JP2022511335A - Artificial tears compositions, contact lens compositions and drug vehicle compositions, and methods of their use. - Google Patents

Abstract

The present invention comprises an artificial tear composition, artificial tears, comprising one or more nonionic surfactants together with one or more non-Newtonic viscosity enhancing excipients and one or more polyols and / or electrolytes. Provided are liquid gel compositions, contact lens preservation compositions, contact lens treatment compositions, ophthalmic drug vehicle compositions and topical drug vehicle compositions, and methods of their use.

Description

The present invention relates to mild dry eye artificial tears compositions, moderate dry eye artificial tears compositions, severe dry eye artificial tears compositions, and extreme dry eye artificial tears compositions for ophthalmic and dermatological use. Dry eye artificial tears composition; contact lens multipurpose preservation solution composition, contact lens wearing treatment composition, contact lens, blister pack preservation composition fortified with physiological saline, and topical drug vehicle platform composition. Regarding. These compositions are one or more nonionic surfactants and two or more excipients selected from non-Newtonic viscosity enhancers, polyols and electrolytes; or hypotonic electrolytes / sodium chloride concentrates. And optionally include ophthalmic antibiotics, steroids, non-steroidal agents, immunosuppressants, glaucoma agents, or other agents for topical delivery on or into the eye. The present invention further relates to a method of treating a spectrum of eye surface disease epithelial disease, including but not limited to dry eye in humans or mammals. The invention further relates to contact lenses, punctal plugs, pellets, or any other device coated or injected with the compositions of the invention, which are used to deliver the agent to the ocular surface.

Artificial tears The eyes produce tears that spread to the eyes during blinking. A unique component of tear film combined with the blinking process creates a tear film made from mucosal, aqueous and lipid layers. This tear film is 1) evaporated, 2) spread along the surface of the eye, driven by high-shear blinking, 3) drainage aided by blink-powered lacrimal gland pumping, and 4) low along the tear meniscus of the eyelid. It receives significant forces that can compromise the integrity of the membrane, including the shear flow. To maintain the tear film, the film is intermittently replenished with new tear film components at each blink, which is triggered by tear destruction and corneal surface nerve excitation. This unique system creates a barrier between the environment and the surface of the eye, removing any irritants that may enter the eye. In addition, tear fluid has important plasma-derived components that are filtered to nourish the surface of the eyeball, reduce the risk of infection, and promote healing of the surface tissue of the eyeball. A healthy tear film is necessary for optimal vision, just as an unhealthy tear film results in poor visual quality and / or intelligibility. Includes internal or external eye surgery affecting eye surface, dry eye syndrome, dry eye following ophthalmic surgery, toxicity of drugs and / or preservatives, and eye surface abnormalities from contact lens solutions and / or contact lens use. There are several events that can cause a decrease in the quantity or quality of tears.

The tear film is the only and most important optical surface. Inhibitions that affect the quality and duration of this membrane on the cornea can dramatically change the quality of vision. These inhibitors include a reduction in volume measured by Schirmer's test, a reduction in tear destruction time, and a reduction in the tear prism (ie, measurements of meniscus along the lower eyelid where tear flow flows). Be done. Unfortunately, it is not easy to measure the thickness / and / or volume of each layer of a healthy tear film, the composition within each layer, and the true measurements of the flow properties and stabilization of the tear film obtained. .. Tear abnormalities range from abnormal composition of one or more of mucosal, aqueous and lipid layers to volume abnormalities including loss of thickness and / or loss of volume of one or more of these layers. It reveals a widespread tear deficiency up to these combinations.

Dry eye is a general term for any abnormality in the thickness of the tear film or the composition of the tear film. Dry eye is a common distress caused by eye failure in either producing the appropriate amount or maintaining the proper balance of tear components in the mucosa, aqueous layer or lipid layer. In either case, the tear film that normally covers the eye becomes unstable (ie, it no longer covers the entire eye uniformly and for a sufficient period of time). The sufficient period is typically about 8 seconds. The instability of the tear film causes the tear film to bead up of residual surface coating dry spots, while being inadequate in removing irritants. These dry spots and irritants cause many of the conditions associated with dry eye, such as burning sensation, stinging sensation, itching and eye strain. Dry eye symptoms can be exacerbated by work that prolongs the time between blinks, such as long-term computer use and reading. Even mild tear film deterioration can reduce tear destruction time (“TBUT”), leading to excessive blinking. Blinking can achieve a short moment of complete and uniform tear film coverage where vision is optimized. However, this reassurance is sporadic and short-lived, can result in complete deterioration of the tear film, and even nullifies frequent blinks.

Dry eye often follows any incisive or excision procedure that cuts the corneal nerve, either by reducing the neurological trigger for tear secretion or by disrupting the external surface. By creating abnormal spreads and rising dry spots (corneal marginal pits). Procedures include, but are not limited to, corneal or scleral ophthalmic surgery, including, but not limited to, cataract incision, corneal transplant surgery, glaucoma surgery filtration foam, and any open or resecting surgery. Dry eye following eye surgery can lead to increased pain to the patient, increased risk of infection, decreased vision, and increased susceptibility to topical medications and preservatives. This increased susceptibility can exacerbate eye surface disease, have general symptoms similar to dry eye, and can lead to prolonged healing time of the epithelium.

Current artificial tears compositions designed to reduce or alleviate dry eye include the mucosa, aqueous layer and layer of tear film to maintain membrane stability and prevent rapid evaporation. / Or contains a polymer that acts to mimic the lipid layer. The high viscosity artificial tears composition maintains a longer lasting tear film. However, these compositions cause a viscous pull on the eyelids, create an unpleasant "sticky" sensation during blinking, can be difficult to apply, and can create scabs on the eyelids. These highly viscous compositions also typically result in blurred vision for a few minutes or longer. Low-viscosity compositions do not, in part, maintain a long-lasting tear film due to the faster loss of these aqueous solutions to evaporation and drainage aided by blink-powered lacrimal gland pumping.

Current artificial tear composition for treating dry eye is defective for many reasons, including: i) They typically produce a stable tear film for only a short period of time, not less than 15 minutes. Not maintained, then tear properties return to baseline, ii) higher viscous formulations only last moderately longer (about 25 minutes or less) and they blur for a relatively long time. Causes vision (Refresh® Celluvisc (400 cps) is as long as 12 minutes and often requires an agitated blink until it is sufficiently thinned and stabilized, iii). They either do not provide evaporative shields to reduce dryness, or they have a synthetic and / or oily sensation from the addition of lipids or meibomian glands that do not stabilize the aqueous layer. There, iv) they do not provide a protective coating on the conjunctival of the eyelids and / or do not sufficiently dissolve the dry solids of lipids within the meibomian glands, and both qualities of dry eye are such meibomian glands. Characterized by dryness and dysfunction (“MGD”), v) they do not provide a physiologically enhanced environment for healing of epithelial cells and do not maintain integration, vi) they contact. Does not prevent, reduce, or aid the dissolution of proteins, cholesterol, or dry mucous membranes that deposit on the lens surface, on the meibomian epithelium, or on the meibomian glands and stimulate or otherwise degrade these cell membranes. No, vii) They do not significantly promote tear secretion, or existing tear fluids (prescription agents such as Restasis® or Xiidra® attempt to increase tear secretion, but Does not result in prolonged exposure and retention (which causes only a slight increase), and viii) they result in higher osmotic pressure and greater wetting angles that make tear spread more difficult and non-uniform. ..

Efforts to create an evaporation shield to retain the aqueous tear layer, such as the addition of lipids or lipid phosphates, not only result in an unnatural perception of the synthetic oiliness obtained, but also poor aqueous layer stability. , And also impaired by the very short duration of the instilled eye drops, or by the longer duration of the more viscous, slightly longer lasting artificial tears blur. The goal is retention of artificial tears in the conjunctival sac, which limits this benefit associated with conventional tear preparations, with each blink pulling more of the artificial tears across the cornea. There is tremendous lacrimal duct drainage through the capillary attraction. The longest-lasting artificial tears on the market use high concentrations of viscosity enhancers. Celluvisc® (Celluvisc is a registered trademark of Allergan, Inc.) uses a high viscosity carboxymethyl cellulose (“CMC”) 1% – about 350 centipores (“cps”) viscosity and is a Refresh Liquid. (Registered Trademark) (Refresh Liquigel is a registered trademark of Allergan, Inc.) uses a blend of 0.35% high viscosity CMC and 0.65% low viscosity CMC-about 70 cps. These two types are such compositions. These highly viscous artificial tears compositions last for a long time, but cause significantly blurred vision that lasts for less than 10 minutes.

Artificial tears compositions have made progress. This advance has been based on the TBUT, which is the added wetting period, and the improvement in the difficulty of measuring the degree and duration of blurring to viscosity. The first generation of artificial tears is a simple aqueous solution of physiological saline with the addition of other electrolytes, and certain minerals are still present in eye drops such as Theterates® (Theterates are Advanced Vision Research, Inc.). (It is a registered trademark of) found in. The second generation was developed by adding viscous agents of natural and synthetic polymers, especially polyvinyl alcohol and cellulose derivatives. The most natural sensation and therefore popular formulation from the second generation is Refresh® tears (Refresch is a registered trademark of Allergan Pharmaceuticals, Inc.). The third generation was developed by adding hyaluronic acid (hyaluronate). The third generation promotes slower lacrimal duct drainage and greater retention on the eye by conferring the properties of non-Newtonian flow. However, the third generation has only moderate stability and retention of the tear film. The third generation also shortens the period of blurring and stabilizes the tear film. However, third generation formulations are more oily and their unnatural "water deficiency" perception makes them less popular than many products on the market today from the second generation. Moreover, the 3rd generation has little explicit therapeutic clinical difference from the 2nd generation. The fourth generation was developed to consist of lipid-based oil-in-water (“O / W”) emulsions. The 4th generation O / W emulsion reduces evaporation of the tear film, stabilizes the lipid layer and prolongs its duration. These formulations require the addition of nonionic or cationic surfactants for stabilization. However, these formulations do not promote increased spreadability over the eyes, do not provide any useful auxiliary aqueous layer stabilizers, or delay high shear blinking lacrimal gland pumping to minimize retention enhancement. To reach. These formulations may be limited to low concentrations of surfactant due to their known toxicity at 1.0% or higher in conventional artificial tears. In addition, as with 3rd generation, 4th generation artificial tears have minimal therapeutically verifiable clinical benefit and are synthetic and less comfortable. Have.

Contact Lens Solution Contact lenses must be loaded for a long time each day to be most effective and, if tolerant, can be loaded overnight. During this time, debris consisting of macromolecular components of tear fluid and fine particles from the environmental build-up on the surface of the lens causes irritation to the wearer and impairs vision. Conventional methods of removing such debris and particles from the surface of a contact lens include separate steps of cleaning and rinsing, both of which require the contact lens to be removed from the eye. There are also multipurpose solutions that can be used for both cleaning and rinsing contact lenses. However, these multipurpose solutions tend to do a lesser job in cleaning, because the multipurpose solutions do not remain comfortable to the user when placed in the eye after rinsing. Is. Effective cleaning is important because even sporadic bacterial binding to the contact lens surface via van der Waals forces creates a biofilm. This biofilm is a mixture of proteins, polysaccharides and lipids with varying degrees of hydrophilic and / or hydrophobic components. Biofilms reduce the efficacy of antibacterial solutions and increase the rate of microbial adhesion. The most dangerous of these microorganisms include Acanthamoeba spp. Embryonic species and Fusarium fungal spores. Adhesion of these pathogenic microorganisms can result in serious and difficult treatment of keratitis, which can cause partial or even complete visual loss from the resulting infection. Many contact lenses incorporate antimicrobial compounds in their contact lenses to counter such invasion. However, these efforts are not always effective and long wearing times increase the risk of pathogenic infections.

For long-term wear users, there are several products such as Alcon Opti-tears Comfort Contact Lens Drops that can be applied while the contact is on the eye. These eye drops help moisturize contact lenses and remove debris only slightly. However, the ability of these eye drops to dissolve or prevent deposits does not really exist. Moreover, these eye drops have lower detergency than either multipurpose or two-step solutions, and they are only slightly effective against many biofilms.

Currently available contact lens solutions do not provide much reassurance for contact lens wearers. As a category of artificial tears, these eye drops provide very short-term, clinically almost trivial relief from dry eye, primarily with no advantage in the removal of deposits or biofilms. A solution of electrolyte is provided. As conservative solutions, these solutions only disinfect the lens and allow it to retain its shape. However, the basic challenges associated with wearing contact lenses are the proteins, mucous membranes, and lipids or lipid esters that deposit on the lens surface. As mentioned above, these deposits form a stronger matrix that binds to the contact lens surface. These deposits then irritate the epithelium, trigger microbial invasion and infection, dramatically reduce vision, and especially mesopic vision caused by diffracting light along the interior of the contact lens surface. Can be dramatically reduced. These challenges are indirectly related to dry eye due to the smaller volume of the aqueous layer that forms more deposits on the surface of the lens.

Drug Vehicle The efficacy of ophthalmic drugs is very limited by non-adherence. Adherence is adversely affected by reduced comfort, irritation, and the temporary quality of visual impairment that lasts minutes to tens of minutes, which is common with many medications. In particular, these side effects are caused by the need for suspensions commonly used for highly lipophilic agents, or very high local concentrations for highly hydrophilic agents.

The basic challenges of an ophthalmic delivery vehicle are greater intraocular by improving comfort, minimizing visual blurring when instilled, increasing drug solubility, prolonging drug residence time and increasing permeability through the cornea. Achieving delivery, reducing systemic drug absorption, and minimizing local side effects caused. Unfortunately, these objectives have not been encountered by current ophthalmic formulations.

Current artificial tears vehicles can be used for drug solubilization, but do not confer extended drug residence time or confer the benefits of other indications. More viscous artificial tears are high-concentration viscous enhancers such as Celluvisc® (Celluvisc is a registered trademark of Allergan, Inc.), High Viscosity Carboxymethyl Cellulose (CMC) 1% -about 350. Centipoise (cps) viscosity, and Refresh Liquigel® (Refresh Liquigel is a registered trademark of Allergan, Inc.), 0.35% high viscosity CMC and 0.65% low viscosity CMC-about 70 cps. Although blended with, these formulations have a prolongation of visual blurring that can last for more than 10 minutes and greatly reduce medication compliance. These artificial tear vehicles also do not slowly filter the drug, but rather release more into the drainage.

Gelling agents have been used somewhat successfully to increase the residence time of the drug and to improve the solubility of the drug. The provision that such agents are instilled as a liquid and then almost immediately triggered by the gel phase here prolongs the drug residence time and extends the drug release time. Timoptic XE® Gel (Gellan gum, Timotic XE is a registered trademark of Merck & Co, Inc.), AzaSite® (AzaSite is a registered trademark of Institute Vision, Inc.). ) (Polycarivophyll, poroxamar), and Besivance® (Besivance is a registered trademark of Bausch & Lomb, Inc.) (Polycarivophyll, poroxamar), 0.3% alginate Geltorol (registered). Trademark)) (Keltrol is a registered trademark of CP Kelco US, Inc.) is an example of such an agent, wherein the polycarbophyll-poroxamar gel is commercially available. , Durasite® (Durasite is a registered trademark of Inside Vision, Inc.).

However, most gelling agents: 1) increase blurring when instilled, 2) cause the eyelids and eyelashes to be covered with gel residue, 3) cause irritation / stinging sensation when instilled, and 4). It can release substantial active agents systemically and have systemic side effects. Drugs with minimal systemic side effects, or drugs intended for acute use for only a few days, alleviate these problems somewhat, but have a higher systemic effect profile, specifically lipophilic. As a drug, more specifically a conjunctive drug, these problems can seriously affect medication compliance.

Gelling agents experience phase transitions to highly viscous states, typically achieving 500-1000 cps or higher after those transitions. Ionic, pH and heat triggers are typically used. However, the high shear forces of each blink tend to expel such phase-altered membranes into the nasolacrimal duct of the turbinate, where the rest of the drug can quickly enter the systemic circulation. Break into particles. Many gelling agents combine poloxamers of various molecular weights with viscosity enhancers or other gelling agents to create the desired phase transition from liquid to gel upon instillation. Typically, for formulations using poloxamers without a second gelling agent, a poloxamer concentration of 15% or higher is required to achieve the gel transition temperature at body temperature (37 ° C.).

Patel (Int. J. of Pharm. Chem. Sci., Volume 1, October-December 2012) is a poloxamer and viscosity enhancer-low molecular weight, low viscosity hydroxypropylmethylcellulose (HPMC E50LV) 1.5%. Has described its use with brimonidine, specifying test concentrations of 1% to 19% of poloxamers with HPMC and no clinically useful gelling ability in vitro below 15%. Given a dilution of the tear film, it typically requires about 21% poloxamer to achieve a phase transition to the gel during ophthalmic instillation. For example, Qian (Drug Dev. And Industrial Therapy, 2010, 36 (1): pp. 1340-1347) is an in-situ gelling system for metazolamide, 21%, to achieve a preferred gel-to-gel phase transition. Describes a carbonic anhydrase inhibitor (glaucoma) using poloxamer 407 and 10% poloxamer 188. High-viscosity gels have been described with limitations similar to in-situ gels, specifically the worst non-adaptive factors for eyelid and eyelash residues, and lesser amounts and lesser of both. There is still a trade-off with viscous eyelid pull for substantially extended visual blur.

The use of low viscosity agents reverses the predicament. Other compositions attempt to optimize compliance for formulations with low viscosity agents so that comfort is good, vision is good, and surface residues are absent. However, in such formulations, tear dilution is almost immediate and drug residence time is strictly limited compared to in situ gels or viscous liquid gels. Thus, the formulation either improves compliance or enhances efficacy, but not both. This is often seen in vehicles for dry eye. Refresh Liquigel® at 70 cps and Celluvisc® at 300 cps are examples of where visual blurring is observed.

Patel (Int.J.of Palm.Chem.Sci., Volume 1, October-December 2012 Qian (Drug Dev. And Industrial Pharmacy, 2010, 36 (1): pp. 1340-1347

Therefore, in the art, there is a need for long-lasting artificial tears for those who generally have eye surface disease, specifically those who have dry eye syndrome, and the artificial tears are tears. It can promote and stimulate long-lasting tear capture through fluid secretion and / or reduction of lacrimal duct drainage and creation of evaporative shields and can be irritating or otherwise deposited on the ocular surface or on the lens. Dissolve the organic matrix of the particles. This artificial tear preparation should impart these qualities without causing blurry visual prolongation or unpleasant synthetic and / or oily perception. In addition, this artificial tear preparation should allow safe use of surfactant concentrations above 1% by eliminating the toxicity of the surfactant.

In addition, there is a need for cleaning compositions, preservative compositions and / or wet compositions for contact lenses in the art. The composition should reduce discomfort, reduce debris and particulate deposits, and increase wearing time while being comfortable to the wearer. In particular, this composition should reduce the formation and attachment of biofilms of Acanthamoeba spores and Fusarium filaments.

Finally, there is a need in the art for topical drug vehicles capable of retaining the drug on the surface of the eye or skin. This vehicle should be comfortable for the user and should increase the residence time, absorbency, safety or efficacy of the drug on the surface of the eye or skin.

(Gist of the invention)
Artificial tears In certain embodiments, the present invention comprises one or more nonionic surfactants and at least one excipient selected from viscosity enhancers, polyols and electrolytes for therapeutic tears. With respect to artificial tears compositions containing surprising and unexpected combinations that confer enhancement of the desired properties of fluid enhancement.

In certain embodiments, the present invention relates to an artificial tear composition comprising means for inducing tears and means for capturing tears.

In a preferred embodiment, the means for inducing tears is selected from a pH of about 5 to about 6, terpenoids, and an osmotic pressure of about 270 to about 550 milliosmol.

In another preferred embodiment, the means of capturing the tear fluid are one or more nonionic surfactants with a total volume of about 1.5 w / v% to about 5.9 w / v%, and one or more. The viscosity enhancer, including the viscosity enhancer, imparts a viscosity of about 50 to about 10,000 centipores at 0 shear to 1 second.

In a preferred embodiment, the one or more nonionic surfactants consist of the group consisting of poloxamers, polysorbates, cyclodextrins (alpha, beta or gamma), alkylarylpolyethers, polyoxyethylene glycol alkyl ethers, tyroxapols and polyoxyls. Be selected.

In another preferred embodiment, the one or more viscosity enhancers consist of cellulose derivatives, carbomer, gum, dextran, polyvinyl alcohol, polyacrylic acid, povidone, polyethylene glycol, propylene glycol, chitosan, and hyaluronate and hyaluronic acid. Selected from the group, more preferably the cellulose derivatives are carboxymethyl cellulose (“CMC) high molecular weight blends, CMC low molecular weight blends, CMC medium molecular weight blends, methyl cellulose, methyl cellulose 4000, hydroxymethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl. It is selected from the group consisting of methyl cellulose (“HPMC”) high molecular weight blends, hydroxypropyl methyl cellulose 2906, carboxypropyl methyl cellulose (CPMC) high molecular weight blends, hydroxyethyl celluloses, hydroxymethyl celluloses, and combinations thereof.

In another embodiment, the artificial tears composition of the invention further comprises a polyol selected from the group consisting preferably of mannitol, xylitol, sorbitol, isosorbide, erythritol, glycerol, maltitol, and combinations thereof.

In another embodiment, the artificial tears composition of the invention further comprises one or more electrolytes, preferably selected from the group consisting of magnesium ions, sodium chloride, potassium chloride, and combinations thereof.

In another embodiment, the artificial tears composition of the present invention does not contain magnesium ions, including magnesium chloride.

In another embodiment, the artificial tear composition of the present invention further comprises one or more lipids, preferably omega 3 fatty acids.

In another preferred embodiment, the invention relates to an artificial tear composition comprising one or more nonionic surfactants and polyols.

In another preferred embodiment, the invention relates to an artificial tear composition comprising one or more nonionic surfactants and electrolytes.

In another preferred embodiment, the invention relates to an artificial tear composition comprising one or more nonionic surfactants, polyols and electrolytes.

In another preferred embodiment, the invention relates to an artificial tear composition comprising one or more nonionic surfactants, viscosity enhancers and polyols.

In another preferred embodiment, the invention relates to an artificial tear composition comprising one or more nonionic surfactants, viscosity enhancers and electrolytes.

In another preferred embodiment, the invention relates to an artificial tear composition comprising one or more nonionic surfactants, viscosity enhancers, polyols and electrolytes.

In another preferred embodiment, the invention preferably comprises one or more nonionic surfactants, one or more viscosity enhancers, at concentrations of about 1.25 w / v% to about 10.0 w / v%. And preferably mediated by nociceptive acceptance, selected from the group consisting of a pH of <6.0, an osmotic pressure of about 250 milliosmoles or less, an osmolality of 350 milliosmoles or more, an osmolality of 400 milliosmoles or more, and an osmolality of 450 milliosmoles or more. An artificial tear composition comprising a means for inducing lacrimation, about 0.05 to about 4.0 mM menthol, and a combination thereof, preferably resulting in prolongation of lacrimation and capture. , Artificial tears composition.

In another preferred embodiment, the invention is one or more nonionic surfactants with a total concentration of about 1.5 w / v% to about 5.9 w / v%, one or more viscosity enhancers, 6. It relates to an artificial tear composition comprising a tear-inducing means selected from the group consisting of a pH of less than 0.0 and an osmotic pressure of 350 milliosmoles or more, a menthol, and a combination thereof.

In another preferred embodiment, the invention consists of one or more nonionic surfactants and viscosity enhancers, polyols and electrolytes with a total concentration of about 1.5 w / v% to about 5.9 w / v%. Containing an artificial tear composition comprising one or more excipients selected from the group.

In another preferred embodiment, the invention is described.
It is selected from the group consisting of poloxamers, polysorbates, cyclodextrins, alkylaryl polyethers, polyoxyethylene glycol alkyl ethers, tyloxapols and polyoxyls, and has a total concentration of about 1.25 w / v% to about 7.0 w / v%. Preferably, a polysorbate of about 0.01 w / v% to about 4.0 w / v%, one or more poloxamers of about 0.01 w / v% to about 3.0 w / v%, about 0.01 w / v%. One or more nonionic surfactants selected from the group consisting of ~ 1.0 w / v% polyoxyl and about 0.01 w / v% ~ 5.0 w / v% hydroxypropyl-gamma-cyclodextrin. Activator,
Viscosity enhancer selected from the group consisting of cellulose derivatives, carbomer, gum, dextran, polyvinyl alcohol, polyacrylic acid, povidone, polyethylene glycol, propylene glycol, chitosan, hyaluronate, hyaluronic acid, and combinations thereof.
An electrolyte of about 0.01 w / v% to about 3.0 w / v% selected from the group consisting of sodium chloride, potassium chloride, magnesium ions, and combinations thereof, preferably the electrolyte is about 0. 01w / v% to about 0.90w / v% magnesium ion, about 0.10w / v% to about 2.0w / v% sodium chloride, about 0.1w / v% to about 0.5w / v% Potassium chloride, and a combination of these, selected from
A polyol of about 0.1 w / v% to about 4 w / v%, preferably the polyol is 0.25 w / v% to about 2.5 w / v% mannitol or 0.5 w / v% to about 2.5 w. / V% glycerol,
Means for inducing tears, selected from the group consisting of pH <6.0, osmolality above 350 milliosmoles, menthol, and combinations thereof, optionally comprising about 0.1 w / v% sorbate. , An artificial tear composition,
Preferably, the concentration of the viscosity enhancer imparts the composition to a viscosity of about 0.1 to about 1,000 centipores (cps), preferably the low shear viscosity is from about 1 to about 1000 ps. The final high shear viscosity is about 30 cps or less.
Regarding artificial tears composition.

In another preferred embodiment, the invention is described.
It is selected from the group consisting of poloxamers, polysorbates, cyclodextrins, alkylarylpolyethers, polyoxyethylene glycol alkyl ethers, tyloxapols and polyoxyls, with a total concentration of about 1.25 w / v% to about 7.0 w / v%. One or more nonionic surfactants, preferably the one or more nonionic surfactants are about 0.01 w / v% to about 4.0 w / v% polysorbate, about 0.01 w. One or more poloxamers from / v% to about 3.0 w / v%, polyoxyl from about 0.01 w / v% to about 1.0 w / v%, and optionally from about 0.01 w / v%. Optionally selected from the group consisting of about 5.0 w / v% hydroxypropyl-gamma-cyclodextrin, about 0.1 w / v% to about 0.75 w / v% sodium chloride,
About 0.01 mM to about 0.50 mM menthol,
Optionally, it is a polyol of about 0.1 w / v% to about 4 w / v%, preferably the polyol is mannitol or glycerol at a concentration of about 1.0 w / v% to about 2.5 w / v%. And
Artificial tears containing cellulose derivatives, carbomer, gum, dextran, polyvinyl alcohol, polyacrylic acid, povidone, polyethylene glycol, propylene glycol, chitosan, hyaluronic acid, hyaluronic acid, and viscous agents selected from the group consisting of combinations thereof. It is a liquid composition
It preferably has a viscosity of about 1 to about 1,000 centipores and has a viscosity of about 1 to about 1,000 centipores.
Optionally relating to an artificial tear composition comprising magnesium ions from about 0.01 w / v% to about 0.90 w / v%.

In one preferred embodiment, the invention is described.
One or more nonionic surfactants of about 2.0 w / v% to about 4.0 w / v% selected from the group consisting of polysorbate, poloxamer, polyoxyl castor oil, cyclodextrin, and combinations thereof. ,
A viscosity enhancer of about 0.5 w / v% to about 2.0 w / v%, selected from the group consisting of carboxymethyl cellulose and carbomer 940.
About 1.0 w / v% to about 5.0 w / v% mannitol,
It is selected from about 0.5 w / v% to about 1.0 w / v%, preferably polyethylene glycol 400, polyethylene glycol 6000, polyethylene glycol 10000, polyethylene glycol 20000, and combinations thereof, and about 400 to about 20,000. Polyethylene glycol with Dalton molecular weight,
About 0.1 w / v% to about 2.0 w / v% sodium chloride, and about 0.1 w / v% to about 0.12 w / v% sodium chloride,
An artificial tear composition comprising a citric acid buffer having a concentration of about 3.0 to about 10.0 mmol.
w / v indicates weight / total volume of composition and has a pH of about 5.0 to about 7.4, preferably about 5.0 to about 6.0.
Regarding artificial tears composition.

In another preferred embodiment, the invention further relates to a method of treating dry eye, comprising administering the composition of the invention to a subject in need thereof.

In another preferred embodiment, the invention presents punctate superficial keratitis, resection of the epithelium, postoperative eye surface abnormalities such as post-cataract shunt, post-cataract, post-refractive surgery dry eye syndrome, keratoconjunctivitis sicca. , A group consisting of dry eye following incisional or excision surgery such as corneal / glaucoma surgery, cataract incision, corneal transplantation, glaucoma surgery filtering blisters, drugs, preservatives, contact lens solutions and eyeball surface abnormalities caused by contact lens use. Further relating to a method of treating defects, deficiencies, and diseases of the eyeball surface selected from, or a method of treating endophthalmitis.

In another preferred embodiment, the invention further relates to a method of treating eye pain, comprising administering the composition of the invention to a subject in need thereof.

In another preferred embodiment, the invention further relates to a method of enhancing wound healing following corneal surgery, comprising administering the composition of the invention to a subject in need thereof.

In another preferred embodiment, the invention further relates to a method of treating meibomian gland dysfunction, comprising administering the composition of the invention to a subject in need thereof.

In another preferred embodiment, the invention further relates to an artificial tear composition comprising one or more nonionic surfactants, one or more viscosity enhancers, polyols, one or more electrolytes and menthol. ..

In another preferred embodiment, the one or more nonionic surfactants are polysorbate 80, poloxamer 407, poloxamer 188 and polyoxyl castor oil.

In another preferred embodiment, the viscosity enhancer is selected from cellulose derivatives.

In another preferred embodiment, the polyol is mannitol.

In another preferred embodiment, the one or more electrolytes are magnesium chloride and sodium chloride.

In another preferred embodiment, the one or more nonionic surfactants are polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin.

In another preferred embodiment, the artificial tear composition of the present invention further comprises polyethylene glycol.

In another preferred embodiment, the polyethylene glycol is polyethylene glycol 400.

In another preferred embodiment, the artificial tear composition of the present invention further comprises ascorbic acid or d-alpha tocopherol.

In another preferred embodiment, the cellulose derivative has a concentration of hydroxypropyl from about 0.01 w / v% to about 2.5 w / v%, more preferably from about 0.01 w / v% to about 1.5 w / v%. It is a concentration that imparts an equivalent viscosity to methyl cellulose or a high molecular weight carboxymethyl cellulose having a concentration of about 0.01 w / v% to about 1.5 w / v%, and the "high molecular weight" is 3,500 cps or more.

In another preferred embodiment, menthol has a concentration of about 0.01 to about 4.0 mmol, more preferably about 0.01 to about 0.50 mmol, even more preferably about 0.01 to about 0.40. The concentration of mmol.

In another preferred embodiment, the invention is a polysolvate 80 of about 0.5 w / v% to about 1.5 w / v%, preferably a polysorbate 80 of about 1.00 w / v% to about 1.50 w / v%. , About 0.5 w / v% to about 1.5 w / v% poroxamer 407, preferably about 0.7 w / v% to about 1.00 w / v% poroxamer 407, about 0.20 w / v% to about. 1.00 w / v% poroxamer 188, about 0.01 w / v% to about 0.50 w / v% polyoxyl castor oil, preferably about 0.01 w / v% to about 0.30 w / v% polyo. Kisil Himashi oil, about 0.1 w / v% to about 2.0 w / v% carboxymethyl cellulose, preferably about 0.1 w / v% to about 1.5 w / v% carboxymethyl cellulose, and about 0.01 to. Mentor with a concentration of about 0.50 mmol, preferably menthol with a concentration of about 0.01 to about 0.40 mmol, and optionally about 0.1 w / v% to about 1.5 w / v% polyethylene glycol 400. , Preferably about 0.50 w / v% polyethylene glycol 400, about 0.5 w / v% to about 1.5 w / v% mannitol, preferably about 0.75 w / v% or about 1.00 w / v%. Mannitol, about 0.10 w / v% magnesium chloride, about 0.35 w / v% to about 0.45 w / v% sodium chloride, and about 3 to about 4 mmol concentrations selected from phosphoric acid and citric acid. Further related to the artificial tear solution composition containing the buffer solution of.

In another preferred embodiment, the artificial tear composition of the present invention has a sorbate of about 0.1 w / v% to about 0.15 w / v%, preferably about 0.11 w / v% to about 0.12 w /. Further contains v% sorbate.

In another preferred embodiment, the artificial tear composition of the present invention further comprises more than 0.1 w / v%, preferably 0.11 w / v% to about 10.0 w / v% sorbate.

In another preferred embodiment, the artificial tear composition of the present invention is about 0.25 w / v% to about 5.5 w / v%, preferably about 1.5 w / v% to about 2.0 w / v%. Also contains hydroxypropyl-gamma-cyclodextrin.

In another preferred embodiment, the artificial tear composition of the present invention further comprises about 1 to about 200 international units, preferably about 30 to about 50 international units of d-alpha tocopherol.

In another preferred embodiment, the artificial tear composition of the present invention has a pH of about 5.7 to about 8.0, preferably about 5.7 to about 6.5.

In another preferred embodiment, the invention is a polysorbate 80 of about 0.5 w / v% to about 1.5 w / v%, preferably a polysorbate 80 of about 1.00 w / v% to about 1.50 w / v%. , About 0.5 w / v% to about 1.5 w / v% poroxamer 407, preferably about 0.7 w / v% to about 1.00 w / v% poroxamer 407, about 0.20 w / v% to about. 1.00 w / v% poroxamer 188, about 0.01 w / v% to about 0.50 w / v% polyoxyl castor oil, preferably about 0.01 w / v% to about 0.30 w / v% polyo. Xylhimashi oil, about 0.1 w / v% to about 2.0 w / v% hydroxypropylmethyl cellulose, preferably about 0.1 w / v% to about 1.2 w / v% hydroxypropyl methyl cellulose, about 0.1 w. / V% to about 1.5 w / v% polyethylene glycol 400, preferably about 0.50 w / v% polyethylene glycol 400, about 0.5 w / v% to about 1.5 w / v% mannitol, preferably about 0.50 w / v%. About 0.75 w / v% or about 1.00 w / v% mannitol, about 0.10 w / v% magnesium chloride and about 0.35 w / v% to about 0.45 w / v% sodium chloride, about 0 .1 w / v% to about 0.11 w / v% sorbate, about 1.5 w / v% to about 2.5 w / v% hydroxypropyl-gamma-cyclodextrin, about 10 to about 200 international units of d- The present invention relates to an artificial tear solution composition containing alpha tocopherol, which has a pH of about 5.7 to about 8.0.

Selected from about 3.5 w / v% polysorbate 80, about 0.8 w / v% to about 1.2 w / v% hydroxypropylmethyl cellulose and about 1 w / v% to about 1.4 w / v% carboxymethyl cellulose. Viscosity enhancer, about 0.75 w / v% polyethylene glycol 400, about 0.5 w / v% to about 0.75 w / v% mannitol, about 0.6 w / v% to about 1.25 w / v% Artificial tear composition comprising sodium chloride, menthol at a concentration of about 0.1 to about 3.0 mmol, and sorbate from about 0.1 w / v% to about 0.12 w / v%. An artificial tear composition having a pH of ~ about 6.5.

About 1 w / v% polysorbate 80, about 1 w / v% poloxamer 407, about 0.2 w / v% poloxamer 188, about 0.25 w / v% polyoxyl hypromellose, about 1.5 w / v%. Viscosity enhancement selected from hydroxypropyl-gamma-cyclodextrin, about 0.8 w / v% to about 1.2 w / v% hydroxypropyl methyl cellulose and about 1 w / v% to about 1.4 w / v% carboxymethyl cellulose. Agent, about 0.75 w / v% polyethylene glycol 400, about 0.5 w / v% to about 0.75 w / v% mannitol, about 0.6 w / v% to about 0.7 w / v% sodium chloride , An artificial tear composition comprising menthol having a concentration of about 0.1 to about 3.0 mmol, having a pH of about 6 to about 6.5.

Contact Lens Compositions In one embodiment, all artificial tears compositions of the present invention can be used as contact lens compositions.

In another preferred embodiment, the invention is described.
One selected from the group consisting of polysorbate, polyoxyl, cyclodextrin, poloxamer, alkylaryl polyether and polyoxyethylene glycol alkyl ether, with a total concentration of about 1.5 w / v% to about 5.9 w / v%. The above nonionic surfactants,
Sodium chloride,
Further related to contact lens storage compositions comprising, optionally, polyols, and optionally viscous agents.

In another preferred embodiment, the invention is a punctal plug coated or infused with one or more nonionic surfactants having a total concentration of about 1.25 w / v% to about 7.0 w / v%. Punctal plugs or pellets, preferably one or more nonionic surfactants selected from poloxamers, polysorbates, cyclodextrins, alkylaryl polyethers, polyoxyethylene glycol alkyl ethers and polyoxyls. Regarding pellets.

In another preferred embodiment, the invention further relates to a method of extending contact lens wearing time, comprising administering the composition of the invention to a subject in need thereof.

In another preferred embodiment, the invention reduces the count of Acanthamoeba spp. On contact lenses, comprising administering the composition of the invention to a subject in need thereof. Regarding the method.

In another preferred embodiment, the invention is the step of applying the artificial tears composition of the invention to the surface of a contact lens, optionally the eye of the subject in need thereof. A step of storing or applying immediately prior to instillation of the contact into the eye, a step of inserting the contact lens into the eye of the subject in need of it, and optionally a book prior to the insertion of the contact lens. Further relating to a method of treating dry eye, comprising the step of administering the composition of the invention to a subject's eye.

In another preferred embodiment, the invention comprises applying the contact lens composition of the invention to the surface of a contact lens and, optionally, to the eye into which the contact lens is inserted. Further on how to reduce deposits.

Drug Vehicle In one embodiment, all artificial tears compositions of the present invention can be used as a drug vehicle.

In another preferred embodiment, the invention relates to an ophthalmic agent composition comprising a means for capturing tear fluid and an ophthalmic agent, which are preferably available from trehalose, cyclosporine (cyclosporine is available from Allergan, Inc.). Is an active ingredient in the registered trademark, Restasis®, and the registered trademark, Cequa®, which is available from Sun Pharma Global FZE), Refitegrast (Refitegrast). Is an active ingredient in Xiidra®, a registered trademark available from SARcode Bioscience Inc.), Diquahosol (Diquahosol is a trademark available and registered from Santen Pharmaceutical Co., Ltd.). Is the active ingredient in Diquas®), the C-terminal 25 amino acid fraction of lacritin (TearSolutions, known as Lacripep®, a registered trademark available from TearSolutions, LLC), lactilin. , KPI-121 (KPI-121 is an active ingredient in Inventions ™ available from Kala Pharmaceuticals), Cibanisilane (Cibanisilane is a registered trademark available from Cyclosporine, S.A.U.). Is an active ingredient in Cyclosporine®), omega-3 fatty acids, antibiotics, steroid anti-inflammatory agents, non-steroidal anti-inflammatory agents, glaucoma drugs, prostaglandins, muscarinic receptor stimulants, dilated pupils. Drugs; selected from the group consisting of drugs known to cause dry eye, such as topical antihistamines and alpha 2 stimulants (brimonidine), and combinations thereof.

In another preferred embodiment, the invention comprises an ophthalmic agent, as well as one or more non-ionic surfactants, and at least one excipient selected from viscosity enhancers, polyols and electrolytes. With respect to the drug vehicle composition, preferably the ophthalmic drug is diquafosol, cyclosporin, prostaglandin, antibiotics, muscarinic receptor stimulant, non-steroidal anti-inflammatory drug, steroidal anti-inflammatory drug, GLC, acetyl. It is selected from the group consisting of salicylic acid, salicylic acid, and combinations thereof.

In another embodiment, the compositions of the invention are capable of dissolving or encapsulating an ophthalmic agent and prolonging exposure to the ocular surface. This prolongation of exposure can allow the drug to both act longer and increase the permeability of the drug into the eye. Suitable ophthalmic agents for use in the present invention include, but are not limited to, diquafosol, cyclosporin, prostaglandins, antibiotics, non-steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, or combinations thereof.

In another preferred embodiment, the invention relates to an ophthalmic agent delivery means preferably selected from the group consisting of contact lenses, punctal plugs and pellets coated or infused with the composition of the invention.

In another embodiment, the ophthalmic agent compositions of the present invention include standard eye drop bottles, preservative-free bottles for multiple doses, and unit volume delivery.

In another preferred embodiment, the invention is described.
A step of creating an ophthalmic drug composition by suspending or dissolving an ophthalmic drug in the composition of the present invention.
A step of instilling the ophthalmic drug composition into the eyes of a subject in need thereof.
Further relates to a method for extending the drug residence time on the ocular surface.

In a preferred embodiment, the activator for the treatment of dry eye achieves greater efficacy through residence time and permeability and greater efficacy through vehicle capture of induced tears.

In another preferred embodiment, the invention further relates to a method of reducing eye infections, comprising instilling the composition of the invention into the eye of a subject in need thereof.

In another preferred embodiment, the invention is a method of treating age-related dry macular deterioration, age-related wet macular deterioration or diabetes, comprising administering the ophthalmic agent vehicle of the present invention to a subject in need thereof. Regarding further matters.

In another preferred embodiment, the invention comprises a topical agent and a topical agent comprising one or more nonionic surfactants and at least one excipient selected from viscosity enhancers, polyols and electrolytes. With respect to the vehicle composition, preferably the ophthalmic agent is selected from the group consisting of cyclosporine, prostaglandins, antibiotics, non-steroidal anti-inflammatory drugs, steroidal anti-inflammatory drugs, GLC, and combinations thereof. ..

Lidocaine gel composition In one embodiment, the present invention relates to a topical lidocaine gel composition for ophthalmology, which comprises lidocaine or a salt thereof and magnesium chloride.

In a preferred embodiment, the invention relates to an ophthalmic topical lidocaine gel composition comprising lidocaine or a salt thereof, magnesium chloride, a nonionic surfactant, polyethylene glycol, mannitol, a viscosity enhancer and sodium chloride.

In another preferred embodiment, the invention is described.
Lidocaine hydrochloride from about 3w / v% to about 4w / v%,
Polysorbate 80 of about 3w / v% to about 4w / v%,
Polyethylene glycol having a molecular weight of about 400 to about 20,000 daltons, from about 0.25 w / v% to about 2.5 w / v%,
It relates to an ophthalmic topical lidocaine gel composition comprising about 0.25 w / v% to about 1.5 w / v% mannitol and about 0.05 w / v% to about 0.2 w / v% magnesium chloride.

In another preferred embodiment, the invention is described.
Approximately 3.5 w / v% lidocaine hydrochloride,
Approximately 3.5 w / v% polysorbate 80,
Polyethylene glycol having a molecular weight of about 400 to about 20,000 daltons, from about 0.75 w / v% to about 1.50 w / v%.
Approximately 0.75 w / v% mannitol,
Approximately 0.1 w / v% magnesium chloride,
About 0.9w / v% to about 1.25w / v% sodium chloride,
Citric acid buffer, about 3 mmol concentration,
It relates to a topical lidocaine gel composition for ophthalmology comprising about 1.25 w / v% to about 1.50 w / v% carboxymethyl cellulose and about 0.1 w / v% sorbate.

In another embodiment, the invention relates to a method of inducing local anesthesia in a patient's eye, comprising topically applying the composition of the invention to the patient's eye.

The patent or application file contains at least one drawing made in color. A copy of this patent or patent application publication with color drawings will be provided by the office upon request and payment of the required fees.

FIG. 3 is a graph of Moisture-Lock ™ Index for the concentration of nonionic surfactant. Moisture-Lock is described by PS Therapies, Ltd. It is a trademark owned by. It is a graph of the value of the Moisture-Lock ™ effect over time for the concentration of various w / v% nonionic surfactants. Tear destruction (percentage over time) following insertion of contact lenses stored in saline / Refresh® CL into the eye. Tear destruction (percentage over time) following insertion of a contact lens stored in the composition Y of the invention into the eye. The area under the curve (percentage to seconds) for tear destruction specified in FIGS. 3+ and 4. It is a contact lens that follows storage in the composition of the present invention. The shear rate of the composition containing 5.0 w / v% poloxamer 407 and 0.75 w / v% high molecular weight carboxymethyl cellulose. Schirmer's test of tear volume after instillation of compositions # C12 and Restasis®. The average micelle size of composition # C12 panel A and Restasis® panel B.

Discoveries of the Invention Artificial tears The present invention is formulated to cover a sufficient surface area of the eye without the addition of lipids to stabilize the aqueous and lipid layers of the tear film. With respect to the amazing discovery that tear film evaporation shields can be created. Of particular surprise was the discovery that the total concentration of nonionic surfactant may be increased to well above 1.0 w / v% in the presence of the composition of the invention, which is the prior art. It has been clearly shown to be toxic in the ophthalmic preparations of. Even more surprising is that the compositions of the invention having a total concentration of nonionic surfactant of 7.0 w / v% or less can be routinely instilled in the eye without toxicity. Moreover, the compositions of the present invention can, surprisingly, be formulated to cause the formation of an evaporation shield and induce the natural tear flow maintained under this tear evaporation shield. The discovery of such compositions is novel because current artificial tears containing lipids do not create a tear evaporation shield, leaving an oily, unnatural sensation. Further, the artificial tear composition of the present invention stabilizes the lipid layer of the tear film and stabilizes and spreads the aqueous layer. The components of all three layers of the tear film are important for the successful functioning of tear film. Finally, the shape of the nano-micelles formed by the artificial tears composition of the present invention provides an improved barrier to evaporation by covering a substantial portion of the ocular surface. These nano-micelles may be about 12 to about 20 nanometers in diameter, about 12 to about 14 nanometers in diameter, about 15 to about 20 nanometers in diameter, or about 19 nanometers in diameter.

Specifically, the presence of a nano-micelle layer created with a nonionic surfactant in a particular concentration range consists of a non-polar surface and a polar surface. This double surface allows the composition of the invention not only to stabilize the natural lipid and aqueous layers of the tear film, but also to create an evaporative barrier. The nano-micelle layer finds its preferred lowest energy level when against any hydrophobic surface by extending along its interface. The hydrophobic surface of the eye contains both the original tear lipid layer and the air-tear interface. Perhaps most important is the effect brought about by the interaction of these designations. Specifically: 1) non-polar encapsulation, 2) polar and non-polar stabilization of lipid and aqueous layers, 3) improvement of spreadability per blink, and 4) so-called Moisture- A larger tear film prism imparted by the compositions of the invention, which creates the Polar effect. The Moisture-Lock ™ effect can be somewhat quantified by Sylmer strip measurement or tear volume analysis via phenol threads. However, these tests are, in a bad way, extremely difficult to use accurately due to many environmental variables, including reflex lacrimation, which can be compromised with these measurements. A more accurate representation of the effect is a qualitative measure of the duration of the added moist sensation. It is particularly susceptible to the particular combination of nonionic surfactant components of the invention, and more specifically to the total concentration of nonionic surfactant. In addition, the viscosities of the compositions and additional excipients play an important role in the present invention with respect to the range of conditions under which these variables need to be customized. However, analyzing the Moisture-Lock ™ effect using these fixed variables produces a well-defined range where the Moisture-Lock ™ effect occurs. See Example 1 below.

The Moisture-Lock ™ effect results from any natural secretion of the tear component, particularly the aqueous component encapsulated under the nano-micellar layer created by the compositions of the invention. Such capture creates a prolongation of contact with important aqueous elements, much like that found in plasma eye drop applications, resulting in great therapeutic and comfort benefits. Mild to extreme Moisture-Lock ™ effects can be triggered by creating even a slight tear, eg, by adjusting the pH or osmotic pressure, which is then the nature of tear capture of the invention. It has been discovered that it will be amplified by.

Equally important, the concentration range and unique combination of the particular nonionic surfactants utilized in the artificial tears composition of the invention dissolves lipids that would otherwise block the meibomian glands. .. The meibomian glands are responsible for secreting the components of natural tears that reduce tear evaporation. This clinical condition, known as meibomian gland dysfunction, not only afflicts many patients with dry eye, but is also a common distress for patients with glaucoma and other patients who must constantly use eye drops.

The artificial tear composition of the present invention also stimulates the secretion of aqueous components of natural tears. The created evaporation shield then prevents evaporation of the natural aqueous layer, which the patient perceives as a Moisture-Lock ™ effect. The net effect of stimulation of natural tears, in combination with the ability to capture it, is Restasis® and Xiidra® (Restasis is a registered trademark of Allergan, Inc. It is a registered trademark of SARcode Bioscience Inc.) and can result in additional exposure of the eye to natural tear components that are greater than those conferred by prescription medications. In clinical trials, Restasis® and Xidra® each only slightly enhance tear production (ie, less than 50%) when mixed with clinical results in the treatment of dry eye. It has been found that the benefits take months and often have no or very little clinical significance to conventional artificial tears).

The compositions of the present invention provide an extensive shield that seals in natural tear production through the means of tear capture found. Benefits of the invention by exposing the eye to a larger volume of natural tears, even the slightest trigger of natural tears that can be triggered by pH adjustment, osmolality adjustment, or the addition of ingredients such as menthol. Amplification can be created. This exposure to tear volume is greater than that provided by Restasis® or Xidra®, which increases tear volume solely by natural tear secretion. In addition, these topical medicines are naturally prescription drugs and are extremely expensive, at around $ 300 per month. However, the present invention combines artificial tears compositions, which are generally considered to be safe ingredients to formulate, with truly surprising and unexpected results for these prior art formulations. , Discovering new means.

Artificial tears have traditionally been an external source of glitch for the eye. However, the artificial tears compositions of the present invention expose the eye to growth factors, lysozyme, and other tear components that aid healing and protect the eye, and are natural for eye surface contact and moist extension. Further seal in tears. Although not bound by any particular theory, the protective shield provided by the artificial tear composition of the present invention involves the formation of a large, tightly packed nano-micellar structure that seals the entire surface area. The tears wetting angle is reduced, resulting in unexpected results of the Moisture-Lock ™ effect. This effect was not possible with any artificial tears of the previous generation. The Moisture-Lock ™ effect is synonymous with triggering natural tear synthesis, which is more substantial than blocking the punctal canal over a long period of time. Closing the punctal canal is less frequent and / or less effective than the compositions of the invention and captures any tear fluid released by a dry eye patient. Moreover, the compositions of the present invention normalize tear drainage in the eye, with visual blurring of only 0 to tens of seconds, even for the most extreme viscosities, which are only needed for the most extreme therapeutic needs. Trigger, capture and limit. This stands out in contrast to prior art formulations that require more than 10 minutes of visual blur at 400 centipoise, for example to stabilize.

In a preferred embodiment, the invention is a desired fluid flow and non-Newtonian (non-linear pair) in which the composition is dramatically affected by the electrolyte concentration and optimized by the electrolyte concentration, which is preferably low osmotic pressure. Eyelid Shear) Containing an artificial tear fluid composition comprising one or more non-ionic surfactants and electrolytes to achieve viscous properties.

In another preferred embodiment, the invention is an artificial tear composition that is capable of extending the duration on the eye and stabilizing the natural aqueous and lipid layers. Regarding further. Preferably, the composition further prolongs the duration of eye exposure to a stabilized natural aqueous layer containing growth factors, antibacterial factors, and other proteins and nutrients.

The benefits of this long-term exposure to the aqueous layer are currently only possible by centrifuging the blood, preserving plasma or platelet-rich plasma, and subsequently instilling it locally into the eye. Benefits from this long-term exposure to the natural aqueous layer can be partially assessed by measuring tear decay time. However, tear tear time is an outdated means of quantifying tear function and is less clinically relevant than the actual amount and duration of exposure of the corneal epithelium to the nutrient-rich aqueous layer. .. Commercially, the leading market-dominated formulation (Allergan® Refresh® product line) demonstrates the freshest perception of added water rather than the synthetic oily sensation. There is. For the present invention, the "Moisture-Lock ™ Index" described in Example 1 below correlates well with the degree and duration of this important perception of the most acceptable and desired artificial tears. do.

In another preferred embodiment, the invention further relates to a method of treating dry eye, comprising administering the composition of the invention to the eye of a subject in need thereof, wherein the administration is a nonionic surfactant. It results in the capture of the tear layer beneath the active agent layer, preferably the nonionic surfactant layer allows the retention of the aqueous layer via a hydrophobic outer layer or air in line with the hydrophobic lipid layer. do. This layer is permeable and impermeable and imparts a hydrophilic opposite surface. This contralateral surface stabilizes the aqueous layer and provides normal and induced aqueous components of tear fluid, as well as therapeutic components of the invention such as polyols and electrolytes to maintain prolonged contact with the eye.

A further advantage of the present invention is the addition of viscosity enhancers, especially cellulose derivatives, carbomer, gum, dextran, polyvinyl alcohol, polyacrylic acid, povidone, polyethylene glycol, propylene glycol, chitosan, and hyaluronate and hyaluronic acid. It is a surprising finding that it results in low shear non-Newtonian high viscosity between blinking and high shear low viscosity during blinking. The low shear viscosity between blinks helps spread the artificial tears composition of the invention over the eyes, and the high shear viscosity during blinking prevents destruction and drainage of the evaporative shield. As such, the ability to change viscosity aids in amplifying the Moisture-Lock ™ effect by strongly delaying tear evaporation and drainage. Furthermore, the addition of the particular viscosity enhancer of the present invention imparts a viscosity of 300-400 centipoise (“cps”) upon instillation, but within 60 minutes no longer results in visual blurring. Further, these viscous agents result in a difference of about 70 cps between blinks (low shear conditions) and a difference of less than 30 cps, preferably 20 cps during each blink (high shear conditions). This is about 10 times faster than the visual recovery of conventional eye drops with similar viscosities such as Refresh Celluvisc®.

Still further discoveries of the invention are the inclusion of polyols and electrolytes that can protect the ocular surface and promote healing. These additional excipients can also reduce the toxic effects of preservatives from other prescription eye drops such as antibiotics, steroids, non-steroidal and / or glaucoma eye drops. The present invention has found that a concentration of polyol greater than about 0.5 w / v%, specifically above about 1.25 w / v%, is preferred.

In summary, surprising discoveries of the compositions of the present invention include:
i) 10 ^-3 M to 10 ^-4 M, nonionic surfactants above the critical micelle concentration of about 1.5 w / v% to about 7.0 w / v%, preferably less than about 5.5 w / v%. Creation of a nano-micelle layer with sufficient surface coating to provide a substantial evaporation shield by utilizing the concentration of
ii) More than about 0.005 w / v% but less than about 0.20 w / v%, more preferably due to the addition of polyoxyl at about 0.01 w / v% to about 0.10 w / v%. Dissolution of lipids and / or lipid deposits on the ocular surface or on contact lenses by the addition of polyoxyl castor oil,
iii) Rapid equilibration to normal tear viscosity, then by adding certain viscous agents, fluctuates between normal and high viscosities between and during blinking, respectively. And thus to reduce visual blurring and prolong the duration of the composition on the eye, provide a composition with high viscosity at the time of instillation,
iv) Providing additional benefits, including possible improvements in nerve regeneration and epithelial healing, by the addition of polyols, and magnesium ions in the form of salts.

Prior to the present invention, nonionic surfactants were used in artificial tears or as storage / immersion solutions for contact lenses at very low concentrations. The use of nonionic surfactants in the concentration range of the present invention was considered to be too toxic for topical application. Approximately 1.25w / v% to approximately 7.0w / v%, preferably approximately 1.5w / v% to approximately 6.0w / v%, approximately 2.8w / v% to approximately 5.9w / v%, Nonionic surfactant with a total concentration of about 2.0 w / v% to about 4.0 w / v%, about 3.0 w / v% to about 3.5 w / v%, and about 0.5 w / v%. It is the discovery of the present invention that the inclusion of a unique combination of a polyol with the above concentration and a viscous agent imparting a viscosity of 10 cps or more prevents toxicity.

Several over-the-counter (“OTC”) eye drops provide an external source of the lipid component of natural tears. These eye drops include Soothe® XP (Soothe is manufactured by Bausch & Lomb Incorporated, available from it and is a registered trademark thereof), and Retaine®. , OcuSoft, Inc., which is available from the company and is a registered trademark thereof), each containing light oil and mineral oil, and Systemane Balance® (Systemane Balance is Alcon, Inc.). (Manufactured by Inc., available from it and is a registered trademark thereof), which contains propylene glycol, and Refresh Optive® Advanced (Refresh Optive), Allergan, Inc. (It is manufactured by, available from it and is a registered trademark thereof), which contains sodium carboxymethyl cellulose, glycerin and polysorbate 80.

These OTC tear formulations have the following disadvantages: 1) minimal stabilization of nonionic surfactants in the natural lipid layer, 2) minimal reduction in wetting angle that enhances the spread of the aqueous layer. 3) Insufficient nonionic surfactants for the discovered advantages of improved nano-micellar geometry, and 4) surface area coverage for emulsion shielding protection is required.

It was surprisingly discovered that the compositions of the present invention created a "tear gush" over a long period of time, reflecting in the creation of a large tear prism thickness along the edge of the lower eyelid. Although not bound by any particular theory, natural lacrimation and, in some compositions, evoked lacrimation remain captured under a low-evaporative nanomicelle bulk shield. It is believed to create an increase in the thickness of the aqueous layer and the stable lipid layer. This perception is further enhanced in most compositions of the present invention by an increase in the thickness of the blink and a non-Newtonian viscosity with a very small wetting angle, resulting in tears on the edges of the eyelids. Despite the larger tear prism along, it does not tend to cross the hydrophobic air interface or run down the cheek. Where conventional tear fluid can provide some additional comfort and smoothness over 10-20 minutes, the disclosed invention provides novel perception over an hour or more. This new perception is the perception of trapped tears, which results in a 60-minute spill over the rim of the eyelids, as the inside of both eyelids overflows with water. As a result, the unique phenomenon of prolongation of tear trapping is brought about with great therapeutic potential for dry eye patients with "tear gush", and with an extremely fresh perception. This phenomenon, hereinafter referred to herein as the Moisture-Lock ™ effect, is measured by Moisture-Lock ™ Index.

The total concentration range of the nonionic surfactant is now fully filled to dramatically cover the surface of the eyeball and spreads at extremely small wetting angles that act like lipids and aqueous stabilizers. It is convinced that the micelle layer will be created. This layer also extends along the hydrophobic interface of air or lipids, straightening the non-polar ends to create a bulky non-evaporable surface. At a critical concentration above the critical micelle concentration (“CMC”) of the added nonionic surfactant, there is a concentration micelle trigger (“CMT”) created therein, which collects along the surface of the eyeball. It was surprisingly found to reduce evaporation without the need for the addition of lipids that trigger dense or near-concentration and impart a synthetic oily sensation. Furthermore, this CMT can occur within about 15-600 times greater than each of the discovered non-evaporative shield and the resulting ionic surfactant CMC in the Moisture-Lock ™ effect. Surprisingly discovered. This effect is maintained up to the peak within this range, and at the upper limit of concentration (“CUL”), surface toxicity and effectiveness begin to decline. This reduction in effect is probably the result of changes in the geometry of the micelle layer.

At CUL, the upper limit of the micelle layer in and / or on the CMT, in which the coating / shielding effect results in two or more of some of the following novel properties observed: It is convinced that it will bring a concentration range of:
i) Creation of an evaporation shield that causes reduced evaporation of the tear film and insensitivity to humidity, tear volume or tear destruction time (tear destruction time is driven by beading vs. time). It is a variable that is measured by chemistry and difficult to measure accurately because it is influenced by stimuli and other factors).
ii) Applying extremely low surface tension to most immediately cover the corneal surface and any corneal marginal pits (ie, irregular topography along the corneal epithelium that creates dry spots).
iii) Non-Newtonic fluid flow that results in a substantial state between blinks, and ease of flow during blinking primarily along the high shear vertical component of this blink, which is tear secretion drainage. Is minimized and the tear film coating along the corneal surface is optimized with reuse at each blink until the conjunctival sac depot of the new tear-filled eyelid is slowly depleted. be,
iv) Low viscosity, no blur, even slight blur for less than about 15 seconds even at viscosities as high as 400 cps, while conventional tear products (Liquigel® 150 cps, Celluvisc® 400 cps). ), Each of which results in blurred vision for about 10 to 20 minutes, so that the highly viscous tears of conventional tear preparations have the comfort and vision of conventional tears with extremely minimal viscosity. Brings advantages over or over liquid substitutes,
v) Non-neutral non-Newtonian properties under a non-evaporative shield and over an hour, unlike those found in conventional tear fluids that provide a "welling" effect for tens of minutes along the edge of the eyelid. Capturing, meaning apparent "trapping" of the tear fluid produced, under the condition of an added viscous agent with enhanced shear effect, imparting prolonged contact of human tear fluid components with the corneal epithelium. do,
vi) Above v of induced natural tears, in particular, in a preferred embodiment where the addition of a low pH with altered osmotic pressure or an excipient such as menthol results in such induction and retention for a long period of time. Capture, as in
vii) The addition of excipients in the form of polyols and / or magnesium ions added comfort, epithelial protection, and enhancement of miryu for the integration of regenerating epithelial surfaces.
viii) The coating once placed on the contact lens prior to insertion provides a long-lasting coating effect, which reduces deposits on the contact lens surface, enhances vision during instillation, and is instilled during wearing. Occasionally, it promotes improved comfort, especially when instilled at least 16 hours after contact instillation, thus reducing epithelial disease and normal tear destruction compared to 8 seconds. Surprisingly, it was discovered that the minimum tear dispersal rate spans at least 24 seconds,
ix) May be concomitantly prescribed for protection from meibomian gland dysfunction, reduction of accumulation of lipid deposits that adhere to the palpebral conjunctiva and are difficult to remove, and treatment of cholesterol esters, other conditions. Or other eye drops that may be requested-such as, but not limited to, reduction of irritation in the tear film, including but not limited to antibiotics, non-steroidal, steroidal and preservatives from topical meibomian glands.
x) Cumulative effects from the combination of two or more of the above-mentioned features that improve the comfort and health of the corneal surface, such as growth factors from tears, various external surface-related physiological stresses and Due to the condition, it imparts beneficial prolongation of protection and healing benefits.

Polysorbate 20, 60 and 80; tyroxapol, poloxamer 188 and 407; polyoxyl 30 and 40 castor oil; cyclodextrins including: hydroxypropyl-gamma-cyclodextrin, which are not desired to be bound by a particular theory. Gamma-cyclodextrin, Brij® 35, 78, 98 and 700 (polyoxyethylene glycol alkyl ether; Brij is a registered trademark of Uniqema Americas LLC); Span® 20, 40, 60. And 80 (sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate and sorbitan monooleate; Span is a registered trademark of Uniqema Americas Inc.), or about 1.5 w / v% to about 5. These combinations in the concentration range of 5 w / v% include, but are not limited to, the threshold of the critical micelles is in the range of about 1 × 10 ^-3 M to 1 × 10 ^-4 M for ophthalmic use. It was convinced that most nonionic surfactants available for the purpose provide important properties such as:
i) The lowest energy shape through stratification due to the juxtaposition of the hydrophobic surface upon instillation onto the eye, from the closest to the furthest from the surface of the eyeball, which is the epithelium, lipid layer and air interface.
ii) Due to juxtaposition on one or more hydrophobic surfaces on the eye upon instillation, which comprises the epithelium of the cornea and conjunctiva, the natural lipid tear film layer and the air interface, to which they may be exposed. Or the lowest energy shape through stratification, which will also be closely packed to function effectively as a protective shield or coating.
iii) Sufficient density, within a preferred concentration range, which significantly delays evaporation when layered on top of the aqueous layer or when packed closely.
iv) Smoothing of the lipid layer to maintain a smoother and more uniform surface and dissolve the lipids of the meibomian glands to further increase their thickness,
v) Due to low surface tension and wet angle of the epithelium and surface coating, with each high shear blink, especially with corneal marginal pits (the ascending area of the corneal topography tear film cannot be coated uniformly or at all). Excellent spreadability,
vi) Thereby each of the above functions can be facilitated by different surfactants, with concentration ranges from about 1.5 w / v% to about 5.5 w / v% summarizing the concentrations of the individual surfactants. Where one or more nonionic surfactants representing the sum are provided, and vii) polyoxyl, specifically polyoxyl castor oil, can preferentially solubilize meibomian gland secretions.

Inclusion of hydroxypropyl-gamma-cyclodextrin in the compositions of the present invention results in, in particular, longer lasting tear capture.

A further surprising finding of the present invention is an extension of the even lighter, higher osmotic Moisture-lock ™ effect, provided, for example, by increasing the concentration of electrolyte to about 0.20 w / v% or higher. Specifically, sodium chloride is preferred for this purpose. It is convinced that the extremely gentle but slight stimulus created by the hyperosmolar tear fluid triggers an initial increase in tear flow, which becomes "locked" under the micelle layer. This tear secretion is then further sealed by the nature of non-Newtonian flow, imparting valuable inotropic growth factors and other nutrients and physiological components to the ocular surface. The nature of these non-Newtonian flows is mediated by an increase in viscosity at low shear between blinks, while improving visual intelligibility by high shear-triggered low viscosity during blinking. , Seal by limiting tear gland drainage.

Further surprising findings are that polyols, specifically mannitol and / or magnesium ions, and in particular combinations thereof, include, but are not limited to, the effects of preservatives and / or antioxidants on the cornea from epithelial disease. It is a new discovery that provides surface protection.

A further unexpected finding is that the addition of antioxidants added an extension of the duration of effect. This finding is surprising in light of the long-standing view that antioxidants in tear formulations, specifically ethylenediaminetetraacetic acid (“EDTA”), cause epithelial toxicity.

Fluctuations in a) concentration, especially the concentration of viscous agent, b) protective excipients of the epithelium, such as polyols such as mannitol, and c) addition of electrolytes, especially magnesium ions and NaCl, have a wetting effect (ie, Moisture-Lock). The means are provided for the titration period of ™ effect), the degree of initial blurring (i.e., about 0-15 seconds), and the range of other effects including protective and therapeutic effects. This variability of the compositions of the invention allows treatment of a range of conditions.

Certain conditions, such as meibomian gland dysfunction (“MGD”), can benefit from eyelid massage and oil expression techniques, such as cotton ball rolls along the edges of the eyelids. These conditions are also within the CMT range for the total concentration of nonionic surfactant (i.e., from about 1.5 w / v% to about 5.9 w / v%, more preferably from about 2.5 w / v% to about. Benefits can also be obtained from the surface layer of bulky nonionic surfactants created at 4.0 w / v%). Specific nonionic surfactants such as polyols having a concentration of about 0.001 w / v% to about 2.0 w / v%, more preferably about 0.010 w / v% to about 1.0 w / v%. Such formulations for the treatment of MGD can be further enhanced where there is an increase in the concentration of, preferably polyoxyl castor oil, most preferably polyoxyl 30 or 40 castor oil. It has been further discovered that the addition of polyethylene glycol enhances the stability of the composition.

The present invention combines a high degree of mucosal adhesion in the nature of rheology between blinks and during blinking with a temperature sensitivity change. These rheological properties allow for unblurred physiological blink and, after equilibration, create a thin tear film of about 5-10 μm within about 15-60 seconds, depending on the embodiment selected. It was surprising that the invention was:
a) Create prolongation of wetting and hydration, typically about 1 hour or more b) Tens of seconds at the time of instillation, typically 30 seconds or less (see Table 2 above) Creates minimal blur c) Does not produce lacrimation of the eyelids or eyelids, only prolongation of moisturizing effect is felt along the edges of the eyelids d) At very low (less than 4) or high (> 7) pH E) Prolonged tear capture and exposure to induced Moisture-Lock ™ effects, and natural tears through the bulky hydrophobic barrier of the nonionic surfactant layer. Current generation prescription dry eye products Restasis® and / or Xidra® that result in fluid (see Table 12 and FIGS. 1 and 2) and f) show only a slight increase in tear secretion. It offers the potential for increased tear exposure to the eye drop surface equal to or greater than the trademark).

Excipients of the present invention that can reduce the toxicity of the epithelium include one or more polyols and electrolytes, and the combination of the nonionic surfactants of the present invention is about 0.10 w / v% to about 0. Further enhanced by .90 w / v%, more preferably about 0.20 w / v% to about 02.00 w / v%, most preferably about 0.25 w / v% to about 2.00 w / v% NaCl. It was surprisingly discovered. A normal isotonic solution may typically require 2.00 w / v% NaCl. The second electrolyte in the preferred embodiment is magnesium ion. In a more preferred embodiment, the source of magnesium ions is MgCl ₂ . In an even more preferred embodiment, MgCl ₂ is about 0.01 w / v% to about 0.25 w / v%, more preferably about 0.05 w / v% to about 0.15 w / v%, most preferably about. The concentration is 0.07 w / v% to about 0.125 w / v%. The polyol is preferably mannitol, more preferably about 0.25 w / v% to about 4.0 w / v%, and even more preferably about 0.75 w / v% to about 4.0 w / v%. , More preferably, the concentration is from about 1.5 w / v% to about 4.0 w / v%. Without being bound by any particular theory, these excipients, alone or in combination, enhance epithelial healing, recovery of injured nerve components, reduce pain and faster smoothing of epithelial surfaces. And is believed to promote health and reduce or eliminate punctate superficial keratopathy. Point superficial keratopathy is a common eye surface abnormality from exposure to irritants. These stimulants are specifically preservatives found in most eye drops, including antibiotics, steroids, non-steroidal and glaucoma agents. In view of the post-cataract surgery toxicity caused by these irritants and the toxicity in pharmaceuticals for chronic eye diseases such as glaucoma, the compositions of the present invention can significantly alleviate the associated symptoms.

The present invention is at least 1.0 w / v%, preferably about 1.0 w / v% to about 10 w / v%, more preferably about 1.0 w / v% to about 5.9 w / v%, even more preferably. Is about 1.5 w / v% to about 5.9 w / v%, even more preferably about 2.5 w / v% to about 5.5 w / v%, and most preferably about 3.0 w / v% to about 5. Benefits from the total concentration of 0.0 w / v% surfactant, the one or more nonionic surfactants each have a critical micelle concentration in the range of 10 ^-3 to 10 ^-4 M (where). The concentration at which micelle formation has occurred and the surface tension is no longer reduced). The nonionic surfactant is one or more cyclodextrins (hydroxypropyl-gamma-cyclodextrin, gamma-cyclodextrin, and beta-cyclodextrin are most preferred); Tween® 80, 60, 40 or Polyoxyl sorbates, including all Tween® sorbates, including 20 (polysolvates, Tween is a registered trademark of Uniqema Americas, LLC); other polyoxyls (most preferably polyoxydextrin oil and stear). Polyoxyl acid); Alkylarylpolyether (most preferred is tyroxapole); All Brij® alkyl ethers (most preferred are Brij® 35, 78, 98 and 700); It may consist of an alkyl ether containing Span® 20, 40, 60 and 80 (sorbitan monolaurate, sorbitan monopalmitate, sorbitan monostearate and sorbitan monooleate), as well as tocopherol (vitamin E).

The non-Newtonian viscosity component is a more important proportion of the clinical need for the treatment of dry eye or dry eye-related conditions. Non-Newtonian viscosity components are of particular importance in the absence of inserted devices including contact lenses and punctal plugs. The non-Newtonian viscosity component has a viscosity of more than about 30 cps, preferably about 35 to about 50 cps, most preferably about 70 to about 400 cps; less than about 30 cps, preferably less than about 30 cps in each blink, between blinks. Less than about 25 cps, most preferably less than about 20 cps, results in a reduction in tear drainage between blinks. In a preferred embodiment, the non-linear shear viscosity ratio is a blink-to-blink viscosity of about 5: 1 to about 10: 1. Surprisingly, the combination of nonionic surfactants in the preferred range with viscous agents at low cps (less than about 20 cps to less than about 500 cps) is visually surprising in improving high viscosity and flow properties. Create a power equilibrium. As seen in FIG. 4 for composition # 64 from Table 3 below, it has an initial 400 cps formulation and is visually equilibrated to excellent vision in 50 seconds. Over-the-counter high-viscosity tear solution formulations such as Refresh Celluvisc® have also been shown in numerous studies to require 10-15 minutes to balance to normal vision at 400 cps, which is the present invention. 10 times longer than the surprising discovery of preferred nonionic surfactants and viscous agents between 10 cps and 500 cps. Viscosants for preferred embodiments of the invention include cellulose derivatives such as HPMC, HPC, HPEC and CMC; Carbopol® compounds such as Carbopol® 90 and 940; hyalronates; and gums such as gum. Guar gum and locust gum include, but are not limited to.

The application of an optimized tear film utilizing a preferred embodiment, specifically polysorbate, poloxamer, polyoxyl or cyclodextrin, alone or in combination with each other and / or in combination with other nonionic surfactants. Having the property of retaining membrane moisture is a surprising finding of the present invention. See FIG. Even more unexpectedly, the use of viscous agents, specifically cellulose agonists and / or their derivatives, and more specifically the use of hydroxypropylmethyl cellulose or carboxymethyl cellulose or Carbomer 940, is the water retention capacity of the tear film. Dramatically enhances and has only a slight temporary blur of a few seconds to 30 seconds or less, even at static low shear viscosities as high as 200-400 cps in their packaged delivery bottles or unit dose tubes. .. This water retention capacity of the tear film is known herein as Moisture Lock ™. Storage of soft contact lenses, including but not limited to those consisting of silicones and / or hydrogel polymers, in blister packs or other packages holding liquids with the compositions of the invention reduces deposits. It is even more surprising that it results in a substantial attachment of the composition to the surface of the contact lens. Once these contacts stored in the composition of the invention are placed on the eye of the subject, the composition greatly increases the tear destruction time while reducing the tear dispersal rate. .. This adhesion creates a strongly bonded non-evaporable coating that stabilizes the tear film, increases comfort, and provides optional dry eye treatment even for contact lens intolerant patients. As described in Example 5 below, and as shown in FIG. 3, application of normal saline to the contact lens and to the eye prior to insertion begins with tear destruction in 8 seconds. It results in reaching a dispersion rate of 40% in 20 seconds. Replacing normal saline with composition # 64 in Table 3 below resulted in a 0% dispersion in 20 seconds and a dispersion of only 8% in 24 seconds. In addition, the intelligibility of mesopic vision is significantly improved and contact lens deposits are noticeably reduced. See FIG. 6B.

One of the most serious headaches for contact lens wearers is severe keratitis that can result in severe visual loss, specifically Pseudomonas, acanthamoeba and fusalium infections. It is an incident. Simmons PA et al., Effect of patient wear and extension of protein deposition on attachment of acanthamoeba to fibe type s s See Pseudomonas aeruguinosa to hydrophiliccontact lenses and other substrata, J Clin Microbiol, August 1987, 25 (8), pp. 1392-1397. Following the application of the preferred embodiment of the invention described in Example 5 and shown in FIG. 6B, the dramatic reduction in bioburden with reduction of contact lens deposits is due to the bacterial and / or fungal reduction in contact lens wearers. A surprising and unexpected finding that substantially reduces the risk of severe keratitis. Such applications prior to lens attachment block deposits through a long-term coating with or without additional eye drops during attachment and / or either before insertion or during attachment. At the time of application, dissolve the sediment. This reduction in sediments probably reduces bacterial and / or fungal bioburden.

The artificial tears compositions 36 to 57 in Table 2 and the artificial tears compositions 58 to 89 in Tables 3 to 8 have excellent wettability and Moisture-Lock with respect to the artificial tears compositions 1 to 35 in Table 2. (Trademark) Brings effect. It is hypothesized that this superior effect is caused by the unique combination and concentration of nonionic surfactants. Furthermore, the addition of the polyol and magnesium ions to the compositions 36-57 is hypothesized to further enhance the wetting and Moisture-Lock ™ effects on the composition containing no polyol and magnesium ions.

There appears to be a clearly surprising effect on the combinations, concentrations and ratios of the present invention. In particular, the range and combination of nonionic surfactants related to viscosities, electrolytes and protective excipients such as polyols and magnesium ions will bring surprising effects. Of particular surprise is the relationship between the final viscosity of the electrolyte, the absence of blurring or blurring, and comfort. Preferred embodiments result in increased stability of the tear film, prolongation of the Moisture-Lock ™ effect, and a single drop resulting in gushing of the aqueous layer from tens of minutes to an hour. For viscosity, there is a reduction in blurred visual time when compared to current artificial tears, and for a variety of conditions there is a longer prolongation of effect and clinical effect.

Contact Lens Compositions It has been further discovered that novel means of trapping tears imparted by the compositions of the present invention can be applied to contact lens surfaces. Application to contact lenses creates a bulky seal layer that allows patients with dry eye contact lens intolerance to achieve contact lens therapeutic effects and treatment modalities that simply involve coating the lens in the package or at the time of instillation. It has been further discovered that novel means of tear capture provided by the compositions of the present invention can be applied to the surface of punctal plugs or pellets.

One or more of about 1.5 w / v% to about 5.9 w / v%, preferably about 2.5 w / v% to about 3.5 w / v%, most preferably about 3.0 w / v%. A comfortable topical formulation of saline and other commercially available contact lenses by immersing or applying the composition of the invention having the total concentration of nonionic surfactant in the contact lens prior to insertion into the eye. It has been further discovered that for both of these, it results in a dramatic reduction in tear destruction time (“TBUT”) and tear dispersal rate. See Examples 8-11 below. The contact lens industry has failed to find an answer to the challenge of diminishing contact lens tolerance, which is consistent with wearing duration during the day or over the cumulative wearing time. Specifically, prior to the compositions of the present invention, no additives that are both safe and effective have been found.

When contact lenses are manufactured, the resulting product is polished to create as smooth a surface as possible to aid in visual correction. However, none of the contact lenses currently manufactured have a perfectly smooth surface. It has been discovered that the nano-micelles formed by the composition of the invention penetrate and adhere to the contact lens and improve the visual correction power of the lens by about one row on the Snellen chart. Although not bound by any particular theory, this visual improvement creates a much smoother lens surface where the nano-micelles of the invention bind to water and retain it on the lens surface. Probably due to the fact that it results in both improved light transmission and reduced deposits. In addition, dilution of the compositions of the invention in over-the-counter contact lens solutions does not reduce the ability of nano-micelles to smooth the lens.

Preferred embodiments also improve the safety of the epithelium, which is an advantage of the invention, both topically and for application, as a composition for contact lens storage and quality retention in blister packs. Is. First, viscous agents containing cellulose derivatives, carbomer, gum, dextran, polyvinyl alcohol, polyacrylic acid, povidone, polyethylene glycol, propylene glycol, chitosan, and hyaluronate, hyaluronic acid, and combinations thereof, must not. It further reduces the slight epithelial toxicity of nonionic surfactants, which increases with concentration. In terms of toxicity, the following order appears to be from highest to lowest toxicity: Brij®, polyoxyl stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, poloxamer, polyoxylaryl ether. And poloxamer oil. Second, polyols such as mannitol further reduce epithelial toxicity. A preferred embodiment of the invention for use as a contact lens preservation composition or as a topical eye drop during contact lens use is a viscous agent that provides a viscosity at a low shear of 5-25 cps, and about 0.50 w / v. It contains a polyol such as mannitol in a preferable concentration of% to about 2.5 w / v%. A further advantage of the present invention is that when used as a contact lens preservative composition, the composition is reactivated by simply adding a preservative-free 0.09% aqueous saline solution to the composition. It is a surprising discovery that it can provide all the original benefits of things.

Ophthalmic Drug Vehicle A further surprising finding of the present invention is that the ophthalmic drug added to the present invention prolongs the duration of the drug on the surface of the eye, increases permeability across the cornea and reduces systemic absorption. Created an ideal platform vehicle for drug delivery, while dry eye symptoms and other possible effects with many such active agents such as non-steroidal, antibiotics and glaucoma drugs. Reduce irritation. This drug vehicle may be particularly useful for enhancing the treatment duration and benefits of cyclosporine-A currently found in Restasis®. These compositions may be capable of formulating up to 0.09% and from about 0.05% to about 0.09% cyclosporin-A without the need to create an emulsion. In a preferred embodiment, the cyclosporin-A drug vehicle of the present invention may not contain an emulsifier. The cyclosporin-A drug vehicle of the present invention imparts nano-micelles with a diameter of about 12 to about 20 nanometers. In addition, the cyclosporin-A drug vehicle of the present invention delivers tear bleeding for up to 60 minutes.

A further surprising finding of the invention is the toxicity-suppressing effect of the preservatives resulting from one or more preservatives in the presence of the invention, especially in the presence of therapeutic excipients such as polyols and / or magnesium ions. Is. This finding is surprising and potentially very important in light of the long-standing view that preservatives of tear preparations cause epithelial toxicity, often because of glaucoma or inflammation. This is because the continuous use of ophthalmic agents is impaired by the effects of induced epithelial toxicity, which often limits their duration of use.

A further surprising finding of the present invention is the sustained release of the drug. The peak concentration of the agent can increase by about 50% during the period (eg 2-4 hours).

Skin Compositions and Drug Vehicles The compositions of the invention are parenteral agents in anesthetic gels, as anti-adhesive agents for the prevention of scars, in implantable devices, in time-releasing impregnated bandages. In inhalants, in sprays, in topical lotions, in topical gels, in topical liquids, in anti-aging skin products such as daytime and nighttime products, and in products under the eyes, in sunscreens, bodies. Ben-Gay, including Ben-Gay®, in wash, therapeutic shampoo, anti-skinning agent, for pregnancy lines, in shaving cream as a blade slip coating, in OTC lidocaine composition, in OTC cortisone composition. In (registered trademark) -like products, to treat acne, in collagen-based products, in retinal-based products, to treat dry skin, to treat dermatitis, psoriasis, scars or port wine-like stains. It has been further discovered that it can be used as a non-irritating hair dye and for facial atrophy to reduce or eliminate hair growth.

It is unexpected that the ophthalmic compositions of the present invention can be used for the prevention, treatment and minimization or eradication of age-related and other defects in the skin. However, administration and use of the nanomicelle nonionic surfactant compositions disclosed herein at physiologically based pH is washable, gently exfoliating, and repairable on facial tissue. Has the benefit of providing a moisturizing effect. The effect is in the area of controlling fine to moderate wrinkles, lightening, and reducing the size of chloasma on sunlight, age and / or skin, based on the prescribed treatment regimen. A visible improvement can be delivered.

The long-term moisturizing effect that penetrates the apex of the skin can also result in long-term hydration for the skin, which maintains the tone and texture of the skin. Further consideration is to remove common wounds, reduce skin thickness (supportive use in removing bruises over time), improve dry skin and elasticity and collagen. Further considered for use in the compositions of the present invention is the maintenance of normal pore size and increased hydration, which can also increase the firmness of the facial skin and thus improve the overall smoothness. Is.

The compositions of the invention may contain droplets, which are a topical mix of an aqueous phase, at least one oil, and four or more nonionic surfactants in a specified concentration range. It may be included in an applicable lotion or other compatible and pharmaceutically acceptable form. In mild cases, this base composition may be used as the only treatment method for the skin. However, in more severe cases, the highly compatible base formulation is combined with any of the known active agent substances, such as Botox®, retinoids, and any other proven topical treatment. Can be done. Specifically, the designated nonionic nanoparticles enhance the permeability into the apical layer of the skin, which enhances efficacy.

Within the category of liquid cleansers, the mildest cleansers will contain nonionic / silicone surfactants combined with moisturizers, because they are a skin moisture barrier and normal. This is because the disintegration caused by the skin flora is minimized. Although this explains the quality of the cleanser, these same benefits and some new findings indicate that its use after cleansing benefits the patient's skin condition and is used as directed. When it does, it shows that it can effectively manage hosts with skin conditions that would otherwise have a negative impact on pride and interpersonal acceptance. The findings of the invention that most problems with skin aging can be effectively controlled by nonionic surfactants, either alone or in combination with designated active agent treatments used on the skin. Is.

Definitions As used herein, the term "composition" is a product that contains a specified ingredient in a specified amount, and the result is directly from the combination of the specified ingredient in a specified amount. Intended to include any product that occurs in or indirectly.

As used herein, all numerical values relating to quantity, weight, etc., defined as "about" each particular value, are plus or minus 10%. For example, the phrase "about 5w / v%" will be understood to be "4.5w / v% to 5.5w / v%". Therefore, the amount within 10% of the claimed value is included in the claims.

As used herein, "w / v%" refers to the percentage weight of all compositions.

As used herein, the term "subject" refers to, but is not limited to, humans or other animals.

Throughout this application, the singular forms "a", "an" and "the" include multiple references unless the context clearly states otherwise.

As used herein, the term "polyol" refers to compounds with multiple hydroxyl functional groups that can be used in organic reactions, such as monomeric polyols such as glycerin, pentaerythritol, ethylene glycol and sucrose. Further, the polyol can refer to a polymeric polyol containing glycerin, pentaerythritol, ethylene glycol and sucrose that react with propylene oxide or ethylene oxide.

As used herein, the phrase "means for inducing tears" includes any means by which the production of natural tears can be induced in the subject to which the compositions of the invention are applied. .. Preferably, the tear fluid is prepared by modifying the pH of the composition to the range of about 5.0 to about 6.0 and the osmotic pressure of the composition to the range of about 350 to about 550 milliosmol. And / or can be induced by including terpenoids such as menthol.

As used herein, the phrase "means for capturing tears" is such that the natural tears induced by the compositions of the invention and the artificial tears compositions of the invention are on the eye. Includes any means that can be captured in. Preferably, a combination of a particular concentration and type of nonionic surfactant and a particular concentration and type of viscosity enhancer is used as a means of capturing tear fluid.

Ingredients of the Invention Nonionic surfactants that can be used in accordance with the present invention include, but are not limited to, poloxamers, polysorbates, cyclodextrins, alkylaryl polyethers, polyoxyethylene glycol alkyl ethers, tyloxapols and polyoxyls. Poloxamers are nonionic triblock copolymers consisting of a central hydrophobic chain of polyoxypropylene (poly (propylene oxide)) located flanked by two hydrophilic chains of polyoxyethylene (poly (propylene oxide)). be. Polysorbate is an oily liquid derived from ethoxylated sorbitan esterified with fatty acids. Cyclodextrins are composed of 5 or more α-D-glucopyranoside units linked together at the 1- and 4-positions. Polyoxyl is a mixture of stearate mono- and diesters with polyoxyethylene diol. Preferred embodiments include poloxamar poloxamar 188 and poloxamar 407; polysorbate-polysorbate 20, polysorbate 60, polysorbate 80, tyroxalol, Brij® 35, Brij® 78, Brij® 98. And Brij® 700, Span® 20, Span® 40, Span® 60, Span® 80; cyclodextrin-2-HP-cyclodextrin, with butylated salts With or without ionic charge (eg, anionic) beta-cyclodextrin (Captisol®, sulfobutyl ether β-cyclodextrin, Captisol is a registered trademark of Cydex Pharmaceuticals), hydroxypropyl-. Gamma-cyclodextrin, gamma-cyclodextrin; and polyoxyl-polyoxyl 40 stearate, polyoxyl 30 castor oil, polyoxyl 35 castor oil, and polyoxyl 40 hydrogenated castor oil; or combinations thereof are included, but are not limited to these. Polyols are not included in the term "nonionic surfactant". The total concentration of the nonionic surfactant of the present invention is about 1.0 w / v% to about 7.0 w / v%, preferably 1.5 w / v% to about 7.0 w / v%, preferably about. 1.5w / v% to about 6.0w / v%, more preferably about 1.5w / v% to about 5.9w / v%, more preferably about 1.5w / v% to about 5.5w / v%, more preferably more than about 2.0 w / v% and less than 6.0 w / v%, about 2 w / v% to about 4 w / v%, more preferably about 2.5 w / v% to about 5.9 w. Less than / v%, more preferably about 2.5w / v% to about 5.5w / v%, more preferably about 2.5w / v% to about 3.5w / v%, more preferably about 2.8w. / V% to about 5.9 w / v%, more preferably about 3 w / v% to about 5 w / v%, more preferably about 3 w / v% to about 3.5 w / v%.

In another preferred embodiment, the one or more nonionic surfactants include poloxamer, eg, poloxamer 188 and / or poloxamer 407, polyoxyl, eg, polyoxyl castor oil, including polyoxyl 35 castor oil or polyoxyl 40. Hydrous castor oil, which includes cyclodextrins such as hydroxypropyl-gamma-cyclodextrin and tyloxapol.

In another preferred embodiment, for one or more nonionic surfactants, about 0.01 w / v% to about 3.5 w / v%, preferably about 0.2 w / v% to about 3.5 w. / V%, preferably about 0.1 w / v%, 0.2 w / v%, 0.7 w / v%, 1 w / v%, 3 w / v% and 3.5 w / v% polysorbate 20. ..

In another preferred embodiment, for one or more nonionic surfactants, about 0.01 w / v% to about 3.5 w / v%, preferably about 0.2 w / v% to about 3.5 w. / V%, preferably about 0.1 w / v%, 0.2 w / v%, 0.7 w / v%, 1 w / v%, 3 w / v% and 3.5 w / v% poloxamer 407. ..

In another preferred embodiment, for one or more nonionic surfactants, about 0.01 w / v% to about 3 w / v%, preferably about 0.1 w / v% to about 1 w / v%. Preferably about 0.01w / v%, 0.1w / v%, 0.14w / v%, 0.2w / v%, 0.4w / v%, 0.5w / v% and 0.75w / v. % Poloxamer 188.

In another preferred embodiment, for one or more nonionic surfactants, about 0.001 w / v% to about 2.0 w / v%, preferably about 0.005 w / v% to about 0.25 w. / V%, preferably about 0.01 w / v% to about 1 w / v%, preferably about 0.01 w / v% to about 0.1 w / v%, preferably about 0.15 w / v% to about 0. .25w / v%, preferably about 0.001w / v%, 0.01w / v%, 0.1w / v%, 0.15w / v%, 0.18w / v%, 0.25w / v% , 0.5 w / v% and 1 w / v% polio castor oil.

In another more preferred embodiment, for one or more nonionic surfactants, about 0.01 w / v% to about 5 w / v%, preferably about 0.5 w / v% to about 5 w / v%. , Preferably about 1.5 w / v% to about 3.0 w / v%, preferably about 0.25 w / v%, 0.5 w / v%, 0.7 w / v%, 0.75 w / v%, 1w / v%, 1.05w / v%, 1.5w / v%, 2w / v%, 2.5w / v%, 3w / v%, 3.5w / v%, 4w / v% and 5w / Included is v% hydroxypropyl-gamma-cyclodextrin.

In another preferred embodiment, the addition of 0.005 w / v% to 4.0 w / v% tyroxapol or about 1.75 w / v% to about 3.00 w / v% sorbitol may be added in combination. It may be added well or as a replacement for one or more nonionic surfactants so that the total concentration of the surfactant does not exceed 7 w / v%.

In another preferred embodiment, the one or more nonionic surfactants are polyoxyl 35 castor oil from about 0.25 w / v% to about 5.00 w / v%, preferably about 0.15 w / v%. It may be contained in an amount of about 0.25 w / v%.

Visco-enhancing agents that can be used in accordance with the present invention are non-Newtonal viscous enhancers, which include cellulose derivatives, carbomer (Carbopol®), gum and hyaluronic acid (hyallonate), dextran, polyvinyl alcohol, etc. Polyacrylic acid, povidone, polyethylene glycol, propylene glycol and chitosan are, but are not limited to; particularly preferred cellulose derivatives are carboxymethyl cellulose (“CMC”) high molecular weight blends, CMC low molecular weight blends, CMC medium molecular weight. Blend, CMC Sodium, Methyl Cellulose, Methyl Cellulose 4000, Hydroxymethyl Cellulose, Hydroxypropyl Cellulose (“HPC”), Hydroxypropyl Methyl Cellulose High Polymer Blend (“HPMC”), Hydroxylpropyl Methyl Cellulose 2906, Carboxypropyl Methyl Cellulose High Polymer Blend (“CPMC”) , Hydroxyethyl cellulose, or hydroxyethyl cellulose and one or more of hyaluronic acids, for example, those whose concentration is cumulatively in situ and does not create a phase transition in the gel. The non-Newtonian properties imparted to the compositions of the invention by this type of viscosity enhancer can be seen in FIG. 7, which illustrates the difference in viscosity during and between blinks during blinking. ing. This viscosity can be modified for the specific clinical procedure of the target. The particular viscosity and viscosity enhancer can achieve a blinking (high shear rate) viscosity of about 30 cps or less, more preferably about 25 cps or less, most preferably about 20 cps or less. Certain clinical procedures can use the following (low shear rate) viscosities in the blink:
i. Use contact lenses: about 1 to about 5 cps,
ii. Artificial tears, mild to moderate dry eye: about 5 cps to about 100 cps,
iii. Artificial tears, moderate to severe dry eye: about 100 cps to about 250 cps, and iv. Artificial tears, severe dry eye: about 250-about 5000 cps.

In a preferred embodiment, the viscosity enhancing excipient is selected from the group consisting of CMC sodium, CMC low molecular weight blends, CMC medium molecular weight blends, CPMC, HPC, HPMC and carbomer 940, or combinations thereof.

In a more preferred embodiment, the amount of CMC is from about 0.01 w / v% to about 1.75 w / v%, 0.05 w / v%, 0.10 w / v%, 0.20 w / v%, 0.25w / v%, 0.3w / v%, 0.4w / v%, 0.5w / v%, 0.55w / v%, 0.62w / v%, 0.65w / v%, 0 Includes .75w / v%, 1.0w / v%, 1.25w / v%, 1.35w / v%, 1.38w / v%, 1.40w / v% and 1.45w / v%.

In another more preferred embodiment, the amount of CMC sodium is from about 0.01 w / v% to about 1.5 w / v%, more preferably from about 0.04 w / v% to about 1.25 w / v%, most preferably. It is preferably about 0.04 w / v%, about 1.00 w / v% and about 1.25 w / v%.

In other more preferred embodiments, the amount of HPC is from about 0.10 w / v% to about 1.75 w / v%, 1.0 w / v%, 1.25 w / v%, 1.40 w / v. %, 1.50 w / v% or 1.75 w / v%.

In another more preferred embodiment, the amount of HPMC is from about 0.10 w / v% to about 1.75 w / v%, preferably about 0.1 w, based on the molecular weight of Metothell® (Dow-Corning). / V% to about 1.5w / v%, about 0.5w / v% to about 1.25w / v%, about 0.65w / v% to about 1.0w / v%, about 1w / v% to About 1.35w / v%, about 1.25w / v% to about 1.35w / v%, about 1.35w / v% to about 1.5w / v%, about 1.35w / v% to about 1 .45w / v%, preferably about 0.10w / v%, 0.20w / v%, 0.25w / v%, 0.3w / v%, 0.4w / v%, 0.5w / v% , 0.55w / v%, 0.62w / v%, 0.65w / v%, 0.75w / v%, 0.85w / v%, 1.0w / v%, 1.25w / v%, It is 1.3w / v%, 1.35w / v%, 1.38w / v%, 1.40w / v%, 1.45w / v% and 1.48w / v%.

In a more preferred embodiment, the amount of carbomer 940 is from about 0.01 w / v% to about 2.0 w / v%, preferably from about 0.8 w / v% to about 1.3 w / v%, more preferably about. It is 0.01 w / v%, 0.8 w / v%, 0.9 w / v%, 1.1 w / v%, 1.2 w / v% or 1.3 w / v%.

In certain embodiments, polyvinyl alcohol (“PVA”) can be used as a viscosity enhancer in the compositions of the present invention. Preferably, PVA has a concentration of about 0.1 w / v% to about 0.5 w / v%.

In another embodiment, the invention further comprises glycerin in an amount of about 0.05 w / v% to about 2.0 w / v%, preferably about 0.1 w / v% to about 0.4 w / v%. include.

Suitable polyols for use in the present invention include, but are not limited to, mannitol, glycerol, erythritol, lactitol, xylitol, sorbitol, isosorbide and maltitol. In a more preferred embodiment, the polyol is mannitol. In another more preferred embodiment, the polyols are from about 0.1 w / v% to about 4 w / v%, about 0.25 w / v% to about 5.5 w / v%, about 0.25 w / v% to about. 4.0w / v%, about 0.25w / v% to about 2.5w / v%, about 1w / v% to about 4w / v%, about 1w / v% to about 2.5w / v%, about 1.5w / v% to about 3.0w / v%, about 1.5w / v% to about 2.5w / v%, about 2w / v% to about 2.5w / v%, and about 1w / v % And 2.5 w / v% concentration.

Suitable electrolytes for use in the present invention include, but are not limited to, magnesium ion, sodium chloride (“NaCl”), potassium chloride (“KCl”), and combinations thereof. In a more preferred embodiment, magnesium ions are derived from magnesium chloride. In another more preferred embodiment, the total concentration of electrolyte is from about 0.01 w / v% to about 2.0 w / v%. In a more preferred embodiment, the magnesium ion, as MgCl ₂ , is about 0.01 w / v% to about 0.90 w / v%, preferably about 0.05 w / v% to about 0.15 w / v%, and about. The concentration is 0.075 w / v% to about 0.125 w / v%, and NaCl is about 0.01 w / v% to about 2.0 w / v%, preferably about 0.1 w / v% to about 2. .0w / v%, about 0.2w / v% to about 2.0w / v%, about 0.25w / v% to about 2.0w / v%, more preferably about 0.01w / v%, 0 .07w / v%, 0.2w / v%, 0.25w / v%, 0.3w / v%, 0.35w / v%, 0.37w / v%, 0.4w / v%, 0. 5w / v%, 0.62w / v%, 0.7w / v%, 0.75w / v%, 1.0w / v%, 1.25w / v%, 1.5w / v%, 1.75w There are concentrations of / v% and 2.0 w / v%, and KCl has a concentration of about 0.1 w / v% to about 0.5 w / v%. In another embodiment, the artificial tears composition of the present invention does not contain magnesium ions, including magnesium chloride.

Suitable preservatives for use in the present invention include benzalkonium chloride (“BAK”), sorbate, methylparaben, polypropylparaben, chlorobutanol, thimerosal, phenylmercury acetate, perborate, phenylmercury nitrate, and the like. Combinations of, but are not limited to these. In a preferred embodiment, the preservative is BAK, sorbate, or a combination thereof. In one preferred embodiment, the preservative is at a concentration of about 0.005 w / v% to about 0.15 w / v%. In a more preferred embodiment, BAK is at a concentration of about 0.005 w / v% to about 0.02 w / v% and sorbate is at a concentration of about 0.015 w / v% to about 0.15 w / v%. be.

Suitable antioxidants for use in the present invention include, but are not limited to, citrate, EDTA, sodium sulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene, and combinations thereof. .. In one preferred embodiment, the preservative is at a concentration of about 0.05 w / v% to about 0.2 w / v%.

In certain embodiments, terpenoids can be used in the compositions of the invention. In a preferred embodiment, terpenoids include, but are not limited to, citral, WS-12, cilin and menthol.

In certain embodiments, menthol can be used in the compositions of the invention. Preferably, the menthol is about 0.01 to about 4.00 mM, about 0.01 to about 2.5 mM, about 0.01 to about 2.0 mM, about 0.025 to about 0.07 mM, about 0.07. ~ About 0.3 mM, about 0.07 ~ about 0.1 mM, about 0.1 ~ about 0.40 mM, about 0.1 ~ about 0.2 mM, about 0.15 ~ about 0.25 mM, about 0.02 ~ About 1.5 mM, about 0.25 ~ about 2.0 mM, and about 0.01, 0.07, 0.1, 0.14, 0.15, 0.2, 0.27, 0.30, 0.32, 0.34, 0.36, 0.37, 0.38, 0.40, 0.42, 0.44, 0.46, 0.48, 0.5, 0.6, 0. Concentrations of 65, 0.7, 0.75, 0.8, 0.85, 1.0, 1.2, 1.5, 1.75, 2.0 or 4.0 mM.

Buffers and pH regulators that can be used in accordance with the present invention include, but are not limited to, acetate buffers, carbonate buffers, citrate buffers, phosphate buffers and borate buffers. In a preferred embodiment, the buffer and pH regulator are at a concentration of about 1 to about 100 mmol, more preferably about 3 to about 10 mmol, most preferably about 3, 4, 5, 5.5, 6, 6. It has a concentration of 5.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 mmol. It is understood that a variety of acids or bases can be used to adjust the pH of the composition, if desired. Examples of the pH adjuster include, but are not limited to, sodium hydroxide and hydrochloric acid. Surprisingly, no pH was found to alter comfort in the artificial tear composition. The pH of the composition can be 4.0 to 8.0, more preferably about 5.0 to about 8.0, about 5.0 to about 6.0, and less than 6.0.

Compositions of the Invention The present invention is designed to improve the protection of non-Newtonic viscosity excipients, electrolytes, or epithelium, and to improve both comfort and efficacy with regular use or even a single instillation. We have discovered a narrow therapeutic range of nonionic surfactant concentrations in one preferred embodiment that require any of the other excipients that provide a good cure. The components and concentrations of the compositions represented herein are the best known embodiments, but are not intended to be inclusive.

In certain embodiments, the present invention relates to an artificial tears composition comprising means for inducing tears and means for capturing tears.

In a preferred embodiment, the means for inducing tears is selected from a pH of about 5 to about 6, terpenoids, and an osmotic pressure of about 270 to about 550 milliosmoles, preferably about 350 to about 350 milliosmoles.

In another preferred embodiment, the means of capturing the tear fluid are one or more nonionic surfactants with a total volume of about 1.5 w / v% to about 5.9 w / v%, and one or more. The viscosity enhancer, including the viscosity enhancer, imparts a viscosity of about 50 to about 10,000 centipores at 0 shear to 1 second.

In a more preferred embodiment, the one or more nonionic surfactants are selected from the group consisting of polysorbate, poloxamer, polyoxyl castor oil, cyclodextrin, and combinations thereof.

In another more preferred embodiment, the viscosity enhancer is a cellulose derivative, carbomer, gum, and hyaluronic acid, dextran, polyvinyl alcohol, polyacrylic acid, povidone, polyethylene glycol, propylene glycol, chitosan, and these. It is selected from the group consisting of combinations, and even more preferably, one or more viscosity enhancers are selected from the group consisting of cellulose derivatives, carbomeres, polyvinyl alcohols, polyethylene glycols, and combinations thereof.

In another embodiment, the artificial tears composition of the present invention further comprises a polyol selected from the group consisting preferably of mannitol, xylitol, sorbitol, isosorbide, erythritol, glycerol, maltitol, and combinations thereof.

In another embodiment, the artificial tears composition of the present invention further comprises one or more electrolytes selected from the group consisting preferably of magnesium ions, sodium chloride, potassium chloride, and combinations thereof.

The present invention
It is selected from the group consisting of poloxamers, polysorbates, cyclodextrins, alkylaryl polyethers, polyoxyethylene glycol alkyl ethers, tyroxapols and polyoxyls, with a total concentration of about 1.5 w / v% to about 6.0 w / v%. One or more nonionic surfactants, preferably the one or more nonionic surfactants are about 0.01 w / v% to about 4.0 w / v% polysorbate, about 0. 01w / v% to about 3.5w / v% poloxamer, about 0.01w / v% to about 2.0w / v% polyoxyl and about 0.01w / v% to about 5.0w / v% hydroxy Selected from the group consisting of propyl-gamma-cyclodextrin,
One or more viscosity enhancers selected from the group consisting of cellulose derivatives, carbomer, gum, dextran, polyvinyl alcohol, polyacrylic acid, povidone, polyethylene glycol, propylene glycol, chitosan, and hyaluronate and hyaluronic acid.
One or more electrolytes of about 0.01 w / v% to about 2.0 w / v% selected from the group consisting of sodium chloride, potassium chloride and magnesium ions, preferably the one or more electrolytes. About 0.01w / v% to about 0.25w / v% magnesium ion, about 0.10w / v% to about 2.0w / v% sodium chloride and about 0.1w / v% to about 0.5w Selected from / v% potassium chloride,
Optionally, the polyol is from about 0.1 w / v% to about 4 w / v%, preferably the polyol is selected from 0.25 w / v% to about 4.0 w / v% mannitol or glycerol. ,
Optionally, about 0.01 w / v% to about 2.0 w / v% polyethylene selected from the group consisting of polyethylene glycol 400, polyethylene glycol 6000, polyethylene glycol 10000, polyethylene glycol 20000, and combinations thereof. Glycol,
Optionally, about 0.01 to about 4.0 mM menthol and / or about 0.1 w / v% to about 0.12 w / v% sorbate.
An artificial tear composition comprising, optionally, a citrate buffer or a phosphate buffer having a concentration of about 3 to about 10 mmol.
The concentration of the viscosity enhancer imparts a viscosity of about 0.1 to about 1,000 centipores (cps) to the composition, preferably a low shear viscosity of 1 to 1000 cps and a final high shear viscosity. 30 cps or less,
Further on the artificial tears composition.

The present invention
Selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin, from about 0.1 w / v% to about 1.0 w / v%, or 1.0 w / v. One or more nonionic surfactants with a total concentration of% to about 5.9 w / v%, the upper limit of which is greater tear water retention and greater tear water retention due to more severe dry eyes. One or more nonionic surfactants that provide therapeutic efficacy,
About 0.1 w / v% to about 2.0 w / v% hydroxypropylmethyl cellulose, or about 0.1 w / v% to about 1.5 w / v%, preferably about 0.1 w / v% to about 1. A cellulose derivative having a concentration that produces a total viscosity of the composition equal to the total viscosity of the composition imparted by 35 w / v% hydroxypropylmethyl cellulose, from about 0.9 w / v% to about 1.45 w / v% carboxy. Contains Methyl Cellulose or Carbomer 940,
About 0.1 w / v% to about 2.0 w / v%, preferably about 0.25 w / v% to about 1.0 w / v% sodium chloride,
Approximately 0.05 w / v% to approximately 0.1 w / v% magnesium chloride,
Optionally, about 0.25 w / v% to about 4.0 w / v%, preferably about 0.75 w / v% to about 2.5 w / v% mannitol,
Optionally, about 0.1 w / v% to about 0.75 w / v% polyethylene glycol 400 or polyethylene glycol 20000,
Optionally, a citrate buffer or phosphate buffer at a concentration of about 4-8 mmol,
Optionally, preferably at a concentration of about 0.1 to about 1.75 mmol, more preferably about 1.0 to about 1.75 mmol, and optionally optionally, preferably 0.1 w / v%. Or an artificial tear composition comprising a sorbate at 0.12 w / v%.
Optionally, having a pH of about 5.0 to about 7.0,
Further on the artificial tears composition.

In one preferred embodiment, the invention is described.
One or more nonionic surfactants of about 2.0 w / v% to about 4.0 w / v%, selected from the group consisting of polysorbate, poloxamer, polyoxyl castor oil, and combinations thereof.
A viscosity enhancer of about 0.5 w / v% to about 2.0 w / v%, selected from the group consisting of carboxymethyl cellulose and carbomer 940.
About 1.0 w / v% to about 5.0 w / v% mannitol,
It is selected from about 0.5 w / v% to about 1.0 w / v%, preferably polyethylene glycol 400, polyethylene glycol 6000, polyethylene glycol 10000, polyethylene glycol 20000, and combinations thereof, and about 400 to about 20,000. Polyethylene glycol with Dalton molecular weight,
About 0.1 w / v% to about 2.0 w / v% sodium chloride,
About 0.1w / v% to about 0.12w / v% solve,
An artificial tear composition comprising a citric acid buffer having a concentration of about 3.0 to about 10.0 mmol.
w / v indicates weight / total volume of composition, wherein the composition has a pH of about 5.0 to about 7.4, preferably about 5.0 to about 6.0.
Regarding artificial tears composition.

In another embodiment, polio castor oil has at least 30 moles of ethylene oxide, preferably about 30 to about 40 moles of ethylene oxide.

In another embodiment, the artificial tear composition of the present invention further comprises menthol at a concentration of about 0.25 to about 4.00 mmol.

In another embodiment, the artificial tear composition of the present invention further comprises about 0.1 w / v% magnesium chloride.

In another embodiment, the artificial tear composition of the present invention is selected from the group consisting of about 0.1 w / v% ethylenediaminetetraacetic acid, 0.5 w / v% polyvinyl alcohol, and combinations thereof. Further contains a shaping agent.

In a more preferred embodiment, the invention
Surfactants selected from the group consisting of about 3.50 w / v% poloxamer 407 or about 0.25 w / v% poloxamer 407 and 1.75 w / v% sorbitol.
Approximately 0.25w / v% polyoxyl 40 castor oil,
Polyethylene glycol having a molecular weight of about 400-about 20,000 daltons of about 0.75 w / v%,
Approximately 1.00 w / v% mannitol,
About 0.45 w / v% to about 0.75 w / v% sodium chloride,
Carbomer 940, from about 0.90 w / v% to about 1.20 w / v%,
Menthol at a concentration of about 0.4 to about 2.75 mmol,
Citric acid buffer, about 4.00 mmol concentration,
Approximately 0.10 w / v% ethylenediaminetetraacetic acid,
It relates to an artificial tear composition comprising about 0.10 w / v% polyvinyl alcohol and about 0.12 w / v% sorbate.

The present invention
Polysorbate 80 of about 0w / v% to about 3.5w / v%,
Poloxamer 407, from about 0 w / v% to about 2.75 w / v%,
Poloxamer 188, from about 0 w / v% to about 2.75 w / v%,
About 0w / v% to about 2.0w / v% polio castor oil,
About 0.1 w / v% to about 2.0 w / v% hydroxypropylmethyl cellulose,
Polyethylene glycol 400 from about 0 w / v% to about 2.0 w / v%,
About 0w / v% to about 3.0w / v% mannitol,
About 0w / v% to about 0.90w / v% sodium chloride,
Menthol at a concentration of about 0.04 to about 0.50 mmol,
An artificial tear composition comprising a citric acid buffer having a concentration of about 4 mmol and optionally about 0.1 w / v% sorbate.
It has a pH of about 7.0 and the total concentration of nonionic surfactant is from about 1.5 w / v% to about 5.0 w / v%.
Further on the artificial tears composition.

The present invention
Selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin, with a total concentration of about 1.5 w / v% to about 5.9 w / v%, 2 More than a species of nonionic surfactant,
About 1w / v% mannitol,
Carboxymethyl cellulose at a concentration that produces a total viscosity of the composition equal to the total viscosity of the composition imparted by about 0.1 w / v% hydroxypropylmethyl cellulose, or about 0.1 w / v% hydroxypropylmethyl cellulose.
About 0.1 w / v% to about 0.75 w / v%, preferably about 0.3 w / v% to about 0.4 w / v% sodium chloride,
Approximately 0.1 w / v% magnesium chloride,
Optionally, a phosphate buffer having a concentration of about 3 mmol, or a citrate buffer having a pH of less than 6.0,
An artificial tear composition optionally comprising menthol at a concentration of about 0.1 to about 0.50 mmol, and optionally about 0.1 w / v% sorbate.
Optionally, having a pH of about 5.0 to about 7.0,
Further on the artificial tears composition.

The present invention
Selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin, with a total concentration of about 1.5 w / v% to about 5.9 w / v%, 2 More than a species of nonionic surfactant,
Approximately 1.0 w / v% -2.5 w / v% mannitol,
With the total viscosity of the composition imparted by about 0.10 w / v% to about 1.5 w / v% hydroxypropylmethyl cellulose, or about 0.1 w / v% to about 1.5 w / v% hydroxypropylmethyl cellulose. Carboxymethyl cellulose at concentrations that produce the total viscosity of equal compositions,
About 0.1 w / v% to about 0.5 w / v%, preferably about 0.2 w / v% to about 0.4 w / v% sodium chloride,
Approximately 0.1 w / v% magnesium chloride,
Optionally, a phosphate or citric acid buffer at a concentration of about 3 mmol,
Optionally, menthol at a concentration of about 0.1 to about 0.50 mmol,
Optionally, an artificial tear composition comprising about 0.1 w / v% sorbate.
Optionally, having a pH of about 5.0 to about 7.0,
Further on the artificial tears composition.

The present invention
Selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin, with a total concentration of about 1.5 w / v% to about 5.9 w / v%, 2 More than a species of nonionic surfactant,
Approximately 2.5 w / v% mannitol,
To the total viscosity of the composition imparted by about 0.65 w / v% to about 1.0 w / v% hydroxypropylmethyl cellulose, or about 0.65 w / v% to about 1.0 w / v% hydroxypropylmethyl cellulose. Carboxymethyl cellulose, a concentration that produces the total viscosity of the same composition,
About 0.1 w / v% to about 0.75 w / v%, preferably about 0.3 w / v% to about 0.4 w / v% sodium chloride,
Approximately 0.1 w / v% magnesium chloride,
Optionally, a phosphate buffer solution at a concentration of about 3 mmol or a citrate buffer solution at a concentration of about 4 mmol,
Optionally, menthol at a concentration of about 0.1 to about 0.50 mmol,
Optionally, an artificial tear composition comprising about 0.1 w / v% sorbate.
Optionally, having a pH of about 5.5 to about 7.0,
Further on the artificial tears composition.

The present invention
Selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin, with a total concentration of about 1.5 w / v% to about 5.9 w / v%, 2 More than a species of nonionic surfactant,
Approximately 2.5 w / v% mannitol,
With the total viscosity of the composition imparted by about 1.0 w / v% to about 1.35 w / v% hydroxypropylmethyl cellulose, or about 1.0 w / v% to about 1.35 w / v% hydroxypropylmethyl cellulose. Carboxymethyl cellulose, a concentration that produces the total viscosity of the same composition,
About 0.1 w / v% to about 0.75 w / v%, preferably about 0.3 w / v% to about 0.4 w / v% sodium chloride,
Approximately 0.1 w / v% magnesium chloride,
Optionally, a phosphate buffer solution at a concentration of about 3 mmol or a citrate buffer solution at a concentration of about 4 mmol,
Optionally, menthol at a concentration of about 0.1 to about 0.50 mmol,
Optionally, an artificial tear composition comprising about 0.1 w / v% sorbate.
Optionally, having a pH of about 5.5 to about 7.0,
Further on the artificial tears composition.

The present invention
Selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin, with a total concentration of about 1.0 w / v% to about 5.9 w / v%, 2 More than a species of nonionic surfactant,
Approximately 2.5 w / v% mannitol,
With the total viscosity of the composition imparted by about 1.35 w / v% to about 1.45 w / v% hydroxypropylmethyl cellulose or from about 1.35 w / v% to about 1.45 w / v% hydroxypropylmethyl cellulose. Carboxymethyl cellulose, a concentration that produces the total viscosity of the same composition,
About 0.1 w / v% to about 0.75 w / v%, preferably about 0.3 w / v% to about 0.4 w / v% sodium chloride,
Approximately 0.1 w / v% magnesium chloride,
Optionally, a phosphate buffer solution at a concentration of about 3 mmol or a citrate buffer solution at a concentration of about 4 mmol,
Optionally, menthol at a concentration of about 0.1 to about 0.50 mmol,
Optionally, an artificial tear composition comprising about 0.1 w / v% sorbate.
Optionally, having a pH of about 5.5 to about 7.0,
Further on the artificial tears composition.

The present invention
Selected from the group consisting of polysolvate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin, with a total concentration of about 1.5 w / v% to about 5.9 w / v%, 2 More than a species of nonionic surfactant, one of the two or more nonionic surfactants is about 0.25 w / v% to about 1.0 w / v% poloxamer oil. Two or more nonionic surfactants,
Approximately 2.5 w / v% mannitol,
With the total viscosity of the composition imparted by about 1.25w / v% to about 1.35w / v% hydroxypropylmethylcellulose or from about 1.25w / v% to about 1.35w / v% hydroxypropylmethylcellulose. Carboxymethyl cellulose, a concentration that produces the total viscosity of the same composition,
About 0.1 w / v% to about 0.75 w / v%, preferably about 0.3 w / v% to about 0.4 w / v% sodium chloride,
Approximately 0.1 w / v% magnesium chloride,
Optionally, a phosphate or citric acid buffer at a concentration of about 3 mmol,
Optionally, menthol at a concentration of about 0.1 to about 0.50 mmol,
Optionally, an artificial tear composition comprising about 0.1 w / v% sorbate.
Optionally, having a pH of about 5.0 to about 7.0,
Further on the artificial tears composition.

The present invention
Approximately 2.0 w / v% polysorbate 80,
Approximately 0.2 w / v% poloxamer 407,
Approximately 0.5 w / v% poloxamer 188,
Approximately 1.0 w / v% hydroxypropyl-gamma-cyclodextrin,
With the total viscosity of the composition imparted by about 0.5w / v% to about 1.25w / v% hydroxypropylmethylcellulose, or about 0.5w / v% to about 1.25w / v% hydroxypropylmethylcellulose. Cellulose derivatives with concentrations that produce the total viscosity of equal compositions,
About 0.20 w / v% to about 0.75 w / v% sodium chloride,
Further related to an artificial tear composition comprising about 0.1 w / v% magnesium chloride and menthol at a concentration of about 0.025 to about 0.07 mmol.

The present invention
Approximately 2.0 w / v% polysorbate 80,
Approximately 0.2 w / v% poloxamer 407,
Approximately 0.5 w / v% poloxamer 188,
Approximately 1.0 w / v% hydroxypropyl-gamma-cyclodextrin,
With the total viscosity of the composition imparted by about 1.25w / v% to about 1.35w / v% hydroxypropylmethylcellulose or from about 1.25w / v% to about 1.35w / v% hydroxypropylmethylcellulose. Cellulose derivatives with concentrations that produce the total viscosity of equal compositions,
Approximately 0.25w / v% to approximately 0.75w / v% sodium chloride,
Further related to an artificial tear composition for severe dry eye, comprising about 0.1 w / v% magnesium chloride and menthol at a concentration of about 0.07 to about 0.1 mmol.

The present invention
Approximately 2.0 w / v% polysorbate 80,
Approximately 0.2 w / v% poloxamer 407,
Approximately 0.5 w / v% poloxamer 188,
Approximately 1.0 w / v% hydroxypropyl-gamma-cyclodextrin,
With the total viscosity of the composition imparted by about 1.35 w / v% to about 1.5 w / v% hydroxypropylmethyl cellulose, or about 1.35 w / v% to about 1.5 w / v% hydroxypropylmethyl cellulose. Cellulose derivatives with concentrations that produce the total viscosity of equal compositions,
Approximately 0.25w / v% to approximately 0.75w / v% sodium chloride,
Further related to an artificial tear composition for severe dry eye, comprising about 0.1 w / v% magnesium chloride and menthol at a concentration of about 0.1 to about 0.20 mmol.

The present invention
Approximately 3.5 w / v% polysorbate 80,
Approximately 0.7 w / v% poloxamer 407,
Approximately 1.0 w / v% poloxamer 188,
Approximately 0.01 w / v% polio castor oil,
Approximately 0.85 w / v% hydroxypropylmethyl cellulose,
Approximately 2.5 w / v% mannitol,
Approximately 0.1 w / v% magnesium chloride,
Approximately 0.25 w / v% sodium chloride,
Menthol at a concentration of about 0.07 to about 0.50 mmol, preferably menthol at a concentration of 0.07, 0.10, 0.14, 0.20 or 0.40 mmol.
An artificial tear composition comprising optionally about 0.1 w / v% sorbate and a phosphate buffer or citric acid buffer of about 4 mmol concentration.
Has a pH of about 7.0,
Further on the artificial tears composition.

The present invention
Approximately 3.5 w / v% polysorbate 80,
Approximately 0.2 w / v% poloxamer 407,
Approximately 0.2 w / v% poloxamer 188,
Approximately 0.01 w / v% polio castor oil,
About 0.70 w / v% to about 0.80 w / v%, preferably 0.70 w / v%, 0.75 w / v% or 0.80 w / v% hydroxypropylmethyl cellulose,
Approximately 2.5 w / v% mannitol,
Approximately 0.1 w / v% magnesium chloride,
Approximately 0.25 w / v% to approximately 0.35 w / v%, preferably 0.25 w / v%, 0.30 w / v% or 0.35 w / v% sodium chloride,
Menthol with a concentration of about 0.07 to about 0.14 mmol, preferably menthol with a concentration of 0.07, 0.10, or mmol.
Optionally, an artificial tear composition comprising about 0.1 w / v% sorbate and a phosphate buffer or citric acid buffer of about 4 mmol concentration.
Has a pH of about 7.0,
Further on the artificial tears composition.

The present invention
Approximately 2.0 w / v% polysorbate 80,
Approximately 0.2 w / v% poloxamer 407,
Approximately 0.5 w / v% poloxamer 188,
Approximately 1.0 w / v% hydroxypropyl-gamma-cyclodextrin,
With the total viscosity of the composition imparted by about 0.5w / v% to about 1.25w / v% hydroxypropylmethylcellulose, or about 0.5w / v% to about 1.25w / v% hydroxypropylmethylcellulose. Cellulose derivatives with concentrations that produce the total viscosity of equal compositions,
About 0.2 w / v% to about 0.75 w / v% sodium chloride,
Further related to an artificial tear composition comprising about 0.1 w / v% magnesium chloride and menthol at a concentration of about 0.025 to about 0.07 mmol.

The present invention
Approximately 2.0 w / v% polysorbate 80,
Approximately 0.2 w / v% poloxamer 407,
Approximately 0.5 w / v% poloxamer 188,
Approximately 1.0 w / v% hydroxypropyl-gamma-cyclodextrin,
With the total viscosity of the composition imparted by about 1.25w / v% to about 1.35w / v% hydroxypropylmethylcellulose or from about 1.25w / v% to about 1.35w / v% hydroxypropylmethylcellulose. Cellulose derivatives with concentrations that produce the total viscosity of equal compositions,
Approximately 0.25w / v% to approximately 0.75w / v% sodium chloride,
Further related to an artificial tear composition comprising about 0.1 w / v% magnesium chloride and menthol at a concentration of about 0.07 to about 0.1 mmol.

The present invention
Approximately 3.0 w / v% polysorbate,
Approximately 0.10 w / v% poloxamer 188,
Approximately 0.01 w / v% polio castor oil,
About 0.0 w / v% to about 2.0 w / v% hydroxypropylmethyl cellulose,
About 0.5 w / v% to about 2.5 w / v% mannitol,
Approximately 0.10 w / v% magnesium ion,
An artificial tear composition comprising a buffer solution containing about 0.0 w / v% to about 0.75 w / v% NaCl and a concentration of about 1 mM to about 100 mM.
The composition has a pH of about 5.5 to about 8.0 and has a viscosity of less than 500 centipores or less than 500 centipores.
Further on the artificial tears composition.

The present invention
Approximately 4.0 w / v% Captisol®,
HPMC of about 1.35w / v%,
BAK of about 0.02w / v%,
Approximately 0.10 w / v% solve,
Approximately 0.10 w / v% EDTA,
About 3 mM citric acid buffer and about 0.3 w / v% to about 0.5 w / v% NaCl
An artificial tears composition comprising:
Has a pH of about 6.0,
Further on the artificial tears composition.

Approximately 0.70 w / v% polysorbate 80, approximately 0.7 w / v% poroxamer 407, approximately 0.14 w / v% poroxamer 188, approximately 0.18 w / v% polyoxyl frost oil, approximately 1.05 w. / V% hydroxypropyl-gamma-cyclodextrin, about 0.04 w / v% sodium carboxymethyl cellulose, about 0.70 w / v% polyethylene glycol 400, about 0.53 w / v% mannitol, about 0.07 w An artificial tear composition comprising / v% magnesium chloride, about 0.55 w / v% sodium chloride, about 0.12 w / v% potassium sorbate, and 3 mM phosphate buffer. An artificial tear solution composition having a pH of 7.

About 1.00 w / v% polysorbate 80, about 1.00 w / v% poloxamer 407, about 0.20 w / v% poloxamer 188, about 0.25 w / v% polyoxyl castor oil, about 1.50 w. / V% hydroxypropyl-gamma-cyclodextrin, about 1.00 w / v% sodium carboxymethyl cellulose, about 0.75 w / v% polyethylene glycol 400, about 0.50 w / v% mannitol, about 0.65 w An artificial tear composition comprising / v% sodium chloride, about 0.15 mmol concentration menthol, about 0.12 w / v% potassium sorbate, and about 4.5 mM citrate buffer. An artificial tear composition having a pH of about 6.5.

About 1.00 w / v% polysorbate 80, about 1.00 w / v% poloxamer 407, about 0.20 w / v% poloxamer 188, about 0.25 w / v% polyoxyl castor oil, about 1.50 w. / V% hydroxypropyl-gamma-cyclodextrin, about 1.25 w / v% sodium carboxymethyl cellulose, about 0.75 w / v% polyethylene glycol 400, about 0.50 w / v% mannitol, about 0.70 w 6. An artificial tear composition comprising / v% sodium chloride, about 2.0 mmol concentration menthol, about 0.12 w / v% potassium sorbate, and about 2.0 mM menthol. An artificial tears composition having a pH of 0.

Selected from about 3.5 w / v% polysorbate 80, about 0.8 w / v% to about 1.2 w / v% hydroxypropylmethyl cellulose and about 1 w / v% to about 1.4 w / v% carboxymethyl cellulose. Viscosity enhancer, about 0.75 w / v% polyethylene glycol 400, about 0.5 w / v% to about 0.75 w / v% mannitol, about 0.6 w / v% to about 1.25 w / v% Sodium chloride, about 0.1 to about 3.0 mmol, preferably about 0.1 to about 0.15 mmol or about 2.5 to about 3.0 mmol of menthol, and about 0.1 w / V% to about 0.12 w / v% chloride, optionally about 0.25 w / v% polyoxyl cellulose oil, optionally from about 0.5 w / v% to about 1.5 w / v An artificial tear composition comprising% hydroxypropyl-gamma-cyclodextrin and optionally about 4 mmol concentration of citrate buffer, having a pH of about 6 to about 6.5, artificial. Tear composition.

Approximately 1 w / v% polysorbate 80, approximately 1 w / v% poroxamer 407, approximately 0.2 w / v% poroxamer 188, approximately 0.25 w / v% polyoxyl honey oil, approximately 1.5 w / v%. Viscosity enhancement selected from hydroxypropyl-gamma-cyclodextrin, about 0.8 w / v% to about 1.2 w / v% hydroxypropyl methyl cellulose and about 1 w / v% to about 1.4 w / v% carboxymethyl cellulose. Agent, about 0.75 w / v% polyethylene glycol 400, about 0.5 w / v% to about 0.75 w / v% mannitol, about 0.6 w / v% to about 0.7 w / v% sodium chloride , And menthol at a concentration of about 0.1 to about 3.0 mmol, preferably about 0.1 to about 0.2 mmol or about 2.0 to about 3.0 mmol, and optionally about 0. .1 w / v% ethylenediaminetetraacetic acid, optionally about 0.1 w / v% ethylenediaminetetraacetic acid, optionally about 0.1 w / v% to about 0.12 w / v% sorbate, And optionally, an artificial tear solution composition comprising a phosphate buffer solution having a concentration of about 4 mmol, having a pH of about 6 to about 6.5.

AQus ™ CL-Tears is a component and concentration:
3.0% polysorbate 80
0.10% poloxamer 188
0.01% polio castor oil 0.50% HPMC
0.5% to 2.5% mannitol (preferably 1.0%)
0.10% MgCl ₂
0.1% to 0.75%, preferably 0.2% to 0.5% NaCl
Optionally, a composition comprising 1.0% glycerin 2-3 mM phosphate buffer.
pH 7.0
Can represent the composition of.

AQus ™ CL-Tears also has ingredients and concentrations:
0.0% -1.5% polysorbate 80
0.10% poloxamer 188
0.01% polyoxyl castor oil 1.5% -3.0% hydroxypropyl-gamma-cyclodextrin 0.50% HPMC
0% to 2.5% mannitol (preferably 1.0%)
0% to 0.10% MgCl ₂
0.1% to 0.75%, preferably 0.2% to 0.5% NaCl
Optionally, a composition comprising 1.0% glycerin 2-3 mM phosphate buffer.
pH 7.0
The composition of can also be represented.

AQus ™ CL-Tears can also represent the compositions in Table 3.

AQus ™ Tears Plus can represent the compositions in Table 4.

AQus ™ Tears Advanced can represent the compositions in Table 5.

AQus ™ Tears Advanced Plus or AQus ™ Tears Extreme can represent the compositions in Table 6.

AQus ™ Tears MGD can represent the compositions in Table 7.

In a preferred embodiment, the artificial tears composition of the invention was Pemulen® (Pemulen was a registered trademark of BF Goodrich Company for Polymer Emulsifiers, but is now Lubrizol. It does not contain polyacrylates such as (owned by Advanced Materials, Inc. and available from it). Pemulen® materials include high molecular weight copolymers of acrylic acid and long chain alkyl methacrylate crosslinked with acrylate / C10-30 alkyl acrylate crosspolymer or allyl ether of pentaerythritol.

Contact Lens Compositions In one embodiment, all artificial tears compositions of the present invention can be used as contact lens compositions.

Examples of the contact lens composition of the present invention include a contact lens preservation composition, a contact lens injection composition, and a contact lens wetting solution.

In another preferred embodiment, the contact lens preservative compositions of the invention are Optifree PureMoist®, Optifree Replenish® and Complete Moisture Plus®; Renu; Clear Care®. Registered Trademarks), Suaflon® One Step; All Comfort Formula®; Purecon® Puresoft; Members Mark® Multi-Purpose Solution; It may be combined with, but not limited to, an enhancer for available contact lens immersion solutions, or it can be used as an enhancer. These compositions can be used in blister packages.

As used herein, "available contact lens dipping solution" refers to a contact lens dipping solution that may be purchased by the end user.

When an available contact lens immersion solution such as Puremoist® or Replenish® is used as a vehicle, the contact lens preservation compositions of the present invention eliminate the addition of sodium chloride and phosphate buffers. You may.

When an available contact lens immersion solution such as Puremoist® or Replenish® is used as a vehicle for the contact lens preservation compositions of the present invention, the vehicle is in 0.9% sodium chloride. May be further diluted with. In a preferred embodiment, the vehicle is an available contact lens dipping solution of about 45% to about 55%, preferably about 45% or about 55%, and about 45% to about 55%, preferably about 45%. Or it contains about 55% 0.9% sodium chloride.

In another embodiment, the contact lens preservation composition of the invention may be diluted with 0.9% sodium chloride, preferably the diluent is from about 45% to about 55%, preferably about 45% or about. 55% of the contact lens preservative composition of the invention and about 45% to about 55%, preferably about 45% or about 55% 0.9% sodium chloride.

In one preferred embodiment, the contact lens preservation composition is:
2.0w / v% polysorbate 80,
0.2w / v% poloxamer 407,
1.0 w / v% poloxamer 188,
0.5w / v% hydroxypropyl-gamma-cyclodextrin,
1.0 w / v% mannitol,
0.1w / v% or 0.2w / v% hydroxypropylmethylcellulose,
0.1w / v% magnesium chloride,
Contains 0.35 w / v% sodium chloride and 3 mM phosphate buffer.
It is used to soak contact lenses and is sold under the trade names Oasis®, Accuvue® or AirOptix® Aqua.

In one preferred embodiment, the contact lens preservation composition is:
3.0w / v% polysorbate 80,
0.2w / v% poloxamer 407,
0.1w / v% or 0.2w / v% poloxamer 188,
0.01w / v% polio castor oil,
1.0 w / v% mannitol,
0.1w / v% or 0.2w / v% hydroxypropylmethylcellulose,
Contains 0.1 w / v% magnesium chloride and 0.3 w / v% sodium chloride.
Further includes a contact lens immersion solution under the trade name Puremoist® or Replenish®.

In another embodiment, the invention
The step of immersing the monovision contact lens in the composition of the present invention,
A method of improving distance vision in a contact lens wearer, comprising the step of inserting the monovision contact lens into the eye of the contact lens wearer.
The distance vision of the contact lens wearer is improved as compared to the distance vision of the contact lens wearer after inserting the monovision contact lens that was not immersed in the composition of the present invention.
Regarding the method.

As used herein, Optifree PureMoist® is sodium citrate, sodium chloride, boric acid, sorbitol, aminomethylpropanol, EDTA disodium, and two wetting agents (TETRONIC® 1304). And HydraGlyde Moisture Matrix [EOBO-41-polyethylene-polybutylene]) in a sterile buffered state containing 0.001% POLYQUAD (polyquaternium-1) and 0.0006% ALDOX (myristamidopropyldimethylamine) preservatives. Refers to the aqueous solution. HydraGlyde Moisture Matrix is a proprietary polyfunctional copolymer designed primarily for moistening and smoothing silicone hydrogel lenses.

As used herein, Optifree PureMoist® is a dual action readjustment system (TETRONIC® 1304, nonanoyl) exclusively for sodium citrate, sodium chloride, sodium borate, propylene glycol, TEAGLYDE. Ethylenediamine triacetic acid) refers to a sterile buffered isotonic aqueous solution containing 0.001% POLYQUAD (polyquaternium-1) and 0.0005% ALDOX (myristamidopropyldimethylamine) preservatives.

As used herein, Renu Clear Care® contains 3% precision filtered sodium chloride, 0.79% phosphoric acid-stabilized sodium chloride, a phosphate buffering system and PLURONIC 17R4. Refers to the sterile solution contained.

As used herein, Biotrue® contains a double disinfection system (polyaminopropyl biguanide) containing hyaluronan, sulfobetaine, poroxamine, boric acid, sodium borate, disodium edetate and sodium chloride. Refers to a sterile isotonic solution stored at 0.00013% and 0.0001% polyquaternium.

As used herein, Complete® is stored in polyhexamethylene biguanide (0.0001%), phosphate buffer, poroxamar 237, disodium edetate, sodium chloride, potassium chloride and purified water. Refers to a sterile, isotonic, buffered solution.

In another more preferred embodiment, the artificial tears composition described herein further comprises the ability to clean contact lenses.

The present invention
It is selected from the group consisting of polysorbate 80, polyoxyl, poloxamer 407, poloxamer 188, polyoxyl castor oil, and hydroxypropyl-gamma-cyclodextrin, and has a total concentration of about 1.5 w / v% to about 5.9 w / v%. Two or more nonionic surfactants,
About 0.1 w / v% to about 0.4 w / v% polyol,
A contact lens preservative composition comprising a cellulose derivative, carbomer, gum, dextran, polyvinyl alcohol, polyacrylic acid, povidone, polyethylene glycol, propylene glycol, chitosan, and a viscous agent selected from the group consisting of hyaluronate and hyaluronic acid. There,
With a viscosity of about 5 to about 500 centipores,
Further related to contact lens preservation compositions.

The present invention
It is selected from the group consisting of polysorbate 80, polyoxyl, poloxamer 407, poloxamer 188, polyoxyhimashi oil, and hydroxypropyl-gamma-cyclodextrin, and has a total concentration of about 1.5 w / v% to about 5.9 w / v%. Two or more nonionic surfactants, preferably the two or more nonionic surfactants are about 0.01 w / v% to about 4.0 w / v% polysorbate 80, about. 0.01w / v% to about 3.0w / v% poloxamer 407, about 0.01w / v% to about 3.0w / v% poloxamer 188, about 0.01w / v% to about 0.25w / Selected from the group consisting of v% polyoxamer castor oil and about 0.01 w / v% to about 5.0 w / v% hydroxypropyl-gamma-cyclodextrin.
About 0.5 w / v% to about 2.5 w / v% mannitol,
Cellulose derivatives of about 0.05 w / v% to about 1.5 w / v%, preferably about 0.05 w / v% to about 0.37 w / v% carboxymethyl cellulose.
Further relating to a contact lens preservative composition comprising from about 0.1 w / v% to about 0.75 w / v% sodium chloride and about 0.1 w / v% magnesium chloride.

The present invention
Approximately 3.0 w / v% polysorbate 80,
Approximately 0.2 w / v% poloxamer 407,
Approximately 0.1 w / v% poloxamer 188,
Approximately 1.0 w / v% mannitol,
Approximately 0.1 w / v% magnesium chloride,
Approximately 0.25w / v% to approximately 0.4w / v% sodium chloride,
With the total viscosity of the composition imparted by about 0.1 w / v% to about 0.25 w / v% hydroxypropylmethyl cellulose, or about 0.1 w / v% to about 1.5 w / v% hydroxypropylmethyl cellulose. Cellulose derivatives with concentrations that produce the total viscosity of equal compositions,
Further related to a contact lens preservation composition comprising a phosphate buffer solution having a concentration of 3 mmol.

The present invention
Selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin, with a total concentration of about 1.5 w / v% to about 5.9 w / v%, 2 More than a species of nonionic surfactant,
About 0.1 w / v% to about 2.5 w / v% mannitol,
Cellulose derivatives of about 0.1 w / v% to about 2.0 w / v%, preferably about 0.05 w / v% to about 0.37 w / v% carboxymethyl cellulose.
Phosphate or citric acid buffer at a concentration of about 3.0 to about 5.5 mmol,
Optionally, about 0.1 w / v% to about 0.3 w / v% magnesium chloride,
Optionally, about 0.25 w / v% to about 5.0 w / v% polyethylene glycol, propylene glycol, or a combination thereof.
Optionally comprising about 0.1 w / v% to about 0.75 w / v% sodium chloride, and optionally about 0.1 w / v% to about 0.12 w / v% sodium chloride. Further related to contact lens coating compositions.

The present invention
About 2.0 w / v% to about 3.5 w / v% polysorbate 80, about 0.1 w / v% to about 0.2 w / v% poloxamer 407, about 0.1 w / v% to about 0.5 w Selected from the group consisting of / v% poloxamer 188, about 0.01 w / v% polyoxyl castor oil, and about 0.25 w / v% to about 1.5 w / v% hydroxypropyl-gamma-cyclodextrin. , Two or more nonionic surfactants, with a total concentration of about 1.5 w / v% to about 5.9 w / v%.
Phosphate or citric acid buffer at a concentration of about 3.0 to about 5.5 mmol,
About 0.1 w / v% to about 2.5 w / v% mannitol,
Approximately 0.1 w / v% magnesium chloride,
Optionally, about 0.25 w / v% to about 0.45 w / v% sodium chloride,
Cellulose derivatives of about 0.1 w / v% to about 0.75 w / v%, preferably about 0.05 w / v% to about 0.37 w / v% carboxymethyl cellulose.
And optionally further to contact lens preservation compositions comprising about 0.1 w / v% sorbate.

The present invention
Approximately 3.0 w / v% polysorbate 80,
Approximately 0.2 w / v% poloxamer 407,
Approximately 0.2 w / v% poloxamer 188,
Approximately 0.01 w / v% polio castor oil,
Approximately 1.0 w / v% mannitol,
Approximately 0.1 w / v% magnesium chloride,
About 0.3w / v% sodium chloride,
A concentration that yields a total viscosity of the composition equal to the total viscosity of the composition imparted with about 0.1 w / v% or 0.2 w / v% hydroxypropylmethyl cellulose, or about 0.1 w / v% hydroxypropylmethyl cellulose. Further relates to a contact lens preservation composition comprising a cellulose derivative of the above, and a phosphate buffer solution having a concentration of 3 mmol.

The present invention
Approximately 1.0 w / v% polysorbate 80,
Approximately 1.0 w / v% poloxamer 407,
Approximately 0.2 w / v% poloxamer 188,
Approximately 0.25 w / v% polio castor oil,
Carboxymethyl cellulose from about 0.05 w / v% to about 0.37 w / v%,
Polyethylene glycol of about 0.5 w / v% to about 1.75 w / v%, selected from the group consisting of polyethylene glycol 400, polyethylene glycol 6000, polyethylene glycol 10000, polyethylene glycol 20000, and combinations thereof.
Approximately 0.75 w / v% mannitol,
Approximately 0.1 w / v% magnesium chloride,
About 0.4 w / v% to about 0.9 w / v% sodium chloride,
Phosphate buffer at 3 mmol concentration,
Optionally, a contact lens preservative composition comprising about 1.5 w / v% hydroxypropyl-gamma-cyclodextrin and optionally about 0.1-to about 0.2 mmol menthol. Regarding.

All contact lenses and artificial tears compositions of the present invention may contain either a 3 mmol phosphate buffer or a 4 mmol citrate buffer with 0.1 w / v% sorbate. ..

In a preferred embodiment, the contact lens compositions of the invention do not contain a Pemulen® material containing a polyacrylate, eg, an acrylate / C10-30 alkyl acrylate crosspolymer, or acrylic acid and pentaerythritol. It does not contain high molecular weight copolymers of allyl ethers and crosslinked long chain alkyl methacrylates.

Drug Vehicle In one embodiment, all artificial tears compositions of the present invention can be used as drug vehicle compositions.

The present invention
Preferred are diquafosol, antibiotics, steroidal anti-inflammatory agents, non-steroidal anti-inflammatory agents, glaucoma agents, prostaglandins, muscarinic receptor stimulants, pupillary constrictors, acetylsalicylic acid (“ASA”), and combinations thereof. An activator selected from the group consisting of, more preferably, the activator is diquafosol, bimatoprost, cyclosporin-A, GLC, prednisolone forte, ketrolac, gentamicin, polytrim, ciprofloxacin, moxyfloxacin, Selected from the group consisting of gatifloxacin, refitegrasto, vesifloxacin, pyrocarpine, brimonidine, timolol, dexmedetomidin, thymoptic, dolsolamide, latanoprost, and combinations thereof.
Approximately 2.0 w / v% polysorbate 80,
Approximately 1.0 w / v% poloxamer 188,
Approximately 1.0 w / v% hydroxypropyl-gamma-cyclodextrin,
HPMC of about 1.35w / v%,
Approximately 2.5 w / v% mannitol,
Approximately 0.10 w / v% magnesium chloride,
Of about 0.30 w / v% sodium chloride, and about 3 mmol concentration of citric acid buffer, and about 0.005% to 0.02% BAK, 0.10% EDTA and 0.10% sorbate. A drug vehicle composition comprising a combination of one or more optional preservatives of the above.
Has a pH of about 5.0,
Further on the drug vehicle composition.
This latter combination of preservatives and antioxidants demonstrated an enhancement of anterior chamber permeability and a period of time to achieve greater clinical benefit in some cases.

The present invention
Activator,
It is selected from the group consisting of poroxamar, polysorbate, cyclodextrin, alkylarylpolyether, polyoxyethylene glycol alkylether, tyloxapol, and polyoxyl, and has a total concentration of about 1.5 w / v% to about 5.9 w / v%. One or more nonionic surfactants, about 0.5 w / v% to about 5 w / v% hydroxypropylmethyl cellulose (hypromerose), or cellulose derivatives, carbomer, gum, dextran, polyvinyl alcohol, polyacrylic acid, With the total viscosity of the composition selected from the group consisting of povidone, polyethylene glycol, propylene glycol, chitosan, and hyaluronate and hyaluronic acid and imparted with about 0.5w / v% to about 5w / v% hydroxypropylmethylcellulose. An amount of viscous agent that produces the total viscosity of the same composition,
Approximately 2.5 w / v% mannitol,
Approximately 0.10 w / v% magnesium chloride,
About 0.20 w / v% to about 0.30 w / v% sodium chloride,
A drug vehicle gel composition comprising citric acid or phosphate buffer at a concentration of about 3 mmol, and optionally menthol at a concentration of about 0.07 mmol to about 0.2 mmol.
Have a pH of at least 5.0,
Further related to the drug vehicle gel composition.

The present invention
Cyclosporine-A of about 0.05 w / v% to about 2.0 w / v%, preferably about 0.05 w / v% to about 0.09 w / v%,
A combination of Captisol®, β-cyclodextrin, or Tween®, β-cyclodextrin of about 1 w / v% to about 5 w / v%, preferably about 3 w / v% to about 4 w / v%. ,
Optionally, about 0.25 w / v% polyoxyl 40 castor oil,
Optionally, it is an alcohol of about 0.1 w / v% to about 1 w / v%, preferably about 0.5 w / v% to about 1 w / v%, preferably the alcohol is polyvinyl alcohol, glyco. Selected from the group consisting of flor, octoxinol 40, and combinations thereof,
Optionally, a composition imparted by about 0.5 w / v% to about 1.25 w / v% hydroxypropylmethyl cellulose, or about 0.5 w / v% to about 1.25 w / v% hydroxypropylmethyl cellulose. Carboxymethyl cellulose at a concentration that produces the total viscosity of the composition equal to the total viscosity of the object,
Optionally, about 0.1 w / v% to about 0.9 w / v%, preferably about 0.3 w / v% sodium chloride,
Optionally, about 0.5 w / v% to about 2.5 w / v% mannitol,
Optionally, about 0.1 w / v% magnesium chloride,
Optionally, a phosphate buffer solution at a concentration of about 3 mmol or a citrate buffer solution at a concentration of about 4 mmol,
A drug vehicle composition optionally comprising about 0.1 w / v% sorbate and optionally about 0.1 mmol concentration of menthol.
Optionally, having a pH of about 7.0,
Further on the drug vehicle composition.

The present invention
Approximately 0.09 w / v% cyclosporine-A,
Poloxamer 407, from about 3.0 w / v% to about 4.0 w / v%,
Approximately 0.25 w / v% sodium chloride,
About 0.2 w / v% or about 0.75 w / v% hydroxypropylmethyl cellulose,
Phosphate buffer at about 3 mmol or citric acid buffer at about 4 mmol,
Optionally, about 1.0 w / v% polysorbate 80,
Optionally, about 0.01 w / v% polio castor oil,
Optionally, about 0.1 w / v% sorbate,
Optionally, a drug vehicle composition comprising menthol at a concentration of about 0.1 mmol.
Has a pH of about 7.0,
Further on the drug vehicle composition.

The present invention
About 0.01 w / v% to about 2.0 w / v%, preferably about 0.05 w / v% to about 0.09 w / v%, more preferably about 0.05 w / v%, about 0.075 w / v% or about 0.09 w / v% cyclosporine-A,
About 1.0 w / v% to about 5.0 w / v%, preferably about 1.0 w / v% to about 4.0 w / v%, more preferably about 1.0 w / v% to about 1.5 w / v% polysorbate 80,
About 0.1 w / v% to about 2.0 w / v%, preferably about 0.5 w / v% to about 0.7 w / v%, more preferably about 0.5 w / v% or about 0.7 w / v%. v% poloxamer 407,
About 0.1 w / v% to about 2.0 w / v%, preferably about 0.5 w / v% to about 1.5 w / v%, more preferably about 1.0 w / v% poloxamer 188.
About 0.001 w / v% to about 1.0 w / v%, preferably about 0.005 w / v% to about 0.01 w / v%, and even more preferably about 0.01 w / v% polio castor oil. ,
About 0.5 w / v% to about 4.0 w / v%, preferably about 0.5 w / v% to about 3.0 w / v%, more preferably about 0.5 w / v% to about 2.5 w / v% mannitol,
About 0.05 w / v% to about 0.1 w / v%, more preferably about 0.05 w / v% magnesium chloride,
About 0.1 w / v% to about 2.0 w / v%, preferably about 0.5 w / v% to about 1.35 w / v% hydroxypropylmethyl cellulose,
About 0.1 w / v% to about 0.5 w / v%, preferably about 0.25 w / v% polyethylene glycol 400 (“PEG-400”),
About 0.0 w / v% to about 0.9 w / v%, preferably about 0.1 w / v% to about 0.40 w / v% sodium chloride,
Phosphate buffer at about 3 mmol or citric acid buffer at about 4 mmol,
About 0.05 w / v% to about 2 w / v%, preferably about 0.10 w / v% sorbate,
Optionally, menthol at a concentration of about 0.07 to about 0.3 mmol, and optionally one or more of about 0.005% to 0.02% BAK and 0.10% EDTA. A drug vehicle composition comprising a combination of preservatives of
Has a pH of about 7.0,
Further on the drug vehicle composition.

The present invention
Optionally, diquafosol from about 3.0 w / v% to about 3.5 w / v%, preferably about 3.0 w / v% or about 3.37 w / v%.
It is preferably selected from the group consisting of polysorbate, poloxamer, polyoxylhime oil and cyclodextrin, and more preferably selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxylhimashi oil and hydroxypropyl-gamma-cyclodextrin. One or more nonionic surfactants of about 2.0 w / v% to about 6.0 w / v%,
Polyethylene glycol having a molecular weight of about 400 to about 20,000 daltons, from about 0.5 w / v% to about 0.75 w / v%,
About 0.75 w / v% to about 3.0 w / v% mannitol,
Approximately 0.1 w / v% magnesium chloride,
Carboxymethyl cellulose from about 1.1 w / v% to about 1.45 w / v%,
About 0.4 w / v% to about 1.25 w / v% sodium chloride,
Phosphate buffer with a concentration of about 3 mmol or citrate buffer with a concentration of about 4-5 mmol,
About 0.1w / v% to about 0.12w / v% solve,
Optionally, a concentration of about 0.1 to about 5.0 mmol, preferably a concentration of about 0.2 to about 2.5 mmol, more preferably a concentration of about 0.2 to about 1.6 mmol, most preferably about. A drug vehicle composition comprising menthol at a concentration of 0.1 to about 0.45 mmol and optionally about 2.0 w / v% hydroxypropyl-gamma-cyclodextrin.
It has a pH of about 5.5 to about 7.0,
Further on the drug vehicle composition.

The present invention
About 3.0w / v% Diquafosol,
Approximately 3.00 w / v% polysorbate 80,
Approximately 0.75 w / v% polyethylene glycol 400,
Approximately 1.50 w / v% mannitol,
Approximately 0.1 w / v% magnesium chloride,
Approximately 1.40 w / v% carboxymethyl cellulose,
Approximately 0.90 w / v% sodium chloride,
Menthol at a concentration of about 0.5 mmol,
Citric acid buffer, about 4 mmol concentration,
Further to the drug vehicle composition comprising about 1.0 w / v% sorbate and about 2.0 w / v% hydroxy-propyl-gamma-cyclodextrin.

The present invention
Optionally, about 1.0 w / v% to about 1.5 w / v% trehalose,
One or more nonionic surfactants of about 2.0 w / v% to about 6.0 w / v%, preferably the one or more nonionic surfactants are polysorbate, poloxamer, polyoxyl. It is selected from the group consisting of castor oil and cyclodextrin, more preferably selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl castor oil and hydroxypropyl-gamma-cyclodextrin, preferably about 1.00 w /. Includes v% polysorbate 80, about 1.00 w / v% poloxamer 407, about 0.20 w / v% poloxamer 188 and about 0.25 w / v% polyoxyl castor oil.
Polyethylene glycol having a molecular weight of about 400 to about 20,000 daltons, from about 0.50 w / v% to about 1.50 w / v%.
About 0.50 w / v% to about 0.75 w / v% mannitol,
Approximately 0.07 w / v% to approximately 0.10 w / v% magnesium chloride,
Citric acid buffer with a concentration of about 2.5 to about 6.0 mmol,
Optionally, about 0.1 w / v% to about 1.30 w / v% carboxymethyl cellulose,
Optionally, about 0.4 w / v% to about 0.65 w / v% sodium chloride,
Optionally, menthol at a concentration of about 0.1 to about 0.45 mmol,
Optionally, a drug vehicle composition comprising about 0.12 w / v% sorbate.
It has a pH of about 5.5 to about 6.5,
Further on the drug vehicle composition.

The present invention
Cyclosporin-A of about 0.05 w / v% to about 0.09 w / v%, preferably 0.05 w / v%, 0.075 w / v% or 0.09 w / v%,
Polysorbate 80 of about 1.0 w / v% to about 3.5 w / v%, preferably 1.5 w / v% or 3.5 w / v%,
About 0.5 w / v% to about 0.7 w / v%, preferably about 0.7 w / v% poloxamer 407,
Approximately 1.0 w / v% poloxamer 188,
About 0.01 w / v% to about 0.75 w / v% polio castor oil, preferably about 0.01 w / v% polio castor oil,
Approximately 1.75 w / v% to approximately 2.5 w / v% mannitol,
Approximately 0.05 w / v% to approximately 0.1 w / v% magnesium chloride,
About 0.5w / v% to about 1.35w / v%, preferably about 1.25w / v% to about 1.35w / v%, more preferably about 0.5w / v%, 0.75w / v. %, 0.85 w / v%, 1.0 w / v%, 1.25 w / v% or 1.35 w / v% hydroxypropylmethyl cellulose,
Approximately 0.25 w / v% sodium chloride,
Phosphate buffer at about 3 mmol or citric acid buffer at about 4 mmol,
Optionally, menthol at a concentration of about 0.02 to about 0.09 mmol, preferably about 0.02, 0.04, 0.06 or 0.09 mmol.
Optionally, a drug vehicle composition comprising a combination of about 0.005% to 0.02% BAK, 0.10% EDTA and one or more preservatives out of 0.10% sorbate. hand,
Has a pH of about 7.0,
Further on the drug vehicle composition.

The present invention
About 0.1 w / v% to about 1 w / v%, preferably 0.5 w / v% ketrolactromethamine,
Polysorbate 80, from about 1.0 w / v% to about 3.5 w / v%, preferably 1.5 w / v% or 3.5 w / v%,
About 0.5 w / v% to about 0.7 w / v%, preferably about 0.7 w / v% poloxamer 407,
Approximately 1.0 w / v% poloxamer 188,
About 0.01 w / v% to about 0.75 w / v% polio castor oil, preferably about 0.01 w / v% polio castor oil,
Approximately 1.75 w / v% to approximately 2.5 w / v% mannitol,
Approximately 0.05 w / v% to approximately 0.1 w / v% magnesium chloride,
About 0.5w / v% to about 1.35w / v%, preferably about 1.25w / v% to about 1.35w / v%, more preferably about 0.5w / v%, 0.75w / v. %, 0.85 w / v%, 1.0 w / v%, 1.25 w / v% or 1.35 w / v% hydroxypropylmethyl cellulose,
Approximately 0.25 w / v% sodium chloride,
Phosphate buffer at about 3 mmol or citric acid buffer at about 4 mmol,
Optionally, menthol at a concentration of about 0.02 to about 0.09 mmol, preferably about 0.02, 0.04, 0.06 or 0.09 mmol, and optionally about 0.005. A drug vehicle composition comprising a combination of one or more of a preservative of% to 0.02% BAK, 0.10% EDTA and 0.10% sorbate.
Has a pH of about 7.0,
Further on the drug vehicle composition.

The present invention
Approximately 0.09 w / v% cyclosporine-A,
Approximately 3.5 w / v% polysorbate 80,
Approximately 0.25 w / v% sodium chloride,
Optionally, about 0.7 w / v% poloxamer 407,
Optionally, about 1.0 w / v% poloxamer 188,
Optionally, about 2.5 w / v% mannitol,
Optionally, about 0.5 w / v% hydroxypropylmethyl cellulose,
Phosphate buffer at about 3 mmol or citric acid buffer at about 4 mmol,
Optionally, menthol at a concentration of about 0.07 mmol, and optionally, one of about 0.005% to 0.02% BAK, 0.10% EDTA and 0.10% sorbate. A drug vehicle composition comprising the above combinations of preservatives.
Has a pH of about 7.0,
Further on the drug vehicle composition.

In a preferred embodiment, the ratio of cyclosporine-A to polyoxyl castor oil is greater than 0.08: 1, more preferably about 10: 1 to about 9: 1, and even more preferably about 5: 1 to about 9. It is 1.

The present invention
Approximately 0.06 w / v% dexmedetomidine,
Approximately 3.5 w / v% polysorbate 80,
Approximately 0.7 w / v% poloxamer 407,
Approximately 1.0 w / v% poloxamer 188,
Approximately 0.01 w / v% polio castor oil,
Approximately 2.5 w / v% mannitol,
Approximately 0.1 w / v% magnesium chloride,
Approximately 1.25 w / v% hydroxypropylmethyl cellulose,
A drug vehicle composition comprising about 0.25 w / v% sodium chloride and a phosphate buffer solution at a concentration of about 3 mmol.
Has a pH of about 7.0,
Further on the drug vehicle composition.

The present invention
Effective amount of Refite Glast,
Approximately 3.5 w / v% polysorbate 80,
Approximately 0.7 w / v% poloxamer 407,
Approximately 1.0 w / v% poloxamer 188,
Approximately 0.01 w / v% polio castor oil,
About 0.65 w / v% to about 1.25 w / v%, preferably 0.65 w / v%, 0.85 w / v%, 1.0 w / v% or 1.25 w / v% hydroxypropylmethyl cellulose,
Approximately 2.5 w / v% mannitol,
A drug vehicle composition comprising about 0.1 w / v% magnesium chloride and about 3 mM phosphate buffer.
Has a pH of about 7.0,
Further on the drug vehicle composition.

The present invention
Approximately 0.09 w / v% cyclosporine-A,
Further relating to the drug vehicle composition comprising about 4 w / v% polysorbate 80 and about 0.01 w / v% polio castor oil.

The present invention
Approximately 0.09 w / v% cyclosporine-A,
Approximately 3.5 w / v% polysorbate 80,
Further relating to the drug vehicle composition comprising about 4.0 w / v% poloxamer 407 and about 0.01 w / v% polio castor oil.

The present invention
Further related to the drug vehicle composition comprising about 0.09 w / v% cyclosporin-A and about 0.5% glycoflor.

The present invention
About 1.0w / v% ASA,
Approximately 3.5 w / v% polysorbate 80,
Approximately 0.7 w / v% poloxamer 407,
Approximately 1.0 w / v% poloxamer 188,
Approximately 0.01 w / v% polio castor oil,
Approximately 2.5 w / v% mannitol,
Approximately 0.25 w / v% sodium chloride,
Approximately 0.1 w / v% magnesium chloride,
Approximately 1.25 w / v% hydroxypropylmethyl cellulose,
Phosphate buffer at about 3 mmol or citric acid buffer at about 4 mmol,
A pharmaceutical vehicle composition comprising about 1.0 w / v% polyethylene glycol 400 and about 0.12 w / v% sorbate.
It has a pH of about 7.0 and is optionally due to MGD or allergies.
Further on the drug vehicle composition.

The present invention
About 5.0w / v% ASA,
Approximately 3.5 w / v% polysorbate 80,
Approximately 0.7 w / v% poloxamer 407,
Approximately 1.0 w / v% poloxamer 188,
Approximately 0.01 w / v% polio castor oil,
Approximately 2.5 w / v% mannitol,
Approximately 0.25 w / v% sodium chloride,
Approximately 0.1 w / v% magnesium chloride,
Approximately 1.25 w / v% hydroxypropylmethyl cellulose,
Phosphate buffer at about 3 mmol or citric acid buffer at about 4 mmol,
A pharmaceutical vehicle composition comprising about 1.0 w / v% polyethylene glycol 400 and about 0.12 w / v% sorbate.
It has a pH of about 7.0 and is optionally due to acne.
Further on the drug vehicle composition.

The present invention comprises, in the composition of the invention, about 5.0 w / v% to about 10 w / v% ASA, and optionally about 1 w / v% to about 10 w / v% benzoyl peroxide. Alternatively, further relates to a drug vehicle composition comprising octinol comprising octinol 11 or 309.

The present invention
Preferably, it is an active agent selected from the group consisting of antibiotics, steroid anti-inflammatory, non-steroidal anti-inflammatory, glaucoma drugs, prostaglandins, muscarinic receptor stimulants, diploid drugs, acetylsalicylic acid, and combinations thereof. More preferably, the active agent is bimatoprost, cyclosporin-A, GLC, prednisolone forte, ketrolac, gentamicin, polytrim, ciprofloxacin, moxyfloxacin, gatifloxacin, refitegrast, vesifloxin, pyrocarpine, brimonidine. , Timorol, Dexmedetomidin, Timoptic, Dorzolamide, Latanoprost, and combinations thereof.
Selected from the group consisting of poloxamers, polysorbates, cyclodextrins, alkylarylpolyethers, polyoxyethylene glycol alkylethers, tyroxapols and polyoxyls, with a total concentration of about 1.5w / v% to about 5.9w / v%. One or more nonionic surfactants, preferably about 2.0 w / v% polysorbate 80, about 1.0 w / v% poloxamer 188 and about 1.0 w / v% hydroxypropyl-gamma-cyclo. dextrin,
About 0.5 w / v% to about 20 w / v%, preferably about 0.5 w / v% to about 10 w / v%, and even more preferably about 0.5 w / v% to about 5.0 w / v%. HPMC,
Approximately 2.5 w / v% mannitol,
Approximately 0.10 w / v% magnesium chloride,
About 0.2 w / v% to about 0.30 w / v% sodium chloride,
Citric acid or phosphate buffer at a concentration of about 3 mmol, and optionally about 0.01 w / v% to about 0.12 w / v% sorbate, about 0.01 w / v% to about 0.12 w /. One or more excipients selected from v% EDTA and about 0.005% to about 0.02% benzalkonium chloride.
A drug vehicle gel composition comprising:
Has a pH of about 5.0,
Further related to the drug vehicle gel composition.

The present invention relates to brimonidine from about 0.0075 w / v% to about 0.02 w / v%, preferably about 0.015 w / v% to about 0.02 w / v%, and poloxamers, polysorbates, cyclodextrins, alkylaryls. One or more nonionic surfactants selected from the group consisting of polyethers, polyoxyethylene glycol alkyl ethers, tyroxapols, and polyoxyls having a total concentration of about 1.5 w / v% to about 5.9 w / v%. Addition to a drug vehicle gel composition comprising an agent, preferably about 2.0 w / v% polysorbate 80, about 1.0 w / v% poloxamer 188 and about 1.0 w / v% hydroxypropyl-gamma-cyclodextrin. Regarding.

The present invention further relates to compositions comprising one or more nonionic surfactants and at least one excipient selected from the group consisting of one or more viscosity enhancers, polyols and electrolytes. Micelle with an average diameter of 12 to about 20 nanometers, preferably about 15 to about 20 nanometers, more preferably about 16 nanometers is formed.

The present invention relates to bimatoprost, cyclosporin-A, GLC, prednisolone forte, ketrolac, gentamicin, polytrim, ciprofloxacin, moxyfloxacin, gatifloxacin, refiteglast, vesifloxacin, pyrocarpine, brimonidine, thymorol, dexmedetomidin, An activator selected from the group consisting of tymoptic, dorzolamide, latanoprost, acetylsalicylic acid, and combinations thereof, preferably cyclosporine-A, one or more nonionic surfactants, and one or more viscosity enhancers, polyols. And a composition comprising at least one excipient selected from the group consisting of electrolytes, of about 12 to about 20 nanometers, preferably about 15 to about 20 nanometers, more preferably about 16 nanometers. Micelle with average diameter is formed.

In a preferred embodiment, the drug vehicle composition of the invention is a polyacrylate, eg, a Pemulen® material containing an acrylate / C10-30 alkyl acrylate crosspolymer, or an acrylic crosslinked with allyl ether of pentaerythritol. It does not contain high molecular weight copolymers of acid and long chain alkyl methacrylate.

Lidocaine gel composition In one embodiment, the present invention relates to a topical lidocaine gel composition for ophthalmology, which comprises lidocaine or a salt thereof and magnesium chloride.

In a preferred embodiment, the lidocaine is lidocaine hydrochloride.

In another preferred embodiment, lidocaine or a salt thereof has a concentration of about 1 w / v% to about 5 w / v%.

In another preferred embodiment, the invention further comprises one or more excipients selected from the group consisting of nonionic surfactants, polyethylene glycol, mannitol, carboxymethyl cellulose and sodium chloride.

In another preferred embodiment, magnesium chloride is from about 0.01 w / v% to about 0.5 w / v%.

In another preferred embodiment, the nonionic surfactant is polysorbate 80.

In another preferred embodiment, the polysorbate 80 has a concentration of about 1.5 w / v% to about 5.9 w / v%.

In another preferred embodiment, polyethylene glycol having a molecular weight of about 400 to about 20,000 daltons includes polyethylene glycol 400 and polyethylene glycol 20000. Preferably, polyethylene glycol has a concentration of about 0.1 w / v% to about 5 w / v%.

In another preferred embodiment, mannitol has a concentration of about 0.1 w / v% to about 5 w / v%.

In another preferred embodiment, carboxymethyl cellulose has a concentration of about 1 w / v% to about 5 w / v%.

In another preferred embodiment, sodium chloride has a concentration of about 0.1 w / v% to about 2 w / v%.

In a preferred embodiment, the invention relates to an ophthalmic topical lidocaine gel composition comprising lidocaine or a salt thereof, magnesium chloride, a nonionic surfactant, polyethylene glycol, mannitol, a viscosity enhancer and sodium chloride.

In another preferred embodiment, the invention is described.
Lidocaine hydrochloride from about 3w / v% to about 4w / v%,
Polysorbate 80 of about 3w / v% to about 4w / v%,
Polyethylene glycol having a molecular weight of about 400 to about 20,000 daltons, from about 0.25 w / v% to about 2.5 w / v%,
It relates to an ophthalmic topical lidocaine gel composition comprising about 0.25 w / v% to about 1.5 w / v% mannitol and about 0.05 w / v% to about 0.2 w / v% magnesium chloride.

In another preferred embodiment, the invention is described.
Approximately 3.5 w / v% lidocaine hydrochloride,
Approximately 3.5 w / v% polysorbate 80,
Polyethylene glycol having a molecular weight of about 400 to about 20,000 daltons, from about 0.75 w / v% to about 1.50 w / v%.
Approximately 0.75 w / v% mannitol,
Approximately 0.1 w / v% magnesium chloride,
About 0.9w / v% to about 1.25w / v% sodium chloride,
Citric acid buffer, about 3 mmol concentration,
It relates to a topical lidocaine gel composition for ophthalmology comprising about 1.25 w / v% to about 1.50 w / v% carboxymethyl cellulose and about 0.1 w / v% sorbate.

In another preferred embodiment, the invention is described.
Approximately 3.5 w / v% lidocaine hydrochloride,
Approximately 3.5 w / v% polysorbate 80,
Approximately 0.75 w / v% polyethylene glycol 400,
Approximately 0.75 w / v% mannitol,
Approximately 0.1 w / v% magnesium chloride,
About 0.9w / v% sodium chloride,
Citric acid buffer, about 3 mmol concentration,
With respect to an ophthalmic topical lidocaine gel composition comprising about 1.25 w / v% carboxymethyl cellulose and about 0.1 w / v% sorbate.

In another preferred embodiment, the invention is described.
Approximately 3.5 w / v% lidocaine hydrochloride,
Approximately 3.5 w / v% polysorbate 80,
Approximately 0.75 w / v% polyethylene glycol 400,
Approximately 0.75 w / v% mannitol,
Approximately 0.1 w / v% magnesium chloride,
Approximately 1.25 w / v% sodium chloride,
Citric acid buffer, about 3 mmol concentration,
With respect to an ophthalmic topical lidocaine gel composition comprising about 1.40 w / v% carboxymethyl cellulose and about 0.1 w / v% sorbate.

In another preferred embodiment, the invention is described.
Approximately 3.5 w / v% lidocaine hydrochloride,
Approximately 3.5 w / v% polysorbate 80,
Approximately 1.5 w / v% polyethylene glycol 20000,
Approximately 0.75 w / v% mannitol,
Approximately 0.1 w / v% magnesium chloride,
Approximately 1.25 w / v% sodium chloride,
Citric acid buffer, about 3 mmol concentration,
With respect to an ophthalmic topical lidocaine gel composition comprising about 1.50 w / v% carboxymethyl cellulose and about 0.1 w / v% sorbate.

In another embodiment, the invention relates to a method of inducing local anesthesia in a patient's eye, comprising topically applying the composition of the invention to the patient's eye.

Methods of the Invention In conditions that can be treated by combining micelle nonionic surfactants, the discovered range (about 1.5 w / v% to about 5) for emulsion shields of Moisture-Lock ™ effect. .5w / v%) is capped by an increased risk of epithelial toxicity. Within this critical range with varying viscosities, electrolytes and preferred excipients allow a wide range of properties suitable for differentiated treatment opportunities. Opportunities for these treatments range from enhanced water and protection to more effective and potential treatments for severe eye diseases. Increased and prolonged exposure to natural tears, which may be locked by the findings herein along with long-term exposure to excipients found to be protective against the corneal epithelium, is the cornea. It can improve the currently inappropriate treatments available for eye surface disorders, especially with regard to irritation and inappropriate tear function and / or volume.

Autologous serum is often used to treat severe dry eye with greater efficacy than any other drug to date. Autologous serum consists of centrifuging the blood and removing the serum for topical application. It is believed that this plasma contains many growth factors that are particularly useful in optimizing therapeutic benefits to the eyeball surface and corneal epithelium. Induced plasma capture triggered by the nature of the discovered formulation of the invention combined with the triggering of the trigeminal nerve via TPV stimulation (terpenoids are an example of this) has great potential for alternative autologous serum. Brings therapeutic benefits. Induced plasma can be maintained on the surface longer than autologous serum and is less expensive to apply and more practical than autologous serum. Further benefits are derived from the combined discovery of tear capture and lacrimation induction, predominantly from plasma, which is the creation of the effect of alternative autologous serum.

The present invention
1) at least one nonionic surfactant from 0.2 w / v% to 7.0 w / v%, and 2) about 0.1 centipores (cps) to about 3,000 cps at 1%, 27 ° C. Further to a method for treating eye discomfort, comprising administering an artificial tear composition comprising one or more non-Newtonic viscosity enhancing excipients of a high molecular weight blend to a subject in need thereof. Regarding.

The artificial tears composition of the present invention is suitable for administration to a subject in need thereof twice, three or four times a day.

Each + refers to a disease state: early (1), moderate (2), moderate to severe (3), severe (4), extreme (5 or 5!).

As seen in Table 13, varying concentrations of viscosity enhancer and polyol provide different compositions that can serve different purposes. For example, a concentration of 0.10 w / v% viscosity enhancer and a concentration of 1.00 w / v% polyol are best for use in dry eye diseases classified as either I or II by the International DEWS Classification System. Can be suitable for. In addition, subjects with diseases that have reached severe conditions can benefit from the compositions of the invention comprising Captisol® or hydroxypropyl-gamma-cyclodextrin.

AQus ™ CL-Tears can be used to treat mild dry eye and / or contact lens dryness. AQus ™ CL-Tears is particularly useful for international dry eye workshop (“DEWS”) classifications I and II dry eye disorders. In addition, AQus ™ CL-Tears has an osmotic pressure of less than about 320 osmoles and does not cause visual blurring when instilled.

AQus ™ Tears Plus can be used to treat moderate dry eye. AQus ™ Tears Plus is particularly useful for DEWS classification III dry eye disease. In addition, AQus ™ Tears Plus has an osmotic pressure of less than about 340 osmoles, causing visual blur for about 5 seconds upon instillation.

AQus ™ Tears Advanced can be used to treat moderate to severe dry eye. AQus ™ Tears Advanced is particularly useful for DEWS Category IV dry eye disease. In addition, AQus ™ Tears Advanced has an osmotic pressure of less than about 360 osmoles, causing visual blur for about 15-30 seconds upon instillation.

AQus ™ Tears Advanced Plus and AQus ™ Tears Extreme can be used to treat moderate to severe dry eye. AQus ™ Tears Advanced Plus and AQus ™ Tears Extreme are particularly useful for DEWS classification V dry eye disease. In addition, AQus ™ Tears Advanced Plus and AQus ™ Tears Extreme have an osmotic pressure of more than about 360 osmoles, causing visual blur for about 30-60 seconds when instilled.

AQus ™ Tears MGD can be used to treat meibomian gland dysfunction (“MGD”). AQus ™ Tears MGD is particularly useful for treating dry eye diseases of DEWS classifications I-IV. In addition, AQus ™ Tears MGD has an osmotic pressure of about 300 to about 360 osmoles, causing visual blur for about 10 to 15 seconds when instilled. Finally, AQus ™ formulations specifically specified to treat DEWS classifications III-IV dry eye diseases can also be used to treat MGD.

AQus is described in PS Therapies, Ltd. It is a trademark owned by.

Example 1
Moisture-Lock ™ effect as a function of the concentration of nonionic surfactant Moisture-Lock ™ is defined by Moisture-Lock ™ Index. Moisture-Lock ™ Index calculated the duration of the moisturizing effect by a minute, multiplied by the qualitative moistness felt along the tear meniscus of the lower eyelid, and sampled at equal increments for a specific time. The period was rated from 0 to 4.0 at the maximum. Alternatively, Moisture-Lock ™ Index can calculate the duration of the moisturizing effect by multiplying it by a tear prism in millimeters, which is created as Moisture-Lock ™ Index 2. The value of the qualitative method to the quantitative method is the perception of water. Moisture is a good reasoning for the dryness that 10 million Americans are suffering from. In most cases of dry eye syndrome, the most common debilitating symptoms are the sensation of dryness and the associated burning and stinging sensations. Further symptoms include contrast intelligibility, diminished snellen intelligibility, more severe discomfort and candid pain. The lower threshold of Moisture-Lock ™ Index showing the Moisture-Lock ™ effect is 10. For example, for a 40-minute period sampled at a 10-minute increase, 10-20 Moisture-Lock ™ Index shows a slight Moisture-Lock ™ effect and 21-75 shows moderate-moderate Moisture. -Lock ™ effect is shown, 76-100 show a high Moisture-Lock ™ effect, and over 100 show a very high Moisture-Lock ™ effect. Shown in Table 14 below is the Moisture-Lock ™ Index for an increase in the total concentration of nonionic surfactant (“NIS”) from 0.0 w / v% to 7 w / v%. ..

As can be seen in Table 14 and FIG. 1, the Moisture-Lock ™ effect is the total of 5.0 w / v% nonionic surfactant with the normal distribution shown by the bell-shaped curve in FIG. It peaks around the concentration. Moreover, as seen in Table 14 and FIG. 2, the use of all nonionic surfactants of about 5.0 w / v% results in maximum Moisture-Lock ™ effect.

Example 2
Moisture-Lock ™ effect after induced lacrimation The following experiments were performed to test the enhancement of the Moisture-Lock ™ effect of the composition of the invention inducing lacrimation. The Moisture-Lock effect was measured as a period of perception of increased water content and compared to control artificial tears (Nanotears® XP). Polysorbate 1.5w / v%, poloxamer 407 0.20w / v%, poloxamer 188 1.0w / v%, hydroxypropyl-gamma-cyclodextrin 1.0w / v%; mannitol 2.5w / v%; MgCl ₂ The composition of the present invention contains 0.10 w / v%; hydroxypropylmethyl cellulose 1.30 w / v%, NaCl 0.45 w / v%, citrate buffer 3 mM; and menthol 0.07 mM and has a pH of 5.5. Two drops of the substance (“Composition S2-2”) were instilled into one eye of the first patient. Two drops of Nanotears® XP were instilled in one eye of the second patient. Moisture was quantified at 5 minute intervals for 5-50 minutes, 1-4. The results can be seen in Table 15 below.

As shown in Table 15, composition S2-2 maintained moisture for at least twice as long as Nanotears ™ XP.

Example 3
Composition for enhancing comfort and early eye drop quality X:
3.00% polysorbate 80
0.10% poloxamer 188
0.01% polio castor oil 0.50% HPMC
2.50% mannitol 0.10% MgCl ₂
0.75% NaCl
3 mM phosphate buffer pH 7.00

Method One drop of Composition X was applied to the right eye and one drop of Refresh Liquid® was applied to the left eye. After 30 minutes, the qualitative tear destruction time was calculated. We believe that qualitative studies are more meaningful in terms of assessing clinical benefit, because observing and measuring quality typically requires the addition of dyes such as fluorescein. Is. Furthermore, the purpose of measuring tear tear time is to assess when the tear film breaks and begins to form corneal marginal pits (dry spots). This test was based on a) onset of stinging sensation and b) onset of lacrimation of reflex action without blinking vs. time. Visual blurring following instillation was evaluated as the time required to read a 4-point font at 40 cm and was maintained for two blink cycles (first, blink regenerated the surface of the viscous membrane). Can cause).

Results Visual blurring in the right eye lasted 15 seconds, compared to 90 seconds in the left eye. This 6-fold reduction in visual blur was unexpected compared to the commercially available Refresh Liquigel®. The onset of stinging sensation is 4 seconds later than Refresh Liquigel®, because composition X does not induce stinging sensation until 12 seconds after instillation, compared to Refresh Liquigel®. This is because it was 8 seconds. Finally, the initiation of reactive lacrimation also did not induce reactive lacrimation until 20 seconds after instillation, as compared to 16 seconds for Refresh Liquigel®. , 4 seconds slower than Refresh Liquigel®.

Example 4
(Hypothesis) Eyelid Wipe The application of the preferred embodiment, specifically the compositions 86, 87 and 88 from Table 4 above, was applied to the eyelid wipe. Preferably, the user is first applied with a warm pack or, in some ways, heated the eyelid wipe and then rubbed violently along the edge of the eyelid in the area of the meibomian glands. An eyelid massage in the form of a swab Q-tip®, following a vigorous eyelid wipe with the composition of the invention, can be beneficial. The results, when performed prophylactically, greatly reduce incidents and are of substantial therapeutic benefit to patients with meibomian gland dysfunction (MGD). Dissolution of lipid deposits is initiated by this application of the invention, with reduced obstruction of the lacrimal gland duct.

Example 5
Reduction of Contact Lens Deposits A drop of composition # 36 from Table 2 above was placed on the surface of Air Optix® Night and Day® contact lenses and before insertion of the contact lens into the right eye. (Air Optix® Night and Day is a registered trademark of Novartis AG corporation). One contact lens was exposed to the preservation solution overnight and then rinsed with saline. The contact lens was then placed in the person's left eye.

Results As seen in Table 16 below, composition # 36 from Table 2 above reduced deposits on the surface of contact lenses much more effectively than conservative solutions. Specifically, the use of composition # 36 results in a deposit score of 0.75 out of 4 (4 is the most sediment), which is a deposit score of 2.5 out of 4. Was the opposite of the preservation solution that resulted in. See FIG. In addition, composition # 36 resulted in no stinging, burning, or dry eye sensation. Finally, composition # 36 was four times more effective than the storage solution in reduced glare halo.

Example 6
AQus ™ Thera-lens ™ Dry Eye Contact Lens Creation Composition # 36 applied to Night and Day® planano® contact lens surfaces with moderate dry eye. Applied to the right eye of a 64-year-old subject with. The left eye was given Link® artificial tears only when instilled (Blink is a registered trademark of Abbott Medical Optics Inc.). The visual test was performed with a contact lens placed in the right eye and with distance vision completely corrected with a spectacle lens in both eyes. There-lens is described in PS Therapies, Ltd. It is a trademark owned by.

result

Application of composition # 36 in Table 2 to the contact lens surface prior to instillation resulted in greater relief of dry eye symptoms than application of artificial tears alone. Although the major nonionic formulation may have been slowly released by the contact lens, the absence / reduction of deposits is due to the protective coating on the lens surface providing tear stability as described in Example 5. Most specifically, it indicates that the contact lens acted as a more permanent evaporation shield, while promoting the stability of the lipid surface tear film to which it was most shallowly exposed.

Example 7
Creation of contact lenses with nonionic surfactants bonded to a material Infused or coated with the composition of the invention or in a unique combination and concentration range of the nonionic surfactants of the invention. It is possible to create a contact lens that is one of the above. Injection or coating can be achieved using methods known in the art.

Example 8
Composition Y for enhancing tear film stability after application to contact lenses and eyes before insertion
3.00% polysorbate 80
0.10% poloxamer 188
0.01% polio castor oil 0.10% HPMC
2.50% mannitol 0.10% MgCl ₂
0.30% NaCl
3 mM phosphate buffer pH 7.00

METHODS: On day 1, an aqueous solution of physiological saline was applied to the surface of a disposable contact lens (Alcon Aqua Air Optix® Lenses) worn daily for 2 weeks, and to the eyes of a 64-year-old subject with moderate dry eye. Applied at 8 am. Contact lenses were then inserted into the eye and no other eye drops were used throughout the day. After 5 hours of wearing time, contact lenses were analyzed using Oculus Keratograph® Tear Analyzer for assessment of the rate of tear film dispersal (ie, tear film destruction time "TBUT"). At 12 hours, stimuli were determined for both eyes on a scale of 0-4 (4 is the most severe stimulus). At 14 hours of wearing time, mesopic intelligibility was analyzed on a scale of 0-4 (4 is the worst intelligibility). On the second day, the same procedure was followed except that the composition N was replaced with an aqueous physiological saline solution.

Results The tear destruction time occurred after 8 seconds for the aqueous saline solution and between 19 and 22 seconds for composition Y. Compare FIG. 3 (Saline / Refresh® CL) with FIG. 4 (Composition Y). The measured value of the area under the curve (“AUC”) (which plots the tear dispersion rate% vs. time (seconds)) is 576% seconds for saline / Refresh® CL, composition Y. Then it was 53.7% seconds. See FIG. Thus, the composition Y manifested a tear dispersion rate that was 10.72 times lower than that of Refresh® CL. The average irritation in both eyes at 12 hours was 1.5+ for saline and 0.25 for composition Y. The mesopic intelligibility at 14 hours was 1.5 glare / halo for saline and 0.5 glare / halo for composition Y. Aqueous saline solution resulted in a high sediment load, while Composition N resulted in a low sediment load. The lens could be worn for 13.5 hours with the aqueous saline solution and 18.0 hours with the composition Y. Thus, after application of the preferred embodiment of the invention, there is a significant increase in lens wearing period, reduction of contact lens deposits, and reduction of symptoms.

Example 9
Enhanced contact lenses prior to insertion and tear film stability after application to the eye Vistakon® contact lenses were immersed in composition # 74B from Table 3 above for 5 minutes. A contact lens was then inserted into the subject's eye. TBUT was measured for more than 20 seconds 5 hours after the insertion of the contact lens.

Example 10
Contact lens preservation composition

Methods Contact lenses were stored overnight in each of the compositions CL1 to CL4 in Table 9 above. The next morning, a drop of saline was instilled into each wearer's eye before inserting the contact lens. No eye drops were used for the rest of the day.

Results Overnight storage of contact lenses in blister packs filled with any of the compositions CL1-CL4 prior to insertion into the wearer's eye prolongs tear destruction time and lipid deposits. Surprisingly, I found that it brought about a decrease or absence of. For each of the compositions CL1 to CL4, 16 to 17 hours after lens removal, they were extremely friction-free and contact lens deposit-free. See Table 16 below. In addition, FIG. 6B demonstrates the absence of lipid deposits following overnight storage in composition # 59 following use throughout the day.

Example 11
Tear destruction time of contact lens composition

METHODS: The following experiments were conducted to evaluate the ability of the composition of the present invention as a contact lens solution to reduce tear destruction time with respect to an aqueous solution of physiological saline. First, Air-Optix ™ Aqua Alcon contact lenses were washed in saline 0.9w / v% NaCl solution and inserted into one eye. Air-Optix ™ Aqua Alcon contact lenses were then washed in composition # 59 and inserted into the person's eye. The tear decay time (“TBUT”) was then indirectly assessed by timing the first appearance of anomalous light diffraction of LED diodes 1 meter apart.

Results Composition # 59 shows an improvement in TBUT over saline after prolonged contact lens wear. Specifically, washing of contact lenses in composition # 59 prior to insertion into the eye resulted in a 350% longer TBUT 17 hours after insertion. These results suggest that increased bonding of the coatings of the invention as an aqueous tear film will reduce the provision of non-evaporable shielding and additional corneal surface protection.

In addition, after 24 hours of continuous wearing, Air-Optix ™ Aqua Alcon contact lenses washed in aqueous saline solution prior to insertion into the eye are manifested in FIG. 6A by an irregular opaque coating over the lens surface. It had a wide range of biofilms. In contrast, after 24 hours of continuous wearing, Air-Optix ™ Aqua Alcon contact lenses washed in composition # 59 prior to insertion into the eye had a nearly transparent lens surface, as shown in FIG. 6B. Had. This demonstrates the ability of the compositions of the invention to reduce biofilm formation.

Example 12
Contact lens storage solution

METHODS: Using a subject wearing contact lenses, tear tear time (“TBUT”” after inserting Air-Optix ™ Aqua contact lenses (right eye-5.25, left eye-2.75) into the subject's eye. ) Baseline results were measured. TBUT was measured immediately, after 15 minutes, and after 14 hours using a single-slit test without blinking. The time to destruction was recorded separately for each eye.

Two days later, a new set of the same contact lenses was opened. While leaving the contact lenses in the package, the solution in the package may be an OPTI-FREE® Multipurpose Contact Lens Solution or OPTI-FREE® Multipurpose Contact Lens Solution. The composition of the present invention in:
Approximately 3.0 w / v% polysorbate 80,
Approximately 0.2 w / v% poloxamer 407,
Approximately 0.2 w / v% poloxamer 188,
Approximately 0.01 w / v% polio castor oil,
Approximately 0.1 w / v% hydroxypropylmethyl cellulose,
Approximately 1.0 w / v% mannitol,
About 0.3w / v% sodium chloride,
Approximately 0.1 w / v% magnesium chloride,
Optionally, a phosphate buffer of about 0.1 w / v% and a phosphate buffer of about 3 mmol or a citric acid buffer of about 4 mmol.
It was replaced with the composition of the present invention having a pH of about 7.0, soaked overnight and left to stand.

OPTI-FREE® (Registered Trademark) Replenish® Multipurpose Contact Lens Solution is available from Alcon, Inc. A proprietary dual-action readjustment system (TETRONIC® 1304, nonanoylethylenediaminetetraacetic acid), available from, sodium citrate, sodium chloride, sodium borate, propylene glycol, TEAGLYDE®, A sterile buffered isotonic aqueous solution containing 0.001% POLYQUAD® (polyquaternium-1) and 0.0005% ALDOX® (myristamidopropyldimethylamine) preservatives. .. OPTI-FREE® (Registered Trademark) Puremoist® Multipurpose Contact Lens Solution is available from Alcon, Inc. Available from Sodium Citrate, Sodium Chloride, Boric Acid, Solbitol, Aminomethyl propanol, EDTA Disodium, Two Wetting Agents (TETRONIC® 1304 and HydraGlyde® Moisture Matrix [EOBO-] 41 (Registered Trademark) -Polyoxyethylene-Polyoxybutylene]) with POLYQUAD (R) (Polyquaternium-1) 0.001% and ALDOX® (Myristamidepropyldimethylamine) 0.0006% preservative. A sterile, buffered aqueous solution containing. The next morning, I inserted contact lenses. TBUT was measured immediately, 15 minutes after insertion and 14 hours after insertion.

Results TBUT after storage of Air-Optix ™ Aqua contact lenses in packaged solution was approximately 8 seconds for all time tested. After replacing the package solution of Air-Optix ™ Aqua contact lenses with the composition of the invention described above, TBUT was 8 seconds immediately after insertion, 15 seconds 15 minutes after insertion, and approximately 20 hours 14 hours after insertion. It was a second. Thus, the use of the compositions of the invention as a contact lens preservation solution results in a delay in TBUT. No deposits were found on the contact lenses stored in the composition of the present invention, whereas the commercially available packaged solutions showed 2-3 + / 4.0 densities.

Example 13
Tear Breaking Time for Additional Contact Lens Compositions Air-Optix ™ Hydraglide and Johnson & Johnson Vistakon® Accuvue® Moist Contact Lenses at Different Times Using Subjects Wearing Contact Lenses After insertion into the eye, tear decay time (“TBUT”) baseline results were measured. TBUT was measured immediately using a single slit test without blinking. Each of the contact lenses was then washed in the composition CL11 from Table 9 above. Contact lenses were inserted into the subject's eye at different times.

The composition CL11 showed an improvement in TBUT with respect to saline after long-term contact lens wear. Specifically, cleaning of contact lenses in composition CL11 prior to insertion into the eye resulted in a 750% longer TBUT. Specifically, when saline was used to wash each of the contact lenses, the subject's TBUT was 8 seconds. Following washing the contact lens in composition CL11 and inserting it into the subject's eye, the subject's TBUT was unexpectedly and surprisingly at least 1 second. These results suggest that increased bonding of the coatings of the invention as an aqueous tear film will reduce the added non-evaporable shielding and additional corneal surface protection.

Example 14
Tear Disruption Time of Additional Contact Lens Compositions Using a subject wearing contact lenses, Alcon Devices® AquaComfort® PLUS contact lenses were inserted into the subject's eyes every morning for 3 days and then TBUT. Baseline results were measured. TBUT was measured immediately using a single slit test without blinking. Each of the contact lenses was then washed in the composition CL29 of Table 9 above and the TBUT was measured again.

The composition CL29 demonstrated an improvement in TBUT with respect to the blister pack solution after long-term contact lens wear. Specifically, contact lens cleaning in composition CL29 prior to insertion into the eye resulted in a 750% greater TBUT. Specifically, when saline was used to wash each of the contact lenses, the subject's TBUT was 8 seconds. Following washing the contact lens in composition CL29 and inserting it into the subject's eye, the subject's TBUT was unexpectedly and surprisingly at least 1 minute. No stinging sensation occurred with the use of the composition CL29. These results suggest that increased bonding of the coatings of the invention as an aqueous tear film will reduce the provision of non-evaporable shielding and additional protection of the corneal surface.

In addition, the composition CL29 demonstrated an improvement in visual quality for the blister pack solution. Specifically, the monovision improved from -4.50 when the contact lens was stored in the blister pack solution and then inserted to -2.75 when the contact lens was washed in the composition CL29. ..

Example 15
The composition AA for improving far-sight vision in a person wearing a monovision contact lens is:
2.0w / v% polysorbate 80,
0.2w / v% poloxamer 407,
1.0 w / v% poloxamer 188,
0.5w / v% hydroxypropyl-gamma-cyclodextrin,
1.0 w / v% mannitol,
0.1w / v% or 0.2w / v% hydroxypropylmethylcellulose,
0.1w / v% magnesium chloride,
0.35 w / v% sodium chloride and 3 mM phosphate buffer, the composition used to immerse the contact lens, which is trade name Oasis® Accuvue® or Sold under Air Optix® Aqua.

A monovision contact lens with a + 1.5-mono formulation was immersed in composition AA prior to insertion into the subject's eye. Following insertion, the patient immediately gained clear vision. In addition, the tear destruction time was extended by more than 3 hours. Finally and surprisingly, the patient gained a distance vision of 20.25. These results are surprising because they far exceed the results achieved when contact lenses were immersed in regular saline prior to insertion.

Example 16
Artificial Tear Gels Artificial tear gels are actually described for the purpose of prolonging surface contact with some initial blurring addition. These artificial tear gels can be used during times when initial blurring is not a problem, such as pre-sleep insertion. Such gels may or may not have an active agent for therapeutic treatment purposes. Examples of the artificial tear gel of the present invention will be described below with and without the active ingredient.

Artificial tear gel 2.0% polysorbate 80
1.0% poloxamer 188
1.0% Hydroxypropyl-Gamma-Cyclodextrin 1.5% to 20% (preferably 1.7% to 2.5%) Hydroxypropyl Methyl Cellulose 2.5% Mannitol 0.10% MgCl ₂
0.75% NaCl
Citric acid buffer with pH 5.0 0.10 mM menthol lidocaine tear gel 1.0% lidocaine 2.0% polysorbate 80
1.0% poloxamer 188
1.0% Hydroxypropyl-Gamma-Cyclodextrin 1.5% to 20% (preferably 1.7% to 2.5%) Hydroxypropyl Methyl Cellulose 2.5% Mannitol 0.10% MgCl ₂
0.75% NaCl
3 mM phosphate buffer pH 6.0
Cyclosporine-A tear gel 1.0% cyclosporine-A
2.0% polysorbate 80
1.0% poloxamer 188
1.0% Hydroxypropyl-Gamma-Cyclodextrin 1.5% to 20% (preferably 1.7% to 2.5%) Hydroxypropyl Methyl Cellulose 2.5% Mannitol 0.10% MgCl ₂
0.75% NaCl
Citrate buffer with pH 5.0 0.15 mM menthol The advantages of these tear gel compositions are extended duration and minimal blurring. Viscosities at low shear range from about 500 cps to about 10,000 cps. Visual blur is less than 5 minutes. Maximum Moisture-Lock is promoted.

Example 17
(Actual) overnight visual composition The composition of the invention may be used as a drug vehicle. An example of its use as a drug vehicle is pilocarpine for use as an inducer of miosis. 0.075 w / v% pilocarpine is suspended in saline (0.9 w / v% NaCl) and in the compositions of the invention detailed below. These two pilocarpine compositions are then instilled into the subject's eye at different times with a sufficient wash period between the instillations. The pupil diameter is measured 1 hour after instillation.

Pilocarpine-enhanced artificial tears 0.075% pilocarpine 2.0% polysorbate 80
1.0% poloxamer 188
1.0% Hydroxypropyl-Gamma-Cyclodextrin 1.30% Hydroxypropyl Methyl Cellulose 2.5% Mannitol 0.10% MgCl ₂
0.30% NaCl
Phosphate buffer solution with pH 7.0

Results After 1 hour of instillation of pilocarpine in the artificial enhanced tear composition, the pupil diameter was reduced to 1.5 mm vs. 0.5 mm in the pupil diameter 1 hour after instillation of pilocarpine in the saline composition. Reduce.

Example 18
(Assumed) cyclosporin-A drug vehicle cyclosporin-A, most preferably about 0.05 w / v% to about 2.0 w / v%, more preferably about 0.075 w / v% to about 1.5 w / v%. Preferably added to the composition of the invention at a concentration of about 0.09 w / v% to about 0.125 w / v%, the composition is from about 1.5 w / v% to about 4.9 w / v%. More preferably, one or more nonionic surfactants having a concentration of about 2.5 w / v% to about 4.0 w / v%, with a low shear interflutter viscosity of 50 cps to 500 cps, more preferably 100 cps to 400 cps. A viscous agent, preferably a cellulose derivative, most preferably HPMC or CMC, optionally containing about 0.01 to about 20 mM, preferably about 0.07 to about 12 mM menthol, optionally reduced. Includes pH, low osmolality and / or high osmolality. The drug vehicle, when combined with cyclosporin-A, results in enhanced duration and efficacy of cyclosporin-A's anti-inflammatory effect on secretory mucin cells and other lacrimal gland-secreting glands of the lacrimal gland and lacrimal gland aids. In addition, the drug vehicle enhances the general anti-inflammatory effect of such compositions on the rim of the eyelids.

Example 19
Dexmedetomidin drug vehicle Dexmedetomidin 0.075w / v%, polysorbate 4.0w / v%, hydroxypropylmethylcellulose 1.35w / v%, saline 0.10w / v%, BAK0.02w / v%, EDTA0.10w / Two drops of a composition (“AQus ™ Dex”) containing v% and phosphate or citrate buffer and having a pH of 6.0 were instilled into one eye of the first patient and saline. Two drops of a composition (“saline Dex”) containing 0.07 w / v% dexmedetomidin in water and phosphate buffer and having a pH of 6.0 were instilled into one eye of the second patient. A test was performed to measure intraocular pressure (“IOP”) in both eyes of each patient, where the opposite eye, which was not instilled, served as a measure of systemic absorption. Let's go. IOP was measured at baseline (1 pm), followed by instillation of eye drops at 8 am and inspected at 1 pm (5 hours after instillation).

Results The baseline IOP for both patients was 18.25 mmHg. Five hours after instillation of the saline Dex composition, the pressure in both eyes dropped to 13.5 mmHg. In contrast, 5 hours after instillation of the AQus ™ Dex composition, the pressure dropped to 12.0 mmHg in the treated eye and 16.5 mmHg in the untreated eye.

These results demonstrate that the compositions of the invention are effective drug vehicles that reduce systemic absorption of the active ingredient, reduce systemic side effects, and provide more effective application.

Example 20
Solubilization of cyclosporine-A

Method 0.09% cyclosporin-A was added to several compositions in an attempt to impart a stable and clear solution. Specifically, these compositions were as follows: 1) 4% Captisol®, 2) 0.5% glycoflor, 3) 0.25% polyoxyl 35 castor oil, 4 ) 4% γ-cyclodextrin, 5) 4% poroxamar 407, 6) 1% polysorbate 80, 7) 4% Captisol® and 0.5% glycoflor, 8) 4% cyclo Dextrin, 0.5% glycoflor and 0.25% polyoxyl 40 castor oil, 9) 4% poroxamar 188, 0.5% glycoflor and 0.02% BAK, 10) 2% polysorbate 80 , 11) 3% polysorbate 80, 12) 3.5% polysorbate 80, 13.4% polysorbate 80 and 0.01% polyoxyl castor oil, and 14) 3.5% polysorbate 80, 4. 0% poroxamer 407 and 0.01% polyoxyl sardine oil.

Results Compositions 1), 4) -6) and 12) did not solubilize cyclosporin-A. The compositions 3), 10) and 11) slightly solubilized cyclosporin-A. The compositions 7) -9) resulted in the formation of a precipitate. Composition 12) solubilized cyclosporin-A, but was not stable or transparent. The compositions 2), 13) and 14) solubilized cyclosporin-A, resulting in a stable and clear solution.

Example 21
Increasing Tear Volume with Cyclosporin-A Composition The composition # C12 from Table 10 above was instilled into each eye of the subject. Tear volume was calculated at intervals of 5 to 45 minutes using a phenol thread via Schirmer's test. After cleaning both eyes of the subject with saline, Restasis® was instilled into each eye of the same subject. Tear volume was calculated at intervals of 5 to 45 minutes using a phenol thread via Schirmer's test. The results from this experiment can be seen in FIG. Specifically, composition # C12 increases the tear volume from 8.5 mm to about 10 mm 15 minutes after instillation, to 15 mm 20 minutes after instillation, and 20 30 minutes after instillation. It peaked in millimeters. After 30 minutes, the subject's tear volume slowly decreased to 9.0 at 45 minutes. In contrast, Restasis® instillation into the subject's eye included a decrease in peak to about 6 mm at 15 and 30 minutes, resulting in a decrease in tear volume at all time points. In addition, the subject reported that the edges of the eyelids felt slightly moist 5 minutes after instillation of Restasis® and dry 10 minutes after instillation. In contrast, subjects reported lacrimal gush along the rim of the eyelids both 5 and 10 minutes after instillation of composition # C12. The moist sensation lasted from 20 minutes after instillation to very slight moistness 30 minutes after instillation. Subjects further reported that Restasis® had minimal stinging and composition # C12 had no stinging. Finally, these subjects reported that each of Restasis® and each had a slight minimal blur lasting 15 seconds.

Example 22
Nano-micellar size distribution of cyclosporine-A composition Compositions # C12 and Restasis® were measured for nano-micellar size distribution, respectively. See FIG. As shown in FIG. 9, the nano-micelles of the composition # C12 of the present invention had an average diameter of 16.3 nanometers and a standard deviation of 5.55 nanometers. Restasis® had an average size of 135.1 nanometers and a standard deviation of 77.81 nanometers.

Example 24
Increased tear flow with all (real) GRAS artificial tears compositions

Method GRAS Composition-
2.0w / v% polysorbate 80
1.45 w / v% carboxymethyl cellulose (high MW 2% = 3,500 cps)
0.34 mM menthol 0.10 w / v% sorbate Q. S. Sterile saline 7.0 pH (adjusted)
A Schirmer test measurement of tear volume was provided using a polyphenol thread (Zone Quick®). The thread was applied to the external eye angle prior to the application of the above-mentioned preparation, and was applied to the external eye angle again at the time-increasing amount shown below. The formulation was administered into the subject's right eye (“OD”) and the subject's left eye (“OS”) was used as a control. The results of this experiment can be seen in Table 17.

result

The results in Table 17 indicate that the subject had dry eye prior to instillation of the GRAS composition. Following instillation, the tear volume of the subject treated with the eye increased for at least 1 hour.

Example 25
Effect of Sorbate Concentration on (Actual) Tear Products

Method The above Example 5 dry eye subject was administered the GRAS composition of Example 5 containing 0.10 w / v% sorbate, with a modified version not containing the sorbate composition and 0.12 w / v%. Two further modified versions of the GRAS composition were also administered, with a modified version containing the sorbate composition.

Results Tears in 5 to 15 minutes:
In the subject, no difference was detected between the three compositions in lacrimation 5 minutes after administration. However, subjects observed enhanced lacrimation with a sharper sensation upon instillation for at least 10-15 minutes following administration of the 0.12 w / v% sorbate composition.

FIG. 3 is a graph of Moisture-Lock ™ Index for the concentration of nonionic surfactant. Moisture-Lock is described by PS Therapies, Ltd. It is a trademark owned by. It is a graph of the value of the Moisture-Lock ™ effect over time for the concentration of various w / v% nonionic surfactants. Tear destruction (percentage over time) following insertion of contact lenses stored in saline / Refresh® CL into the eye. Tear destruction (percentage over time) following insertion of a contact lens stored in the composition Y of the invention into the eye. The area under the curve (percentage to seconds) for tear destruction specified in FIGS. 3+ and 4. It is a contact lens that follows storage in the composition of the present invention. The shear rate of the composition containing 5.0 w / v% poloxamer 407 and 0.75 w / v% high molecular weight carboxymethyl cellulose. Schirmer's test of tear volume after instillation of compositions # C12 and Restasis®. The average micelle size of composition # C12 panel A. The average micelle size of the Restasis® panel B.

Example 22
Nano-micellar size distribution of cyclosporine-A composition Compositions # C12 and Restasis® were measured for nano-micellar size distribution, respectively. See FIGS. 9 and 10 . As shown in FIGS. 9 and 10 , the nano-micelles of the composition # C12 of the present invention had an average diameter of 16.3 nanometers and a standard deviation of 5.55 nanometers. Restasis® had an average size of 135.1 nanometers and a standard deviation of 77.81 nanometers.

Claims (38)

An artificial tear composition comprising means for inducing tears and means for capturing tears. The composition according to claim 1, which does not contain magnesium ions. The composition of claim 1, wherein the means for inducing tears is selected from a pH of about 5 to about 6, terpenoids, and an osmotic pressure of about 270 to about 550 milliosmol. Means for capturing tear fluid include one or more nonionic surfactants and one or more viscosity enhancers with a total volume of about 1.5 w / v% to about 5.9 w / v%. The composition according to claim 1, wherein the viscosity enhancer of the seed or more imparts a viscosity of about 50 to about 10,000 centipores in 0 shear to 1 second. About 1.00w / v% to about 1.50w / v% polysorbate 80, about 0.7w / v% to about 1.00w / v% poroxamer 407, about 0.20w / v% to about 1.00w / V% poroxamar 188, about 0.01 w / v% to about 0.30 w / v% polyoxyl castor oil, about 0.1 w / v% to about 1.2 w / v% hydroxypropylmethyl cellulose, about 0 .50 w / v% polyethylene glycol 400, about 1.00 w / v% mannitol, about 0.10 w / v% magnesium chloride, about 0.35 w / v% to about 0.40 w / v% sodium chloride, An artificial tear composition comprising a menthol having a concentration of about 0.01 to about 0.35 mmol and a buffer having a concentration of about 3 to about 4 mmol selected from phosphoric acid and citric acid, wherein w / v is , Artificial tears composition, indicating weight / total composition volume. The composition according to claim 1, further comprising a solvet of about 0.1 w / v% to about 0.11 w / v%. The composition of claim 1, further comprising about 1.5 w / v% hydroxypropyl-gamma-cyclodextrin. The composition of claim 1, further comprising about 50 international units of d-alpha tocopherol. The composition according to claim 1, which has a pH of about 5.7 to about 8.0. Approximately 0.70 w / v% polysorbate 80, approximately 0.7 w / v% poroxamer 407, approximately 0.14 w / v% poroxamer 188, approximately 0.18 w / v% polyoxyl frost oil, approximately 1.05 w. / V% hydroxypropyl-gamma-cyclodextrin, about 0.04 w / v% sodium carboxymethyl cellulose, about 0.70 w / v% polyethylene glycol 400, about 0.53 w / v% mannitol, about 0.07 w An artificial tear composition comprising / v% magnesium chloride, about 0.55 w / v% sodium chloride and about 0.12 w / v% potassium sorbate, having a pH of about 7.0. , W / v indicates the weight / total volume of the composition, the artificial tear solution composition. Approximately 1.00 w / v% polysorbate 80, approximately 1.00 w / v% poloxamer 407, approximately 0.20 w / v% poloxamer 188, approximately 0.25 w / v% poloxamer oil, approximately 1.50 w. / V% hydroxypropyl-gamma-cyclodextrin, about 1.00 w / v% sodium carboxymethyl cellulose, about 0.75 w / v% polyethylene glycol 400, about 0.50 w / v% mannitol, about 0.65 w An artificial tear composition comprising / v% sodium chloride, about 0.15 mmol concentration menthol and about 0.12 w / v% potassium sorbate, having a pH of about 6.5, w. Artificial tears composition, where / v indicates weight / total volume of composition. The composition according to claim 11, which does not contain magnesium ions. Approximately 1.00 w / v% polysorbate 80, approximately 1.00 w / v% poloxamer 407, approximately 0.20 w / v% poloxamer 188, approximately 0.25 w / v% poloxamer oil, approximately 1.50 w. / V% hydroxypropyl-gamma-cyclodextrin, about 1.25 w / v% sodium carboxymethyl cellulose, about 0.75 w / v% polyethylene glycol 400, about 0.50 w / v% mannitol, about 0.70 w An artificial tear composition comprising / v% sodium chloride, about 2.0 mmol concentration menthol and about 0.12 w / v% potassium sorbate, having a pH of about 6.0, w. Artificial tears composition, where / v indicates weight / total volume of composition. 13. The composition of claim 13, which does not contain magnesium ions. Optionally, diquafosol from about 3.0 w / v% to about 3.5 w / v%,
It is preferably selected from the group consisting of polysorbate, poloxamer, polyoxyl squirrel oil and cyclodextrin, and more preferably selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl squirrel oil and hydroxypropyl-gamma-cyclodextrin. One or more nonionic surfactants of about 2.0 w / v% to about 6.0 w / v%,
Polyethylene glycol having a molecular weight of about 400 to about 6,000 Daltons of about 0.5 w / v% to about 0.75 w / v%,
Approximately 0.75 w / v% to approximately 3.0 w / v% mannitol,
Approximately 0.1 w / v% magnesium chloride,
Approximately 1.1 w / v% to approximately 1.45 w / v% carboxymethyl cellulose,
About 0.4 w / v% to about 1.25 w / v% sodium chloride,
Phosphate buffer with a concentration of about 3 mmol or citrate buffer with a concentration of about 4-5 mmol,
About 0.1w / v% to about 0.12w / v% solve,
Optionally, menthol at a concentration of about 0.3 to about 1.0 mmol,
Optionally, an ophthalmic drug composition comprising about 2.0 w / v% hydroxypropyl-gamma-cyclodextrin.
It has a pH of about 5.5 to about 7.0,
Ophthalmic drug composition. About 3.0w / v% Diquafosol,
Approximately 3.00 w / v% polysorbate 80,
Approximately 0.75 w / v% polyethylene glycol 400,
Approximately 1.50 w / v% mannitol,
Approximately 1.40 w / v% carboxymethyl cellulose,
Approximately 0.90 w / v% sodium chloride,
Menthol at a concentration of about 0.5 mmol,
Citric acid buffer, about 4 mmol concentration,
15. The composition of claim 15, comprising about 1.0 w / v% sorbate and about 2.0 w / v% hydroxypropyl-gamma-cyclodextrin. Optionally, about 1.0 w / v% to about 1.5 w / v% trehalose,
It is preferably selected from the group consisting of polysorbate, poloxamer, polyoxyl squirrel oil and cyclodextrin, and more preferably selected from the group consisting of polysorbate 80, poloxamer 407, poloxamer 188, polyoxyl squirrel oil and hydroxypropyl-gamma-cyclodextrin. One or more nonionic surfactants of about 2.0 w / v% to about 6.0 w / v%,
Polyethylene glycol having a molecular weight of about 400 to about 20,000 Dalton, from about 0.50 w / v% to about 1.50 w / v%.
About 0.50 w / v% to about 0.75 w / v% mannitol,
Magnesium chloride from about 0.07 w / v% to about 0.10 w / v%,
Citric acid buffer with a concentration of about 2.5 to about 6.0 mmol,
Optionally, about 0.1 w / v% to about 1.30 w / v% carboxymethyl cellulose,
Optionally, about 0.4 w / v% to about 0.65 w / v% sodium chloride,
Optionally, menthol at a concentration of about 0.1-about 2.5 mmol,
Optionally, an ophthalmic drug composition comprising about 0.12 w / v% sorbate.
The composition has a pH of about 5.5 to about 6.5, where w / v indicates weight / total volume of composition.
Ophthalmic drug composition. One or more nonionic surfactants are about 1.00 w / v% polysorbate 80, about 1.00 w / v% poloxamer 407, about 0.20 w / v% poloxamer 188 and about 0.25 w / v. 17. The composition of claim 17, which comprises v% polyoxyl holoxamer oil. A method for treating dry eye, which comprises administering the composition of claim 1 to a subject in need thereof. A topical lidocaine gel composition for ophthalmology comprising lidocaine or a salt thereof and magnesium chloride. A topical lidocaine gel composition for ophthalmology comprising lidocaine or a salt thereof, magnesium chloride, a nonionic surfactant, polyethylene glycol, mannitol, a viscosity enhancer and sodium chloride. Lidocaine hydrochloride of about 3w / v% to about 4w / v%,
Polysorbate 80 of about 3w / v% to about 4w / v%,
Polyethylene glycol having a molecular weight of about 400 to about 20,000 Dalton, from about 0.25 w / v% to about 2.5 w / v%.
A topical lidocaine gel composition for ophthalmology comprising about 0.25 w / v% to about 1.5 w / v% mannitol and about 0.05 w / v% to about 0.2 w / v% magnesium chloride. ,
w / v indicates weight / total volume of composition,
Topical lidocaine gel composition for ophthalmology. Approximately 3.5 w / v% lidocaine hydrochloride,
Approximately 3.5 w / v% polysorbate 80,
Polyethylene glycol having a molecular weight of about 400 to about 20,000 Dalton, from about 0.75 w / v% to about 1.50 w / v%.
Approximately 0.75 w / v% mannitol,
Approximately 0.1 w / v% magnesium chloride,
About 0.9w / v% to about 1.25w / v% sodium chloride,
Citric acid buffer, about 3 mmol concentration,
Approximately 1.25 w / v% to approximately 1.50 w / v% carboxymethyl cellulose, and approximately 0.1 w / v% sorbate,
A topical lidocaine gel composition for ophthalmology, comprising:
w / v indicates weight / total volume of composition,
Topical lidocaine gel composition for ophthalmology. Polyethylene glycol is polyethylene glycol 20000 with a concentration of about 1.50 w / v%.
Sodium chloride has a concentration of about 1.25 w / v%,
Carboxymethyl cellulose has a concentration of about 1.50 w / v%,
23. The composition according to claim 23. A method of inducing local anesthesia in a patient's eye, comprising topically applying the composition of claim 20 to the patient's eye. A viscosity enhancer selected from about 3.5 w / v% polysorbate 80, about 0.8% to about 1.2% hydroxypropylmethyl cellulose and about 1 w / v% to about 1.4 w / v% carboxymethyl cellulose. , About 0.75 w / v% polyethylene glycol 400, about 0.5 w / v% to about 0.75 w / v% mannitol, about 0.6 w / v% to about 1.25 w / v% sodium chloride, An artificial tear composition comprising menthol at a concentration of about 0.1 to about 3.0 mmol and sorbate from about 0.1 w / v% to about 0.12 w / v%, wherein the composition is from about 6 to. An artificial tear composition having a pH of about 6.5 and w / v indicating weight / total volume of the composition. The composition according to claim 26, further comprising about 0.25 w / v% of polyoxyl castor oil, further comprising about 0.5 w / v% to about 1.5 w / v% hydroxypropyl-gamma-cyclodextrin. The composition of claim 1. 26. The composition of claim 26, further comprising a citric acid buffer having a concentration of about 4 mmol. 26. The composition of claim 26, wherein the menthol is at a concentration of about 0.1 to about 0.15 mmol. 26. The composition of claim 26, wherein the menthol has a concentration of about 2.5 to about 3.0 mmol. About 1 w / v% polysorbate 80, about 1 w / v% poroxamer 407, about 0.2 w / v% poroxamer 188, about 0.25 w / v% polyoxyl cellulose oil, about 1.5 w / v%. A viscosity enhancer selected from hydroxypropyl-gamma-cyclodextrin, about 0.8% to about 1.2% hydroxypropylmethylcellulose and about 1w / v% to about 1.4w / v% carboxymethylcellulose, about 0. .75w / v% polyethylene glycol 400, about 0.5w / v% to about 0.75w / v% mannitol, about 0.6w / v% to about 0.7w / v% sodium chloride and about 0. An artificial tear composition comprising menthol at a concentration of 1 to about 3.0 mmol, wherein the composition has a pH of about 6 to about 6.5 and w / v is weight / total volume of the composition. An artificial tears composition showing. 31. The composition of claim 31, further comprising about 0.1 w / v% ethylenediaminetetraacetic acid. 31. The composition of claim 31, further comprising a sorbate of about 0.1 w / v% to about 0.12 w / v%. 31. The composition of claim 31, further comprising a phosphate buffer solution having a concentration of about 4 mmol. 31. The composition of claim 31, wherein the menthol has a concentration of about 0.1 to about 0.2 mmol. 31. The composition of claim 31, wherein the menthol has a concentration of about 2.0 to about 3.0 mmol. A method for reducing biofilm formation, comprising applying a composition comprising one or more nonionic surfactants and one or more viscosity enhancers to the surface of a contact lens. A method for reducing biofilm formation, comprising applying a composition comprising one or more nonionic surfactants and one or more viscosity enhancers to a subject's eye prior to insertion of a contact lens.

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