WO2022216769A1 - Rapidly disintegrating allyl isothiocyanate tablet - Google Patents

Abstract

A rapidly disintegrating tablet comprising allyl isothiocyanate oil and a carrier, wherein the tablet rapidly disintegrates in the mouth, releasing the allyl isothiocyanate with immediate pungency.

Description

RAPIDLY DISINTEGRATING ALLYL ISOTHIOCYANATE TABLET

FIELD OF THE INVENTION

[0001] This application claims priority to United States Provisional Application Serial Number 63/171,648, filed April 7, 2021, entitled RAPIDLY DISINTGRATING ALLYL ISOTHIOCYANATE TABLET.

[0002] The present invention relates to compositions and methods for the treatment of dry eye by inducing tearing.

BACKGROUND

[0003] Dry eye disease is a well-known condition which is caused by inadequate lubrication for the eyes.

[0004] Current treatments for dry eye include eye drops or artificial tear substitutes, ointments, gels, nutritional supplements, warm compresses, punctal plugs, medications, topical cyclosporine, nasal sprays, and electrical stimulation devices. Such existing treatments have a number of drawbacks. For example, while some eye drops add moisture to the eyes, they do not mimic tear composition, and when administered may actually wash away or dilute tear components.

[0005] US 2020/0246301 A1, hereby incorporated by reference, proposes a composition for stimulating tearing when orally administered to a subject, the composition comprising: a core comprising water and an amount of allyl isothiocyanate effective for stimulating tearing, and a shell encapsulating the core. The core, can for example, be comprised of a hydrated wasabi paste. Allyl isothiocyanate (AITC), an organosulfur compound with the formula CH₂CHCH₂NCS, is a spicy component of wasabi and is an agonist of transient receptor potential 1 (TRPA1), as described, for example, in Takaya et al, A POTENT AND SITE-SELECTIVE AGONIST OF TRPA1, Journal of the American Chemical Society, 137, 15859-15864 (2015); Eib et al„ EVALUATION OF TRIGEMINAL PUNGENCY PERCEPTION OF ALLYL ISOTHIOCYANATE -A TIME INTENSITY (TI) STUDY. Food Quality and Preference, 87 , 104039 (2021); Eib et al., RELATIONSHIP BETWEEN MUSTARD PUNGENCY AND ALLYL-ISOTHIOCYANATE CONTENT: A COMPARISON OF SENSORY AND CHEMICAL EVALUATIONS, Journal of Food Science, 85 (9) , 2728-2736 (2020); and Eib et al, DETERMINATION OF DETECTION THRESHOLDS OF SINIGRIN IN WATER-BASED MATRIX AND ALLYL ISOTHIOCYANATE IN WATER- AND OIL-BASED MATRICES, Journal of Sensory Studies, 35 (4) (2020). Synthetic or isolated AITC is a colorless to pale yellow oil with a boiling point of 152 C (PubChem, allyl isothiocyanate, C4H5NS).

[0006] As explained in US 2020/0246301 A1, maintaining AITC in its liquid state is important clinically because when administered orally to a human, a composition comprising allyl isothiocyanate in a hydrated state causes substantially more tear production, i.e., lacrimation, than the same composition in a dehydrated state.. As explained therein, once administered in the mouth, wasabi and/or horseradish produce pungent vapors that stimulate the production of tears when the wasabi and/or horseradish are in a hydrated state, such as in a hydrated mixture or paste, but not when the wasabi and/or horseradish are in a dry or powdered form. Dry wasabi and horseradish powder lack pungency. The powder needs to be hydrated for about 10 to 15 minutes before it becomes pungent and able to stimulate tearing.

SUMMARY

[0007] However, administering a composition comprising allyl isothiocyanate as a liquid, paste, or liquid or paste filled capsule is inconvenient and difficult to store and produce.

[0008] It would be desirable to provide allyl isothiocyanate in an orally disintegrating tablet. Known techniques for producing orally fast disintegrating tablets include, but are not limited to, a method involving filling a mold (resin film sheet for PTP) with a suspension of an active ingredient and a saccharide in an aqueous agar solution, and solidifying the suspension into a jelly-like form, followed by reduced pressure drying or aeration drying (JPH07187993 A, assigned to Kiyuukiyuu Yakuhin Kogyo Kk); and a method involving compressing tablet materials in a dry state containing a pharmaceutical agent, a water soluble binder and a water soluble excipient with a minimum pressure necessary for formation of tablets having a hardness enough to keep their shapes during the transition to the next step, wetting the resulting tablets, and drying the wet tablets (U.S. 5,466,464). These techniques are incompatible with allyl isothiocyanate because of its liquid state and its volatility. [0009] In view of the inability of AITC to survive known methods of disintegrating tablet formulation and the clinical utility disparity between hydrated and dehydrated compositions, it is desirable to provide an orally disintegrating dose form or composition containing AITC at clinically meaningful concentrations (e g. equivalent to hydrated forms) in order to provide a more convenient, discreet, and biologically preferable means to treat dry eye disease than prevailing therapies i.e., eye drops, nasal stimulation and nasal sprays and a more stable, cost- effective and convenient means to treat dry eye disease than liquid variants i.e., encapsulated liquids, gummies, soft lozenges.

[00010] In accordance with the present invention, AITC oil is tableted in a formulation which rapidly dissolves in the mouth becoming readily airborne and travels retro nasally causing lachrymatory effects that are mediated through the TRPA1 ion channels associated with the trigeminal nerve, TRPVl ion channels and/or other stimulatory' channels.

[00011] Preferably, the AITC oil is mixed with a carrier and a solvent (preferably water) to form an liquid (preferably aqueous) mixture such as solution, suspension and/or emulsion, then frozen, and subsequently freeze-dried (lyophilization) into a tablet such that the AITC is immediately pungent upon disintegration of the tablet in the mouth. In this regard, the components of the liquid (preferably aqueous) mixture and the lyophilization process are controlled so that the pungency of the AITC survives the lyophilization.

[00012] In accordance with a first variant of this embodiment, the aqueous mixture such as a solution, suspension and/or emulsion includes AITC, water, a carrier, and an edible oil. Preferably, the aqueous mixture includes: allyl isothiocyanate oil, purified water, maltodextrin, METHOCEL®, mannitol, and olive oil; or allyl isothiocyanate oil , purified water, maltodextrin, METHOCEL®, mannitol, and cod liver oil; or allyl isothiocyanate oil, purified water, gelatin, mannitol, and olive oil; or allyl isothiocyanate oil , purified water, gelatin, mannitol, and cod liver oil. The solution, suspension or emulsion is placed in blister packs to define individual dosage forms, then frozen, and then in a freeze-drying process, the air pressure is reduced by applying a vacuum, and the frozen water sublimes, going directly from ice to water vapor, thus removing it from the frozen solution. The result is a tablet which is a highly porous solid form including AITC with only a very' low amount of residual water remaining. [00013] In accordance with a second variant, of this embodiment, the AITC oil, combined with a suitable carrier material such as gelatin, maitodextrin or cyclodextrin, and preferably structure former, such as mannitol, is dissolved and/or dispersed in water. The resulting solution or suspension and/or emulsion is placed in blister packs to define individual dosage forms, then frozen, and then in a freeze-drying process, the air pressure is reduced by applying a vacuum, and the frozen water sublimes, going directly from ice to tvater vapor, thus removing it from the frozen solution. The result is a tablet which is a highly porous solid form including AITC with only a very low amount of residual water remaining

[00014] In other variants, AITC oil is emulsified into the edible oil (e.g. olive oil or cod liver oil), and then combined with a carrier and preferably a structure former as described above.

[00015] In other variants, AITC oil is encapsulated in polyvinyl alcohol-silk particle emulsions or emulsified into the edible oil (e.g. olive oil or cod liver oil), and then combined with a carrier and preferably a structure former as described above. Processes for encapsulation in polyvinyl alcohol-silk particle emulsions are described, for example in Elia et al, Encapsulation of Volatile Compounds in Silk Microparticles, J Coat Technol Res. 2015 July ; 12(4): 793-799, incorporated herein by reference.

[00016] In other variants, it may be desirable to include permeation enhancers to optimize the transmucosal deliver}? of drugs absorbed through pre-gastric tissues. This would serve to as oral cavity absorption of AITC. An exemplar}' permeation enhancer is sodium lauryl sulfate.

[00017] In accordance with further variants of the above, the % w/w of the aqueous mixture is: 1-8% (preferably 5% or 6%) fish gelatin, 1-6% (preferably 3% or 3.5% or 4%) mannitol; 0.1-0.7% (pref. 0.35%) sucralose; 0.001 to 0.8% (or 0.3% to 0.8%, preferably 0.5 %) AITC; qs 100% purified water. In some further embodiments, the aqueous mixture also includes 3-10% (preferably 8,5%) cyclodextrin, or 1-3% (preferably 2%) sesame oil; or 8-12%

(preferably 10%) Magnesium Aluminometasilicate .

DETAILED DESCRIPTION

[00018] The compositions and methods disclosed herein enable the stimulation of therapeutic tearing in a subject. In particular, the compositions and methods stimulate tearing that therapeutically alleviates symptoms of dry eye, reduces dry eye symptoms, or prevents dry eye symptoms. The compositions disclosed herein contain a therapeutically effective amount of allyl isothiocyanate, a compound found in wasabi and horseradish that causes tearing. A subject having dry eye symptoms orally administers a composition containing allyl isothiocyanate so as to stimulate reflex tearing, thereby alleviating dry eye symptoms. Alternatively, a subject anticipating the onset of dry eye symptoms orally administers a composition containing allyl isothiocyanate so as to stimulate reflex tearing, thereby preventing the onset of dry eye symptoms.

[00019] As described herein, once administered in the mouth, wasabi and/or horseradish produce pungent vapors that stimulate the production of tears when the wasabi and/or horseradish are in a hydrated state, such as in a hydrated mixture or paste, but not when the wasabi and/or horseradish are in a dry or powdered form. Dry wasabi and horseradish powder lack pungency. The powder needs to be hydrated for about 10 to 15 minutes before it becomes pungent and able to stimulate tearing.

[00020] The rapidly disintegrating allyl isothiocyanate tablets disclosed herein are designed to stimulate therapeutic tearing after oral administration in the mouth consistently, discreetly, cost-effectively, and with minimal effort, while reducing unpleasant sensations caused by the pungent aroma and the texture of wasabi paste.

[00021] In accordance with the present invention, allyl isothiocyanate (AITC) oil is tableted in a formulation which rapidly dissolves in the mouth becoming readily airborne and travels retro nasally causing lachrymatory effects that are mediated through the TRPA1 ion channels associated with the trigeminal nerve, TRPV1 ion channels, and/or other stimulatory channels..

[00022] Preferably, the AITC oil mixed with water and a carrier to form an aqueous mixture such as solution, suspension and/or emulsion, then the resulting mixture is frozen, and subsequently freeze-dried (lyophilization) into a tablet such that the AITC is immediately pungent upon disintegration of the tablet in the mouth.

[00023] In this regard, the components of the aqueous mixture and the lyophilization process are controlled so that the pungency of the AITC survives the lyophilization. In this regard, ZYDIS ® formulation technology, available from Catalent Pharma Solutions, may be used for lyophilization. This technology is described, for example, in U.S. 2020/0138721 A1, U.S. 5,738,875, U.S. 4,305,502, U.S. 4,371,516, U.S. 9,775,819, U.S. 6,709,669, and H. Seager, Drug-Delivery Products and the Zydis Fast Dissolving Dosage Form, J.Pharm.Pharmacol. 50, pp. 375-382 (1998), all incorporated herein by reference.

[00024] In this regard, the aqueous mixture may include AITC oil, water, a carrier, and an edible oil, wherein, for example, the aqueous mixture includes soluble components in solution, and insoluble components in suspension. Preferably, aqueous mixture includes: allyl isothiocyanate (which is in the form of an oil) , purified water, maltodextrin, METHOCEL®, mannitol, and olive oil; or allyl isothiocyanate oil, purified water, maltodextrin, METHOCEL®, mannitol, and cod liver oil; or allyl isothiocyanate oil , purified water, gelatin, mannitol, and olive oil, or allyl isothiocyanate oil, purified water, gelatin, mannitol, and cod liver oil. The aqueous mixture is placed in blister packs to define individual dosage forms, then frozen, and then, in a freeze-drying process, the air pressure is reduced by applying a vacuum, and the frozen water sublimes, going directly from ice to water vapor, thus removing it from the frozen solution. The resulting tablet is a highly porous solid form including AITC with only a very low amount of residual water remaining.

[00025] In other variants, as an alternative to the edible oil, the AITC oil is encapsulated in polyvinyl alcohol-silk particle emulsions then combined with a carrier and other substances as described above.

[00026] In some implementations, the rapidly disintegrating allyl isothiocyanate tablet stimulates tearing that therapeutically treats one or more symptoms of dry eye in the subject. In some implementations, the core stimulates an increase in tear production by over 3 mm, preferably over 5 mm, and most preferably of 10 mm or more in the subject, as measured on a Schirmer's test, e.g., an increase of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 mm or more on a Schirmer's test.

[00027] In another aspect, the invention provides a method for treating dry eye in a subject in need thereof, the method comprising administering to the mouth of the subject an oral dose form in accordance with an embodiment of the present invention; and wherein administering the oral dose form increases production of tears in the subject. In another aspect, administering the oral dose form increases mucin production (which is an expression of mucin from conuunctiva goblet cells) and/or lipid production (which is an expression of lipids from the meibomian glands of the lids) in the subject.

[00028] In some implementations, administering the oral dose form to a subject to treat dry eye increases tear production by over 10 mm, as measured on a Schirmer's test. In some implementations, administering the oral dose form increases tear production by over 15 mm, as measured on a Schirmer's test. In some implementations, administering the oral dose form increases tear production by over 20 mm, as measured on a Schirmer's test.

[00029] In another aspect, the invention provides a method for treating dry eye in a subject in need thereof, the method comprising administering to the mouth of the subject a rapidly disintegrating tablet containing allyl isothiocyanate; wherein the subject suffers from dry eye; and wherein the administering increases production of tears in the subject. Any of the compositions described herein can be administered to the mouth of the subject as an oral dose form to treat dry eye in the subject in need thereof.

[00030] As used herein, "dry eyes" or "dry eye disease" means a condition wherein the tears produced by a subject's eyes do not provide adequate lubrication for the eyes, leading to symptoms whereby the subject experiences ocular discomfort or pain. Dry eyes can result from insufficient tear coverage on the surface of the eye that can hinder gas exchange, impair nutrient transport for the eyes, and create a poor refractive surface for vision. Poor eye lubrication can occur from decreased aqueous tear production by the lacrimal glands, excessive tear evaporation caused by dysfunction of the Meibomian glands, or from an imbalance in the makeup of tears (poor quality tears). Dry eye disease can be progressive, such that low volumes of tears can lead to inflammation of the ocular surface, which can induce apoptosis of surface cells, which in turn can prevent proper distribution of tear film on the ocular surface. The symptoms of dry eye include a stinging, burning or scratching sensation; mucus in or around eyes; eye redness; a gritty or sandy sensation; blurred vision; eye fatigue; sensitivity to light; difficulty wearing contact lenses; and difficulty seeing while driving. Dry eye can be diagnosed during a comprehensive eye exam, and by measuring tear production (the volume of tears) using the Schirmer's test. In a Schirmer's test, blotting strips of filter paper are placed under the lower eyelids for several minutes (e.g., the eyes are closed for 5 minutes) to measure the production of tears. The filter paper strip is removed, and the amount of strip soaked by tears is measured. Typically, a young person normally moistens 15 mm of each paper strip in 5 minutes, while an older individual may moisten about 10 mm in 5 minutes. The quality of tears may also be determined by applying eye drops containing dyes to assess the surface conditions of the eyes and measure the rate at which tears evaporate.

[00031] As used herein "corneal neuropathic disease" refers to a disease cause by damage to the nerves of the cornea that presents with symptoms that can be very similar to those of dry eye disease. The eyes of a subject with corneal neuropathic disease are also susceptible insufficient tearing. Treatments that increase tearing can reduce the symptoms of corneal neuropathic disease and/or provide a treatment for corneal neuropathic keratitis.

[00032] As used herein, "wasabi" means a product of a plant of the Brassicaceae family, of the genus Wasabia, e.g., Wasabia japonica or W tenui, that is typically used as a food condiment with a strong pungency that produces vapors that stimulate nasal passages and induce tearing. Wasabi contains allyl isothiocyanate (also known as 3-isothiocyanatoprop-l, molecular formula C₄H₅NS), which is responsible for inducing tearing. Wasabi is typically sold as a dry power that takes on flavor and pungency when water is added to become a paste. Wasabi powder lacks taste or potency, even when hydrated with the mouth's natural saliva. When water is added to wasabi powder to form a paste, the paste develops flavor and pungency after about 10 to 15 minutes.

[00033] Allyl isothiocyanate (IUPAC name: 3-Isothiocyanato-l-propene, CAS 57-06-7) is a volatile organic compound with the formula C₄H₅NS that is responsible for the pungent taste of wasabi, mustard, horseradish and radish. Allyl isothiocyanate is a lachrymator, capable of inducing tearing. The pungency and lachrymatory effects of allyl isothiocyanate are mediated through the TRPA1 and TRPV1 ion channels, and/or other stimulatory channels. Allyl isothiocyanate is slightly soluble in water, but well soluble in organic solvents. Allyl isothiocyanate is a colorless to pale yellow oil with a boiling point of 152 C (PubChem, allyl isothiocyanate, C₄H5NS).

[00034] As used herein, allyl isothiocyanate oil or AITC oil refers to synthetic or isolated Allyl isothiocyanate, which is the form of an oil, and not, for example, to compositions such as wasabi or mustard or horseradish which include allyl isothiocyanate. [00035] As used herein, immediately pungent, means pungent within 5-10 seconds or less of tablet disintegration. Preferably, the AITC is pungent in less than 3 seconds, preferably less than 2 seconds, and most preferably less than 1 second after tablet disintegration. In this regard, tablet disintegration preferably occurs within 2-5 seconds after placement of the tablet in the mouth.

[00036] As used herein, "stimulate" or "induce" means to cause the onset of an event. For the purposes of the compositions and methods disclosed herein, "stimulate" or "induce" means to cause the onset of tearing, e.g., tearing in the eyes of a subject. In particular, the compositions described herein stimulate or induce tearing in a subject who has orally administered one of the compositions.

[00037] As used herein, "tearing" means the production of tears for lubrication and coverage of the eyes. A tear film has at least three layers or components, including a mucin layer, an aqueous layer, and a lipid layer. In some cases, "tearing" means an increased production of one or more of mucin, aqueous tears, and/or lipids. In some cases, "tearing" means the increased production of mucin and/or aqueous tears. In some cases, the compositions and methods described herein increase tearing in a subject, and/or increase mucin production (which is an expression of mucin from conuunctiva goblet cells) and/or increase lipid production (which is an expression of lipids from the meibomian glands of the lids) in the subject

[00038] As used herein, "basal tearing" refers to the tears that keep the eye, including the cornea, lubricated and nourished. Basal tears contain several components, including water, mucin, lipids, lysozymes, lactoferrin, lipocalin, lacritin, immunoglobulins, glucose, urea, sodium, potassium, and antioxidants. In some cases, the compositions and methods described herein increase basal tearing in a subject.

[00039] As used herein, "reflex tearing" refers to the automatic or reflexive tearing by the eyes of a subject that occurs in response to the subject's exposure to an environmental cue, compound or substance that induces tearing, e.g., a pungent or lachrymatory compound. In some cases, the compositions and methods described herein increase reflex tearing in a subject.

[00040] As used herein, "subject" refers to an animal. A subject can include a mammalian subject, such as, for example, a human, monkey, dog, cat, horse, cow, sheep, goat, llama, rabbit, or mouse. A subject can be a patient, e.g., a patient suffering from dry eye. [00041] As used herein, administration to the mouth of a subject can include administration to any portion of the oral or buccal cavity or the oropharynx, the lips, gums, or tongue of the subject.

[00042] As used herein "rapidly disintegrating" means that the solid dosage form will disintegrate in water at 37°C. in 60 seconds or less, preferably 5 to 10 seconds or less, most preferably 2-3 seconds or less, when tested by following a procedure which is analogous to the Disintegration Test for Tablets, B.P. 1973, and which is described in British Patent No. 1548022.

[00043] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials are described herein for use in the present invention; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[00044] In some implementations, and effective amount of AITC oil in tablet is 0.001 mg to 900 mg. In some implementations, the effective amount is 0.001 mg to 100mg. In some implementations, the effective amount is 0.001 mg to 10 mg. In some implementations, the effective amount is 0.001 mg to 5 mg. In some implementations, the effective amount is 0.001 mg to 0.5 mg, 0.001 to 8 mg, or 0.3-0.8 mg, or 2.5 mg.

[00045] In some implementations, the content of allyl isothiocyanate in the final tablet composition may be, but is not limited to, between 0.01% to about 80% by weight, based, on the total weight of the final tablet.

[00046] In some implementations, the compositions disclosed herein can be formulated with one or more flavoring agents. Various flavoring agents are well known in the art, and have been used extensively by the food and pharmaceutical industries to add flavor to ingestible products or to mask unpleasant flavors. One of skill in the art would understand that any flavoring agent or combination of flavoring agents can be added to the compositions described herein. For example, flavoring agents that add flavors such as, but not limited to, mint, peppermint, wintergreen, spearmint, vanilla, cinnamon, chocolate, and fruit flavors, such as cherry, strawberry, blueberry, banana, or orange, can be added to the compositions. One or more flavoring agent can be added to the core of a composition, to the shell of a composition, or to the core and to shell of a composition. In some implementations, menthol or a menthol-containing oil (e.g., oil of peppermint or corn mint) is provided in the core as a flavoring agent; the menthol confers other desirable properties, including a cooling or anesthetic effect in the mouth and oropharynx, and additional stimulation of tearing in the eyes. A flavoring agent can include a sweetener, e.g., glucose, fructose, aspartame, or Stevia extract.

EXEMPLARY PROCESS FOR FORMING THE RAPIDLY DISINTEGRATING TABLET

[00047] An exemplary process for forming the rapidly disintegrating tablet includes forming a solution and/or a suspension of allyl Isothiocyanate oil and a carrier in a solvent (preferably water). In this regard, the resulting liquid mixture may include the soluble components in solution and the insoluble components in suspension. The method then includes forming discrete units of the liquid mixture and removing the solvent from the discrete units under conditions whereby a network of the carrier material carrying a unit dosage of the allyl isothiocyanate is formed.

[00048] As described in US 5,738,875, the liquid mixture, which may be contained within the pockets of a suitable mold, is then frozen, for example by passing a gaseous cooling medium, such as liquid nitrogen over the mold, or by inserting the mold into a nitrogen spray freezing chamber, or cooling by passing the mold over a cold surface. Once the dosage forms have been frozen, the mold may be stored in a cold store, prior to drying.

[00049] The frozen discrete units may be dried by freeze drying according to techniques which are well known in the art. The solvent is sublimed in a freeze-drying process under a reduced pressure which transforms the solid solvent directly into a vapor. The freeze-drying process will generally be carried out in a freeze-drying chamber typically operating under a vacuum of 0.1 to 1.0 mBar for a period of time of from 180 to 500 minutes. Other methods are also described in US 5,738,875, incorporated by reference. During this process, the ice crystals formed during the controlled freezing are removed during freeze-drying (lyophilization), thereby creating pores within the matrix of the freeze-dried tablet.

[00050] The carrier material which is used to form the network containing the pharmaceutically active substance may be any water-soluble or water-dispersible material that is pharmaceutically acceptable, inert to ally! isothiocyanate and which is capable of forming a rapidly disintegrating network. The carrier material may for example, be gelatin, maltodexytrin, or cyclodextrin.

[00051] Other materials may also be used, for example, cellulose esters such as METHOCEL® (available as methyl cellulose or hydroxypropyl methylcellulose (HPMC)), hydrolysed dextrose, dextran, dextrin, maltodextrin, alginates, hydroxyethylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, corn-syrup solids, pectin, carrageenan, agar, chitosan, locust bean gum, xanthan gum, guar gum, acacia gum, tragacanth, konjac flour, rice flour, wheat gluten, sodium starch glycolate, soy fibre protein, potato protein, papain, horse radish peroxidase, glycine or mannitol.

[00052] The suspension and/or solution prepared according to the process of the present invention is preferably formed into discrete units by introduction into a mold which preferably comprises a plurality of depressions such as a blister pack, each depression being of the desired shape and size for the desired tablet. The mold preferably comprises a plurality of depressions formed in a sheet of a filmic material which may be similar to the material employed conventionally in the blister packaging of pharmaceuticals.

[00053] A covering material may be adhered to the filmic material in the area surrounding the depressions after the removal of solvent from the solution and/or suspension filling the depressions. The covering sheet is preferably an aluminium foil or aluminium foil laminate which may be adhered to the filmic material around the depressions by, for example a heat sensitive material. The cover sheet may be adhered to the filmic material in a manner such that it can be peeled away by the user to uncover the oral dosage form in the depression in the mold or, alternatively, it may be adapted for the oral dosage forms to be pushed through.

[00054] Alternative methods of forming discrete frozen units of the solution and/or suspension include solidifying the mixtures in dropwise fashion. For example, the solution and/or suspension may be passed through one or more holes to form drops, spheres or a spray of small particles which can be solidified by passage through a cold gas or liquid, for example liquid nitrogen. Alternatively, the drops, spheres or spray may be solidified by contact with a chilled liquid which is immiscible with the solution or suspension and which has a density such that the drops either fall through the immiscible liquid as they solidify, or float on the surface of the immiscible liquid.

[00055] The suspension and/or solution prepared in accordance with the process of the present invention may also contain other additional ingredients such as coloring agents, flavoring agents, sweetening agents or preservatives, or fillers such as mannitol or sorbitol which improve the physical properties of the oral dosage form.

[00056] In some implementations, the compositions disclosed herein can be stored and sold, for example, in blister packs, dispensers, or similar packaging that allow a subject to select and consume individual units or doses of the compositions. Blister packs, dispensers and packaging suitable for the storage of the compositions disclosed herein have long been used by the food and pharmaceutical industries, and are well known in the art.

[00057] In addition, in additional embodiments, the AITC oil is incorporated into bi-layer or tri-layer tablets. In this regard, to create a more "pleasant" (i.e. non-stinging layer) experience, a bi-layer tablet can include a lower AITC dose in a first-contact layer, or provide no AITC in the first contact layer, or a numbing/de-sensitizing active agent (API) in the first contact layer, with the remaining dose of AITC in non-first contact layer. A coloring agent or agents could be used to provide a different appearance for the first contact layer and the non-first contact layer, and instructions for use could indicate which side of the tablet is to be placed on the tongue or other administration site in the oral cavity. A tri-layer tablet could also be provided, with two of the aforementioned first-contact layers sandwiching the non-first contact layer. Methods for preparing fast disintegrating multi-layer tablets are described, for example, in US 2020/0138721 Al, incorporated herein by reference

METHODS OF ADMINISTERING COMPOSITIONS TO INDUCE TEARING

[00058] The present disclosure provides a method for inducing tearing in a subject in need thereof, the method comprising administering to the mouth of the subject an oral dose form according to an embodiment of the present invention; wherein the subject suffers from dry eye; and wherein the administering increases production of tears in the subject. The oral dose form can be any composition disclosed herein. In some embodiments, the administering causes a statistically significant increase in tear production over baseline tear production, as measured on a Schirmer's test, for example, a 5-minute Schirmer's test. In some embodiments, after administering the oral dose form, the Schirmer's test result rises to over 5 mm, over 10 mm, over 15 mm, over 20 mm, over 25 mm, or over 30 mm of the baseline (pre-administering) Schirmer's test result. In some embodiments, after administering the oral dose form, the Schirmer's test result rises to over 125%, over 150%, over 175%, over 200%, over 250%, or over 300% of the baseline (pre-administering) Schirmer's test result. In some embodiments, administering the oral dose form causes a statistically significant reduction in tear osmolality compared to baseline. In some embodiments, after administering the oral dose form, the tear osmolality diminishes to less than 95%, less than 90%, less than 85%, less than 80%, less than 75%, or less than 70% of the baseline (pre-administering) tear osmolality. In some embodiments, administering the oral dose form causes a statistically significant improvement on a patient-reported dry eye symptom score, e.g., the Ocular Surface Disease Index. In some embodiments, after administering the oral dose form, the patient-reported score improves by a margin of at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, or at least 50% compared to the baseline (pre- administering) patient-reported score. With any of the above methods of clinical measurement, assessment can be done after a single administration, after multiple administrations, or after chronic administration of an oral dose form or composition described herein.

[00059] The methods and compositions described herein enable a subject to orally administer the compositions containing allyl isothiocyanate to induce tearing. A subject can orally administer a composition described herein whenever it is desirable to induce tearing, e.g., to temporarily relieve ocular pain or discomfort. The compositions can be orally administered by a subject as many times as is desirable.

[00060] The compositions disclosed herein can be self-administered by a subject based on determination by the subject that tearing is desirable, e.g., to alleviate ocular discomfort or pain. The compositions disclosed herein can be self-administered as many times as the subject believes is necessary during the course of a day, e.g., to alleviate ocular discomfort or pain. In some implementations, the compositions can be orally administered by a subject one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve or more times within 24 hours.

METHODS FOR TREATING DRY EYE

[00061] The present disclosure provides a method for treating dry eye in a subject in need thereof, the method comprising administering to the mouth of the subject an oral dose form comprising: allyl isothiocyanate wherein the subject suffers from dry eye; and wherein the administering increases production of tears in the subject. The oral dose form can be any composition disclosed herein. Measurements and criteria for treating dry eye can include measurements of increased tear production (e.g., Schirmer's test), reduced tear osmolality, and/or improved patient-reported dry eye symptom scores, as described herein.

[00062] The methods and compositions disclosed herein enable a subject to orally administer the compositions to stimulate tearing to prevent or therapeutically treat and/or reduce the severity of one or more symptoms of dry eye or corneal neuropathic pain. For example, a subject experiencing the symptoms of dry eye can orally administer a composition described herein to induce therapeutic tearing, thereby reducing the severity of a dry eye symptom or preventing a dry eye symptom. In some implementations, the subject bites or chews on the composition to induce therapeutic tearing. In some implementations, the subject sucks on the composition to induce therapeutic tearing.

[00063] As used herein, "therapeutic tearing" refers to tearing that is of a sufficient amount and quality to ameliorate or reduce the severity of one or more symptoms of dry eye or corneal neuropathic pain. A reduction in the severity of one or more dry eye symptoms is noticeable to a subject and can be self-reported by a subject who has orally administered a composition as described herein to stimulate therapeutic tearing. Therapeutic tearing can also be confirmed using a diagnostic test, such as a Schirmer's test. For example, therapeutic tearing is at least an amount of tearing that will result in a normal or healthy Schirmer's test result. For example, therapeutic tearing results in at least 10 mm of moisture (wetting) or more on filter paper in 5 minutes using a Schirmer's test. In some implementations, therapeutic tearing will result in 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, 18 mm, 19 mm, 20 mm, 21 mm, 22 mm, 23 mm, 24 mm, 25 mm, 30 mm, or 35mm, e.g., 10 mm-35 mm of wetting on filter paper in 5 minutes using a Shirmer's test. Other methods for measuring tearing are also known in the art, and can be suitable for measuring therapeutic tearing, such as, but not limited to, a phenol red thread test and tear film fluorophotometry/fluorescein clearance, as described in Senchyna and Wax, J. Ocul. Biot. Dis. Infor. 1(1): 1-6, 2008, incorporated herein in its entirety.

In some implementations, tearing can be measured in the volume of tearing, and/or in the duration of tearing. [00064] In some implementations, the subject orally administers a composition described herein to reduce one of more of the symptoms of dry eye, including, but not limited to, general ocular discomfort, a stinging, burning or scratching sensation; mucus in or around eyes; eye redness; a gritty or sandy sensation; watery eyes; blurred vision; eye fatigue; sensitivity to light; difficulty wearing contact lenses; and difficulty seeing while driving. For example, biting, chewing, or sucking on the compositions described herein induces therapeutic tearing that reduces the severity of one or more of the symptoms of dry eye, as described herein.

[00065] In some implementations, the subject orally administers the composition to alleviate symptoms of dry eye or to prevent dry eye symptoms at the subject's discretion. In some implementations, a subject orally administers a composition described herein at a time when the subject is experiencing one or more dry eye symptom. In some implementations, a subject orally administers a composition described herein at a time when the subject is not experiencing a dry eye symptom, e.g., by orally administering a composition prophylactically before the onset of a symptom of dry eye or when a subject expects the onset of a symptom of dry eye or an increase in intensity of a symptom or dry eye. In some implementations, a subject orally administers a composition described herein a certain number of times a day, or at a particular intervals of time throughout the day, so as to prophylactically prevent the onset of dry eye symptoms.

[00066] For example, a subject can orally administer a composition one or more times a day, e.g., two times a day, three times a day, four times a day, five times a day, six times a day, seven times a day, eight times a day, nine times a day, ten times a day, eleven times a day, twelve times a day, thirteen times a day, fourteen times a day, fifteen times a day, sixteen times a day, seventeen times a day, eighteen times a day, nineteen times a day, twenty times a day, twenty one times a day, twenty two times a day, twenty three times a day, twenty four times a day, or more. In some implementations, a subject orally administers a composition described herein every 15 minutes, 30 minutes, 45 minutes, 60 minutes, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours, or more.

[00067] The composition described herein can be administered in combination with one or more other processes or products that are used to treat dry eye or neuropathic corneal disease, including, for example, eye drops, artificial tears, ointments, gels, bulking agents, nutritional supplements (e.g., an omega-3 fatty acid or flaxseed oil supplements), warm compresses, medication (e.g., Shire's XIIDRA®, Allergan's RESTASIS®, topical steroids, antibiotics, such as tetracycline agents e.g., (doxycycline, azithromycin (AZASITE®))), products containing hypochlorus acid (e.g., AVENOVA® (Nova Bay)), punctal plugs, devices for treating meibomian gland dysfunction associated with dry eye (e.g., BLEPHEX®, LIPIFLOW®, LIPIVIEW®®), and electrical neurostimulation devices that induce tearing (e.g., Allergan's TRUETEAR® (OCULEVE®) device). For example, a composition described herein can be administered orally by a subject with dry eye to induce tearing, and the subject can also apply an eye drop or artificial tear that is used to treat dry eye. The co-administration of a composition disclosed herein with another process or product for treating dry eye may be carried out sequentially or simultaneously. For example, a composition containing allyl isothiocyanate can be orally administered at about the same time that another process or product for treating dry eye is administered. In another example, a composition containing allyl isothiocyanate can be orally administered before another process or product for treating dry eye has been administered. In another example, a composition containing allyl isothiocyanate can be orally administered after another process or product for treating dry eye has been administered.

EXAMPLES

[00068] The invention is further described in the following example, which do not limit the scope of the invention described in the claims.

[00069] A freeze-dried rapidly disintegrating allyl isothiocyanate tablet may be prepared as follows:

[00070] The bulk API is formulated into a liquid solution and/or suspension as follows:

-a solution and/or suspension of allyl isothiocyanate oil, purified water, raa!todextrin, METHOCEL®, Mannitol, and Olive Oil in suitable amounts; or

-a solution and/or suspension of allyl isothiocyanate oil, purified water, maltodextrin, METHOCEL®, Mannitol, and Cod liver oil in suitable amounts; or

-a solution and/or suspension of allyl isothiocyanate oil, purified water, gelatin, mannitol, and olive oil in suitable amounts, or

-a solution and/or suspension of allyl isothiocyanate oil, purified water, gelatin, mannitol, and cod liver oil in suitable amounts or -a solution and/or suspension ally] isothiocyanate oil, water, cyclodextrin, and ethanol.

[00071] In this regard, this process includes emulsification of allyl isothiocyanate oil into the edible oil (e.g. olive oil or cod liver oil), and then mixing the resulting emulsion with purified water and Maltodextrin, Methocel, and Mannitol or Gelatin and Mannitol until the soluble components are in solution and the insoluble components in suspension.

[00072] The % w/w of the aqueous mixture may be 1-8% (preferably 5% or 6%) fi sh gelatin, 1-6% (preferably 3%, 3.5% or 4%) mannitol, 0.1-, 7% (pref. 0.35%) sucralose, 0.3 to 0.8% (preferably 0.5 %) AITC; qs 100% purified water. The aqueous mixture may also include 3-10% (preferably 8,5%) cyclodextrin, or 1-3% (preferably 2%) sesame oil; or 8-12%

(preferably 10%) Magnesium Aluminometasilicate .

[00073] The resulting aqueous mixture is then filled into pre-formed blisters sized to provide unit doses and then passed through a cryogenic freezing process to control the ultimate size of the ice crystals. For example, once the mixture is dosed into the preformed blisters, the suspension may be frozen within the blister pockets by passing the blister trays through a liquid nitrogen freezing tunnel. The freezing temperature and duration of transit through the tunnel are controlled to yield frozen units which have the required structural characteristics such as strength, stability and rapid disintegration time.

[00074] The frozen units are then transferred to large-scale freeze dryers for the lyophi !ization process. For example, the freeze drying may be performed with large freeze-dry' ers designed to enable rapid processing by rapid removal of large volumes of vapor without melt- back. The drying process removes all ice by sublimation and produces tablets which are very porous. The pore network of the tablets enables the tablets to disintegrate rapidly in the mouth.

[00075] The blisters containing the freeze-dried units are then sealed via a heat-seal process to protect the product from varying environmental conditions and ensure long-term stability. For example, they may be sealed with aluminum foil or an aluminum foil-paper laminate.

Example 1: AITC Dose 2.5 mg

[00076] Four batches of freeze-dried tablets each containing 2.5 mg of AITC were prepared by preparing a solution or suspension of the ingredients listed in the below table, placing the solution or suspension in pre-formed blisters, followed by rapid freezing and freeze drying according to the process described in H. Seager, Drug-Deliver)' Products and the Zydis Fast Dissolving Dosage Form, J.Pharm. Pharmacol. 50, pp. 375-382 (1998) and discussed above.

Each batch contained 5% w/w High Molecular Weight (HMW) fish gelatin; 4% w/w Mannitol; 0.35% w/w Sucralose; 0.5% w/w AITC; purified water; in Batch 3, Kleptose® 10, a Beta- cyclodextrin; and in Batch 4, Neusilin®. a synthetic, amorphous form of Magnesium Aluminometasilicate; as follows

[00077] The mixing process for batch 1-3 was completed without issue. Batch 4 was difficult to mix but achieved a suspension-based formulation after constant stirring. There was no significant macroscopic change over solution-hold period. The Formulation pH noted to be largely stable with only minor changes dunng holding. All products appear to have acceptable appearance with very minimal defects. However, in batch #4, units popping out of trays and mottled base was observed. Dispersion testing results for all batches was <2 seconds.

Example 2: AITC in b-cvclodextrin:

[00078] Procedure: Encapsulating AITC in ft-cvclodextrin (CD): CD (5 g) was solubilized in 150 ml of distilled water at 60°C for about 10 min (the flask was connected to a condenser cooled with tap water).

The solution was cooled to 40°C with continuous mixing.

AITC in ethanol (1:1, v/v) was slowly added to the solution [molar ratio of AITC/CD was (2/1)] with continuous mixing. Based on this molar ratio, the amount of AITC added was 0.86 ml (with was dissolved in 0.86 ml of ethanol).

The solution was kept under stirring for 3 h.

The resulting mixture was refrigerated overnight at 4°C.

The precipitate was recovered by vacuum-filtration The obtained filtrate was freeze-dried (lyophilized) for 24 h.

The lyophilized complex was weighted (4.932g)

The total recovery was calculated according to the following Equation:

The total recovery is 84.02%

[00079] It is noted that total recovery in the range of 70-99% is also envisioned.

[00080] The resultant freeze dried AITC dosage was immediately pungent upon administration to the mouth.

[00081] Determination of the loading efficiency: The loading efficiency represent the amount of AITC loaded in the cavity of the CD to the amount that fail to be incorporated (known as surface AITC).

[00082] Surface AITC determination : The surface AITC of the complex powder was determined by washing with hexane. Hexane is an organic solvent that is known to solubilize AITC and not CD.

The dry complex (0.10 g) was added to 10 ml of hexane and the mixture was mixed for 20 min at room temperature

Solvent phase containing AITC was separated from the test tube by decantation. The residue was further washed for 10 min with 10 ml of hexane and the procedure was repeated once. The volume (V) of the combined extracts was measured (30 ml), and the UV absorbance at 248 nm was recorded by UV spectrophotometer.

The concentration of AITC in the extracts (C, in ul/ml of extracts) was determined from the absorbance A at 248 nm. CAITC = 0.0959A₂₄₈

The total content of AITC extracted was calculated using the product of V and C. The determination was carried out in triplicate for one sample.

Average absorbance obtained (0.507). CAITC is 0.0049 ul/ml

In 30 ml, the amount of the surface AITC is 0.146 ul

However, this is /O.lg of complex. Hence: Surface AITC is 1.45 ul/g _complex

[00083] Total AITC determination: The total content of AITC in the complex powder was measured according to a solvent (hexane-water) extraction method. Here, water will solubilize the CD which will free the AITC from the cavity and all AITC will be extracted in the hexane. (Water and hexane are immiscible solvents)

- The dry complex (0.10 g) was added to 5 ml of distilled water and 7 ml of hexane (connected to a condenser cooled by tap water) and the mixture mixed at 85°C for 20 min.

- After the first extraction, the flask was cooled to RT and the inner wall of the condenser was washed with 2-3 ml of hexane in order to collect the maximum amount of AITC.

- The upper hexane containing AITC, was separated by pipette.

- The extraction was repeated three times.

- The volume (V) of the combined hexane extracts was measured (27 ml) and the UV absorbance at 248 nm was recorded.

- The concentration of AITC in the extracts (C, in ul/ml of extracts) was determined from the absorbance A at 248 nm. CAITC = 0.0959A₂₄₈

- The total amount of AITC in the complex was calculated using the product of V and C. The determination was carried out in triplicate for one sample.

Average absorbance obtained (3.270). CAITC is 0.3136 ul/ml In 27 ml, the total amount of AITC is 8.46 ul

However, this is /O.lg of complex. Hence: Total AITC is 84.6 ul/g _complex [00084] The CD recovery and inclusion efficiency of AITC in CD were calculated according to the following Equations:

The CD recovery is 90.1%

Encapsulation efficiency is 96.35%

(The theoretical max encapsulation is obtained based on the fact that B-CD in would form CD- AITC complex in 1 : 1 molar ratio)

[00085] It is noted that CD recovery and encapsulation efficiency in the range of 70% to 99.9% is also envisioned.

[00086] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

What is claimed is:

1. A rapidly disintegrating tablet comprising allyl isothiocyanate oil and a carrier, wherein the tablet rapidly disintegrates in the mouth, releasing the allyl isothiocyanate with immediate pungency.

2. The rapidly disintegrating tablet according to claim 1, wherein the carrier includes gelatin, maltodextrin or cyclodextrin.

3. The rapidly disintegrating tablet according to claim 2, wherein the gelatin is fish gelatin, and tablet further includes mannitol and sucralose.

4. The rapidly disintegrating tablet according to claim 2, wherein the carrier includes fish gelatin and cyclodextrin.

5. The rapidly disintegrating tablet according to claim 4, wherein the tablet further includes mannitol and sucralose.

6. The rapidly disintegrating tablet according to claim 2, wherein the tablet further includes sesame oil.

7. The rapidly disintegrating tablet according to claim 2, wherein the tablet further includes Magnesium Aluminometasilicate.

8. The rapidly disintegrating tablet according to claim 2, wherein the tablet is 0.001 mg to 10 mg allyl isothiocyanate.

9. The rapidly disintegrating tablet according to claim 2, wherein the tablet is 0.001 mg to 5 mg allyl isothiocyanate.

10. The rapidly disintegrating tablet according to claim 2, wherein the tablet is 0.001 mg to 0.5 mg allyl isothiocyanate

11. A method of preparing an rapidly disintegrating allyl isothiocyanate tablet, comprising preparing an aqueous mixture including allyl isothiocyanate oil with water and a carrier, freezing the mixture, then freeze-drying the frozen mixture into a tablet.

12. The method of claim 11, wherein the aqueous mixture includes, in % w/w:

0.001 to 0.8% allyl isothiocyanate oil; 1-8% fish gelatin;

1-6% mannitol;

0.1-.7% sucralose, 0.3 to 0.8% ; and qs 100% purified water.

13. The method of claim 12, wherein the aqueous mixture further includes, in % w/w: 3-10% cyclodextrin, or 1-3% sesame oil; or 8-12% Magnesium Aluminometasilicate .

14. The method of claim 11, wherein the allyl isothiocyanate is immediately pungent upon disintegration of the tablet in the mouth.

15. The method of claim 11, wherein the aqueous mixture includes allyl isothiocyanate oil, water, a carrier, and an edible oil.

16. The method of claim 11, wherein the aqueous mixture includes allyl isothiocyanate oil, water, cyclodextrin, and ethanol.

17. The method of claim 11, wherein the mixture is a solution, suspension and/or emulsion.

18. The method according to claim 11, wherein the tablet is 0.001 mg to 10 mg allyl isothiocyanate.

19. The method according to claim 11, wherein the tablet is 0.001 mg to 5 mg allyl isothiocyanate.

20. The method according to claim 11, wherein the tablet is 0.001 mg to 0.5 mg allyl isothiocyanate.