HK1237214A1 - Sweet taste receptor antagonist compositions - Google Patents

Description

Sweet taste receptor antagonist compositions

Priority data

In accordance with 35u.s.c. § 119(e), the present invention claims priority from U.S. provisional patent application serial No. 62/011,096 filed on 12/6/2014 and U.S. provisional patent application serial No. 62/025,725 filed on 17/7/2014, both of which are incorporated herein by reference in their entirety.

Technical Field

The present invention relates to compositions comprising gymnemic acid (gymnemic acid) and a form of zinc, which blocks the unpleasant bitter taste of gymnemic acid and prolongs the sweetness-blocking properties of gymnemic acid, resulting in palatable compositions for delivery to the oral cavity for blocking the sweetness receptors located therein. The invention also relates to methods of reducing sugar intake and reducing calorie intake via administration of such compositions to a subject.

Background

Gymnemic acid is extracted from Gymnema sylvestre (Gymnema sylvestre), a woody vine plant native to India, Africa and China. Gymnemic acid is a dietary supplement sold worldwide, mainly in encapsulated form (see Ogawa et al, j.food Hygienic Soc Japan (2004)45: 8-18). Gymnemic acid is known to temporarily block the perception of sweetness when applied directly to the oral cavity (see, Kurihara,1969and Sanematsu, j.biol.chem. (2014)289: 25711-25720). Studies have shown that subjects given gymnemic acid consume fewer calories than subjects given placebo (see Brala et al, physical. behay. (1983)30: 1-9). However, gymnemic acid is known to have a strong bitter taste that is unpalatable to humans (see, e.g., U.S. publication No. 2004/007180).

Traditionally, in the field of flavor science, one would add sweeteners such as sucrose to the composition to mask the bitter taste of the essential ingredients. Strongly bitter components may require larger amounts of sucrose or possibly stronger artificial sweeteners such as sucralose to mask the bitter taste. However, as a result of the sweetness-blocking properties of gymnemic acid, these conventional bitterness-blocking methods do not work to reduce the bitter taste of gymnemic acid. Furthermore, since sweeteners and gymnemic acid interact and both bind to sweet taste receptors, the use of intense natural or artificial sweeteners may interfere with the expected sweet taste blocking activity of gymnemic acid (Sanematsu, J.biol.chem. (2014)289: 2571-25720).

It is well known in the art of flavor science that when co-acting with compositions comprising bitter tasting ingredients, encapsulated or tablet dosage forms intended for immediate swallowing can be prepared. This approach avoids any bitterness problems as the bitter component never comes into direct contact with the oral cavity. However, such dosage forms are not feasible for compositions containing gymnemic acid intended to be in direct contact with the oral cavity and tongue and subsequently swallowed.

Over a decade attempts have been made to develop dietary products that deliver gymnema sylvestre directly into the oral cavity. However, these attempts have failed because the known flavor science is not able to effectively eliminate the strong bitter taste of gymnema sylvestre. One such attempt is discussed in U.S. publication No. 2004/007180, which describes lozenges combining a Gymnema sylvestre leaf extract with a de-bittering agent, disclosing a bitterness masking agent as "Comax Flavors #2588E 17379". Sugarest manufactured by Genotec Nutritions, Inc^TMChews (gum) were marketed to temporarily block sweet receptors for 20-30 minutes (press news, Sugarest on Philippine television News by MM2 group from MM2G Co.)^TMPrograms (12.4.2007), available in http:// www.pmewswirc.corninews-leases/mm 2-groups-subways-featured-on-t v-news-in-phitadelphia-58283722. html). The product failed and was not used for many years.

Supresalin is a composition comprising gymnemic acid which is said to reduce the craving for sugar by about 30 minutes. (http:// presalin. com/faqs /). Sugar supress 60 is another gymnemic acid containing product which is said to reduce caloric intake and promote weight loss. However, the product has a strong bitter taste and is not palatable. After several attempts have failed, there remains a need for palatable, non-bitter compositions of gymnemic acid that completely block sweetness for an extended period of time in a tongue delivery form.

Summary of The Invention

Described herein are compositions comprising gymnemic acid, which further comprise zinc in a form to block the unpleasant bitter taste of gymnemic acid and to prolong the sweetness blocking properties of gymnemic acid, resulting in palatable compositions intended to be in direct contact with the oral cavity to block the sweetness receptors located therein. Since the sweetness blocking effect of gymnemic acid requires that the medicament remain in the oral cavity, an effective means is needed to reduce the bitter unpalatable taste of gymnemic acid during its delivery to the oral cavity. This need is met by the tongue delivery form (linear delivery form), composition and methodology of the present disclosure, which preferably allows gymnemic acid to be co-delivered to the oral cavity with a form of zinc, blocking the bitter taste of gymnemic acid.

In general and according to some embodiments, the tongue delivery forms and compositions of the present disclosure deliver gymnemic acid and one form of zinc to the sweetness receptor of the tongue, resulting in a particularly long duration of sweetness blockade while reducing or eliminating its bitter taste during application.

The present invention may relate to a tongue delivery form comprising gymnemic acid and at least one form of zinc. Lingual delivery may include, but is not limited to, lozenges (lozenge), orally disintegrating tablets, orodispersible tablets, troches (troche), hard candies, soft candies, jellies (jelly), chews, edible films, orally dissolvable films, wafers (wafer), drops, oral sprays, liquids, powders, and combinations thereof. The disintegration time of an orally disintegrating tablet can range from about 30 seconds to about 5 minutes.

Forms of zinc may include, but are not limited to, zinc acetate, zinc carbonate, zinc chloride, zinc citrate, zinc gluconate, zinc sulfate, zinc hydrosulfite (zinc hydrosulfite), zinc bisulfite (zinc bisulfite), zinc oxide, zinc halide, zinc hydride, zinc carbide, and combinations thereof. Preferably, the zinc is in the form of a GRAS (Generally Recognized as Safe, fda, gov/Food/ingredient labeling/GRAS /) approved zinc salt, most preferably zinc gluconate.

Gymnemic acid may be present as an inorganic salt of gymnemic acid, an organic salt of gymnemic acid, a cyclodextrin complex of gymnemic acid, a cryptand complex of gymnemic acid, a hydrate of gymnemic acid, a solvate of gymnemic acid and combinations thereof. The gymnemic acid solvate may comprise a plurality of ethanol solvates of gymnemic acid.

The tongue delivery form may further comprise peppermint.

The tongue delivery form may further comprise a bitter taste inhibitor. The bitterness inhibitors may include, but are not limited to, sodium salts, lipoproteins, and combinations thereof.

The tongue delivery form may further comprise at least one acidity inhibitor. The sourness inhibitor may be miraculin (miraculin).

The inventors of the present invention provide methods of using the tongue delivery forms and compositions of the present invention. The present invention provides methods of reducing sugar uptake comprising administering to a subject a composition and tongue delivery form of the invention. In addition, the present invention provides methods of reducing caloric intake comprising administering to a subject a composition and a tongue delivery form, and methods of reducing dental caries comprising administering to a subject a composition and a tongue delivery form.

Detailed Description

The following is a detailed description of the invention provided to assist those skilled in the art in practicing the invention. Modifications and variations may be made in the embodiments described herein by those skilled in the art without departing from the spirit and scope of the invention. Unless defined otherwise, 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. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. All publications, patent applications, patents, figures, and other references mentioned herein are expressly incorporated by reference in their entirety.

It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of compounds. In this specification and the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings, unless an opposite purpose is apparent.

It must be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It is to be understood that such a range format is, therefore, to be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For purposes of this specification, a concentration range of "about 0.1% to about 5%" should be read to include not only the explicitly recited concentration of about 0.1 wt% to about 5 wt%, but also individual concentrations (e.g., 1%, 2%, 3%, and 4%) and sub-ranges (e.g., 0.5%, 1.1%, 2.2%, 3.3%, and 4.4%) within the indicated range. In one embodiment, the term "about" may include conventional rounding according to significant figures of the numerical value. In addition, the phrase "about 'x' to 'y'" includes "about 'x' to about 'y'".

The phrase "sweetness blocking" as used herein is defined as a weakening of the perceived sweetness of a food or drink or other substance introduced into the oral cavity. Sweetness blocking and sweetness blocking are synonyms.

The phrase "reduced bitterness" as used herein is defined as a reduction in bitterness associated with a compound (e.g. gymnemic acid). In some embodiments, the reduced bitterness is a reduction of about 50% or more, about 75% or more, about 85% or more, about 90% or more, about 95% or more, or about 99% or more. The phrase "bitterness elimination" as used herein is defined as a reduction of about 100% of the bitterness associated with a compound (e.g., gymnemic acid).

Gymnemic acid is not selective in its sweetness blocking. Thus, any sweetener-containing food or beverage or other substance ingested or introduced into the oral cavity during the post-oral phase of gymnemic acid delivery tastes non-sweet or has its sweetness significantly reduced. In addition, the perception of the presence of any bitter or sour taste in such food or beverage is expanded as the bitter and sour taste is no longer masked by the sweet taste. The use of gymnemic acid by delivery to the oral cavity, including the tongue, prevents the desire for sweeteners in food or beverages, resulting in a reduction of the intake of such high calorie food. The link between sweetness perception and the choice of sweet foods ingested is known (see Brala et al, Physiol. Behay (1983)30: 1-9).

A drawback of using gymnemic acid in this way is that gymnemic acid is known to have an unpleasant and strong bitter taste which is unpalatable to humans. A further drawback is that when gymnemic acid blocks the perception of sweetness, the effect is temporary and only lasts for a short period of time. Thus, there is a continuing need for improved gymnemic acid based compositions that can block the perception of sweetness for a longer period of time while reducing or eliminating the bitter taste of gymnemic acid. Furthermore, there is a need for an effective way to significantly reduce or eliminate the strong bitter and unpleasant taste of gymnemic acid during its delivery to the oral cavity.

Many known sweet taste receptors are involved. Sweetness is one of the five main classes of tastes perceived by humans. The receptor that initiates this sensation is located in one of three taste bud cells known as type I, type II and type III, which are located in taste buds located primarily on the tongue, but are also found in the soft palate and other areas of the mouth. Sweet taste receptors are located in different subsets of type II taste bud cells. Taste bud cells that sense sweetness express separate heterodimeric receptors identified as T1R2/T1R 3.

In contrast, the bitter transduction mechanism is complex and not yet fully understood. Given that human bitter taste is initiated by activation of the 26T2R receptor, it is generally accepted that it exists as a mixture of homo-and heterodimeric species in bitter sensitive taste bud cells, thus providing a total of 346 possible functional receptors, where the relative number of these dimeric species is believed to vary from person to person (see c.kuhn et al, chem.senses 2010,35: 395-406). This diversity among people demonstrates the complexity of bitter taste over other tastes such as sweet and sour. Furthermore, given that gymnemic acid is a complex mixture of more than 20 different triterpenoids, all of which may have different bitter taste properties (see Imoto et al, J Chromatography (1991)557:383-389), blocking the bitter taste of gymnemic acid presents a great challenge.

Given the existence of 26T2R bitter taste receptors responsible for the perception of bitter taste stimuli, it is very difficult to block the associated bitter taste when multiple receptors are activated. The bitter response generated by a complex mixture of molecules comprised in the herbal extract, such as compositions comprising gymnemic acid, is expected to trigger a large number of individual bitter receptors. Thus it is expected that a single agent with bitter blocking properties will not completely eliminate the bitter taste of gymnemic acid.

Zinc is known to have some ability to block both sweet and bitter tastes. The use of zinc salts as taste modifiers has been described in a number of previous publications (Keast, JFS (2003)68: 1871-1877). Although gymnemic acid inhibits the sweetness of all natural and artificial sweeteners, zinc salts are selective in their inhibition and are not universal inhibitors. For example, Keast and bresln have demonstrated that zinc sulfate is a potent bitter inhibitor against quinine, denatonium benzoate and tetralone (tetralone), but does not have significant bitter inhibitory activity against sucrose octaacetate, pseudoephedrine and dextromethorphan (Keast, JFS (2003)68: 1871-. As another example, ZnSO has been observed₄It was noted that zinc only interfered with the mechanisms responsible for bitter transduction of a subset of the bitter compounds (there are thousands but not all of the bitter compounds) (Keast, JFS (2003)68: 1871-.

It is not expected that zinc alone will be fully effective as a taste modifier and it will not be sufficient to provide a palatable composition. To be fully effective, zinc is conventionally accompanied by other flavor masking agents such as sucrose, fructose, sorbitol, xylitol, artificial sweeteners, and/or flavoring compositions (i.e., fruit or citrus flavors). In addition, zinc itself is known to have an objectionable metallic, chalky, astringent aftertaste common to metal ions, and other flavor masking agents are also needed to mask the zinc's unpleasant taste. Thus, zinc is not considered to be a single agent that can be used to completely block bitter components.

Nevertheless, it was surprisingly found that the addition of some form of zinc to gymnemic acid extracts not only results in a composition that is palatable in taste and blocks sweetness without any other taste masking agent, but also extends the duration of sweetness blocking to at least 60-80 minutes, which is greater than the duration of sweetness blocking obtained with gymnemic acid alone.

By the compositions of the present invention it has surprisingly been found that when gymnemic acid is combined with zinc, the bitterness of gymnemic acid is reduced and almost completely eliminated while the sweetness-blocking properties of gymnemic acid are still effective. Furthermore, it has surprisingly been found that a composition of gymnemic acid together with some form of zinc blocks the sweet taste in a human subject for a longer period of time than gymnemic acid alone or zinc alone. It has surprisingly been found that the length of the sweetness blockade can be extended to a duration of at least 60-80 minutes or more when a composition comprising a combination of gymnemic acid and some form of zinc is delivered to the oral cavity, which is greater than the sweetness blockade duration obtained with gymnemic acid alone.

The present invention provides for delivery of gymnemic acid to the oral cavity, thereby blocking the perception of sweeteners. Thus, sweeteners do not result in the perception of sweetness during the ingestion of any sweetened food or beverage. A person or subject using the composition of the invention will no longer be able to experience the sweetness of the substance it consumes or drinks or introduces into the oral cavity, which makes most foods, beverages and other substances no longer palatable. Thus, the present invention provides a composition that allows the user to solve the problem of his immediate craving for confections. Furthermore, with more extended use, the user of the composition can adjust his behavior as the user no longer associates a pleasant sensation with a food that tastes sweet before. Thus, the present invention also provides methods for reducing sugar intake and reducing calorie intake in a subject via administration of a composition comprising gymnemic acid as described herein to the subject.

In general and according to some embodiments, the tongue delivery forms and compositions of the present invention deliver gymnemic acid to the sweetness receptor of the tongue, resulting in an additional sweetness blockade duration during application while reducing or eliminating the bitter taste of gymnemic acid.

The unique and surprising behaviour of compositions comprising gymnemic acid and some form of zinc provides advantages over prior art gymnemic acid formulations, providing longer sweetness blocking and allowing a subject to retain compositions comprising gymnemic acid in the oral cavity for a longer duration without experiencing the unpleasant bitter taste of gymnemic acid.

Applicants have surprisingly found that the use of a composition comprising gymnemic acid and one form of zinc as an additional sweetness inhibitor provides a total sweetness blockade which is greater than the sum of the sweetness blocking effects of zinc alone and gymnemic acid alone. A synergistic effect is defined as the cooperative action of discrete agents, whereby the total effect is greater than the two or more effects taken independently.

Given the complexity of the human bitter receptor system with up to 346 functional receptors, where specific bittering agents are often found to activate multiple bitter receptors and where specific bitter receptors activated by gymnemic acid are not yet known, it is not possible to predict the identification of gymnemic acid specific bitter taste inhibitors. In addition, various forms of zinc are specific in their bitter taste suppression activity and are not widely used. Thus, it is expected that the combination of the zinc form and gymnemic acid will provide complete sweetness blocking without any bitterness, providing itself a synergistic effect of increasing the duration of sweetness blockade. Furthermore, the sites for gymnemic acid and zinc binding to T1R2/T1R3 are unknown. Without knowledge of this, no synergistic effect would be predicted.

The "form of zinc" (the form of zinc(s) ") can be in any form, such as a zinc salt. For example, forms of zinc can include, but are not limited to, forms of zinc generally recognized by the u.s.fda ("GRAS") as safe, such as zinc acetate, zinc carbonate, zinc chloride, zinc gluconate, zinc dithionite, zinc oxide, and zinc sulfate, as well as zinc halides, zinc hydride, zinc carbide, zinc citrate, and zinc bisulfite, and any combination thereof.

The tongue delivery forms and compositions of the present invention provide additional sweetness blocking duration (e.g., about 30 minutes or more, about 60 minutes or more, about 80 minutes or more, about 90 minutes or more, or about 120 minutes or more) while reducing or eliminating the bitter taste associated with gymnemic acid. It was surprisingly found that when a composition comprising a combination of gymnemic acid and one form of zinc is delivered to the oral cavity, the length of sweetness blockage can be extended to be longer than gymnemic acid or zinc alone, e.g. more than 80 minutes. Thus, the tongue delivery forms and compositions of the present invention have the ability to assist people in controlling their intake of sweet food and drink products with high calories.

One aspect of the invention is a tongue delivery form comprising gymnemic acid and one form of zinc. As used herein, the term "tongue" refers to any region of the oral cavity that contains taste receptors, including the tongue and any other region located therein. Oral cavity may include tongue, mouth, sublingual, etc. The term "tongue delivery form" as used herein refers to any solid or liquid form, or vehicle that can be used to deliver gymnemic acid, at least one additional sweetness inhibitor and any other components such as bitterness inhibitors or acidity inhibitors to taste receptors on the tongue and other taste receptors in the oral cavity of a subject.

Examples of such tongue delivery forms include, but are not limited to, lozenges, tablets, orally disintegrating tablets, orodispersible tablets, troches, hard candies, soft candies, jellies, chews, edible films, orally dissolvable films, wafers, drops, oral sprays, liquids, and powders. In some embodiments, the subject holds a solid tongue delivery form comprising gymnemic acid and one form of zinc in the oral cavity for about 3 to 5 minutes. In other embodiments, the subject holds a liquid tongue delivery form comprising gymnemic acid and one form of zinc in the oral cavity for about 3 to 5 minutes. In some other embodiments, the tongue delivery form is an orally disintegrating tablet having a disintegration time of from about 30 seconds to about 5 minutes. Disintegration times can be determined using the USP <2040> method for disintegrating and dissolving dietary supplements. Parameters for this method include deionized water, a temperature of 35-37 degrees celsius, and a number of samples greater than 6.

Another aspect of the present invention is a composition comprising gymnemic acid and a form of zinc, which may further comprise at least one additional sweetness inhibitor, with the proviso that the at least one additional sweetness inhibitor is not lactisole, sodium 3- (4-methoxyphenoxy) propionate, hodulicin or ziziphin.

Another aspect of the invention is a composition comprising gymnemic acid and one form of zinc and at least one acidity inhibitor.

The tongue delivery forms and compositions of the invention comprise gymnemic acid. Gymnemic acid, as used herein, refers to an extract of the plant gymnema sylvestre comprising one or more triterpenoid compounds capable of inhibiting the perception of sweetness in humans. Also contemplated are compositions comprising gymnemic acid comprising synthetic counterparts of these extracted triterpenoids. Examples of such compounds include, but are not limited to, compounds of formula (I):

wherein

(see Di Fabio et al, Molecules (2014)19: 10956-.

In some embodiments gymnemic acid for use in the tongue delivery forms and compositions of the invention comprises one or more compounds of formula (I) as described above. In other embodiments gymnemic acid comprises any one or any combination of gymnemic acid homologues, including but not limited to GA 1 (gymnemic acid I), GA 2 (gymnemic acid II), GA3 (gymnemic acid III), GA 4 (gymnemic acid IV) and GA34 (Gymnemoside C).

Gymnemic acid for use in the tongue delivery forms and compositions of the invention may be of any purity, i.e. content, of any combination of triterpenoid saponin substances, wherein purity is defined as the ratio of gymnemic acid to gymnemic acid and to the sum of other gymnema plant-derived substances. For example, gymnemic acid used may have the following purity: at least 20%, and at least 30%, at least 40%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 99%. In some embodiments, purity can be expressed in terms of weight% or regional% As (AUC). The purity of gymnemic acid can be determined by HPLC. In some embodiments, purity can be determined using USP <621> HPLC methodology. Preferably, HPLC is performed using a Waters XSelect CSH C18 column, 130A, 5 μm, 4.6mm X250 mm.

Gymnemic acid for use in the tongue delivery forms and compositions of the invention may be an inorganic salt, an ammonium salt, an amino salt including polyamino salts, organic salts, cyclodextrin complexes, cryptand complexes, hydrates or solvates of gymnemic acid, or any combination thereof. Examples of inorganic salts of gymnemic acid include, but are not limited to, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as magnesium and calcium salts, transition metal salts such as manganese, iron and zinc salts, and rare earth metal salts such as lanthanum, europium and terbium salts. Examples of ammonium salts of gymnemic acid include, but are not limited to, ammonium salts, monoalkyl-substituted ammonium salts such as methylammonium salts, dialkyl-substituted ammonium salts such as dimethylammonium salts, trialkyl-substituted ammonium salts such as trimethylammonium salts or tetraalkyl-substituted ammonium salts such as tetramethylammonium salts. Examples of polyamino salts of gymnemic acid include, but are not limited to, diamino salts such as ethylenediamine salts, triamino salts such as triethylenetetramine salts and other polyamino salts such as alpha-polyornithine salts, alpha-polylysine salts, gamma-polyornithine salts, -polylysine salts or chitosan salts. Examples of cyclodextrin complexes of gymnemic acid include, but are not limited to alpha-, beta-and gamma-cyclodextrin complexes of gymnemic acid. Examples of gymnemic acid solvates include the various ethanol solvates of gymnemic acid and the various ethyl acetate solvates of gymnemic acid. In some embodiments, gymnemic acid may be in the form of a proteinate having a protein with a pI of about 7 or greater.

In some embodiments of the present invention, the amino salt form of gymnemic acid may be a mono-alkyl substituted derivative of the amino salt form of gymnemic acid, a dialkyl substituted derivative of the amino salt form of gymnemic acid, or a trialkyl substituted derivative of the amino salt form of gymnemic acid. In other embodiments of the present invention the diamino salt form of gymnemic acid may be a mono-alkyl substituted derivative of the diamino salt form of gymnemic acid, a di-alkyl substituted derivative of the diamino salt form of gymnemic acid or a tri-alkyl substituted derivative of the diamino salt form of gymnemic acid. In other embodiments of the present invention the triamino salt form of gymnemic acid may be a mono-alkyl substituted derivative of the triamino salt form of gymnemic acid, a di-alkyl substituted derivative of the triamino salt form of gymnemic acid or a tri-alkyl substituted derivative of the triamino salt form of gymnemic acid. In other embodiments of the present invention the tetraamino salt form of gymnemic acid may be a mono-alkyl substituted derivative of the tetraamino salt form of gymnemic acid, a di-alkyl substituted derivative of the tetraamino salt form of gymnemic acid or a tri-alkyl substituted derivative of the tetraamino salt form of gymnemic acid. In other embodiments of the present invention the polyamino salt form of gymnemic acid may be a mono-alkyl substituted derivative of the polyamino salt form of gymnemic acid, a di-alkyl substituted derivative of the polyamino salt form of gymnemic acid or a tri-alkyl substituted derivative of the polyamino salt form of gymnemic acid.

Gymnemic acid is present in any effective amount to partially or completely block the perception of sweetness in a subject for a period of time. Examples of such amounts include, but are not limited to, those in the range of about 0.01% to about 25%, about 0.01% to about 10%, about 0.01% to about 4%, about 0.05% to about 2%, about 0.01% to about 1%, about 0.01% to about 0.5%, about 0.01% to about 0.2% by weight, based on the total weight of the tongue delivery form or composition. In some embodiments, gymnemic acid may be present in the tongue delivery form at about 0.1 wt% to 5 wt%, 0.01 wt% to 1 wt%, about 0.01 wt% to 0.5 wt%, or about 0.01 wt% to 0.2 wt%. In absolute terms, the tongue delivery forms and compositions of the invention may comprise from about 0.1mg to 200mg gymnemic acid, including but not limited to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150 or 200mg gymnemic acid. The amount of gymnemic acid in the tongue delivery forms and compositions of the invention may vary depending on the composition and the form of the composition (e.g. non-liquid or liquid). In this respect, the amount of gymnemic acid may vary depending on the use and the desired result. The remainder of the tongue delivery form may include other excipients including, but not limited to, sucrose, glucose, lactose, corn syrup solids, maltodextrin, sorbitol, xylitol, erythritol, and other sugars and polyols. In addition, tongue delivery forms may include flavoring agents such as peppermint, spearmint and menthol.

Many flavors such as vanilla and chocolate also require the presence of sweetness as a carrier, i.e., the flavor cannot be tasted unless sweetness is also present. However, mint does not require sweetness as a carrier, and thus can be tasted and enjoyed without the presence of sweetness. Thus, the tongue delivery form may further comprise peppermint. For example, the mint may be peppermint, spearmint, and menthol. Furthermore, although the addition of mint to gymnemic acid does not block the bitter taste, to the extent that no residual bitter taste is left upon application of a tongue delivery form comprising gymnemic acid and zinc forms, the mint will mask or block the bitter taste.

In some embodiments, the compositions of the invention comprise gymnemic acid, a form of zinc and at least one acidity inhibitor. Any sourness inhibitor known in the art may be used. Examples of such acidity inhibitors include, but are not limited to, thaumatin.

The tongue delivery forms and compositions of the invention comprising gymnemic acid and one form of zinc may further comprise at least one bitterness inhibitor. Any bitterness inhibitor known in the art may be used. Examples of such bitter taste inhibitors include, but are not limited to, sodium salts.

When included, the at least one bitterness inhibitor is present in any amount effective to reduce or eliminate the bitter taste of gymnemic acid. In some embodiments, the bitter suppressing agent is present in an amount of about 1 to about 200 mg. Specific examples of such amounts include, but are not limited to, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 150, or 200mg of the bitterness inhibitor. For example, a form of zinc, such as a zinc salt, may be present as a bitterness inhibitor in an amount of, for example, 0.2 wt.%, 1 wt.%, 2 wt.%, or 5 wt.%. In some other embodiments, when the bitterness inhibitor is a zinc salt, the zinc ion is present in an amount of 0.01% to 100%, or 1.0% to 75%, or 1.5% to 70%, or 2% to 65%, or 2.5% to 50% by weight. The percentage by weight of zinc ions is defined as the ratio of zinc ions to the sum of zinc ions plus gymnemic acid. Gymnemic acid content is determined according to the method described above and zinc ions are determined according to zinc ions as a percentage of the zinc form. For example, Zn²⁺Is zinc sulfate (ZnSO)₄) 40% of the molecular weight, 10mg of zinc sulphate is therefore equivalent to 4mg of Zn²⁺。

In some embodiments, the combination of forms of gymnemic acid and zinc act synergistically in terms of the length of sweetness blockage achieved. In some embodiments, such synergistic combinations will result in partial or complete suppression of the perception of sweetness in the subject for about 30 minutes or more, about 60 minutes or more, about 90 minutes or more, or about 120 minutes or more. In some embodiments, the combination of forms of gymnemic acid and zinc surprisingly acts synergistically to prolong the partial or complete blockade of sweetness in a subject for a longer period of time than gymnemic acid (in the absence of at least one other sweetness inhibitor and/or at least one acidity inhibitor and/or at least one bitterness inhibitor) administered to the oral cavity. Surprisingly, applicants have found gymnemic acid (15mg) and ZnSO₄·7H₂The combination of O (107mg) resulted in a complete blockade of sweetness at 60 minutes after administration, whereas the partial recovery of sweetness sensation at 60 minutes was found with administration of gymnemic acid only.

In some other embodiments, when the at least one other sweetness inhibitor is a zinc salt, the weight percentage of zinc ions is 0.01% to 100%, or 1.0% to 75%, or 1.5% to 70%, or 2% to 65%, or 2.5% to 50%. The weight percentage of zinc ions is defined as the ratio of zinc ions to the sum of zinc ions and gymnemic acid, and wherein the content of zinc ions and gymnemic acid is determined according to the method described above.

The methods of the invention comprise administering the tongue delivery forms and compositions to a subject. In one embodiment, the methods of administering the tongue delivery forms and compositions described above to a subject result in a subject's reduced appetite for sweet foods and beverages. In another embodiment, the methods of administering the tongue delivery forms and compositions described above to a subject result in reduced caloric intake in the subject because the subject is no longer craving for sweet foods. In another embodiment, the methods of administering the tongue delivery forms and compositions described above to a subject result in reduced dental caries in the subject due to less sweet food and beverages ingested (consume) by the subject. In some embodiments, the methods of the invention comprise contacting (e.g., treating, chewing, sucking, licking, etc.) the oral cavity of the subject with an amount of the tongue delivery form or composition. The oral cavity may include the tongue, the mouth (inside of the mouth), the mouth, under the tongue, and the like. In other embodiments, the composition is contacted with the oral cavity for a period of time ranging from about 1 minute to about 10 minutes. In other embodiments, the composition may be contacted with the oral cavity multiple times, such as by chewing different portions of the chew at different time frames over a period of time (e.g., multiple hours, days, etc.).

In some embodiments, the methods of the present invention provide a sweetness lock in a subject for a period of about 30-120 minutes or about 60-120 minutes when the composition is contacted with the oral cavity of the subject. In one embodiment, this time frame may begin when the composition is no longer in the mouth, such as when the chews are removed or when the lozenge undergoes complete dissolution.

The invention is further illustrated by the following examples, which should not be construed as limiting. The examples are set forth to provide those of ordinary skill in the art with an illustrative disclosure and description of how to practice the methods and use the compounds disclosed and claimed herein. Those skilled in the art will recognize that the invention may be practiced with variations of the disclosed structures, materials, compounds, and methods, and that such variations are considered to be within the scope of the invention. Unless otherwise indicated, parts are parts by weight, temperature is ° c, and pressure is at or near atmospheric. The standard temperature and pressure are defined as 20 ℃ and 1 atmosphere.

Examples

Formulation examples

Formulation FLLC-F27c 4mg (extended release formulation)

Excipient names	% ratio	Weight (gram)	40X gram	100X gram	240 Xg
						Active (tetra-ccl-15B) [ gymnemic acid]	0.800	0.0040	0.160	0.400	0.960
Sorbitol (Paratech S1150)	62.100	0.3105	12.420	31.050	74.520
						Erythritol and its preparation method	30.000	0.1500	6.000	15.000	36.000
Zinc gluconate	1.300	0.0065	0.260	0.650	1.560
						Firmenich peppermint	2.400	0.0120	0.480	1.200	2.880
Firmenich mint	2.400	0.0120	0.480	1.200	2.880
						Magnesium stearate	1.000	0.0050	0.200	0.500	1.200
Total of	100.000	0.5000	20.000	50.000	120.000

Comments

A 10mm female mold was used to make 500mg tablets.

The preparation process comprises the following steps:

the active ingredient was co-ground with 1 gram erythritol and zinc gluconate to a fine uniform powder

The remaining excipient was sieved through a 30 mesh screen. All excipients except magnesium stearate were then blended.

Blend for 30 minutes.

Adding magnesium stearate

Blending for 1 minute

Compressing the formulation into tablets

Taste blocking examples

Standard methods are established to quantify the duration of the blockade of sweetness of gymnemic acid compositions of the invention. The gymnemic acid fraction used in the examples described below was purified from a crude extract of gymnemic acid and was identified as a mixture of gymnemic acids (81% purity), mainly GA 1 and GA 2, with lesser amounts of GA3 and GA 4, and also including GA acetate/benzoate diesters (i.e. GA34-Gymnemoside C). In all cases, sucrose was used as a sweetener in sweetness blocking quantification. Thus, 10%, 8%, 6%, 4% and 2% (w/v) sucrose solutions in Reverse Osmosis (RO) purified water were freshly prepared and at the beginning of each experiment, 15mL samples of each sucrose solution were used to calibrate the sweetness intensity of the sensory panel. Sensory panelists are described as people who have sensory evaluation training experience for at least 1 year as sensory panelists in the gustation area, and preferably have descriptive analysis training. A standard scale method was used to quantify Sweetness Intensity (SI) on the following scales:

10 percent of cane sugar is 10 percent,

when 8 percent of cane sugar is 8 percent,

6 percent of sucrose is equal to 6 percent,

4 percent of sucrose is equal to 4 percent,

2% sucrose ═ 2, and

0% sucrose ═ 0.

After the panelists calibrated to the sucrose reference standard, the panelists rinsed their mouths with 15mL of RO water and then immediately put a sample of sweetness inhibitor in 15mL of RO water into the mouths and gently stir for 5 minutes. A sample of the sweetness inhibitor was then expectorated and immediately tasted again with 15mL of a 10% sucrose reference solution sample, the SI perceived within 15 seconds was graded on a 0-10 scale, the sample expectorated, and the mouth was rinsed vigorously with 15mL of RO water. The 10% sucrose sample was then tasted again every 15 minutes and rated SI. Panelists were asked to comment on the observation of non-sweet attributes at each sucrose reference test interval. SI results in experiments by this standard protocol are a simple way of rating SI.

Gymnemic acid exhibits a pronounced bitter off-taste. Scaling methodologies are employed to quantify the bitterness of gymnemic acid alone and in combination with various substances in an effort to identify gymnemic acid compositions with reduced or eliminated bitterness. In this methodology, sucrose was used as a scale reference. Thus, as above, the perception of bitterness with bitterness ratings of 10, 8, 6, 4, 2 and 0 is indicative, which equates to the perceived intensity of sweetness with 10, 8, 6, 4, 2 and 0% sucrose, respectively.

Comparative example 1 sweetness inhibition of gymnemic acid (15mg dose)

Gymnemic acid was evaluated to quantify the duration of its sweetness inhibition to determine a baseline value against which the following inventive examples were compared. The results obtained are summarized in table 1.

Table 1:

comparative example 2 sweetness inhibition of Lactisole (3mg dose)

Lactisole was evaluated to quantify the duration of its sweetness inhibition and thereby determine its potential value in combination with gymnemic acid. lactisole acts as a sweetness blocker unlike gymnemic acid, for example, the sweetness blocking provided by lactisole does not entangle after exposure to the tongue (linger). Surprisingly, however, no sweetness inhibition was observed after oral exposure to lactisone, even when the 10% sucrose reference was tasted immediately after the lactisone coughed out.

The results obtained are summarized in table 2.

TABLE 2

Example 1 sweetness inhibition of a blend of gymnemic acid (15mg) and Lactisole (3mg)

Gymnemic acid/lactisole blends were evaluated to quantify the duration of sweetness inhibition. The results obtained are summarized in table 3.

Table 3:

surprisingly, when a 10% sucrose reference sample was tasted immediately after treatment of the oral cavity with the gymnemic acid/lactisole blend, a sweet taste of weak to moderate intensity was observed and not tasteless, as was the case when the pre-treatment was carried out with gymnemic acid alone. This initial sweetness is significantly beneficial for improving the overall perception experience of the sweetness inhibiting composition and is not possible with gymnemic acid or other gymnemic acid formulations. Furthermore, it was surprisingly observed that although lactisole by itself did not cause sweetness inhibition after expectoration, the gymnemic acid/lactisole blend caused an extended duration of sweetness inhibition compared to the duration of sweetness inhibition using gymnemic acid alone. Thus, although the biochemical mechanism is not clear, it is clear that the combination of gymnemic acid with lactisole leads to a synergistic sweetness-inhibiting effect, wherein a weak sweetness is observed during the first 30 minutes after gymnemic acid/lactisole pre-treatment. This effect can be valuable for improving the overall sensory experience of sweetness-inhibited products formulated to provide prolonged sweetness blockade.

Comparative example 3 sweet taste suppression of Zinc sulfate heptahydrate (ZnSO) ₄ 7H ₂ O, 107mg dose)

Evaluation of ZnSO₄.7H₂O to quantify the duration of its sweetness inhibition and thereby determine its potential value in combination with gymnemic acid. Surprisingly, ZnSO was observed₄7H₂O, like gymnemic acid, does cause a prolonged suppression of sweetness although not close to the prolongation in the case of gymnemic acid, since after 60 minutes the sweetness sensitivity is 100% restored. The results obtained are summarized in table 4.

TABLE 4

Example 2 gymnemic acid (15mg) and ZnSO ₄ 7H ₂ Sweetness suppression of O (107mg) blends

Subsequent evaluation of gymnemic acid/ZnSO₄.7H₂Sweetness blocking duration for blends of O. The results are summarized in table 5.

Table 5:

surprisingly, complete blockade of sweetness was observed at 60 minutes when gymnemic acid alone was used, although at 60 minutesThis time partial recovery occurs. Thus, although the mechanism is not clear, ZnSO₄7H₂The combination of O and gymnemic acid clearly has a synergistic sweetness inhibiting effect.

Comparative example 4 sweetness suppression of miraculin (80mg dose)

Miraculin was evaluated to quantify the duration of its sweetness inhibition and thereby determine its potential value in combination with gymnemic acid. No sweetness-inhibiting effect was observed after oral cavity pretreatment with miraculin. The results obtained are summarized in table 6.

Table 6:

example 3 sweetness inhibition of a blend of gymnemic acid (15mg) and miraculin (80mg)

Even if no sweetness inhibiting effect was observed, the combination of miraculin and gymnemic acid was evaluated to determine if any prolongation of the sweetness inhibition duration of gymnemic acid was observed. It was observed that thaumatin did prolong the duration of the blockade of the sweetness of gymnemic acid. Thus, the combination of miraculin and gymnemic acid results in a synergistic inhibitory effect on sweetness. The results are summarized in table 7.

Table 7:

example 4 gymnemic acid (15mg), Lactisole (3mg) and ZnSO4.7H ₂ Sweetness of O (107mg) blend Suppression of

As demonstrated above, lactisole and ZnSO₄7H₂O, when combined independently with gymnemic acid, exhibits a synergistic effect of sweetness inhibition. Ternary blend compositions comprising combinations of these sweetness inhibitors with gymnemic acid were evaluated to determine if there was an increased synergistic effect. The results are summarized in table 8.

Table 8:

when the sweetness inhibition results of the ternary blend were compared to the results of examples 1 and 2, it was shown that no increased synergistic effect was observed. However, a significant advantage of the ternary blend formulation is that gymnemic acid is associated with lactisole and ZnSO₄7H₂The synergistic effect existing in the binary blend of O is retained, and the bitter off-flavor of gymnemic acid is completely inhibited.

Gymnemic acid, when used in liquid compositions or in the formulation of lozenges or tablets, exhibits a weak to moderate or even strong bitter off-taste, which limits its effective use in formulations designed to help consumers control their caloric sweet product intake.

Comparative example 5 bitterness of gymnemic acid (15mg dose)

A solution of 15mg gymnemic acid in 15mL RO water was evaluated and found to have a bitterness score of 10 on a bitterness 15 scale.

Example 5 gymnemic acid (15mg) and ZnSO ₄ 7H ₂ Bitterness of O (107mg) blend

A solution of 15mg gymnemic acid in 10mL RO water and 107mg ZnSO in 5mL RO water₄7H₂Solutions of O were combined and evaluated. A bitterness score of 0 was found. 60, 34, 19, 10.7, 6 and 3.4mg of ZnSO in 5mL of RO water, respectively₄7H₂Aqueous solution of O anda10 mL sample of RO water was combined with 15mg gymnemic acid. The resulting mixtures exhibited bitterness intensities of 0, 1, 4 and 7, respectively. Therefore, when ZnSO is used₄7H₂At O concentrations equal to or greater than about 0.6mg/mL (2mM), these gymnemic acids/ZnSO₄7H₂O compositions exhibit no bitter taste.

It should be emphasized that the above-described embodiments of the present invention are merely possible examples of implementations, merely set forth for a clear understanding of the principles of the disclosure. Many variations and modifications may be made to the above-described embodiments of the disclosure without departing substantially from the spirit and principles of the disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure.

Claims (25)

1. A composition comprising gymnemic acid and at least one form of zinc.

2. The composition of claim 1, wherein the delivery form is selected from the group consisting of: lozenges, orally disintegrating tablets, orodispersible tablets, troches, hard candies, soft candies, jellies, chews, edible films, orally dissolvable films, wafers, drops, oral sprays, liquids, powders, and combinations thereof.

3. The composition of claim 2, wherein the delivery form is an orally disintegrating tablet having a disintegration time of from about 30 seconds to about 5 minutes.

4. The composition of claim 1, wherein the form of zinc is selected from the group consisting of: zinc acetate, zinc carbonate, zinc chloride, zinc citrate, zinc gluconate, zinc sulfate, zinc dithionite, zinc bisulfite, zinc oxide, zinc halides, zinc hydride, zinc carbide, and combinations thereof.

5. The composition of claim 1 wherein said form of zinc is zinc gluconate.

6. The composition of claim 1, wherein said gymnemic acid is selected from the group consisting of: inorganic salts of gymnemic acid, organic salts of gymnemic acid, cyclodextrin complexes of gymnemic acid, cryptand complexes of gymnemic acid, hydrates of gymnemic acid, solvates of gymnemic acid, and combinations thereof.

7. The composition of claim 5, wherein said gymnemic acid solvate is selected from the group consisting of ethanolic gymnemic acid solvates and combinations thereof.

8. The composition of claim 1, wherein the delivery form further comprises peppermint.

9. The composition of claim 1, wherein the delivery form can further comprise a bitter suppressing agent selected from the group consisting of: sodium salts, lipoproteins, and combinations thereof.

10. The composition of claim 1 further comprising at least one acidity inhibitor.

11. The composition of claim 8 wherein the at least one acidity inhibitor is miraculin.

12. A tongue delivery form comprising the composition of claim 1.

13. The lingual delivery form of claim 12, wherein the delivery form is selected from the group consisting of: lozenges, orally disintegrating tablets, orodispersible tablets, troches, hard candies, soft candies, jellies, chews, edible films, orally dissolvable films, wafers, drops, oral sprays, liquids, powders, and combinations thereof.

14. The tongue delivery form of claim 13, wherein the delivery form is an orally disintegrating tablet having a disintegration time of from about 30 seconds to about 5 minutes.

15. The lingual delivery form of claim 12, wherein the form of zinc is selected from the group consisting of: zinc acetate, zinc carbonate, zinc chloride, zinc citrate, zinc gluconate, zinc sulfate, zinc dithionite, zinc bisulfite, zinc oxide, zinc halides, zinc hydride, zinc carbide, and combinations thereof.

16. The composition of claim 12 wherein said form of zinc is zinc gluconate.

17. The composition of claim 12, wherein said gymnemic acid is selected from the group consisting of: inorganic salts of gymnemic acid, organic salts of gymnemic acid, cyclodextrin complexes of gymnemic acid, cryptand complexes of gymnemic acid, hydrates of gymnemic acid, solvates of gymnemic acid, and combinations thereof.

18. The composition of claim 17, wherein said gymnemic acid solvate is selected from the group consisting of ethanolic gymnemic acid solvates and combinations thereof.

19. The composition of claim 12, wherein the delivery form may further comprise peppermint.

20. The composition of claim 12, wherein the delivery form can further comprise a bitter suppressing agent selected from the group consisting of: sodium salts, lipoproteins, and combinations thereof.

21. The composition of claim 12 further comprising at least one acidity inhibitor.

22. The composition of claim 21 wherein the at least one acidity inhibitor is miraculin.

23. A method of reducing sugar uptake comprising administering the composition of claim 1 to a subject.

24. A method of reducing caloric intake comprising administering the composition of claim 1 to a subject.

25. A method of reducing dental caries comprising administering the composition of claim 1 to a subject.