Compositions for the treatment of dry eye and methods of use thereof

Abstract

To provide compositions and methods for inducing tearing to treat dry eye.SOLUTION: A pharmaceutical composition therapeutically treats one or more symptoms of dry eye in a subject and comprises: a core comprising water and an amount effective for stimulating tearing, of allyl isothiocyanate; and a shell encapsulating the core.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Priority claims This application is a continuation of U.S. Provisional Patent Application No. 62 / 547,132, filed August 18, 2017. The entire contents of the foregoing are incorporated herein by reference.

[0002] The present invention relates to compositions and methods for inducing tearing to treat dry eye. The composition contains allyl isothiocyanate and stimulates tearing when ingested by a subject. [Background technology]

[0003] Dry eye disease affects millions of people worldwide and is a common condition in the United States. Dry eye disease occurs when an individual's tears do not provide sufficient lubrication to the eye. This can lead to dry eye symptoms, inflammation, and further loss of tear coverage. These include eye discomfort and sensitivity, and visual impairment that can impair quality of life. The risk of developing dry eye disease increases with age, resulting in The need for ear infection treatment is great and growing.

[0004] Current treatments for dry eye include eye drops or artificial tear substitutes, ointments, gels, and nutritional supplements. These include topical steroids, hot compresses, punctal plugs, medications, topical cyclosporine, and electrical stimulation devices. However, many of these treatments provide only temporary or incomplete relief of dry eye, and administration is difficult or difficult or unpleasant to the recipient of the procedure. For example, some eye drops add moisture to the eye but do not mimic the complex composition of tears. may wash away or dilute beneficial tear compounds, which may not provide lasting relief. Therefore, it is an easy-to-administer, minimally invasive, and lifestyle-friendly treatment for dry eye. Effective treatments are desirable. Summary of the Invention

[0005] The present invention provides a composition containing allyl isothiocyanate in a hydrated state when administered orally to humans. The composition induces substantially more tear production, i.e., lacrimation, than the same composition in a dehydrated state. Both hydrating and dehydrating compositions can be administered directly to the eye. This result was surprising because dehydration triggers active tear production. The composition contains a much higher concentration of allyl isothiocyanate than the corresponding hydrated composition. The difference between oral administration and eye drops is that the orally administered dosage form or composition has a similar effect to the topical administration. acts to promote an immediate increase in tear production and is typically applied directly to the eye A more convenient, gentle, and biologically favorable treatment for dry eye disease than eye drops. This shows that it is possible to provide a means for placing

[0006] The compositions and methods disclosed herein allow for the stimulation of therapeutic tearing in a subject. In particular, the compositions and methods provide therapeutic relief of dry eye symptoms. Stimulates tearing, which reduces or prevents the symptoms of dry eye. The compound is a compound found in wasabi and horseradish that causes tearing. The present invention relates to a method for treating dry eye symptoms, the method comprising administering to a patient a therapeutically effective amount of allyl isothiocyanate. Subjects were given allylisothiocyanate to stimulate reflex tearing and relieve dry eye symptoms. Alternatively, a composition containing the nate may be administered orally in anticipation of the onset of dry eye symptoms. Subjects with dry eye syndrome are given allyl acetaminophen to stimulate reflex tearing and prevent the onset of dry eye symptoms. The composition containing the isothiocyanate is administered orally.

[0007] As described herein, wasabi and / or horseradish may be taken orally. When given, wasabi and / or horseradish form a hydrated mixture or paste-like When hydrated, it produces pungent vapors that stimulate tear production, but wasabi and / or When horseradish is in dried or powdered form, it does not produce irritating vapors. Rust and horseradish powder lack irritating properties. Powder can cause irritation and tearing. It needs to be hydrated for about 10-15 minutes before it can be stimulated. The composition disclosed in the document has the pungent aroma and texture of wasabi paste after administration in the mouth. Reliably, gently, and cost-effectively reduces the discomfort caused by Wasabi paste is designed to stimulate therapeutic tearing with minimal effort. It can be divided into a consumption supply, but it must be preserved, protected from spoilage and dehydration. and delivering metered doses from pastes (such as toothpaste, other ointments and gels). In contrast, hard wasabi candies are commercially available and are probably more established. These candies are capable of delivering quantified amounts, but they are guaranteed to induce tearing. As described herein and without being bound by theory, While not something I'd like to be bound by, the lack of spiciness in commercially available wasabi candy is This is thought to be due to the fact that the wasabi is not in a hydrated state in these candies. Wasabi paste, when consumed alone without food, is particularly effective in stimulating tears. Has a strong and pungent flavor and aroma that can be unpleasant if consumed repeatedly Wasabi paste itself also has a texture that can be unpleasant. The composition provides a measured amount of hydrated wasabi paste or aqueous mixture, Maintains hydration, protects wasabi paste from spoilage, and retains the pungent flavor and aroma of wasabi It may contain flavoring agents to mask the odor.

[0008] In some embodiments, the composition comprises wasabi paste encapsulated in a shell. In some embodiments, the composition comprises a wasabi core encapsulated in a shell. The core contains a hydrated mixture of wasabi paste and In some embodiments, the composition comprises allyl isothiocyanate and water. It consists of a core containing allyl isothiocyanate and water, enclosed in a Allyl isothiocyanate is a naturally occurring compound found in substances such as Wasa The composition may be isolated and / or purified from radish or horseradish. Lozenges, lozenges, and capsules are used to stimulate tears and relieve dry eye symptoms. The composition may be provided as a tablet, pill or chewing gum.

[0009] The shell encapsulating the composition core contains the core, maintains the hydration of the core, and The shell protects the composition from spoilage or contamination. Approximately the same amount of the composition core is orally administered in a capsule, pill, or piece of chewing gum. In some cases, the shell may be designed to prevent the core from corroding. while retaining the ability to prevent rash and / or induce tearing in a subject, for example. Extending the shelf life of the composition by increasing the length of time the composition can be left at room temperature In some embodiments, the shell encapsulates the core, e.g., prevents water from evaporating from the core. In some embodiments, the shell encapsulates the core, thereby preserving hydration by preventing loss of allyl isothiocyanate, which is a volatile organic compound and can be chemically reactive, The shell encapsulating the composition core can be water resistant. In embodiments, the shell encapsulating the composition core is a water-insoluble shell. In an embodiment, the shell encapsulating the composition core is a hypromellose capsule, such as a hypromellose capsule. Alternatively, the shell may be used to coat a hard candy. In some embodiments, two or more shells may be sugar-based. The upper shell encapsulates the core of the composition. For example, the soft shell may surround and contain the core. In another example, a water-resistant shell can cover the soft shell. A sugar-based hard candy shell can surround the core, and a sugar-based hard candy shell can be used to make hypromellose. The case shell can be covered.

[0010] One use of the present invention is to provide an allyl isothiocyanate-containing peptide that is encapsulated in a water-resistant shell. Oral administration of a hydrated paste or mixture, such as wasabi paste. The hydrated paste or mixture is then encapsulated in a water-resistant shell to form an allyl The sothiocyanate-containing paste or mixture is kept in a pungent state and then shelled in the mouth. The allyl isothiocyanate can be released by chewing or dissolving. Anate-containing pastes or hydrating mixtures, such as wasabi paste, induce reflex tearing, thereby reducing and / or preventing the symptoms of dry eye .

[0011] The compositions disclosed herein are typically used to dispense candies such as mints. dispensers used for packing gum, or packs typically used to contain gum. It can be stored at room temperature in a food packaging such as a blister pack.

[0012] In a first aspect, the present invention is a composition that stimulates tearing when orally administered by a subject. and a core containing an effective amount of allyl isothiocyanate to stimulate water and tearing. and a shell encapsulating the core.

[0013] In some embodiments, the core comprises wasabi paste hydrated with water.

[0014] In some embodiments, the shell is water resistant. In some embodiments, the shell is hydroxypropyl. In some embodiments, the shell comprises one or more layers of hard candy. In some embodiments, the shell comprises one or more layers of a hard sugar-containing shell. In some embodiments, the shell is a hard candy shell comprising sugar. In some embodiments, the hypromellose shell is encapsulated in a second shell that is a hydroxybenzoate. It is further encapsulated in a hard candy shell containing sugar.

[0015] In some embodiments, the core comprises a flavoring agent. The gel includes a flavoring agent. In some embodiments, the flavoring agent is menthol or a menthol-containing Contains oil.

[0016] In some embodiments, the core treats one or more dry eye symptoms in a subject. In some embodiments, the core stimulates tearing to therapeutically treat Schirmer's syndrome in a subject. Increased tear production of more than 10 mm as measured by a test, e.g., Schirmer test, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 , 25, 26, 27, 28, 29, or 30 mm or greater increase .

[0017] In another aspect, the present invention provides a method for producing a composition that stimulates tearing when orally administered by a subject. The method comprises: (a) administering to a subject a dose of 100 mg of allylic acid or 100 mg of ... (b) providing a core comprising a sothiocyanate; and (b) encapsulating the core in a shell. The method includes the step of:

[0018] In some embodiments, the core in the manufacturing method comprises wasabi paste hydrated with water. In some embodiments, the shell comprises hypromellose. , one or more layers of hard candy shell. In some embodiments, the shell is In some embodiments, the candy comprises one or more layers of a hard candy shell comprising sugar. The method comprises the steps of encapsulating a hypromellose shell in a hard candy shell comprising sugar. In some embodiments, the method further comprises the step of adding a flavoring agent to the core or shell. It further includes a group.

[0019] In another aspect, the present invention provides a method for treating dry eye in a subject in need thereof. 1. An oral dosage form comprising a core comprising water and allyl isothiocyanate and a shell. into the mouth of a subject, wherein the shell encapsulates the core, and the subject is wherein administering the oral dosage form increases tear production in the subject. to provide.

[0020] In some embodiments, the core in the method for treating dry eye is hydrated with water. In some embodiments, the shell comprises hypromellose. In embodiments, the shell comprises one or more layers of a hard candy shell. In an embodiment, the shell comprises one or more layers of a hard candy shell comprising sugar. In some embodiments, the method comprises distributing a hypromellose shell in a hard candy shell comprising sugar. In some embodiments, the method further comprises encapsulating the core or shell. The method further comprises adding a flavoring agent to the mixture.

[0021] In some embodiments, administering an oral dosage form to a subject to treat dry eye. increases tear production by more than 10 mm as measured by the Schirmer test. In such cases, administering the oral dosage form increases tear production by 15 minutes as measured by the Schirmer test. In some embodiments, the step of administering the oral dosage form comprises increasing the dose above Schirmer m. Increases tear production by more than 20mm as measured by testing.

[0022] In another aspect, the present invention provides a blister pack comprising two or more blisters, each The blister contains a composition that stimulates tearing when orally administered by a subject, the composition comprising: a core containing an effective amount of allyl isothiocyanate to stimulate water and tearing; and an enclosing shell.

[0023] In some embodiments, the blister pack core contains wasabi paste hydrated with water. In some embodiments, the shell of the blister pack comprises hypromellose. In an embodiment, the shell comprises one or more layers of a hard candy shell comprising sugar. In some embodiments, the core of the blister pack is adapted to administer one or more drugs to the subject. Stimulates tearing to therapeutically treat symptoms of eye irritation.

[0024] In another aspect, the present invention provides a method for treating dry eye in a subject in need thereof. 1. An oral dosage form comprising a core comprising water and allyl isothiocyanate and a shell. into the mouth of a subject, wherein the shell encapsulates the core, and the subject suffers from dry eye. The present invention provides a method of administering a compound to a subject, the compound comprising: Any of the compositions described herein may be used to treat dry eye in a subject in need thereof. For treatment, it can be administered to the subject's mouth as an oral dosage form.

[0025] As used herein, "dry eye" or "dry eye disease" refers to a condition in which a subject The tears produced by the eye do not provide sufficient lubrication to the eye, causing the subject to experience discomfort or pain in the eye. Dry eye is a condition that causes symptoms that can be experienced as pain. Coverage of the ocular surface by tears, which can impair nutrient transport and create a poor refractive surface for vision Poor lubrication of the eye can result from inadequate covering of the eye. Excessive tear evaporation caused by decreased tear production, meibomian gland dysfunction, or poor tear structure Dry eye disease can be caused by an imbalance in tear production (poor tear quality). It leads to inflammation of the ocular surface, induces apoptosis of surface cells, and then causes the tear film on the ocular surface to It can be progressive, as it can interfere with proper distribution. sharp burning or scratching sensation, mucus in or around the eye, redness of the eye , gritty or gritty sensation, blurred vision, eye fatigue, sensitivity to light, contact lenses Difficulty wearing lenses and difficulty seeing while driving. Diagnosis is made during a comprehensive eye examination and by measuring tear production (tear volume) using the Schirmer test. The Schirmer test involves placing a strip of blotted filter paper on the lower eyelid for several minutes. After a period of time (e.g., closing the eyes for 5 minutes), tear production is measured. The strip of filter paper is removed and soaked with tears. The amount of soaked strips is measured. Typically, a young person will wet 15 mm of each strip in 5 minutes. However, in elderly people, about 10 mm of tears may become wet in 5 minutes. by applying a sedative to the eye, assessing the condition of the ocular surface, and measuring the rate of tear evaporation. It is possible.

[0026] As used herein, "corneal neuropathic disease" refers to a condition that is a symptom of dry eye disease. It refers to a disease caused by damage to the nerves of the cornea, which can have very similar symptoms. The eyes of subjects with corneal neuropathic diseases are also prone to insufficient tearing. The placement can reduce the symptoms of corneal neuropathic disease.

[0027] As used herein, "wasabi" refers to a vapor that irritates the nostrils and induces tearing. A member of the Brassicaceae family (Brassicaule), typically used as a food seasoning, with a strong pungent assicaceae family), genus Wasabia, e.g., Wasabia japonica It also refers to the product of the plant Yuriwasabi (W. tenui). Wasabi is a factor that induces tears. Allyl isothiocyanate (3-isothiocyanatoprop-1, molecular formula C4H5 Wasabi is typically made into a paste by adding water. It is sold as a dried powder that takes on a pungent flavor when crushed. Even when hydrated with natural saliva, it lacks flavor or potency. When the paste is formed, the paste develops its flavor and stimulating properties after about 10 to 15 minutes. Wasabi is also sold as a paste in tubes or packets. Wasabi, daikon radish, and mustard (e.g., hot mustard) also contain allyl isothiocyanates. The present invention is based on the formulation of a nasal sedative containing acetaminophen, which is capable of causing a nasal sensation that induces tearing. It can be substituted for wasabi in the compositions and formulations disclosed herein. For purposes of disclosure, "wasabi paste" refers to the paste made from fresh wasabi rhizomes or wasabi paste mixed with water. It may include a preparation made from wasabi powder that is made into a paste.

[0028] Allyl isothiocyanate (IUPAC name: 3-isothiocyanato-1-propene, C AS 57-06-7) is a pungent compound found in wasabi, mustard, horseradish, and radish. It is a volatile organic compound with the formula C4H5NS that is responsible for flavor. Cyanates are lachrymatory substances capable of inducing tearing. The irritant and lachrymatory effects of acetaminophen are mediated by the TRPA1 and TRPV1 ion channels. Allyl isothiocyanate is poorly soluble in water but is highly soluble in organic solvents. It is soluble.

[0029] As used herein in reference to a dosage form, a composition refers to a composition that is present in a particular physical arrangement. It may be composed of multiple materials, said materials being composed of more than one physical phase, e.g., solid It may be solid, semi-solid and / or liquid. When used, the composition may comprise a liquid, semi-solid and / or solid core and a solid shell. wherein the shell encapsulates the core, and such compositions can optionally comprise an oral dosage form comprising Optionally, it may include other components that are optionally arranged in a particular physical arrangement.

[0030] As used herein, a "shell" or "coating" refers to a surface of a composition. It refers to a layer of material or substance that is applied to a surface, thereby surrounding the entire surface of the composition. The shell is formed on the surface of the composition so that the shell is of the same thickness at any given location on the composition. Alternatively, the shell may be applied evenly over a range of thicknesses. The composition may be applied unevenly over the surface so that the shell is water-resistant or The shell may be hydrophobic, or alternatively hydrophilic. Shells are like hard candy shells made from a mixture of sugar and corn syrup. It may consist primarily of sugars.

[0031] As used herein, "stimulate" or "induce" refers to the occurrence of an event. For purposes of the compositions and methods disclosed herein, "Stimulate" or "induce" refers to the process of causing lacrimation, e.g., the occurrence of tearing in the eye of a subject. In particular, the compositions described herein are intended to be effective when one of the compositions is administered orally. Stimulates or induces tearing in the subject to which it is administered.

[0032] As used herein, "lacrimation" refers to the production of tears to lubricate and coat the eye. The tear film is composed of at least three layers or structures, including a mucin layer, an aqueous layer, and a lipid layer. In some cases, "tears" are caused by one of mucin, tear fluid, and / or lipids. In some cases, "tearfulness" refers to an increased production of mucin and / or means increased tear production. In some cases, the compositions and The method increases tearing in the subject.

[0033] As used herein, "basal tearing" refers to the process by which tears provide lubrication and nutrition to the eye, including the cornea. Basal tears are composed of water, mucin, lipids, lysozyme, lactoferrin, and lipocalin. , lacritin, immunoglobulin, glucose, urea, sodium, potassium and antioxidants. The compositions and methods described increase basal tearing in a subject.

[0034] As used herein, "reflex tearing" refers to an environmental cue that induces tearing. , occurring in response to a subject's exposure to a compound or substance, e.g., an irritant or lachrymatory compound refers to the automatic or reflex tearing by a subject's eye. The disclosed compositions and methods increase reflex tearing in a subject.

[0035] As used herein, "subject" refers to an animal. A subject may be, for example, a human, a mouse, mammals, such as dogs, cats, horses, cows, sheep, goats, llamas, rabbits or mice The subject may be a patient, e.g., a patient suffering from dry eye. could be.

[0036] As used herein, administration to the mouth of a subject refers to administration to the oral or buccal cavity of a subject. Or it may involve administration to any part of the oropharynx, lips, gums or tongue.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which this invention pertains. Methods and materials are described herein for use in the present invention and are readily available in the art. Other suitable methods and materials known in the art may also be used. Materials, Methods, and Experiments The examples are illustrative only and are not intended to be necessarily limiting. All publications, patent applications, patents, sequences, database entries and Other references are incorporated by reference in their entirety. In the event of a conflict, this document, including definitions, will govern. The specification controls.

[0038] Other features and advantages of the present invention will become apparent from the following detailed description and drawings, as well as from the claims. It becomes clear from the surroundings. [Brief explanation of the drawings]

[0039] [Figure 1] FIG. 1 is a schematic diagram of the structure of allyl isothiocyanate. [Figure 2] 1 is a schematic diagram of a composition described herein. DETAILED DESCRIPTION OF THE INVENTION

[0040] The compositions and methods described herein stimulate tearing in a subject when ingested. Inadequate tear-derived lubrication can cause eye discomfort or visual disturbances. Prevent or therapeutically treat and / or reduce the severity of the symptoms caused The present invention provides an oral allyl isothiocyanate formulation that reduces the risk of steroid use. Anate preparations preventively or therapeutically treat the symptoms of dry eye, and / or It can be used to reduce the severity of dry eye symptoms. Elephants take allyl isothiocyanate to stimulate tearing and relieve dry eye symptoms. Alternatively, a subject who is expecting to develop dry eye symptoms may orally ingest a composition containing the compound. contains allyl isothiocyanate to stimulate tearing and prevent the onset of dry eye symptoms. Allyl isothiocyanate preparations are effective in treating corneal neuropathic disease. to prophylactically or therapeutically treat and / or reduce the severity of symptoms of a disease can also be used.

[0041] Therapeutic tearing-inducing compositions The compositions described herein are more specifically formulated to induce tearing in a subject. It can be used to relieve symptoms of dry eye or corneal neuropathic disorders. The composition comprises a core containing the active ingredient and a soluble polymer that encapsulates the core, maintains hydration, and prevents volatilization. The shell comprises at least one layer containing the compound.

[0042] core The composition comprises a core containing water and a sufficient amount of a substance, the substance being chewable. It has irritating and lachrymatory properties that induce lacrimation in subjects who ingest it, but Contains allyl isothiocyanate, which is harmless to the body. Substances containing allyl isothiocyanate, such as preparations of rust, radish, mustard, etc. Figure 1 illustrates the structure of allyl isothiocyanate. In embodiments, the core comprises one or more of wasabi, horseradish, daikon radish, or mustard. include.

[0043] Wasabi, horseradish, radish, and mustard are prepared from plants (e.g., rhizomes) or as dry powder packets or by mixing the dry powder with water or oil. It can be purchased commercially as a tube of hydrated mixture that forms a paste. As described in the document, wasabi powder itself has almost no flavor or stimulating properties. However, wasabi powder must be allowed to hydrate for approximately 10-15 minutes before it develops its pungent characteristics. The composition described herein is characterized in that the wasabi powder hydrated with water is It has stronger stimulating and lachrymatory effects than untreated or oiled wasabi, and therefore This is based in part on the observation that oral intake of cereals is much more effective at inducing tearing. Therefore, the compositions and methods described herein may be used to preserve the wasabi composition until it is consumed. For example, the composition may need to be consumed to relieve symptoms of dry eye or corneal neuropathic pain. Wasabi (or horseradish, mustard) can be stored stably until needed. In some embodiments, the invention has been developed to encapsulate a hydrated mixture of radish and sesame seeds. The composition comprises a hydrated mixture of wasabi that stimulates therapeutic tearing when consumed by a subject. It is a physiologically acceptable formulation.

[0044] The compositions described herein are administered in effective amounts, e.g., to reliably induce therapeutic tearing. The composition described herein also allows for reliable administration of a sufficient amount of hydrated wasabi. The core of the composition is an effective amount of wasabi paste or water containing allyl isothiocyanate. As used herein, the phrase "effective amount" refers to an amount that is sufficient to reduce tearing. Refers to an amount sufficient to stimulate and reduce dry eye symptoms or corneal neuropathic pain. For example, the core of the composition contains an effective amount of wasabi paste sufficient to induce tearing in a subject. In contrast, a precise amount of paste can be placed in a tube each time a dose is consumed. Without measuring from the tube, a commercially available effective amount of wasabi paste was repeatedly It is difficult to take repeatedly.

[0045] In some embodiments, the composition comprises a water-based extract made from wasabi paste or hydrated wasabi. In some embodiments, the core contains a mixture, such as wasabi powder, mixed with water. In this case, the core is made of horseradish paste or horseradish powder mixed with water. Hydrated mixtures made from mustard paste or mustard powder mixed with water Mixture or mixture of wasabi paste, horseradish paste and / or water In some embodiments, the combination of two or more of commercially available wasabi powder is used. is mixed with water according to the instructions provided by the manufacturer. However, the core of the composition is Any ratio of commercially purchased wasabi powder and paste was used as long as the paste induced lacrimation when ingested. In some embodiments, the wasabi paste may be made using water and The core was a commercially purchased pre-mixed wasabi extract containing hydrated wasabi. It is made from a paste.

[0046] In some embodiments, water is added to wasabi powder to have a moisture content between 10 and 80% by weight. A hydrated paste is produced, where the water content is expressed as a percentage of the total weight of the paste. In some embodiments, the wasabi paste contains between 10 and 20% water by weight. , between 15-25%, between 20-30%, between 25-35%, between 30-40%, 35- Between 45%, between 40-50%, between 45-55%, between 50-60%, between 55-65% The moisture content may be between 60-70%, between 65-75%, or between 70-80%. In some embodiments, the water is as directed by the instructions provided by the manufacturer of the wasabi powder. In some embodiments, water is added to wasabi powder in a ratio of, for example, about 1:2 (w / w, Powder to water) up to 5:3, e.g. 1:2, 2:3, 3:5, 5:7, 1:1, 7:5 Or, in a ratio of 5:3, it is added to wasabi powder. In some embodiments, 2.5 g of wasabi The powder is mixed with 3.5 g of water to form a hydrated paste.

[0047] The core may be synthesized or derived from natural sources of allyl isothiocyanate, such as wasabi. Or made with a mixture containing allyl isothiocyanate isolated from horseradish. In some embodiments, allyl isothiocyanate can be obtained from natural sources. See, for example, U.S. Pat. No. 6,223,999, each of which is incorporated herein by reference in its entirety. Patent Application Publication No. 2005 / 0031768 and Chinese Patent Application Publication No. 105384 As described in U.S. Pat. No. 671, allyl isothiocyanate is synthesized, isolated, and Various methods for the synthesis and / or purification of allylic amino acids are described. Sothiocyanates are obtained by the reaction of allyl chloride with potassium thiocyanate or by the reaction of black glass Shi (Brassica nigra) or brown Indian mustard (Brassica juncea) or the rhizomes of horseradish or horseradish (genus Armoracia) In some embodiments, the core is made from hydrated wasabi or other powder. When prepared, the cores should be hydrated within 10-20 minutes of hydration to preserve the potency of the cores. Encapsulated in a shell.

[0048] In some embodiments, the effective amount of wasabi in the core of the composition is between 50 mg and 2,000 mg In some embodiments, the active ingredient is wasabi paste made from wasabi powder and water. The effective dose is 50mg to 250mg of wasabi paste made from wasabi powder and water. In some embodiments, the effective amount is 100 mg to 300 mg of wasabi powder and water. In some embodiments, the effective amount is 250 mg to 4 50 mg of wasabi paste made from wasabi powder and water. The effective dose is 400 mg to 600 mg of wasabi powder made from wasabi powder and water. In some embodiments, the effective amount is 550 mg to 750 mg of wasabi powder. In some embodiments, the effective amount is 70 Wasabi paste is made from 0mg to 900mg of wasabi powder and water. In one embodiment, the effective amount is 850 mg to 1050 mg of a composition made from wasabi powder and water. In some embodiments, the effective amount is 1000 mg to 1200 mg of wasabi paste. mg of wasabi paste made from wasabi powder and water. The effective amount is 1150 mg to 1350 mg of wasabi powder made from wasabi powder and water. In some embodiments, the effective amount is 1300 mg to 1500 mg of wasa In some embodiments, the effective amount is wasabi paste made from wasabi powder and water. Wasabi paste made from 1450mg to 1650mg of wasabi powder and water. In some embodiments, the effective amount is 1600 mg to 1800 mg of wasabi powder and In some embodiments, the effective amount is 1750 mg of wasabi paste made from water. ~2000mg of wasabi paste made from wasabi powder and water. In an embodiment, an effective amount is made from 200 mg to 800 mg of wasabi powder and water. In some embodiments, the effective amount is 200 mg to 800 mg of wasabi paste. It is a rust paste or hydrating mixture.

[0049] In some embodiments, the content of allyl isothiocyanate in the composition is not limited. However, it may be between 0.0001 and about 5% by weight, based on the total weight of the final composition. In some embodiments, the content of allyl isothiocyanate in the wasabi paste is limited. However, it is recommended to use between 0.0001 and approximately 5% by weight based on the total weight of the final wasabi paste. It's okay to have it.

[0050] In some embodiments, the compositions disclosed herein may be prepared using one or more of the methods known in the art. The food preservatives are formulated to contain one or more food preservatives. The food preservatives are wasabi paste and and / or in addition to the shell to prevent the growth of microorganisms such as bacteria and the risk of spoilage during storage. This can help reduce

[0051] In some embodiments, the compositions disclosed herein contain one or more flavoring agents. A variety of flavoring agents are known in the art and may be used in ingestible products. It is widely used by the food and pharmaceutical industries to add flavor or mask unpleasant flavors. Those skilled in the art will appreciate that any flavoring agent or combination of flavoring agents can be combined with the compositions described herein. It will be appreciated that various additives may be added to the composition, including, but not limited to, mint, Peppermint, spearmint, vanilla, cinnamon, chocolate, and cherry, A fragrance that adds a fruity flavor like chigo, blueberry, banana, or orange. Flavoring agents can be added to the composition. One or more flavoring agents can be added to the core of the composition. The composition may be added to the shell of the composition, or to the core and shell of the composition. In embodiments, menthol or a menthol-containing oil (e.g., peppermint or cornmint) oil) is provided in the core as a flavoring agent, and menthol provides a cooling or stimulating effect in the mouth and oropharynx. and other desirable properties, including stimulation of the eye with increased tearing. Flavoring agents may be sweeteners such as glucose, fructose, aspartame, or steviol. It may contain Stevia extract.

[0052] Enclosed The core formulation of the composition contains a core, which is targeted to maintain hydration of the core and induce tearing. The core is encapsulated to protect it from contamination until it is ready to be consumed by In an embodiment, the core is stably stored in a hydrated state that maintains the lachrymatory activity of the core. The allyl isothiocyanate is encapsulated in at least one shell layer so that the In some embodiments, the core is an allyl isothiocyanate. The core is encapsulated in at least one shell layer to contain the sorbate. It is also encapsulated in a shell to reduce the toxicity and increase the shelf life of the composition. For example, to reduce or mask the pungent flavor of wasabi and / or The flavor of the composition may be altered to mask the aroma of the beer, thereby allowing the subject to consume the composition. It can also be used to enhance the experience.

[0053] In some embodiments, the core can be bitten or chewed to induce rapid tearing. The core can be disintegrated by the action of a suction, thereby allowing immediate and rapid exposure of the core to the subject's mouth. In some embodiments, the shell may be coated with a rapidly lacrimalizing shell. To induce oral administration, the oral administration agent dissolves rapidly in the subject's mouth and reacts with, for example, saliva, thereby In other embodiments, the shell is gently exposed to the subject's mouth. and reacts with, for example, saliva, exposing only a portion of the core to the mouth over time, thereby Stimulates slower tearing over a longer period of time.

[0054] In some embodiments, the shell is made of a hydrophobic material or compound. In some embodiments, the shell is water resistant. In some embodiments, the shell is waterproof. In embodiments, the shell is made of a hydrophilic material or compound. , the shell is not waterproof.

[0055] In some embodiments, the shell is made of hypromellose or a similar material. Romellose is also known in the art as hydroxypropyl methylcellulose (HPMC). It is known and is offered under different trade names by several chemical companies. The type of hypromellose used to produce the shell for the composition described is All types of hypromellose recognized in the art as pharmaceutically acceptable are In some embodiments, the core of the compositions disclosed herein comprises hypromellose. in capsules, for example, pre-formed hypromellose capsules that can be purchased commercially. For example, the core of the composition can be placed in CAPSULGEL®. and placing the capsule in a hypromellose capsule, such as the hypromellose capsule provided by Thus, in some embodiments, allyl isothiocyanate, e.g., The core containing the rust paste or hydration mixture is then used to It can be placed in a Mellosu capsule.

[0056] The compositions described herein can be stored at a variety of temperatures. The composition can be stored refrigerated, for example, at about 4° C. In some embodiments, the composition The composition can be stored at room temperature, for example, at 20° C. to 25° C. In some embodiments, The composition may be stored at room temperature for one or more days, for example, 1 to 365 days or more. In some embodiments, the composition can be stored at room temperature for 1 to 365 days. 40 days, 30-325 days, 45-305 days, 60-290 days, 75-275 days , 100-250 days, 115-235 days, 130-210 days, 145-195 days In some embodiments, the composition can be stored for 160 to 180 days. 2 weeks, 4 weeks, 6 weeks, 8 weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks , 20 weeks, 22 weeks, 24 weeks, 26 weeks, 28 weeks, 30 weeks, 32 weeks, 34 weeks , 36 weeks, 38 weeks, 40 weeks, 42 weeks, 44 weeks, 46 weeks, 48 ​​weeks, 50 weeks , 52 weeks, 54 weeks, 56 weeks or more. In embodiments, the composition is administered for up to 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years. or even beyond.

[0057] In some embodiments, the shell is made of a sugar-based coating. The candy may be made from, for example, hard candy shells, coatings, In some embodiments, the sugar-based shell may be a glaze or shellac. Water resistant. Hard candy shells for products such as candy and pharmaceutical products Various methods for preparing the compositions disclosed herein are known in the art. It can be used to coat products with hard candy shells. A few examples for applying the buckshell are provided in the following sections, which are incorporated herein by reference in their entirety. U.S. Patent No. 4,840,797 and U.S. Patent No. 5,399,354 and U.S. Patent No. 5,616,340. In the case of the core containing wasabi paste, The cores are immersed in a molten mixture of 1 part water, 2 parts sugar, and 0.5 parts corn syrup. and then allowed to cool, thereby hardening the coating to form a hard candy shell. In some embodiments, the composition may be a water-resistant or waterproof candy coat. A core formulation containing an aqueous wasabi mixture or wasabi paste surrounded by a coating. It consists of:

[0058] In some cases, the core of the compositions disclosed herein is encapsulated with two or more shells. For example, two or more shells may be advantageous in containing the core more stably and during storage. The use of two or more shells also allows for the method of making the composition to be more flexible. For example, the core can be shrunk until a second hard candy shell can be applied. A first shell, such as a shell made of hypromellose, is formed to contain and keep the core hydrated. In some embodiments, the compositions disclosed herein may be applied to a surface of a substrate. may contain a hypromellose shell-coated core and a water-resistant shell. In some embodiments, the compositions disclosed herein may be coated with a hypromellose shell. The candy may include a coated core and a hard candy shell. The core 14 is enclosed by the romerose shell 12 and the hard candy shell 10. 1 illustrates a schematic representation of layers of the compositions described herein, including: The core is directly coated with a hypromellose shell, and the hard candy shell is coated with hypromellose. In some embodiments, the core is a hard candy. The hypromellose shell is directly coated by the hard candy shell. In some embodiments, the wasabi paste or hydrated wasabi mixture is layered on top. The core is placed in a hypromellose capsule, and the hard candy shell is made of hypromellose. It is layered on top of the roast capsule.

[0059] In some embodiments, the compositions disclosed herein are prepared for consumption by a subject, May be provided in chewing candy, lozenges, pills, or capsules For example, biting or chewing a candy or sucking a medicated lozenge. and exposing the core mixture to the subject's mouth, thereby inducing tearing in the subject. .

[0060] storage In some embodiments, the compositions disclosed herein are packaged in various containers, e.g., blister packs. , the dispenser or subject selecting and consuming individual units or doses of the composition. The composition may be stored and sold in similar packaging that allows for the same to be stored in a chewable container. In a blister pack similar to that used in the commercial sale of Ingum The present invention may also be in the form of candies and lozenges stored in a blister pack. The dispenser and packaging may be configured to provide a therapeutic effect, such as stimulating tearing, melting or decay of the composition. Reduce the likelihood of losing its ability to prevent spoilage and increase the shelf life of the composition The composition can be kept dry by using a blister pack, dispenser and book. Packaging suitable for storage of the compositions disclosed herein is suitable for long-term use by the food and pharmaceutical industries. For example, suitable blister packs, dispensers, and the like are widely used and known in the art. Ser and packaging are incorporated herein by reference in their entireties. 3,429,426, U.S. Pat. No. 3,743,084, U.S. Pat. No. 5, 911,325, U.S. Pat. No. 5,695,063, U.S. Pat. No. 6,21 No. 9,997, U.S. Patent Application Publication No. 2004 / 0031718, U.S. Patent Publication No. 2016 / 0051443, U.S. Design Patent (US D) No. 444379 No. 455,344 and No. 455,953 It is disclosed in the specification.

[0061] Methods of Administering Compositions to Induce Lacrimation The present disclosure provides a method for inducing tearing in a subject in need thereof, comprising administering water and and administering to the mouth of the subject an oral dosage form comprising a core and a shell comprising allyl isothiocyanate. the shell encapsulating the core, the subject suffering from dry eye, The oral dosage form is a method for administering a pharmaceutical composition comprising administering to a subject a pharmaceutical composition comprising: In some embodiments, the administration step may include administering any of the compositions disclosed in the literature. The smear showed baseline tear production as measured by a Schirmer test, e.g., a 5-minute Schirmer test. In some embodiments, oral administration causes a statistically significant increase in tear production over normal administration. After administration of the drug, the Schirmer test results were compared with the baseline (pre-administration) Schirmer test results. From, over 5mm, over 10mm, over 15mm, over 20mm, over 25 In some embodiments, the oral dosage form is administered. After administration, the Schirmer test results were compared with the baseline (pre-administration) Schirmer test results. Over 125%, over 150%, over 175%, over 200%, and 250% In some embodiments, the oral dosage form is administered The step caused a statistically significant decrease in tear osmolality compared to baseline. In some embodiments, after administration of the oral dosage form, tear osmolality is ) of the osmolality of tears, less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, or In some embodiments, the step of administering the oral dosage form comprises administering to the patient Statistically significant improvements in reported dry eye symptom scores, e.g., Ocular Surface Disease Index In some embodiments, after administration of the oral dosage form, the patient-reported score is , at least 10% less than the patient-reported score at baseline (before administration) at least 15%, at least 20%, at least 25%, at least 30%, at least 4 0% or at least 50% improvement by any of the above clinical measures. after a single dose of the oral dosage form or composition described herein, Evaluations can be performed after administration, or after chronic administration.

[0062] The methods and compositions described herein can be used in conjunction with other methods to treat a variety of conditions, including but not limited to, conditions that may be present in a subject, such as when a subject consumes, ingests, or administers the composition. The composition can be orally administered by swallowing, chewing, or sucking to stimulate tearing. In some embodiments, the subject comprises a core comprising water and allyl isothiocyanate. In some embodiments, the subject can consume a composition containing the compound to induce tearing. Oral administration of a composition containing a core containing hydrated wasabi paste to induce lacrimation. In some embodiments, the subject is administered a composition containing a core comprising a hydrated wasabi mixture. The subject may be orally administered with the compound to induce tearing, for example, by administering the compound to the eye. Whenever temporary relief of pain or discomfort is desired, The compositions described herein can be administered orally. The compositions can be administered as often as desired. It may also be administered orally by

[0063] The compositions disclosed herein can be used, for example, to relieve ocular discomfort or pain. The composition may be self-administered by the subject based on the subject's judgment that tearing is desirable. The compositions disclosed herein may be used in a variety of applications, for example, to relieve ocular discomfort or pain. The subject may self-administer as many times as they deem necessary during the day. The composition is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 1 It may be orally administered by the subject two or more times.

[0064] Methods for treating dry eye The present disclosure provides a method for treating dry eye in a subject in need thereof, comprising: An oral dosage form comprising a core comprising water and allyl isothiocyanate and a shell is administered into the mouth of a subject. wherein the shell encapsulates the core, and the subject suffers from dry eye; wherein the administering step increases tear production in the subject. It may be any of the compositions disclosed herein. Measurements and criteria for treating dry eye include increased tear production (e.g., Schirmer test) , reduction in tear osmolality, and / or improvement in patient-reported dry eye symptom scores. This may include a setting.

[0065] The methods and compositions disclosed herein are for use in treating a condition in which a subject is suffering from one or more dry eye symptoms. To prevent or treat the symptoms or corneal neuropathic pain and / or to reduce the severity To reduce the risk of lacrimation, compositions can be administered orally to stimulate tearing. For example, A subject experiencing dry eye symptoms may orally administer a composition described herein. to induce therapeutic tearing, thereby reducing the severity of dry eye symptoms, or In some embodiments, the subject chews the composition. In some embodiments, the subject licks or chews the composition to induce therapeutic tearing. Induce therapeutic tearing.

[0066] As used herein, "therapeutic tearing" refers to the treatment of one or more dry eye of sufficient quantity and quality to alleviate or reduce the severity of the symptoms or corneal neuropathic pain, Refers to tearing. A reduction in the severity of one or more dry eye symptoms is readily noticeable by the subject. The compositions described herein can be administered orally to provide therapeutic lacrimation. Therapeutic tearing may be self-reported by the subject after stimulation. Clinical testing can also be used to confirm this. For example, therapeutic tearing may be associated with at least a 50% reduction in normal or or a healthy Schirmer test result. Tearfulness was determined by using the Schirmer test to measure the amount of water (wetness) on the filter paper at least 10 mm for 5 minutes. In some embodiments, therapeutic tearing is measured using the Schirmer test in 5 minutes. Between the filter paper, 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm m, 17mm, 18mm, 19mm, 20mm, 21mm, 22mm, 23mm, 24m mm, 25 mm, 30 mm or 35 mm, for example, 10 mm to 35 mm Other methods for measuring tearing are known in the art and are not limited. See Senchyna and Wax, J. Ocul. Biol. Dis, which is incorporated herein in its entirety. phenol red thread test and tear film as described in .Infor.1(1):1-6, 2008 Measure therapeutic tearing, such as fluorophotometry / fluorescein clearance In some embodiments, the tearing may be measured by measuring the volume and / or flow of the tear. It can be measured by the duration of tears.

[0067] In some embodiments, the subject may experience symptoms such as, but not limited to, general eye discomfort, sharp, burning sensations, A sore or scratchy sensation, mucus in or around the eye, redness or grittiness of the eye or gritty sensation, watery eyes, blurred vision, eye fatigue, sensitivity to light, contact lens wear One or more of the symptoms of dry eye, including difficulty seeing while driving and difficulty seeing while driving To reduce the risk of rheumatoid arthritis, the compositions described herein are administered orally. The compositions described herein may be chewed, masticated, or licked as described in the literature. The administration of acetaminophen induces therapeutic tearing, which reduces the severity of one or more of the symptoms of dry eye. Lead.

[0068] In some embodiments, the subject is provided with, at the subject's discretion, a In some embodiments, the composition is administered orally to prevent dry eye symptoms. The subject may be administered the treatment described herein when the subject is experiencing one or more dry eye symptoms. In some embodiments, the subject is orally administered a composition comprising the compound. For example, administering the composition orally prophylactically before the onset of dry eye symptoms when the patient is not experiencing dry eye symptoms. or the subject is prevented from developing or reducing dry eye symptoms. When an increase in strength is anticipated, the compositions described herein are administered orally. In an embodiment, a subject receives a daily dose of 100 mg of acetaminophen or 100 mg of acetaminophen to prophylactically prevent the occurrence of dry eye symptoms. At specific times or at specific time intervals throughout the day, a composition described herein may be administered. Administer orally.

[0069] For example, the subject may administer the composition one or more times per day, e.g., twice per day, three times per day, or 4 times a day, 5 times a day, 6 times a day, 7 times a day, 8 times a day, 9 times a day, 10 times a day, 11 times a day , 12 times a day, 13 times a day, 14 times a day, 15 times a day, 16 times a day, 17 times a day, 1 8 times a day, 19 times a day, 20 times a day, 21 times a day, 22 times a day, 23 times a day, 24 times a day or In some embodiments, the subject is administered orally. The composition described was administered every 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1.5 hours, 2 Every hour, every 3 hours, every 4 hours, every 5 hours, every 6 hours, every 7 hours, every 8 hours, every 9 hours, Orally every 10 hours or more.

[0070] The compositions described herein can be used in a variety of applications, including, for example, eye drops, artificial tears, ointments, gels, fillers, Nutritional supplements (e.g., omega-3 fatty acid or flaxseed oil supplements), warm compresses, and medicines (e.g., Shire's XIIDRA®, Allergan's RESTASIS® topical steroids, tetracyclines, e.g. (doxycycline, azithromycin, Products containing antibiotics, hypochlorous acid, such as AZASITE® (e.g., AVENOVA® (Nova Bay)), punctal plugs, dry eye Devices for treating meibomian gland dysfunction associated with ®), LIPIFLOW®, LIPIVIEW®) and tearing Inducible electrical nerve stimulators (e.g., Allergan's TRUETEAR®) (OCULEVE® device) to treat dry eye or corneal neuropathic disease. administration in combination with one or more other methods or products used to place For example, the compositions described herein may be used by subjects with dry eye. The eye drops used to treat dry eye are ingested to induce tearing, and the subject is then given Artificial tears may also be applied. Co-administration of other methods or products for the treatment of a disease may be performed sequentially or simultaneously. For example, A composition containing hydrated wasabi paste is another method or product for treating dry eye. In another example, hydrated wasabi paste may be orally administered at approximately the same time as the patient is receiving the product. The composition containing the compound may be administered before administering another method or product for treating dry eye. In another example, a composition containing hydrated wasabi paste may be administered orally. It may be administered orally after receiving another method or product for treating ear infections. [Example]

[0071] The invention is further described in the following examples, which are set forth in the claims. The present invention is not limited to the scope of the invention.

[0072] [Example 1] Enclosed Wasabi paste can be encapsulated using various methods to effectively reduce tears. A milder, more stimulating drug that can be stored for later consumption while retaining the stimulating properties needed for induction. , formulated into an ingestible composition (e.g., capsule, lozenge, or lozenge). It was decided whether it could be done.

[0073] Powder or cereal derived from the wasabi plant (purchased from World of Wasabi) Powders produced from horseradish were prepared according to the instructions provided by the manufacturer of each powder. The powder was mixed with water to form a hydrated paste. The mixture was then added to wasabi powder or horseradish powder and left to stand for 5 to 15 minutes. The combined paste was divided into individual doses, each containing a "pea-sized" amount of paste. These individual doses were used to create the cores of the individual units of the ingestible composition. The sharpness of dried or hydrated horseradish begins to fade about 15 minutes after adding water. Therefore, the cores should be encapsulated immediately after adding water to the wasabi or horseradish powder. The cores were encapsulated in one of three different types of shells. First, some The cores were each placed into a commercially available hypromellose capsule (Capsugel). Second, some of the cores were mixed with water (1 part), sugar (2 parts), and corn syrup (0.5 parts). The resulting mixture was encapsulated in a hard outer candy coating made from a melted mixture of the above ingredients. The cores are placed in a hypromellose capsule and then coated with a hard candy outer coating. The dough was coated with a coating (1 part water, 2 parts sugar, 0.5 parts corn syrup).

[0074] [Example 2] Evaluation of tear irritation caused by the enclosed wasabi paste The composition produced as described in Example 1 was used to stimulate tearing after ingestion by a subject. The subjects were tested for their ability to: (2) Hydrated wasabi paste enclosed in a low-sugar capsule; (3) Hard candy coating (3) Hypromellose capsules and hard Hydrated wasabi paste encapsulated in a candy coating, (4) hypromellose (5) Hydrated horseradish paste enclosed in capsules, (6) hard candy coated (6) Hypromellose capsules and hydrated horseradish paste encapsulated in a hard candy coating. After each separate intake, the presence or absence of lacrimation was registered. Before taking the different compositions, the subjects To recover from tearing or other physical symptoms caused by consuming the composition; Each of the compositions was orally administered followed by a waiting period. Each of the three wasabi paste formulations was , lacrimation was induced in the subjects.

[0075] Each of the compositions prepared from wasabi was tested for its ability to induce lacrimation after storage at room temperature for one week. All three wasabi paste formulations were tested for their ability to withstand 1 week of storage at room temperature. or after ingestion following storage in the refrigerator for one week, and each of the encapsulation methods induced different levels of tearing. The stimulating properties of hydrated wasabi paste can be maintained after prolonged storage under the following conditions: This shows that

[0076] [Example 3] Laboratory testing for tear irritation Clinical trials were conducted to determine the extent to which compositions prepared from wasabi can induce lacrimation, and Understand how reliably a composition can induce tearing in different subjects and between different amounts. Compositions containing wasabi or different wasabi paste preparations were tested to determine whether they induce lacrimation. For example, the performance of the mixture containing wasabi paste with different moisture levels was compared. Each wasabi paste formulation was compared to determine whether it was effective in reliably inducing a reflex among subjects. The amount of wasabi paste required is examined. Clinical trials are used to evaluate the efficacy of the wasabi composition. Also understand the amount of inter-subject variability in sensitivity.

[0077] Clinical trials have been used to validate the level of tear production that can be produced to therapeutically relieve dry eye symptoms. The patient's symptoms will be assessed based on the severity of the symptoms and the duration of relief following ingestion of the wasabi composition. A subject with dry eye disease is treated with the method of Example 1 when symptoms of dry eye are present. The subjects with dry eye were observed using an ophthalmic examination and consumed the wasabi composition as prepared above. and determining whether the composition is effective in treating dry eye by asking subjects about the severity of their symptoms. Following oral administration of the composition by subjects with dry eye, the extent to which the composition reduces symptoms is determined. Changes in tearing are also observed using the Schirmer test. Compare with the effect in the subject.

[0078] [Example 4] Evaluating storage conditions for efficacy A series of tests were conducted to assess the effectiveness of wasabi-based compositions in inducing lacrimation versus storage time. The effects of storage temperature and packaging were determined. Testing was carried out to determine the effects of different preparations of wasabi-based compositions. The agent is able to withstand different temperatures and different types of capsules while retaining its ability to induce irritation and lacrimation. Determine the length of time the product can be stored in the packaging. Hypromellose, hard candy coated or encapsulated in hypromellose and hard candy coatings different formulations of wasabi paste (e.g., wasabi paste with different levels of moisture) The compositions containing the compound may be stored at different temperatures for different lengths of time before being orally ingested. For example, different compositions may be tested at room temperature (e.g., between 60°F and 75°F), as well as at High and low temperatures (e.g., between 0°F and 95°F, between 0°F and 4°F, between 0°F and between 32°F, between 32°F and 59°F, or between 76°F and 80°F) for two weeks. Store for 4 weeks, 6 weeks, 8 weeks, 12 weeks, 16 weeks, 32 weeks, and up to 1 year. The compositions are then tested for their ability to induce tearing. The composition is stored in a pack or bottle and compared to a composition stored unpackaged under identical conditions. The composition was ingested in parallel with a newly provided wasabi composition, and the tear production caused by different storage conditions was evaluated. Assess the potential for loss of guidance capability.

[0079] [Example 5] Comparison of dried and hydrated wasabi A crossover study was conducted on four human volunteers, and the results, as measured by the Schirmer test, The effects of dry and hydrated wasabi on tear production when orally administered to volunteers were compared. A Schirmer test was performed on each volunteer to assess baseline tear production. The applicant is then asked to consume dried wasabi powder or hydrated wasabi paste (containing an equivalent amount of dried wasabi powder). They were randomly assigned to receive a 200mg dose of wasabi powder or paste by mouth. At the same time, another Schirmer test was performed for 5 minutes, and the subjects were given either wasabi powder or paste. Once testing was complete, volunteers were asked to continue at least one additional day of treatment. The volunteers were then given the control material (i.e., those who had previously consumed dried wasabi powder). (The volunteers who took the test were given hydrated wasabi paste, and vice versa.) At the same time, another Silma -The test was conducted for 5 minutes.

[0080] The results of this study showed that the baseline Schirmer mean was 7.1 mm. Dried wasabi caused an average increase in Schirmer value of 4 mm, but this was not statistically significant. (paired t-test, p=0.24). All volunteers responded positively to the wet wasabi. In response to the moist wasabi, tear production increased significantly compared to baseline. This resulted in an increase in Schirmer value of 1 mm (p<0.0 by paired t-test). 01 vs. baseline; p=0.015 vs. dried wasabi).

[0081] In conclusion, a controlled crossover study demonstrated that moist wasabi was orally administered to human volunteers. Oral administration of an equivalent amount of dried wasabi caused a significant increase in tear production. It did not significantly increase tear production.

[0082] [Example 6] Clinical trials A prospective, placebo-controlled, investigator-blinded clinical trial was conducted in six patients with dry eye disease. This study was conducted to examine the effect of orally administered hydrated wasabi paste on tear production. The individual performing the MER test will determine whether the patient received wasabi paste or a placebo. A Schirmer test was performed on each patient and baseline tear reduction was recorded. Patients were then given a pea-sized dose of moist wasabi paste or a placebo (watermelon They were randomly assigned to receive oral toothpaste, wasabi paste, or a control. At the same time, another Schirmer test was performed for 5 minutes to compare the results of wasabi or placebo. Changes in tear production were examined.

[0083] The results of this study showed that the baseline Schirmer mean was 5.3 mm. Placebo was associated with a mean decrease in Schirmer values ​​of 0.75 mm, but this was not statistically significant. (p=0.58 by paired t-test). On the other hand, subjects showed a significant increase in tear production compared to baseline. This resulted in an increase in the Schirmer value of 24.2 mm (p < 0.01 by paired t-test). 0.05 vs. baseline; p<0.05 vs. placebo).

[0084] In conclusion, a prospective, placebo-controlled, investigator-blinded clinical trial demonstrated that wet wasabi significantly reduces the risk of heart disease compared with dry wasabi. When administered orally to patients with eye disease, it has been shown to cause a significant increase in tear production. Oral administration of placebo did not increase tear production.

[0085] Other embodiments While the present invention has been described in conjunction with the detailed description thereof, it is understood that the foregoing description is intended to be illustrative and not limiting of the scope of the invention, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the appended claims. The present invention includes the following aspects. <1> A composition that stimulates tearing when orally administered to a subject, the composition comprising a core containing water and an amount of allyl isothiocyanate effective to stimulate tearing, and a shell encapsulating the core. <2> the core comprises hydrated wasabi paste; <1> The composition described in <3> The shell is water resistant. <1> or <2> The composition described in <4> 3. The composition of claim 1 or 2, wherein the shell comprises hypromellose. <5> the shell comprising one or more layers of a sugar-containing hard candy shell; <1> or <2> The composition described in <6> The shell is encapsulated in a second shell which is a hard candy shell comprising sugar. <4> The composition described in <7> the core further comprises a flavoring agent; <1> from <6> The composition according to any one of the preceding claims. <8> The flavoring agent is menthol or a menthol-containing oil. <7> The composition described in <9> the hard candy shell further comprises a flavoring agent; <5> The composition described in <10> wherein the core stimulates tearing to therapeutically treat one or more dry eye symptoms in a subject. <1> from <9> The composition according to any one of the preceding claims. <11> wherein the core stimulates an increase in tear production of more than 10 mm in a subject as measured by a Schirmer test. <1> from <9> The composition according to any one of the preceding claims. <12> 1. A method of making a composition that stimulates tearing when orally administered by a subject, comprising: (a) providing a core comprising an amount of allyl isothiocyanate effective to stimulate water and tearing; and (b) encapsulating said core in a shell A method comprising: <13> the core comprises hydrated wasabi paste; <12> The method described below. <14> The shell comprises hypromellose. <12> or <13> The method described below. <15> the shell comprising one or more layers of a sugar-containing hard candy shell; <12> or <13> The method described below. <16> further comprising the step of encapsulating the hypromellose shell in a hard candy shell comprising sugar. <14> The method described below. <17> further comprising adding a flavoring agent to the core or shell. <12> from <16> A method according to any one of the preceding claims. <18> 1. A method for treating dry eye in a subject in need thereof, comprising: administering to the mouth of the subject an oral dosage form comprising a core comprising water and allyl isothiocyanate and a shell, wherein the shell encapsulates the core, wherein the subject suffers from dry eye, and wherein administering the oral dosage form increases tear production in the subject. <19> the core comprises hydrated wasabi paste; <18> The method described below. <20> The shell comprises hypromellose. <18> The method described below. <21> administering the oral dosage form increases tear production by more than 10 mm as measured by a Schirmer test. <18> from <20> A method according to any one of the preceding claims. <22> 26. The method of any one of <18 to 20, wherein administering said oral dosage form increases tear production by more than 15 mm as measured by Schirmer test. <23> administering the oral dosage form increases tear production by more than 20 mm as measured by a Schirmer test. <18> from <20> A method according to any one of the preceding claims. <24> A blister pack comprising two or more blisters, each containing a composition that stimulates tearing when orally administered by a subject, the composition comprising a core containing an effective amount of allyl isothiocyanate to stimulate tearing, and a shell enclosing the core. <25> The core comprises wasabi paste hydrated with water. <24> 10. The blister pack according to claim 19. <26> The shell comprises hypromellose. <24> or <25> 10. The blister pack according to claim 19. <27> the shell comprising one or more layers of a sugar-containing hard candy shell; <24> or <25> 10. The blister pack according to claim 19. <28> wherein the core stimulates tearing to therapeutically treat one or more dry eye symptoms in the subject. <24> from <27> 1. The blister pack according to any one of claims 1 to 10. [Explanation of symbols]

[0086] 10 Hard Candy Shells 12 Hypromellose shell 14 cores

Claims

1. 1. A pharmaceutical composition for therapeutically treating one or more symptoms of dry eye in a subject, comprising: a core comprising hydrated wasabi paste containing allyl isothiocyanate in an amount effective to stimulate water and tearing; and a shell encapsulating said core, wherein said amount of allyl isothiocyanate is 0.0001 to about 5% by weight, based on the weight of said pharmaceutical composition.

2. 10. The pharmaceutical composition of claim 1, wherein the shell is water-resistant.

3. 10. The pharmaceutical composition of claim 1, wherein the shell comprises hypromellose.

4. 10. The pharmaceutical composition of claim 1, wherein the shell comprises one or more layers of a hard candy shell comprising sugar.

5. 4. The pharmaceutical composition of claim 3, wherein the shell is encapsulated within a second shell that is a hard candy shell containing sugar.

6. 6. The pharmaceutical composition of claim 1, wherein the core further comprises a flavoring agent.

7. 7. The pharmaceutical composition of claim 6, wherein the flavoring agent is menthol or a menthol-containing oil.

8. 5. The pharmaceutical composition of claim 4, wherein the hard candy shell further comprises a flavoring agent.

9. 9. The pharmaceutical composition of claim 1, wherein the core stimulates tearing to therapeutically treat one or more dry eye symptoms in a subject.

10. 9. The pharmaceutical composition of claim 1, wherein the core stimulates an increase in tear production of more than 10 mm in a subject as measured by a Schirmer test.

11. 1. A method of manufacturing a pharmaceutical composition for therapeutically treating one or more dry eye symptoms in a subject, comprising: (a) providing a core comprising hydrated wasabi paste containing water and an amount of allyl isothiocyanate effective to stimulate tearing, wherein the amount of allyl isothiocyanate is 0.0001 to about 5% by weight, based on the weight of the pharmaceutical composition; and (b) encapsulating said core in a shell A method comprising:

12. 12. The method of claim 11, wherein the shell comprises hypromellose.

13. The method of claim 11 , wherein the shell comprises a one or more layer hard candy shell comprising sugar.

14. 13. The method of claim 12, further comprising encapsulating the hypromellose shell in a hard candy shell comprising sugar.

15. 15. The method of any one of claims 11 to 14, further comprising adding a flavoring agent to the core or shell.

16. 1. A blister pack comprising two or more blisters for therapeutically treating one or more dry eye symptoms in a subject, wherein each blister contains a pharmaceutical composition for therapeutically treating one or more dry eye symptoms in a subject, the pharmaceutical composition comprising a core comprising a hydrated wasabi paste containing an effective amount of allyl isothiocyanate to stimulate tearing, and a shell encapsulating the core, wherein the effective amount of allyl isothiocyanate is 0.0001 to about 5% by weight based on the weight of the pharmaceutical composition.

17. 17. The blister pack of claim 16, wherein the shell comprises hypromellose.

18. 17. The blister pack of claim 16, wherein the shell comprises a one or more layer hard candy shell comprising sugar.

19. 19. The blister pack of any one of claims 16 to 18, wherein the core stimulates tearing to therapeutically treat one or more dry eye symptoms in the subject.

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