</td><td> 3,727</td><td> 1,0000</td><td> 0,2588</td>

<td>(3-methacryloyloxypropyl) tris- (trimethylsiloxy) silane</td><td> 422,82</td><td> 0,0347</td><td> 3,010</td><td> 0,1894</td><td> 0,2091</td>

<td>Lucirin</td><td> 348,00</td><td> 0,0011</td><td> 0,080</td><td> 0,0061</td><td> 0,0056</td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td>thinner</td><td></td><td></td><td></td><td></td><td></td>

<td>methanol</td><td> 32,04</td><td> 0,6563</td><td> 4,32</td><td> 3,5863</td><td> 0,3000</td>

<td>Diluent + total hydrogel</td><td></td><td> 1,0000</td><td> 14,400</td><td></td><td> 1,0000</td>

Example 7: SB4B silicone hydrogel

The SB4B silicone hydrogel was prepared and molded into sleeves as in Example 1. The components of the SB4B hydrogel are provided below. The SB4 hydrogel formulation also included a methanol diluent and two different acrylic-terminated siloxane monomers.

<td></td><td colspan="5">SB4B (kinetic study 3)</td>

<td>Monomers</td><td>molecular weight (g / mol)</td><td>Molar fraction</td><td>10 gram hydrogel batch (g)</td><td>molar ratio to main monomer</td><td>weight fraction</td>

<td>Trimethacrylate trimethylolpropane</td><td> 338,00</td><td> 0,0019</td><td> 0,137</td><td> 0,0103</td><td> 0,0095</td>

<td>NVP</td><td> 111,14</td><td> 0,0939</td><td> 2,167</td><td> 0,4963</td><td> 0,1505</td>

<td>GMA</td><td> 160,00</td><td> 0,0333</td><td> 1,106</td><td> 0,1759</td><td> 0,0768</td>

<td>DMA</td><td> 99,13</td><td> 0,1893</td><td> 3,894</td><td> 1,0000</td><td> 0,2704</td>

<td>(3-methacryloyloxypropyl) tris- (trimethylsiloxy) silane</td><td> 422,82</td><td> 0,0307</td><td> 2,696</td><td> 0,1623</td><td> 0,1872</td>

<td>Lucirin</td><td> 348,00</td><td> 0,0011</td><td> 0,080</td><td> 0,0059</td><td> 0,0056</td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td>Thinner</td><td></td><td></td><td></td><td></td><td></td>

<td>methanol</td><td> 32,04</td><td> 0,6497</td><td> 4,32</td><td> 3,4321</td><td> 0,3000</td>

<td>Total</td><td></td><td> 1,0000</td><td> 14,4000</td><td></td><td> 1,0000</td>

Example 8: measurement of the hydration of the hydrogel SB1 as a function of the monomer extraction rate

After curing, the hydration of the SB1 hydrogel formulation was measured as a function of the extraction rate of unreacted DMA and NVP monomers, as shown below. The formulation was immersed in saline (NaCl in deionized water, 0.9% w / w) using 3.5 ml of saline per sleeve containing approximately 60 mg of polymer per sleeve. The temperature was kept constant at 55 ° C and the solution was stirred on the shaker incubated at 100 rpm. The extraction was carried out for 1, 2, 3, 4, 6, 8, 12 and 24 hours, replacing the saline extract with fresh saline after each period. The extraction procedure removes unreacted impurities from the polymer and also allows it to undergo hydration. The electrical resistance is believed to depend on the level of hydration of the polymer.

The extracts were analyzed by GC-MS chromatography, in an Agilent 7890A GC apparatus with Agilent 5975C mass selective quadrupole detector, monitoring N-vinylpyrrolidone (NVP), dimethylacrylamide (DMA). Total ion chromatograms were recorded at each elution and peaks were identified using NVP, DMA, and methanol.

ES 2 812 752 T3 neat as references.

After approximately one hour of extraction (the terms extraction and hydration are used interchangeably in this application), the extraction rate for the SB1 hydrogel formulation was approximately 170 μg / h for DMA (shown in Figure 21A) and approximately 450 µg / h for NVP (shown in Figure 21B).

Example 9: measurement of the hydration of the hydrogel SB2 as a function of the monomer extraction rate

After curing, the hydration of the SB2 hydrogel formulation was measured as a function of the extraction rate of unreacted NVP monomers, as shown in Figure 22A and as described in Example 8, and as a function of the methanol extraction rate, as shown in Figure 22B. Approximately one hour after curing, the extraction rate for the SB2 hydrogel formulation was approximately 1150 µg / hr for NVP, which was much higher than that obtained with the SB1 hydrogel formulation. As noted above, one difference between the SB1 and SB2 formulations is that SB2 contained a methanol diluent. The presence of the diluent substantially accelerated the extraction of unreacted monomers from SB2, as shown by the relative rates of NVP extraction from SB2 and SB1 (1150 µg / hr vs. 450 µg / hr). However, the presence of the diluent also decreased the cure rate of SB2 relative to SB1, by reducing the effective mole fractions of each of the monomers (data not shown).

Example 10: measurement of the hydration of hydrogels SB1 and SB2 as a function of electrical resistance

After curing, hydration of hydrogel formulations SB1 and SB2 was measured as a function of electrical resistance over a 72 hour extraction period (monomer extraction is a procedure that helps complete hydration of the hydrogel). Electrical resistance was measured by a multimeter set to read in series resistance mode. One lead from the multimeter makes contact with the spring on the reference sleeve and the other with the spring on the test sleeve. The resistance measurement was read within 30 seconds. The resistance of the circuit, that is, a resistance other than that of the test sleeve, was estimated to be 2 kQ. "Sleeve strength", as referenced in the examples, means sleeve specific strength values, ie with the 2 kQ removed.

From the data provided in Figures 23A and 23B it is shown that, for both hydrogel formulations, the electrical resistance is high (approximately 145 to 175 kQ) after the first hour of hydration / extraction, but as the hydrogel becomes more hydrated, the resistance decreases (that is, it becomes more conductive). Data is not plotted after 8 hours of hydration given the very low values.

Example 11: measurement of the hydration of hydrogels SB2 and SB3 as a function of electrical resistance

After curing, the hydration of the hydrogel formulations SB2 and SB3 was measured as a function of electrical resistance over a period of one to 8 hours and a period of four to 72 hours, as described in Example 10. The data provided in Figures 24A and 24B show that hydration continues for a long period (in this case 72 hours). These hydrogels were still usable after 8 hours of hydration (they were still conductive). Furthermore, the gel mass of SB3 is significantly greater than that of SB2 after hydration. It should be noted that although the gel mass of SB3 is greater than that of SB2, the gel height is less for SB3. This is due to the presence of the diluent.

Example 12: measurement of the hydration of hydrogels SB4A and SB4B as a function of electrical resistance

After curing, the hydration of the hydrogel formulations SB4A and SB4B was measured as a function of electrical resistance over a period of 144 hours. The data provided in Figure 25 also shows that hydrogels remain hydrated for a long period of time and become more conductive as hydration increases.

Example 13: expansion of hydrogel SB2 and SB3 due to hydration

The mass and height of the SB2 and SB3 hydrogel casts were measured to determine the swelling of the hydrogels as a function of hydration. Measurements are provided in Figures 26A and 26B. Replacing the HEMA monomers with EGDMA monomers in SB3 made it more hydrophilic, resulting in an increase in water uptake relative to SB2 and thus a higher mass.

Example 14: expansion of hydrogel SB4A and SB4B due to hydration

The mass and height of the SB4A and SB4B hydrogels were measured and compared with those of the SB3 hydrogel to determine the swelling of the hydrogels as a function of hydration, as shown in Figures 27A and 27B. The hydrogels SB4A and SB4B, which exhibited high hydration (see example 12) expanded less

ES 2 812 752 T3 than the more hydrophilic SB3 hydrogel. Therefore, with the hydrogels SB4A and SB4B, a higher conductance was achieved with less swelling / expansion.

Example 15: SB5 silicone hydrogel

The SB5 silicone hydrogel formulation was prepared and molded into sleeves as described in Example 1. The components of the SB5 hydrogel are provided below. A methanol diluent was included in the SB5 hydrogel formulation.

<td colspan="6">SB5</td>

<td>Monomers</td><td>molecular weight (g / mol)</td><td>Molar fraction</td><td>10 gram hydrogel batch (g)</td><td>molar ratio to main monomer</td><td>weight fraction</td>

<td>Trimethacrylate trimethylolpropane</td><td> 338,00</td><td> 0,0021</td><td> 0,119</td><td> 0,0151</td><td> 0,01186</td>

<td>NVP</td><td> 111,14</td><td> 0,0686</td><td> 1,278</td><td> 0,4957</td><td> 0,12779</td>

<td>GMA</td><td> 160,00</td><td> 0,0243</td><td> 0,653</td><td> 0,1760</td><td> 0,06530</td>

<td>DMA</td><td> 99,13</td><td> 0,1383</td><td> 2,299</td><td> 1,0000</td><td> 0,22992</td>

<td>(3-methacryloyloxypropyl) tris- (trimethylsiloxy) silane</td><td> 422,82</td><td> 0,0224</td><td> 1,591</td><td> 0,1623</td><td> 0,15914</td>

<td>Lucirin</td><td> 348,00</td><td> 0,0011</td><td> 0,067</td><td> 0,0082</td><td> 0,00666</td>

<td></td><td></td><td></td><td></td><td></td><td></td>

<td>Thinner</td><td></td><td></td><td></td><td></td><td></td>

<td>methanol</td><td> 32,04</td><td> 0,7431</td><td> 3,993</td><td> 5,3738</td><td> 0,39934</td>

<td>Total</td><td></td><td> 1,0000</td><td> 10,0000</td><td></td><td> 1,0000</td>

In formulation SB5, the UV initiator diphenyl oxide- (2,4,6-trimethylbenzoyl) phosphine (CAS # 75980 60-8, Lucirin TPO) was selected as it is capable of being activated by UV radiation in the 400-450 nm wavelength range, a band that transmits the sleeve material (Versaflex OM3060-1, a styrene-ethylene / butylene-styrene copolymer). The addition of trimethylolpropane trimethacrylate improved the crosslinking density and made the mixture more resistant to drying.

Example 16: measurement of the hydration of the hydrogel SB5 as a function of the extraction of monomers

After curing, the hydration of the SB5 hydrogel was measured as a function of the extraction rate of unreacted DMA and NVP monomers and methanol, as shown in Figures 28A-28C and as similarly described. in example 8. Briefly, the extracts were analyzed by GC-MS chromatography, on an Agilent 7890A GC apparatus with Agilent 5975C mass selective quadrupole detector, monitoring N-vinylpyrrolidone (NVP), dimethylacrylamide (DMA) and methanol (MeOH). Total ion chromatograms were recorded at each elution and peaks were identified using pure NVP, DMA, and methanol as controls. The data from the graphs provided in Figures 28A-28C show that the extraction rate of methanol is the fastest followed by that of DMA. NVP extraction is the slowest. The extraction rate depends solely on the solubility of each species in saline solution at the hydration temperature (55 ° C), since the swelling of the hydrogel network is the same in all cases. As shown in the graphs, the extraction rates of all species appear to reach a low plateau after 24 hours of hydration. Based on these results, it was concluded that the SB5 hydrogel was ready for use after 24 hours of hydration.

Example 17: measurement of the hydration of the hydrogel SB5 as a function of the electrical resistance

After curing, the hydration of the SB5 hydrogel formulation was measured as a function of electrical resistance during different extraction periods, similar to that described in Examples 10-12. As shown in Figure 29, electrical resistance was significantly reduced with hydration caused by saline extraction. The electrical resistance of the SB5 hydrogel reached a level greater than 0.6 kQ after 12 hours of extraction and a lower plateau after approximately 24 hours of extraction.

Example 18: expansion of hydrogel SB5 due to hydration

The mass and height (expansion) for the SB5 hydrogel casts were measured to determine the swelling of the

ES 2 812 752 T3 hydrogels as a function of hydration (and extraction period). Referring to the data table in Figure 30A, at 48 hours, the percentage of hydration (defined as 100 * (M48 hours - M0 hours) / M48 hours, where M is the mass in grams) of SB5 (42- 05) is estimated to be approximately 35.5%, which was significantly lower than that of SB1 (42-01) and SB2 (42-02). The reduced percentage of hydration can be attributed to the increased crosslink density and the increased hydrophobicity of SB5 relative to SB1 and SB2. Thus, the benefits of SB5 hydrogel may be that it is capable of achieving a sufficient level of electrical conductivity to perform its electrical function while also having a relatively low level of hydration, and that its processability is improved. Increasing the crosslink density also appeared to raise the glass transition temperature of the non-hydrated hydrogel network (data not shown). These changes in the composition of hydrogel SB5 relative to hydrogels SB1 and SB2 can improve its drying time and its resistance to friction-induced shear forces against nasal tissue.

Referring to the graph of gel mass versus hydration duration provided in Figure 30B, hydrogel SB5 reached a hydration threshold at approximately 24 hours of extraction, compared to hydrogels SB1 and SB2 in which hydration continued to increase. gel mass up to about 72 hours (see eg SB2 data in example 13). This is consistent with the lower percentage of hydration of SB5.

A graph of gel expansion versus hydration duration is provided in Figure 30C, showing data obtained by recording the height increase of hydrogel SB5 obtained from optical photographs of hydrated sleeves. The data indicated that gel height reached a plateau after approximately 24 hours of extraction, compared to hydrogels SB1 and SB2, which continued to show increases in gel height up to and beyond 72 hours of extraction with saline. under identical conditions (see eg SB2 data in example 13).

Overall, the SB5 hydrogel data showed that its equilibrium water content was approximately 35%. Referring to Example 15, the amount of methanol (diluent) used in this formulation is approximately 39.9%. These values ​​indicate that the SB5 hydrogel is a zero expansion hydrogel. The data provided on gel height expansion showed an increase from 5.0mm (measured before hydration) to 5.2mm (after hydration was completed in approximately 24 hours), indicating that an increase of about 4% is attributable to the additional complexation of water molecules by the polymeric network relative to methanol.

Example 19: contact angle of the silicone hydrogel formulation SB5

The contact angle of the SB5 hydrogel used as electrical contact at the tip of a nasal stimulation device was measured by placing 1 μl of deionized water on its surface and then photographing the drop using a Leica M-80 microscope that had a L80nmnm digital camera, and that it had LAS optical capture software, version 4.3.0. The contact angle was estimated from the photograph. The measurement was repeated using an electrical contact tip that had been hydrated by immersion in deionized water for 30 minutes just prior to measurement. The contact angle was measured to be 90 degrees in both cases. These results indicate that the surface of SB5 is hydrophobic, although the overall gel mass is highly hydrophilic. Thus, the SB5 hydrogel appears to have a complex polymer morphology composed of a hydrophilic core and a hydrophobic surface, for example, as shown in Figure 7.

Example 20: biocompatibility of the hydrogel formulation SB5

MEM studies were performed on SB5 hydrogel samples hydrated in saline for 12 and 24 hours at 55 ° C to determine the biocompatibility of the hydrogel, as shown below. Studies were completed by Acta Laboratories, Inc., per compendium USP 36 / NF 31 supplement 2, (87) Biological activity tests, in vitro, elution test.

<td colspan="7">KS5 14043, 12 hours</td>

<td colspan="7">Elution Results</td>

<td>Culture</td><td>% intracytoplasmic granules</td><td>Confluent monolayer</td><td>% round and slightly joined</td><td>% cell lysis</td><td>Grade</td><td>Reactivity</td>

<td>Sample # 1</td><td> 100</td><td> (+)</td><td> 0</td><td> 0</td><td> 0</td><td>None</td>

<td>Sample # 2</td><td> 100</td><td> (+)</td><td> 0</td><td> 0</td><td> 0</td><td>None</td>

<td>Reagent Control # 1</td><td> 100</td><td> (+)</td><td> 0</td><td> 0</td><td> 0</td><td>None</td>

<td>Control of</td><td> 100</td><td> (+)</td><td> 0</td><td> 0</td><td> 0</td><td>None</td>

ES 2 812 752 T3

<td>reagent # 2</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Negative Control # 1</td><td> 100</td><td> (+)</td><td> 0</td><td> 0</td><td> 0</td><td>None</td>

<td>Negative Control # 2</td><td> 100</td><td> (+)</td><td> 0</td><td> 0</td><td> 0</td><td>None</td>

<td>Positive Control # 1</td><td> 0</td><td> (-)</td><td> 0</td><td> 100</td><td> 4</td><td>Strong</td>

<td>Positive Control # 2</td><td> 0</td><td> (-)</td><td> 0</td><td> 100</td><td> 4</td><td>Strong</td>

KS5 14043, 24 hours Elution Results Culture % intracytoplasmic granules Confluent monolayer % round and slightly joined % cell lysis Grade Reactivity Sample # 1 100 (+) 0 0 0 None Sample # 2 100 (+) 0 0 0 None Reagent Control # 1 100 (+) 0 0 0 None Reagent Control # 2 100 (+) 0 0 0 None Negative Control # 1 100 (+) 0 0 0 None Negative Control # 2 100 (+) 0 0 0 None Positive Control # 1 0 (-) 0 100 4 Strong Positive Control # 2 0 (-) 0 100 4 Strong