BE1030928B1 - SOFT GUMMY - Google Patents

Abstract

The present invention relates to a soft gummy for oral use, wherein the soft gummy comprises an outer shell encapsulating an inner liquid, the outer shell comprising 0.5-25% by weight of pectin with respect to the weight of the outer shell and having a viscosity of 25-1000 Pa·s measured at 20°C and wherein said inner fluid has a moisture content of 5-99 wt.% as measured according to ISO 760:1978 and a viscosity of 0.01-20 Pa·s measured at 20°C .

Description

1 BE2022/5913

SOFT GUMMY

FIELD OF THE INVENTION

The present invention relates in a first aspect to a soft gummy for therapeutic oral use. In a second aspect, the present invention also relates to a use of a soft gummy for therapeutic oral use.

BACKGROUND

Medicines typically include drugs with analgesic and fever-reducing properties, such as ibuprofen (IBU), but also active substances of natural origin such as dry extracts of ivy willow are more common for this medical purpose. The medicines are offered in liquid or solid form, such as syrups, sprays, tablets, pills, capsules, pastilles or hard candies, starch cast strips.

Individuals may have difficulty swallowing tablets and capsules, especially if they are large. Avoiding taking medications may lead to low drug efficacy, which may lead to prolonged or worsening of symptoms and/or failure to treat or cure the indicated condition.

Syrups do not have these swallowing problems. Syrups also offer a mechanical mode of action; by providing a sweet and soothing layer to the throat, providing immediate relief from dry coughs and/or sore throats. However, syrups are generally sticky liquids that are difficult to handle, difficult to dose accurately, and cannot be used discreetly.

Hydrophilic cellulose polymers are commonly used as the excipient base in tableted slowly eroding matrix systems. The effectiveness of these erodible hydrophilic matrix systems is due to a sequential physicochemical process of hydration of the cellulose polymers. US9877971 describes sustained-release oral pharmaceutical compositions suitable for chewing or sucking, consisting of soft non-systemic corticosteroid lozenges. Said composition includes gelatins, plasticizers, sweeteners, corticosteroids, release modifiers, pH modifiers and water. The

2 BE2022/5913 composition disintegrates orally within approximately 30-45 minutes after oral administration to a patient in need thereof. It is known that gelatin-based gels are not suitable for encapsulating fillings with a high moisture content. Water can migrate and destroy the gelatin structure.

Another problem concerns active pharmaceutical ingredients (APIs) that lose their active properties or are completely lost due to the physical conditions (e.g. temperature, humidity, flow, etc.) present during the development and /or production phase of the formulation. Exposure to extreme temperatures and humidity causes structural degradation and changes in the chemical behavior of an API. For example, certain APIs have shown that they are not suitable for hot melt extrusion, a common production method for polymers.

In addition, certain APIs also chemically interact with residual solvents commonly used for polymer processing, or in certain cases the APIs may even react with the polymer itself when coupled together. All these situations lead to impurities in the API formulation that have no therapeutic value and may even be harmful (i.e. genotoxic).

The present invention aims to find a solution for at least some of the above-mentioned problems and disadvantages.

SUMMARY OF THE INVENTION

The present invention and embodiments thereof serve to provide a solution for one or more of the above-mentioned disadvantages. To this end, the present invention relates in a first aspect to a soft gummy according to claim 1.

The soft gummy of claim 1 provides an easy-to-use dosage form. There is no need to handle or dose sticky liquids or swallow large pills or capsules. The soft gummy combines the advantages of a solid dosage form, i.e. ease of use, reduced risk of spillage, improved dosage control and single dose packaging, with the advantages of a syrup, i.e. application of a sweet syrup that can provide relief from many symptoms.

3 BE2022/5913

The soft gummy according to claim 1 is designed to disintegrate in the oral cavity. Soft gummies can be chewed or dissolved slowly in the mouth. When the outer shell breaks, the inner fluid is immediately released into the oral cavity, providing immediate relief as usual with syrups.

These dosage forms are flavorable and thus can be administered to both pediatric and geriatric patients. The advantage is that the outer shell exhibits excellent chemical and physical properties. The outer shell in particular forms a strong capsule that allows the storage of a relatively large amount of liquid with a high moisture content. Although center-filled gels are known, the amount of liquid and their moisture content is usually too limited.

Said outer shell exhibits excellent chemical and physical properties.

The outer shell creates a strong capsule around the inner liquid that bursts.

Preferred embodiments of the soft gummy are shown in any of claims 2-13.

In a second aspect, the present invention relates to a use according to claim 14. The soft gummy can be used for many applications. The composition can be easily adapted to include multiple components, even if these components would otherwise not be suitable for mixing in one dosage. The therapeutic oral use of said soft gummy is suitable to prevent or reduce many symptoms, for example caused by many respiratory diseases or infections of the gastrointestinal tract. Furthermore, active ingredients can be absorbed into the inner liquid.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise defined, all terms used in the description of the invention, including technical and scientific terms, have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains. As further guidance, term definitions are included to better appreciate the teachings of the present invention.

As used herein, the following terms have the following meanings:

4 BE2022/5913 'A', 'the' and 'het', as used herein, include both singular and multiple referents, unless the context clearly indicates otherwise. By way of example, 'a sub-fund' refers to one or more than one sub-fund. 'Include', 'comprising' and 'includes' and 'consisting of' as used herein are synonymous with 'include', 'containing' 'entails' or 'containing', 'containing', 'containing' and are inclusive or open terms that specify the presence of what follows (e.g., a component) and do not exclude the presence of additional, unnamed components, features, elements, parts, steps, which are well known in the art or described therein out.

Quoting numerical ranges by endpoints includes all numbers and fractions included within that range, as well as the quoted endpoints.

The expression 'weight%', 'weight%', 'wt%', '%wt' or 'wt%', here and in the description, unless otherwise defined, refers to the relative weight of the respective component based on total weight of the formulation. 'Pectin' is a heterogeneous complex polysaccharide found in higher plants, but commercially it is most commonly derived from citrus fruit peels or apple pulp. Structurally, pectin is composed of linear segments of 1,4-linked α-D-galactopyranosyluronic acid units in which some of the carboxyl groups are esterified with methanol. 'Tannins' are widespread in plants and can be divided into 3 groups: hydrolyzable tannins, condensed tannins and phlorotannins. 'Hydrolyzable tannins' are a group of compounds formed by phenolic acids and their derivatives via glycosidic bonds or ester bonds with glucose or polyols. They are further subdivided into gallotannins containing only galloyl groups, ellagitannins containing hexahydroxydiphenoyl group(s) and hydrolyzable tannin oligomers which are subdivided into dimers, trimers and tetramers according to the number of glucose nuclei. Examples of hydrolyzable tannins are pentagalloylglucose, pedunculagin, castalin and castalagin. A source of hydrolyzable tannin is any food-grade plant extract that contains hydrolyzable tannins. Hydrolyzable tannins can be extracted from a wide variety of vegetable plants, such as chestnut wood (Castanea sativa), oak wood (Quercus robur, Quercus petraea and Quercus alba), tara pods (Caesalpinia spinosa), gall nuts (Quercus infectoria and Rhus semialata), myrobalan

(Terminalia chebula), sumac (Rhus coriaria) and Aleppo gall nuts (Andricus kollari).

Any suitable extract from these plants, which still contains the hydrolyzable tannins, falls within the definition of 'source of hydrolyzable tannins'. When the amount of hydrolyzable tannins is specified, it refers to the weight of the hydrolyzable tannins, excluding plant extract and other compounds not included in the group of hydrolyzable tannins.

The term 'active pharmaceutical ingredient' (API) is used interchangeably with the terms 'drug', 'drug', 'compound', 'therapeutic agent', etc. It includes small molecules, either free base, free acid, or pharmaceutically acceptable salts or solvates thereof, large molecules, such as peptides and proteins, nucleosides, nucleotides, or the like. first aspect

In a first aspect, the invention relates to a soft gummy for oral use, wherein the soft gummy comprises an outer shell encapsulating an inner liquid. In one embodiment, the outer shell comprises 0.5-25% by weight pectin relative to the weight of the outer shell and has a viscosity of 25-1000

Pa:s measured at 20°C. In one embodiment, said inner fluid has a moisture content of 5-99% by weight as measured according to ISO 760:1978 and a viscosity of 0.01-20 Pa:s measured at 20°C.

The soft gummy provides a double effect, each phase can be assigned a special function. For example, the inner fluid may contain components that are suitable for immediate operation and the components in the outer shell can provide long-term operation. The soft gummy is safe because it is easy to chew and poses little choking hazard. The soft gummy is convenient to dose, especially for water-based liquids. Therapy compliance is improved by chewability and optimal taste. The combination of incompatible ingredients in a single dose is possible as one ingredient can be stored per phase. The soft gummy provides a solution to pre-dissolve ingredients.

The inventors have found that pectin is suitable for forming a gel suitable for containing a liquid with a high moisture content. Moreover, this gel remains stable for a sufficiently long time. The resulting outer shell exhibits excellent properties to release the inner liquid in the mouth. The outer shell is strong enough to store the inner liquid for long periods of time, limiting moisture penetration through the outer shell. When it

6 BE2022/5913 is placed in the mouth, the outer shell will crack and the inner liquid will be spread over the mouth. The inner liquid, preferably a syrup, can form a thin layer in the throat, immediately eliminating bad breath or relieving an irritated or sore throat.

The outer shell, if not chewed through, will slowly erode in saliva.

When the outer shell cracks, the inner fluid is suddenly released. As such, the soft gummy provides a dosage of inner liquid suitable for oral delivery, with the inner liquid being provided from the oral cavity.

The outer shell exhibits excellent properties for encapsulating an inner liquid. The outer shell provides an oxygen-free environment for the inner liquid, improving shelf life. The soft gummy for therapeutic oral use contains a predetermined amount of inner liquid.

So the amount of the inner liquid is strictly regulated and controlled. If there is an active pharmaceutical ingredient (API) in the inner liquid, the dosage of this API can be strictly controlled. Human error is less likely to affect the dose taken and special measuring instruments or cups are not necessary. Differences in household spoons cannot affect the dose. In addition, the soft gummy is not sticky and cannot be spilled, while conventional syrups can cause these problems.

Pectin has a complex heterogeneous structure and is mainly composed of polygalacturonic chains with a wide range of molecular weights. Some of the carboxyl groups are esterified with methyl alcohol, some are neutralized with cations and some are free acids. Pectins are predominantly linear polymers of mainly α-(1-4)-linked D-galacturonic acid residues interrupted by 1,2-linked L-rhamnose residues.

In a preferred embodiment, the inner fluid has a viscosity of 0.01-20 Pa:s (Pa.s) measured at 20°C. Because the inner fluid has a viscosity of up to 20 Pa:s measured at 20°C, the inner fluid is suitable to burst from the outer shell when the outer shell tears. The inner fluid has a sufficiently lower viscosity to produce a bursting effect. When the soft gummy bursts, a liquid syrup is noticeably spread throughout the oral cavity and later down the throat. This further enhances the rapid formation of a soothing layer over the pharynx, providing immediate relief. In a

7 BE2022/5913 preferred embodiment, the inner liquid has a viscosity of maximum 18

Pa:s measured at 20°C, more preferably a viscosity of maximum 15 Pa:s measured at 20°C, more preferably a viscosity of maximum 10 Pa:s measured at 20°C, more preferably a viscosity of maximum 8 Pa:s measured at 20°C, more preferably a viscosity of maximum 6 Pa:s measured at 20°C, more preferably a viscosity of maximum 5 Pa:s measured at 20°C. The viscosity is preferably measured according to ISO2555. In one embodiment, the viscosity of the inner fluid measured at 20°C is between 0.1 and 15.0 Pass, preferably between 0.5 and 10.0 Pa:s and more preferably between 1.0 and 10.0 Pa:s :s.

Tannin

In one embodiment, the soft gummy comprises a hydrolyzable tannin or a source of hydrolyzable tannin. In one embodiment, the soft gummy comprises a hydrolyzable tannin. In one embodiment, the inner fluid comprises hydrolyzable tannin or a source of hydrolyzable tannin. The hydrolyzable tannin is suitable for soothing damaged mucus layers by tightening the tissue. The combination of pectin with a hydrolyzable tannin produces synergistic results. In one embodiment, the outer shell comprises a hydrolyzable tannin. The inventors have unexpectedly found that the combination of pectin, a hydrolyzable tannin and a source of sugar creates a strong and stable gel, capable of retaining liquids, even with a high moisture content. In other words, hydrolyzable tannin aids in the gelation of pectin. Furthermore, the inventors have noted that hydrolyzable tannin in the inner liquid can still provide a thin impermeable layer at the gel-liquid interface between outer shell and inner liquid. In a more preferred embodiment, the hydrolyzable tannin or source of hydrolyzable tannin is tannic acid.

In one embodiment, the hydrolyzable tannins include gallotannins.

Gallotannins include galloyl groups. In one embodiment, the hydrolyzable tannins include ellagitannins. Ellagitannins include hexahydroxydiphenoyl groups. In one embodiment, the hydrolyzable tannins comprise two glucose nuclei. In one embodiment, the hydrolyzable tannins include tannins with three glucose nuclei. In one embodiment, the hydrolyzable tannins include tannic acid.

In one embodiment, the outer skin and/or the inner liquid comprises a hydrolyzable tannin or a source of hydrolyzable tannin, wherein the

8 BE2022/5913 hydrolyzable tannin is present in an amount of 0.2-20% by weight relative to the weight of the soft gummy, preferably 0.3-10% by weight. In one embodiment, the outer shell comprises hydrolyzable tannin or a source of hydrolyzable tannin, wherein the hydrolyzable tannin is present in an amount of 0.2-20% by weight relative to the weight of the soft gummy, preferably 0.3-10 wt%. In one embodiment, the inner liquid comprises hydrolyzable tannin or a source of hydrolyzable tannin, wherein the hydrolyzable tannin is present in an amount of 0.2-20% by weight relative to the weight of the soft gummy, preferably 0.3-10 wt%.

Pectin

In one embodiment, this pectin is selected from the group of: high methoxyl pectin (HM), low methoxyl pectin,

LM) or low methoxyl amidated pectin (LMA).

High methoxyl pectin (HM) is a type of pectin with a degree of methoxylation (DM) of more than 50%. The DM refers to the number of carboxyl groups esterified with methanol on the pectin-galacturonic acid backbone. HM pectins require a system with greater than 55% solids and a low pH to gel. Low methoxyl pectins (LM) are pectins with a DM lower than 50% (less than 50% of the carboxyl groups are methoxylated). LM pectins gel in the presence of calcium ions, as well as with sugars and acids, but their distinguishing feature is the ability to gel in systems with low soluble solids. Low methoxyl amidated (LMA) pectin is a type of pectin similar to the LM pectins, although some of the free carboxyl groups are 'amidated', meaning they have -CONHz groups on them. LMA pectins also require calcium ions to gel, although usually much less than LM pectins. In one embodiment, said pectin is high methoxyl pectin (HM). In one embodiment, said pectin is high methoxyl pectin (HM), wherein said high methoxyl pectin (HM) has a degree of esterification (DE) of at least 60, more preferably said HM pectin has a degree of esterification of at least 65 , more preferably said HM pectin has a degree of esterification of at least 70, more preferably said HM pectin has a degree of esterification of at least 75, more preferably said HM pectin has a degree of esterification of at least 80, more preferably said HM pectin has a degree of esterification of at least 85. It turned out that a higher degree of esterification

9 BE2022/5913 resulted in an outer shell with better chemical and mechanical properties, in particular a longer shelf life of the soft gummy.

In a preferred embodiment, said pectin is high methoxyl pectin (HM), said high methoxyl pectin (HM) is at least partially cross-linked, preferably said cross-linking is supported by said hydrolyzable tannin. Because the HM pectin is at least partially cross-linked, the outer shell is elastic and less brittle. The soft gummy has improved mechanical strength properties thanks to this crosslinking. In one embodiment, the HM pectin is at least partially cross-linked to the hydrolyzable tannin. The resulting product acquires a greater compressive modulus than the HM pectin alone. In one embodiment, the pectin and a hydrolyzable tannin are at least partially cross-linked. In one embodiment, the pectin and a hydrolyzable tannin are chemically cross-linked. In one embodiment, the pectin and a hydrolyzable tannin are physically cross-linked.

In one embodiment, the pectin is extracted from biomass via microwave-assisted extraction, enzymatic extraction, supercritical water extraction or ultrasonic extraction. In another embodiment, the pectin is extracted from biomass via hydrolysis with acids and then precipitated with ethanol. In one embodiment, the pectin is extracted from biomass selected from: apple, pear, citrus, chicory, cauliflower, orange, lemon, cocoa, beet, melon, watermelon and passion fruit. dicarboxylic acid

In one embodiment, the outer shell further comprises a dicarboxylic acid or a tricarboxylic acid. The dicarboxylic acid or tricarboxylic acid improved gel formation and resulted in a stronger and more elastic outer shell. In one embodiment, the outer shell further comprises a dicarboxylic acid, preferably a linear saturated dicarboxylic acid, more preferably oxalic acid, malonic acid, succinic acid, glutaric acid or adipic acid. In one embodiment, said outer shell further comprises a dicarboxylic acid, preferably an unsaturated dicarboxylic acid, more preferably maleic acid, fumaric acid, glutamic acid, traumatic acid or citraconic acid. In one embodiment, the outer shell further comprises a dicarboxylic acid, preferably a substituted dicarboxylic acid, more preferably tartronic acid, mesoxalic acid, malic acid, tartaric acid or glutamic acid. In one embodiment

The outer shell mentioned in BE2022/5913 furthermore contains a tricarboxylic acid, preferably citric acid, isocitric acid, aconitic acid or agaricic acid. In a preferred embodiment, the outer shell comprises a dicarboxylic acid or tricarboxylic acid in an amount of at least 0.05% by weight with respect to the weight of the outer shell, more preferably in an amount of at least 0.1% by weight with respect to the weight of the outer shell, more preferably in an amount of at least 0.3% by weight relative to the weight of the outer shell, more preferably in an amount of at least 0.5% by weight relative to the weight of the outer shell, more preferably in an amount of at least 0.8% by weight relative to the weight of the outer shell, more preferably in an amount of at least 1.0% by weight relative to the weight of the outer shell . other features

In one embodiment, said inner liquid has a moisture content of at least 10% by weight relative to the weight of the inner liquid, as measured according to ISO 760:1978. Because the outer shell contains a combination of pectin and a hydrolyzable tannin, the outer shell is suitable for containing an inner liquid with a moisture content of more than 10% by weight, measured according to

ISO 760:1978, can be encapsulated for a longer period of time. Other materials, such as gelatin, can also form an outer shell, but gelatin outer shells would not be suitable for encapsulating a liquid of such moisture content for extended periods of time. The water would migrate and could hydrolyze the outer shell. In a preferred embodiment, the inner fluid has a moisture content of at least 11% by weight relative to the weight of the inner fluid as measured according to ISO 760:1978, more preferably a moisture content of at least 12% by weight relative to the weight of the inner liquid as measured according to ISO 760:1978, more preferably a moisture content of at least 13% by weight with respect to the weight of the inner liquid as measured according to ISO 760:1978, more preferably a moisture content of at least 14% by weight with respect to relative to the weight of the inner fluid as measured according to ISO 760:1978, more preferably a moisture content of at least 15% by weight relative to the weight of the inner fluid as measured according to ISO 760:1978, more preferably a moisture content of at least at least 16% by weight relative to the weight of the inner liquid as measured according to ISO 760:1978. In another preferred embodiment, the moisture content is a maximum of 30% by weight with respect to the weight of the inner liquid as measured according to ISO 760:1978, more preferably the moisture content is a maximum of 25% by weight with respect to the weight of

11 BE2022/5913 the inner liquid as measured according to ISO 760:1978, most preferably the moisture content is a maximum of 20% by weight compared to the weight of the inner liquid as measured according to ISO 760:1978.

In a preferred embodiment, the inner fluid has a viscosity of at most 50 Pa:s (Pa.s) measured at 20°C. Because the inner fluid has a viscosity of maximum 50 Pa:s measured at 20°C, the inner fluid is suitable to burst from the outer shell when the outer shell tears. The inner fluid has a sufficiently lower viscosity to produce a bursting effect. When the soft gummy bursts, a liquid syrup is noticeably spread throughout the oral cavity and later down the throat. This further enhances the rapid formation of a soothing layer over the pharynx, providing immediate relief. In a preferred embodiment, the inner liquid has a viscosity of maximum 25

Pa s measured at 20°C, more preferably a viscosity of a maximum of 20 Pas measured at 20°C, more preferably a viscosity of a maximum of 10 Pa s measured at 20°C, more preferably a viscosity of a maximum of 8 Pa s measured at 20°C, more preferably a viscosity of maximum 6 Pa s measured at 20°C, more preferably a viscosity of maximum 5 Pa s measured at 20°C. The viscosity is preferably measured according to ISO2555. In one embodiment, the viscosity of the inner liquid measured at 20°C is between 0.1 and 50.0 Pa:s, preferably between 0.5 and 25.0 Pa:s and more preferably between 1.0 and 10. 0 Pa:s.

In a preferred embodiment, the soft gummy comprises the inner liquid in an amount of at least 0.1 g, more preferably at least 0.2 g, more preferably at least 0.3 g, more preferably at least 0.4 g, more preferably at least 0.5 g, more preferably at least 0.6 g, more preferably at least 0.7 g, more preferably at least 0.8 g, more preferably at least 0.9 g, more preferably at least 1.1 g, more preferably at least 1.29, more preferably at least 1.3 g, more preferably at least 1.4 g, more preferably at least 1.5 g, with more preferably at least 1.6 g, more preferably at least 1.7 g, more preferably at least 1.8 g, more preferably at least 1.9 g, more preferably at least 2.0 g. An advantage of the present invention is the ability to store and deliver a relatively large amount of liquid with a relatively high moisture content to the oral cavity compared to the prior art. This is necessary to deliver sufficient syrup to the oral cavity to obtain the benefits of the mechanical action of syrup, and to generally be able to administer higher doses.

12 BE2022/5913

In a preferred embodiment, the soft gummy comprises the inner liquid in an amount of at least 5% by weight relative to the weight of the soft gummy, more preferably in an amount of at least 10% by weight relative to the weight of the soft gummy, more preferably in an amount of at least 15% by weight relative to the weight of the soft gummy, more preferably in an amount of at least 20% by weight relative to the weight of the soft gummy, with more preferably in an amount of at least 25% by weight relative to the weight of the soft gummy, more preferably in an amount of at least 30% by weight relative to the weight of the soft gummy, more preferably in an amount of at least 35% by weight relative to the weight of the soft gummy, more preferably in an amount of at least 40% by weight relative to the weight of the soft gummy, more preferably in an amount of at least 45 wt% relative to the weight of the soft gummy, more preferably in an amount of at least 50 wt% relative to the weight of the soft gummy, more preferably in an amount of at least 55 wt% relative to the weight of the soft gummy, more preferably in an amount of at least 60% by weight relative to the weight of the soft gummy, more preferably in an amount of at least 65% by weight relative to the weight of the soft gummy, more preferably in an amount of at least 70% by weight relative to the weight of the soft gummy. Larger amounts of inner fluid are desirable when both mechanical and pharmaceutical modes of action are desired. A mechanical mode of operation generally requires a larger amount of fluid. To ensure that the soft gummy remains manageable in size and weight, larger relative amounts of inner liquid are therefore desirable or necessary.

In a preferred embodiment, the soft gummy comprises the inner liquid in an amount of up to 90% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 85% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 80% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 75% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 70% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 65% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 60% by weight compared to the weight of the soft

13 BE2022/5913 gummy, more preferably in an amount of maximum 55% by weight relative to the weight of the soft gummy, more preferably in an amount of maximum 50% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 45% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 40% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 35% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 30% by weight relative to the weight of the soft gummy. The trade-off for large amounts of inner fluid is lower long-term stability and greater difficulty with quality assurance. In particular, reducing the amount of outer shell material increases the chance of the soft gummy prematurely cracking, breaking, or leaking.

When the inner liquid is a syrup, it results in a sticky, difficult to clean and very unpleasant mess. A single soft gummy that bursts in a jar, bag, or other type of bulk container can easily ruin the contents of all other items inside. It is therefore very important that both sufficient strength and long-term stability are guaranteed. As a result, commercial products are typically oversized compared to laboratory counterparts. While it is possible to produce gels with a large amount of inner liquid on a laboratory scale, it is much more difficult to produce such soft gummies in bulk, while ensuring long-term stability and avoiding premature leakage.

In a preferred embodiment, the weight ratio of the outer shell to the inner liquid is a maximum of 100 to 1, more preferably a maximum of 75 to 1, more preferably a maximum of 50 to 1, more preferably a maximum of 25 to 1, more preferably a maximum of 20 to 1, with more preferred maximum 15 to 1, more preferred maximum 10 to 1, more preferred maximum 9 to 1, more preferred maximum 8 to 1, more preferred maximum 7 to 1, more preferred maximum 6 to 1, more preferred a maximum of 5 to 1, more preferably a maximum of 4 to 1, more preferably a maximum of 3.5 to 1, more preferably a maximum of 3.0 to 1, more preferably a maximum of 2.5 to 1, more preferably a maximum of 2.0 to 1, more preferably a maximum of 1.5 to 1, more preferably a maximum of 1.0 to 1. A low ratio of outer shell to inner liquid is desirable when the mode of action is directed towards the inner liquid, i.e. in the case of a syrup.

However, a low outer shell to inner liquid ratio is generally difficult to achieve, especially when stability is concerned. In general, reducing the ratio of the outer shell material to the

14 BE2022/5913 inner fluid material the permeability through the outer shell and therefore the migration of moisture from the inner fluid. In addition, reducing the ratio of the outer shell to the inner fluid material increases the risk of the outer shell cracking or breaking at times where it should not.

In one embodiment, the soft gummy consists of an inner liquid and an outer shell, wherein the weight ratio of the inner liquid over the outer shell is between 1:1 and 1000:1, preferably between 5:1 and 100:1.

In one embodiment, the soft gummy comprises compositions with multiple actions. In one embodiment, each phase is assigned a special function. In one embodiment, the inner liquid contains compounds with an immediate action, such as sugars, and the outer shell contains compounds with a long-term action, such as fats. In one embodiment, the soft gummy includes a combination of incompatible ingredients. The soft gummy has the advantage of being able to deliver two or more incompatible ingredients in a single dose. It is possible to dissolve ingredients in advance. The soft gummy also provides convenient dispensing of water-based liquids.

Nevertheless, the soft gummy is easy to chew and has an optimal taste with little choking hazard. In one embodiment, the soft gummy is vegetarian. In one embodiment, the soft gummy is essentially free of gelatin.

In one embodiment, the soft gummy is vegan. In one embodiment, the soft gummy is essentially free of carbohydrates with 12 or fewer carbon atoms.

In one embodiment, the soft gummy disintegrates orally within about 1-10 minutes after oral administration to a patient in need thereof, preferably within 2-6 minutes. The soft gummy has a faster disintegration time compared to most gelatin-based pharmaceutical formulations.

This may be particularly useful for delivering API to the esophagus and oral cavity of impatient people, such as pediatric patients.

In one embodiment, the soft gummy comprises a carbohydrate. Examples of the carbohydrate that can be used include saccharides such as sugar, sucrose, glucose, fructose, trehalose and palatinose; sugar alcohols such as xylitol, maltitol, sorbitol, erythritol, lactitol and reduced palatinose; starch syrup, reduced starch syrup and maltitol syrup. In addition, acidifying agents such as citric acid, malic acid, fumaric acid and tartaric acid; high-intensity sweeteners such as aspartame, acesulfame potassium, sucralose, neotame and stevia; polysaccharides such as oligosaccharides; plasticizers such as glycerine; natural colors; artificial

15 BE2022/5913 colours; and functional materials such as plant extracts can be used arbitrarily as needed.

In one embodiment, the soft gummy includes crystalline sugar alcohols such as xylitol, erythritol, sorbitol and lactitol; and non-crystalline sugar alcohols such as maltitol syrup and reduced starch syrup.

In one embodiment, the soft gummy comprises a gelatinizing agent, wherein the gelatinizing agent is selected from the group consisting of gelatin, gum arabic, agar and carrageenan.

In one embodiment, the pressure within the soft gummy is greater than 1 atm, preferably between 1.01 and 1.10 atm.

In one embodiment, the thickness of the outer shell is 0.1-2.5 mm, preferably 0.3 to 1.2 mm.

In some embodiments, the soft gummy further includes a humectant. In some embodiments, the humectant is selected from propylene glycol, propylene glycol alginate, glycerol, sorbitol, polyethylene glycol, maltitol syrup, lecithin and any combination thereof. In some embodiments, the soft gummy includes the humectant in an amount ranging from about 0.1% w/w to about 20% w/w. In some embodiments, the soft gummy further comprises an acidity regulator. In some embodiments, the acidity regulator is one or more acids selected from citric acid, fumaric acid, malic acid, phosphoric acid, succinic acid, tartaric acid, maleic acid, acetic acid, hydrochloric acid, lactic acid, propionic acid, salts thereof, and derivatives thereof. In some embodiments, the acidity regulator is malic acid, salts thereof, or derivatives thereof. In some embodiments, the acidity regulator is citric acid, salts thereof, or derivatives thereof. In some embodiments, the acidity regulator is succinic acid, salts thereof, or derivatives thereof. In some embodiments, the soft gummy further comprises one or more base carriers. In some embodiments, the base carrier(s) is selected from maltitol, maltodextrin, maltitol syrup, corn syrup, xylitol, sucrose, dextrose, maltose, fructose, mannitol, erythritol, glycerol, isomalt, polydextrose, lactitol, lycasin, sorbitol, and any combination thereof. . In one embodiment, the soft gummy comprises 0.1-30% by weight of one or more base carriers, preferably 1-10% by weight. In some embodiments, the soft gummy further comprises one or more sweeteners. In some embodiments

16 BE2022/5913, the one or more sweeteners are selected from sucrose, aspartame, sucralose, saccharin, sodium saccharin, acesulfame potassium, stevia, sodium cyclamate, inulin, isomalt, maltose, neohesperidin dihydrochalcone, trehalose, thaumatin, sorbitol, maltitol, and any other combination thereof. In one embodiment, the soft gummy comprises 0.01-20% by weight of one or more sweeteners, preferably 0.1-2% by weight. In some embodiments, the soft gummy further comprises a flavoring agent. In some embodiments, the flavoring comprises one or more flavors selected from a mixed berry flavor, a mulberry flavor, a cherry flavor, a strawberry flavor, a citrus flavor, a lemon flavor, a lime flavor, an orange flavor, a grape flavor, a vanilla flavor, a chocolate flavor, a caramel flavor, a mint flavor, a spearmint flavor, a wintergreen flavor and a menthol flavor. In one embodiment, the soft gummy comprises 0.1-20% by weight of one or more flavorings, preferably 0.1-10% by weight. In some embodiments, the soft gummy further comprises one or more colorants. In some embodiments, the one or more colorants are selected from FD&C Red 40, D&C Red 3, 22, 28, 33 and 36, FD&C Yellow 5 and 6, D&C Yellow 10, FD&C Blue 1 and 2, FD&C Green 3, iron oxide red, caramel , beta-carotene, carmine and any combination thereof. In one embodiment, the soft gummy comprises 0.1-20% by weight of one or more colorants, preferably 0.1-5% by weight. In one embodiment, the inner liquid comprises 0.001-0.5% by weight of dyes relative to the weight of the inner liquid. natural product

In one embodiment, the soft gummy comprises a natural product, preferably a plant. In one embodiment, the soft gummy comprises any part of a plant that may be suitable for human or animal consumption. In one embodiment, the soft gummy comprises an extract of a plant that may be suitable for human or animal consumption. A plant can consist of fruits, vegetables, seeds, grains and legumes. In some embodiments, the plant, such as a fruit or vegetable, can be left whole, or cut into pieces, such as slices, strips, rings, cubes, disks, straws, fingers, or wedges, or ground into a powder. The size of the pieces will depend on the size of the whole vegetable product, but can typically have a thickness of 0.002-10 mm, such as 0.02-5 mm, or 0.2-2 mm. The plant may optionally be one or more of the following: peeled, seeded, seeded or cored, as appropriate, for example in a step prior to osmotic dehydration. In some embodiments, the plant is not peeled, or only partially peeled, and the peel or skin is left on the vegetable

17 BE2022/5913 product remains, can advantageously increase the nutritional benefit of the end product.

In one embodiment, said inner liquid comprises menthol or a mint extract. In one embodiment, the soft gummy comprises 0.001-2% by weight menthol or mint extract.

In an embodiment, said inner liquid comprises at least one flavor compound selected from: grape flavor, a lemon flavor, a citrus flavor, a wintergreen flavor, a spearmint flavor, a peppermint flavor, a coffee flavor, a cocoa flavor, a pomegranate flavor, an acai berry flavor, a cinnamon flavor, a cranberry flavor, a ginseng flavor, a rosehip flavor, a rosemary flavor, a passion fruit flavor, a licorice flavor, a ginger flavor, a honey flavor, tartar, malic acid, and citric acid. In one embodiment, the aroma is extracted from a plant and the extract is added to the soft gummy. In one embodiment, the flavor compound is mixed into the soft gummy by adding particles of said plant to the soft gummy. In one embodiment, the soft gummy comprises 0.01-20% by weight of said at least one flavor compound relative to the weight of the soft gummy, preferably 0.5-5% by weight.

In one embodiment, said inner liquid comprises a plant extract obtained from one or more plants selected from: kava (Piper methysticum), chamomile, melatonin, valerian (Valeriana officinalis), valerian root, skullcap (genus

Scutellaria), or lemon balm (Melissa officinalis). In one embodiment, the inner fluid includes extracts of: kava (Piper methysticum), chamomile, melatonin, valerian (Valeriana officinalis), valerian root, skullcap (genus Scutellaria), or lemon balm (Melissa officinalis). In one embodiment, the soft gummy comprises 0.01-20% by weight of the plant extract relative to the weight of the soft gummy, preferably 0.5-5% by weight.

In one embodiment, said inner liquid comprises at least one vegetable product selected from: ginger, coffee, coffee bean, gotu kola root, gotu kola extract, kola nut, cocoa, guarana, yerba mate and yerba mate extract, maca extract,

L-theanine, Huperzia serrata, huperzine serrate, milk thistle leaf, milk thistle powder, milk thistle extract, blueberry extract, grape extract, green tea or green tea extract, propolis, turmeric, fennel, gingko biloba, ginseng, rose hips, pomegranate, acai berry, grape seed, lemon , lemon peel, lemon juice powder,

18 BE2022/5913 cranberry, mint, cinnamon, cocoa, mint, spearmint (Mentha spicula), ivy-willow, willow, wintergreen (Gaultheria procumbens), rosemary, passion flower, Glycyrrhiza root (licorice root), cocoa, ginger, bee pollen, peppermint, peppermint leaf powder, lemon balm (Melissa officinalis), Cannabis sativa, tetrahydrocannabinol (THC), cannabidiol (CBD), propolis, honey, honey powder, monk fruit extract, Stevia, agave, fruit juice concentrates, kava (Piper methysticum), chamomile, melatonin, valerian (Va/eriana officinalis), valerian root, lemon balm (Melissa officinalis), skullcap (genus Scutellaria), linseed oil, hemp seed oil, tartar, malic acid, citric acid and sodium gluconate. In one embodiment, the inner liquid comprises 0.01-80% by weight of the at least one vegetable product relative to the weight of the soft gummy, preferably 0.5-5% by weight.

In one embodiment, said inner liquid comprises at least one herbal product selected from: Black pepper, cinnamon, cumin, ginger, rose hip, coltsfoot, mongoose, thyme leaf, wild cherry bark, quercetin, sundew, butterbur, grape seed extract or any combination thereof. In one embodiment, the inner liquid comprises 0.01-80% by weight of the at least one herbal product relative to the weight of the soft gummy, preferably 0.5-5% by weight.

In one embodiment, the inner liquid comprises 0.1-10% by weight of hydrolyzable tannin or a source thereof relative to the weight of the inner liquid. In one embodiment, the inner liquid comprises 0.01-5.0% by weight of flavorings and fragrances relative to the weight of the inner liquid, in particular selected from the list of: anethole, benzaldehyde, ethyl vanillin, menthol, methyl salicylate, monosodium glutamate, orange blossom oil, peppermint, mint oil, peppermint spirit, rose oil, rose water, thymol, tolu balsam tincture, vanilla, vanilla tincture, vanillin or a mixture thereof. In one embodiment, the inner liquid comprises 0.2-5.0% by weight di- or tricarboxylic acid relative to the weight of the inner liquid, preferably citric acid.

In one embodiment, the soft gummy comprises a processed vegetable product.

Plant products that may be suitable for the soft gummy described herein include any product with a water content such that removal of at least a portion of that water can result in an extended shelf life by removing the water content. Examples of such products include: apples, pears, nashi pears, stone fruit (including plums, apricots, peaches, nectarines and cherries), berries (including blueberries, strawberries,

10 BE2022/5913 raspberries, cranberries, goji berries, loganberries, blackberries, barberries, chokeberries, mulberries and gooseberries), citrus fruits (such as oranges, mandarins, grapefruits, lemons, limes, kumquats, clementines and tangelos), mango, pineapple, papaya , kiwis, grapes, bananas, plantains, sapota, breadfruit, star fruit, lychee, melon, durian, mongoosetan, guava, pomegranate, dates, figs, olives, tomato, beetroot, pumpkin, potato, sweet potato, yam, taro, carrot , parsnip, zucchini, pumpkin, legumes (including beans, such as green, lima, kidney, cannellini, haricot, soy and broad beans, peas and chickpeas), capsicum, peppers, chili, celery, cabbage, broccoli, cauliflower , Brussels sprouts, cabbage, mushroom, onions, garlic, leafy green vegetables (including spinach, kale, lettuce, Swiss chard, choi and Swiss chard), sweet corn, celeriac, radish, mint, kohlrabi, turnips, artichokes and asparagus. Some embodiments of the disclosure may be particularly useful with respect to apples, pears and stone fruit. In one embodiment, the plants are processed via osmotic dehydration. The process of osmotic dehydration involves the immersion or soaking of the plant product for a specified period of time in a (typically) aqueous solution of an osmotic agent, the time and the concentration of the solution being such that the water in the cellular structure of the plant product diffuses from the plant product into the solution and the osmotic agent in the plant product migrates. In one embodiment, the vegetable products are processed via infrared radiation.

Infrared radiation treatment involves the generation of infrared radiation, which strikes the plant product and penetrates the inner layers without heating the surrounding air. In one embodiment, the plant products are processed via extraction, preferably extraction with extraction solvents containing 90% by weight water. In one embodiment, the soft gummy comprises at least 0.01% by weight of one or more processed plant products, preferably 0.01-80% by weight, more preferably 1-80% by weight, more preferably 3-50% by weight. % by weight, more preferably 5-25 % by weight, all relative to the total weight of the soft gummy.

In one embodiment, the outer shell comprises: 1-10% by weight (i) pectin relative to the weight of the outer shell; 0.1-70% by weight (ii) processed vegetable product relative to the weight of the outer peel; 0.5-20% by weight (iii) of a hydrolyzable tannin or source of hydrolyzable tannin relative to the weight of the outer skin; and wherein said inner liquid comprises: 10-80% by weight (i) processed vegetable product relative to the weight of the inner liquid; 5-89% by weight (ii) moisture relative to the weight of the

20 BE2022/5913 inner fluid as measured according to ISO 760:1978; 0.5-20% by weight (iii) of a hydrolyzable tannin or source of hydrolyzable tannin relative to the weight of the inner liquid.

In another embodiment, the outer shell comprises: 1-10% by weight (i) pectin relative to the weight of the outer shell; 0.5-20% by weight (ii) tannic acid based on the weight of the outer shell.

In one embodiment, the outer shell comprises: 1-10% by weight (i) pectin relative to the weight of the outer shell; 0.5-20% by weight of (ii) a hydrolyzable tannin or source of hydrolyzable tannin relative to the weight of the outer skin; and wherein said inner liquid comprises: 0.10-50% by weight (i) processed vegetable product with respect to the weight of the inner liquid, wherein the processed vegetable product is obtained by grinding or extracting raspberries, cranberries, goji berries, mulberries , mint, oranges, tangerines, grapefruits or lemons; 5-89% by weight (ii) moisture relative to the weight of the inner liquid as measured according to ISO 760:1978; 0.5-20% by weight (iii) of a hydrolyzable tannin or source of hydrolyzable tannin relative to the weight of the inner liquid.

API

In one embodiment, said inner liquid comprises a pharmaceutically active ingredient (API). APIs may be synthetic APIs such as aspirin, diphenhydramine, etc. or natural APIs such as Humira, Remicade, Rituxan, etc. In one embodiment, said API is an alkaloid, anesthetic, antibiotic, antiparasitic, antipyretic analgesic, biochemical, cardiovascular drug system, central nervous system drug, digestive system drug, hormone, anti-infective, phospholipid, prostaglandin, respiratory system drug, sulfonamides, vitamin or other active pharmaceutical ingredient.

In one embodiment, said inner fluid comprises at least one corticosteroid. In one embodiment, said inner fluid comprises at least one antibiotic and at least one corticosteroid as active pharmaceutical ingredients (API). In another embodiment, said inner fluid comprises a pharmaceutically active ingredient, said API being selected from: lidocaine, prilocaine, levofloxacin, betamethasone, cyproheptadine, tricholine citrate,

21 BE2022/5913 acetaminophen, phenylephrine, guaifenesin, dextromethorphan, aspirin, ibuprofen, diphenhydramine, antihistimine, naproxen sodium, fluticasone, budesonide, and their mixtures.

In one embodiment, said inner fluid comprises a pharmaceutical active ingredient (API), preferably a corticosteroid, more preferably the corticosteroid comprises one or more of alclometasone, amcinonide, beclometasone, betamethasone, budesonide, ciclesonide, clobetasol, clobetasone, clocortolone, cloprednol, cortivazole , deflazacort, deoxycorticosterone, desonide desoximetasone, dexamethasone, dextromethorphan, diflorasone, diflucortolone, difluprednate, fluclorolone, fludrocortisone, fludroxycortide, flumetasone, flunisolide, fluocinolone acetonide, fluocinonide, fluocortin, flucortolone, fluorometholon, fluperolone, fluticasone , fluticasone propionate, fluprednidene, formocortal, halcinonide, halometasone, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone butyrate, loteprednol, medrysone, meprednisone, methylprednisolone, methylprednisolone aceponate, mometasone furoate, paramethasone, prednicarbate, prednisone, prednisolone, prednylidene, rimexolone, tixocortol, triamcinolone, ulobetasol , combination thereof, pharmaceutically acceptable salts thereof, or esters thereof.

The soft gummy is suitable for local, non-systemic administration of one or more active pharmaceutical ingredients to the oral cavity and upper gastrointestinal tract, including the esophagus.

In one embodiment, the soft gummy comprises additional pharmaceutical excipients. Additional pharmaceutical excipients useful for the soft gummy described herein include, for example, the following: acidifying agents (acetic acid, glacial acetic acid, citric acid, fumaric acid, hydrochloric acid, dilute hydrochloric acid, malic acid, nitric acid, phosphoric acid, dilute phosphoric acid, sulfuric acid, tartaric acid); alkalizing agents (ammonia solution, ammonium carbonate, diethanolamine, di-isopropanolamine, potassium hydroxide, sodium bicarbonate, sodium borate, sodium carbonate, sodium hydroxide, trolamine); antifoaming agents (dimethicone, simethicone); antimicrobial preservatives (benzalkonium chloride, benzalkonium chloride solution, benzethonium chloride, benzoic acid, benzyl alcohol, butylparaben, cetylpyridinium chloride, chlorobutanol, chlorocresol, cresol, dehydroacetic acid, ethylparaben, methylparaben, methylparaben sodium, phenol, phenylethyl alcohol, phenylmercuric acetate, phenylmercury nitrate, potassium benzoate, potassium sorb ate,

22 BE2022/5913 propylparaben, propylparaben sodium, sodium benzoate, sodium dehydroacetate, sodium propionate, sorbic acid, thimerosal, thymol); antioxidants (ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate, sodium formaldehyde sulfoxylate, sodium metabisulphite, sodium thiosulphate, sulfur dioxide, tocopherol, tocopherols excipient); buffering agents (acetic acid, ammonium carbonate, ammonium phosphate, boric acid, citric acid, lactic acid, phosphoric acid, potassium citrate, potassium metaphosphate, monobasic potassium phosphate, sodium acetate, sodium citrate, sodium lactate solution, dibasic sodium phosphate, monobasic sodium phosphate); chelating agents (disodium edetate, ethylenediamine tetraacetate and salts, edetic acid); coating agents (sodium carboxymethyl cellulose, cellulose acetate, cellulose acetophthalate, ethyl cellulose, gelatin, pharmaceutical glaze, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, methacrylic acid copolymer, methyl cellulose, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, zein); colorants (caramel, red, yellow, black or mixtures, iron oxide); complexing agents (ethylene diamine tetraacetate and salts (EDTA), edetic acid, gentisic acid ethanolamide, oxyquinoline sulphate); drying agents (calcium chloride, calcium sulphate, silicon dioxide); emulsifying and/or solubilizing agents (acacia, cholesterol, diethanolamine (excipient), glyceryl monostearate, lanolin alcohols, mono- and diglycerides, monoethanolamine (excipient), lecithin, oleic acid (excipient), oleyl alcohol (stabilizer), poloxamer, polyoxyethylene 50 stearate, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether, polyoxyl 40 stearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, diacetate, monostearate, sodium lauryl sulfate, sodium stearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, stearic acid, trolamine , emulsifying wax); filter aids (cellulose powder, purified silica); flavorings and fragrances (anethole, benzaldehyde, ethyl vanillin, menthol, methyl salicylate, monosodium glutamate, orange blossom oil, peppermint, peppermint mint oil, peppermint spirit, rose oil, 'stronger rose water'

Stronger Rose Water), thymol, tolu balsam tincture, vanilla, vanilla tincture, vanillin); humectants (glycerol, hexylene glycol, sorbitol); plasticizers (e.g. castor oil, diacetylated monoglycerides, diethyl phthalate, glycerol, mono- and di-acetylated monoglycerides, propylene glycol, triacetin, triethyl citrate); polymers (e.g. cellulose acetate, alkylcelluloses, hydroxyalkyl, acrylic polymers and copolymers); solvents (acetone, alcohol,

23 BE2022/5913 diluted alcohol, amylene hydrate, benzyl benzoate, butyl alcohol, carbon tetrachloride, chloroform, corn oil, cottonseed oil, ethyl acetate, glycerol, hexylene glycol, isopropyl alcohol, methyl alcohol, methylene chloride, methyl isobutyl ketone, mineral oil, peanut oil, propylene carbonate, sesame oil, water for injections, sterile water for injection, sterile water for rinsing, purified water); sorbents (cellulose powder, charcoal, purified silica); carbon dioxide sorbents (barium hydroxide lime, soda lime); stiffening agents (hydrogenated castor oil, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, hard fat, paraffin, polyethylene additive, stearyl alcohol, emulsifying wax, white wax, yellow wax); Suspension and/or viscosity increasing agents (acacia, agar, alginic acid, aluminum monostearate, bentonite, purified bentonite, magma bentonite, carbomer, carboxymethylcellulose calcium, carboxymethylcellulose sodium, carboxymethylcellulose sodium 12, carrageenan, microcrystalline and carboxymethylcellulose sodium cellulose, dextrin, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, magnesium aluminum silicate, methylcellulose, pectin, polyethylene oxide, polyvinyl alcohol, povidone, alginate, silicon dioxide, colloidal silicon dioxide, sodium alginate, tragacanth, xanthan gum); sweeteners (aspartame, dextrates, dextrose, excipient dextrose, fructose, mannitol, saccharin, calcium saccharin, sodium saccharin, sorbitol, sorbitol solution, sucrose, compressible sugar, icing sugar, syrup); tablet binders (acacia, alginic acid, sodium carboxymethylcellulose, microcrystalline cellulose, dextrin, ethylcellulose, gelatin, liquid glucose, guar gum, hydroxypropylmethylcellulose, methylcellulose, polyethylene oxide, povidone, pregelatinized starch, syrup); diluents for tablets and/or capsules (calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, cellulose powder, dextrates, dextrin, dextrose excipient, fructose, kaolin, lactose, mannitol, sorbitol, starch, pregelatinized starch, sucrose, compressible sugar, icing sugar ); disintegrating agents for tablets (alginic acid, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, starch, pregelatinized starch);

Tablet and/or capsule lubricants = (calcium stearate, glyceryl behenate, magnesium stearate, light mineral oil, sodium stearyl fumarate, stearic acid, purified stearic acid, talc, hydrogenated vegetable oil, zinc stearate); tonicity agent (dextrose, glycerol, mannitol, potassium chloride, sodium chloride); carrier: flavored and/or sweetened (aromatic elixir, compound benzaldehyde elixir, isoalcoholic elixir, peppermint water, sorbitol solution, syrup, tolu balsam syrup); carrier: oily (almond oil, corn oil,

24 BE2022/5913 cottonseed oil, ethyl oleate, isopropyl myristate, isopropyl palmitate, myristyl alcohol, octyldodecanol, olive oil, peanut oil, persic oil, sesame oil, soy oil, squalane); solid carrier (sugar balls); sterile vehicle (bacteriostatic water for injection, bacteriostatic sodium chloride injection); viscosity increasing agent (see suspension agent); water repellent (cyclomethicone, dimethicone, simethicone); and/or solubilizer (benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, docusate sodium, nonoxynol-9, nonoxynol-10, octoxynol-9, poloxamer, polyoxyl-35-castor oil, polyoxyl-40, hydrogenated castor oil, polyoxyl-50 stearate, polyoxyl-10- oleyl ether, polyoxyl-20, cetostearyl ether, polyoxyl-40 stearate, polysorbate-20, polysorbate-40, polysorbate-60, polysorbate-80, sodium lauryl sulfate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan monostearate, tyloxapol). This list is not intended to be exclusive, but instead is merely representative of the classes of excipients and the specific excipients that may be used in oral dosage forms described herein.

In one embodiment, the outer shell comprises: 1-10% by weight (i) pectin relative to the weight of the outer shell; 0.5-20% by weight of (ii) a hydrolyzable tannin or source of hydrolyzable tannin relative to the weight of the outer skin; and wherein said inner liquid comprises: 0.00001-10% by weight of (i) an API relative to the weight of the inner liquid; 5-90% by weight of (ii) moisture as measured according to ISO 760:1978; 0.5-20% by weight (ii) of a hydrolyzable tannin or source of hydrolyzable tannin relative to the weight of the inner liquid.

In one embodiment described herein, the API is present in any effective amount in the soft gummy described herein. In some embodiments, an effective amount is an amount sufficient to reduce inflammation or symptoms of inflammation associated with an allergic or caustic inflammatory condition or condition of the gastrointestinal tract (e.g., esophagus) as compared to the level of inflammation or symptoms of inflammation associated with an inflammatory disease prior to administration of the effective amount. In certain embodiments, an effective amount is an amount sufficient to maintain a reduction in inflammation or inflammatory symptoms achieved by any means, including, but not limited to, by administering an effective amount sufficient to maintain such reduction. achieve reduction in inflammation.

25 BE2022/5913

In one embodiment, the amount of one or more APIs used in a soft gummy or in a method described herein is from about 7 µg to about 700 mg.

In one embodiment, the amount of API used in a method, in a composition, or in a dose of a composition described herein includes about 500 µg to about 2 mg, 500 µg to about 1 mg, about 1 mg to about 2 mg, about 1 mg, about 3 mg, about 1 mg to about 4 mg, about 1 mg to about 5 mg, or any suitable amount.

In one embodiment, the dosage is delivered in a volume that treats the esophagus in an effective amount. In one embodiment, the effective amount is about 0.5 mg, about 1 mg, about 1.5 mg, or about 2 mg

API.

Another embodiment described herein is a soft gummy suitable for chewing, sucking or buccal dissolution as described herein for treating a disease, allergic, idiopathic, immunogenic, traumatic, caustic or general inflammation of the oral cavity, esophagus or upper part of the gastrointestinal tract, or a symptom thereof comprising about 0.5 mg to about 5 mg API, about 0.5 mg to about 1 mg API, about 1 mg to about 2 mg API, about 2 mg to about 3 mg API, about 3 mg to about 4 mg API, or about 4 mg to about 5 mg API.

In one embodiment, the effective amount is about 0.5 mg to about 5 mg, about 0.5 mg to about 1 mg, about 0.5 mg to about 2 mg, about 0.5 mg to about 3 mg; about 0.5 mg to about 4 mg; about 1 mg to about 5 mg, about 1 mg to about 2 mg, about 1 mg to about 3 mg, about 1 mg to about 4 mg, about 2 mg to about 3 mg, about 2 mg to about 4 mg, about 2 mg to about 5 mg, about 3 mg to about 4 mg, about 3 mg to about 5 mg, or about 4 mg to about 5 mg. In another embodiment, the effective amount of API is about 0.25 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg, about 3.5 mg , about 4 mg, about 4.5 mg, or about 5 mg API. In another embodiment, the API is present in a soft gummy at any concentration suitable to deliver a therapeutically effective amount of API to a surface of the gastrointestinal tract (e.g., the surface of the esophagus), for example, at a dosage of approximately 0.01 mg to approximately 2 mg composition. In another

26 BE2022/5913 embodiment, the API is present in a soft gummy in a dose of about 0.5 mg to about 1 mg, about 0.5 mg to about 1.5 mg, about 0.5 mg to about 2 mg, about 0.5 mg to about 2.5 mg, about 0.5 mg to about 3 mg, about 0.5 mg to about 3.5 mg, about 0.5 to about 4 mg, about 0.5 to about 4.5 mg or about 0.5 mg to about 5 mg. In another embodiment, the API is present in a soft gummy in a dose of about 0.5 mg to about 1 mg.

Breath

In one embodiment, the invention relates to a soft gummy for use in the treatment of bad breath odor. In one embodiment, the soft gummy comprises compositions suitable for improving the odor of breath. In one embodiment, the inner liquid comprises an active liquid and the outer shell comprises prebiotics. These prebiotics are suitable for restoring the healthy oral microbiome, preferably in the mouth of the consumer of the soft gummy. In one embodiment, the prebiotic is fructan, xylan, galactooligosaccharides, pectins, glucans, beta-glucans, inulin or oligofructose.

In one embodiment, said active fluid comprises an antibacterial agent such as one or a mixture of: tin ions; metal salts; aminoglycosides; carbapenems; cephalosporins; fluoroquinolones; glycopeptides; lipoglycopeptides, macrolides; monobactams; oxazolidinones; penicillins; polypeptides; rifamycins; sulfonamides; streptogramins; tetracyclines. In another embodiment, the antibacterial agent is selected from: cetylpyridium chloride; zinc acetate; azithromycin; tedizolid; eugen acetate; silver salts; Cu salts; chlorhexidine; chlorine dioxide; eucalyptol; menthol; thymol; methyl salicylate; and any combination thereof.

In one embodiment, said active liquid comprises a deodorant or odor neutralizing agent. In another embodiment, said deodorant or odor neutralizing agent is selected from: 4-methoxybenzaldehyde; p-ionone; alpha-ionone; menthol, anise, eucalyptol; vegetable components; essential oils; glycols, betaines, salts of organic acids; amine compounds; activated carbon; trans-1,4-diphenyl-2-butene-1,4-dione; cyclodextrin; terpene; 3-butene-2-one; and any combination thereof.

In one embodiment, the soft gummy consists of an outer shell that encapsulates an inner liquid, the outer shell comprising 0.5-25% by weight of a pectin relative to the weight of the outer shell; 10-90% by weight (ii) prebiotics

27 BE2022/5913 with respect to the weight of the outer shell, and wherein said inner liquid comprises 10-100% by weight of (i) an active liquid comprising an antibacterial agent, a deodorant or odor neutralizing agent.

Energy

In one embodiment, the invention relates to a soft gummy for use in the treatment of fatigue or energy dips. In one embodiment, the soft gummy comprises compounds suitable for preventing energy dips. This soft gummy provides an immediate energy boost and a long-lasting stimulating effect. In one embodiment, the soft gummy comprises one or more stimulating ingredients selected from: honey; coconut; berries; seeds; caffeine; taurine; D group vitamins; C group vitamins; B group vitamins; D-glucurono-γ-lactone; sugar; theine; guarana; theophylline; theobromine; ginseng; gingko biloba; folate; zinc, magnesium, selenium, iron; matein; fatty acids; kola nut; ginger; coffee; tea; guarana; Yerba; L-carnosine; inositol; chlorella; chia; turmeric; cinnamon; Quinoa; Bell pepper; Chili; goji; spirulina; macadamia; chocolate; curcumin; licorice; wheatgrass berries; matcha or a mixture thereof. In one embodiment, the inner liquid comprises a sugar-rich or stimulating mixture and the outer shell comprises fats or vitamins, preferably the soft gummy comprises 5-600 mg caffeine, more preferably 50-200 mg caffeine.

In one embodiment, the soft gummy comprises guarana; honey; coffee; coconut or a combination thereof.

In one embodiment, the soft gummy consists of an outer shell that encapsulates an inner liquid, wherein the outer shell comprises 0.5-25% by weight of pectin relative to the weight of the outer shell, and wherein the inner liquid comprises 10-100% by weight of stimulant ingredients compared to the weight of the inner liquid. In one embodiment, the soft gummy comprises 5-600 mg of caffeine.

In one embodiment, the soft gummy comprises 10-40% by weight sugars. In one embodiment, the soft gummy comprises 1 µg - 1 g of vitamins, preferably 200-600 mg.

Irritable bowel syndrome

In one embodiment, the invention relates to a soft gummy for use in the treatment of irritable bowel syndrome. In one embodiment, the soft gummy comprises compounds suitable for preventing irritable bowel syndrome. This soft gummy relieves the symptoms of irritable bowel syndrome. In one embodiment, the soft gummy product comprises

28 BE2022/5913 and prebiotics. Probiotics and prebiotics are known to play a key role in reducing the aforementioned symptoms. In one embodiment, the soft gummy includes probiotics such as Lactobacillus; Bifidobacterium; Saccharomyces boulardii; or a combination thereof, preferably the said prebiotics are present in the inner liquid. Other conditions can also be helped by increasing the probiotics in your body. In one embodiment, the invention relates to a soft gummy for use in the treatment of diarrhea; constipation; inflammatory bowel disease (IBD); fungal infections; urinary tract infections; gingivitis; lactose intolerance; eczema; upper respiratory infections or sepsis. In one embodiment, the soft gummy comprises prebiotics such as fructan, xylan, galactooligosaccharides, pectins, glucans, beta-glucans, inulin or oligofructose, with the prebiotics preferably present in the outer shell. In one embodiment, the soft gummy comprises compounds suitable for preventing irritable bowel syndrome, wherein the outer shell comprises prebiotics and the inner liquid comprises probiotics. In one embodiment, said probiotics are Bifidobacterium or Saccharomyces species and said probiotics are a combination of pectins with fructans, xylans, glucans or inulin.

In one embodiment, the soft gummy consists of an outer shell that encapsulates an inner liquid, the outer shell comprising 0.5-25% by weight of a pectin relative to the weight of the outer shell; and 0.5-80% by weight prebiotics relative to the weight of the outer shell and wherein said inner liquid comprises 10-100% by weight probiotics relative to the weight of the inner liquid.

Urinary tract infection

In one embodiment, the invention relates to a soft gummy for use in the treatment of urinary tract infections. In one embodiment, the soft gummy comprises compounds suitable to provide a rapid and long-lasting effect against urinary tract infection. This soft gummy relieves the symptoms of the urinary tract infection. In one embodiment, the soft gummy comprises prebiotics, preferably in the outer shell. In one embodiment, the soft gummy includes prebiotics such as fructan, xylan, galactooligosaccharides, pectins, glucans, beta-glucans, inulin, D-mannose or oligofructose. In a special embodiment, the soft gummy comprises D-mannose. In one embodiment, the soft gummy comprises anti-biofilm compounds, preferably in the outer shell. In one embodiment, the soft gummy includes painkillers, preferably in the inner liquid. These painkillers are suitable for quick action against acute pain

29 BE2022/5913 caused by urinary tract infections. In one embodiment, said anti-biofilm compounds are phenols, essential oils, terpenoids, lectins, N-acetylcysteine, berberine, alkaloids, polypeptides or polyacetylenes. In one embodiment, said anti-biofilm compounds include compounds extracted from: garlic, marjoram, cinnamon, curcumin, cranberries, blueberries, raspberries or ginger. In one embodiment, said anti-biofilm compounds comprise plant parts, preferably garlic, marjoram, cinnamon, curcumin, cranberries, blueberries, raspberries or ginger. In one embodiment, said anti-biofilm compounds are antibiotics. In one embodiment, said painkiller is paracetamol, ibuprofen, aspirin, diclofenac, lidocaine, naproxen, capsaicin, codeine, nefopan, flupirtine, ziconotide, dihydrocodeine or an opioid. In one embodiment, the soft gummy includes extracts of cranberries, blueberries, juniper berries, raspberries, ginger, horsetail (Eguisetum arvense), uva ursi or a combination thereof.

In one embodiment, the soft gummy consists of an outer shell that encapsulates an inner liquid, the outer shell comprising 0.5-25% by weight of a pectin relative to the weight of the outer shell; and 0-80% by weight of said prebiotics relative to the weight of the outer shell and 0.1 µg - 1 g of said anti-biofilm compounds and wherein said inner liquid comprises 0.1 µg - 1 g of said analgesic. In one embodiment, the soft gummy consists of an outer shell that encapsulates an inner liquid, the outer shell comprising 0.5-25% by weight of a pectin relative to the weight of the outer shell; and 10-30% by weight of said prebiotics relative to the weight of the outer shell and 50 mg - 500 mg of said anti-biofilm compounds and wherein said inner liquid comprises 10 mg - 100 mg of said analgesic.

Pain and fever

In one embodiment, the invention relates to a soft gummy for use in the treatment of pain and fever. In one embodiment, the soft gummy includes painkillers, preferably in the inner liquid. In one embodiment, said painkiller is paracetamol, ibuprofen, aspirin, diclofenac, lidocaine, capsaicin, codeine, nefopan, flupirtine, ziconotide, dihydrocodeine, naproxen, cannabinoids or an opioid. In one embodiment, the soft gummy comprises an antipyretic, preferably in the inner liquid. In one embodiment, the antipyretic is selected from: salicylates (e.g., sodium salicylate and acetylsalicylic acid), ibuprofen and the other non-steroidal, anti-inflammatory drugs (NSAIDs), and acetaminophen.

30 BE2022/5913

In one embodiment, the soft gummy consists of an outer shell encapsulating an inner liquid, the outer shell comprising 0.5-25% by weight of pectin relative to the weight of the outer shell and the inner liquid comprising 0.1 µg - 1 g of said analgesic and from 0.1 µg - 1 g of an antipyretic, not chosen as an analgesic. In one embodiment, the soft gummy consists of an outer shell that encapsulates an inner liquid, wherein the outer shell comprises 0.5-25% by weight of a pectin relative to the weight of the outer shell and wherein the inner liquid comprises 10-600 mg of paracetamol, ibuprofen or aspirin and 100-500 mg sodium salicylate.

In one embodiment, the inner liquid comprises: 25-99% by weight honey; 0.1-10% by weight hydrolyzable tannin or a source thereof; 0.001-0.5% by weight dyes; 0.01-5.0% by weight flavorings and fragrances, selected in particular from the list of: anethole, benzaldehyde, ethyl vanillin, menthol, methyl salicylate, monosodium glutamate, orange blossom oil, peppermint, mint oil, peppermint spirit, rose oil, rose water, thymol, tolu balsam tincture, vanilla, vanilla tincture, vanillin or a mixture thereof; and 0.2-5.0% by weight di- or tricarboxylic acid; all wt% relative to the weight of the inner liquid. In another embodiment, the inner liquid of one soft gummy further comprises 1 µg - 1 g, preferably 100 µg - 400 mg of analgesic or antipyretic.

In one embodiment, the outer shell comprises 0.02-5.0% by weight of a salt of a di- or tricarboxylic acid relative to the weight of the outer shell. In one embodiment, the outer shell comprises: 0.1-30% by weight pectin; 1-25% by weight water; 0.02-5.0% by weight di- or tricarboxylic acid; 0.02-5.0% by weight of a salt of a di- or tricarboxylic acid; all wt.% relative to the weight of the outer shell.

In one embodiment, the soft gummy comprises antihistamines, preferably hydroxyzine, promethazine, carisoprodol or tripelennamine.

In one embodiment, said inner liquid comprises 10-90% by weight of the total weight of said soft gummy. In one embodiment, said inner liquid + said outer shell comprises 90-100% by weight of the total weight of said soft gummy, preferably at least 95% by weight, more preferably at least 99% by weight, more preferably the soft gummy consists from the inner liquid and the outer shell.

31 BE2022/5913

In a preferred embodiment, the soft gummy comprises the inner liquid in an amount of up to 90% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 85% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 80% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 75% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 70% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 65% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 60% by weight relative to the weight of the soft gummy, more preferably in an amount of maximum 55% by weight relative to the weight of the soft gummy, more preferably in an amount of maximum 50% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 45% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 40% by weight relative to the weight of the soft gummy, with more preferably in an amount of up to 35% by weight relative to the weight of the soft gummy, more preferably in an amount of up to 30% by weight relative to the weight of the soft gummy. The trade-off for large amounts of inner fluid is lower long-term stability and greater difficulty with quality assurance. In particular, reducing the amount of outer shell material leads to a greater chance of the soft gummy prematurely cracking, breaking or leaking.

When the inner liquid is a syrup, it results in a sticky, difficult to clean and very unpleasant mess. A single soft gummy that bursts in a jar, bag, or other type of bulk container can easily ruin the contents of all other items inside. It is therefore very important that both sufficient strength and long-term stability are guaranteed. As a result, commercial products are typically oversized compared to laboratory counterparts. While it is possible to produce gels with a large amount of inner liquid on a laboratory scale, it is much more difficult to produce such soft gummies in bulk, while ensuring long-term stability and avoiding premature leakage.

In a preferred embodiment, the soft gummy comprises the weight ratio of the outer shell to the inner liquid of a maximum of 100 to 1, more preferably a maximum of 75 to 1, more preferably a maximum of 50 to 1, more preferably a maximum of 25 to 1, more preferably a maximum of 20 at 1, with more preference

32 BE2022/5913 a maximum of 15 to 1, more preferably a maximum of 10 to 1, more preferably a maximum of 9 to 1, more preferably a maximum of 8 to 1, more preferably a maximum of 7 to 1, more preferably a maximum of 6 to 1, with more preferred maximum 5 to 1, more preferred maximum 4 to 1, more preferred maximum 3.5 to 1, more preferred maximum 3.0 to 1, more preferred maximum 2.5 to 1, more preferred maximum 2 .0 to 1, more preferably a maximum of 1.5 to 1, more preferably a maximum of 1.0 to 1. A low ratio of outer shell to inner liquid is desirable when the mode of action is directed towards the inner liquid, i.e., in the case of a syrup. However, a low ratio of outer shell to inner liquid is generally difficult to achieve, especially when stability is concerned.

In general, reducing the ratio of the outer shell material to the inner fluid material increases permeability through the outer shell and thus the migration of moisture from the inner fluid. In addition, reducing the ratio of the outer shell to the inner fluid material increases the risk of the outer shell cracking or breaking at times where it should not.

In one embodiment, the soft gummy included 30-40% by weight inner liquid and 60-70% by weight outer shell.

General use and ingestion

In a second aspect, the invention relates to the use of a soft gummy as described herein, for oral use. In one embodiment, the soft gummy is used in the treatment or prevention of cough, cold, bad breath, fatigue, pain, bacterial infection, viral infection, irritable bowel syndrome.

An advantage of using the soft gummy is the ability to offer one product consisting of two components that cannot be mixed in storage, such as Prebiotics and Probiotics. Other advantages of the soft gummy presented herein are its ability to mask the taste of some components, its rapid onset of action, and its improved bioavailability. The easy production method and dosage allow personalized products to be developed.

Another embodiment described herein is a soft gummy suitable for chewing, sucking, or buccal dissolution as described herein for treating, slowing the progression of, prophylaxis of, delaying the onset of, ameliorating, reducing the symptoms of , or promote it

33 BE2022/5913 of the health of, including but not limited to one or more of esophageal, oral or buccal inflammation, eosinophilic esophagitis, oral lichen planus, aphthous stomatitis, odynophagia, acid reflux, dysphagia, oral, esophageal or peptic ulcers, heartburn, chest pain, abdominal pain, nausea, vomiting, coughing, sore throat, loss of appetite or growth retardation.

The soft gummy comprises one dosage and is administered at least once a day, for example in five, four, three, two or one dosage per day. In an illustrative example, the dose is administered once per day. In specific embodiments, administration of each composition described herein is once per day. In other specific embodiments, administration is twice daily. In yet other embodiments, administration is three times daily. In another embodiment, administration is four times daily. In another embodiment, the dose is administered at night. In another aspect, the dose is administered approximately 30 minutes before bedtime, without food or water being given after administration of the compositions herein. In another embodiment, the dose is administered before bedtime, with the patient or individual lying essentially supine for at least 30 minutes, at least 1 hour, at least 2 hours, at least 4 hours after administration of the composition. , at least 8 hours, about 30 minutes to about 8 hours, about 30 minutes to about 4 hours, about 1 hour to about 8 hours, or about 1 hour to about 6 hours. In some embodiments provided herein, the dose is administered before the subject is substantially supine for at least 30 minutes, at least 1 hour, at least 2 hours, at least 4 hours, at least 8 hours, about 30 minutes to about 8 hours, about 30 minutes to about 4 hours, about 1 hour to about 8 hours, or about 1 hour to about 6 hours. In specific embodiments, an API or composition is administered according to any method described herein, wherein administration of the API or composition is once per day, no more than once per day, more than once per day, twice per day, two to four times a day, three times a day or four times a day. In some embodiments, the administration of the API or composition provided herein is administered at night, for example, no more than once per day at night.

In another embodiment described herein, the dosage form may be administered, for example, 1x, 2x, 3x, 4x, 5x, 6x, 7x or 8x per day. For example, one or more dosage forms may be administered for 1, 2, 3, 4, 5, 6, 7 days or even longer. One or more dosage forms can be, for example, 1, 2,

34 BE2022/5913 be administered for 3, 4 weeks or even longer. For example, one or more dosage forms may be administered for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months or even longer. One or more dosage forms may be administered until the patient, person, mammal, mammal in need thereof, human or human in need thereof does not require treatment, prophylaxis or improvement of a disease or condition, such as inflammation or pain, needs. In some embodiments, the dosage form may be administered together with other pharmaceutical compositions until the patient, person, mammal, mammal in need thereof, human or human in need thereof is not requiring treatment, prophylaxis or amelioration of any disease or condition. , including but not limited to inflammation or pain.

For example, initial treatment may be continued for about 3 days to 2 weeks for an acute condition, or about 4 weeks to about 16 weeks for a chronic condition, or about 8 weeks to about 12 weeks for a chronic condition. Longer therapy may also be necessary, such as therapy similar to chronic therapy for persistent asthma. For example, patients can be treated for up to 6 months or up to a year. Maintenance treatment can last up to a year or more. Depending on the severity of the condition, patients may be treated on a maintenance basis or as needed during a problematic episode.

Patients may also be treated on a rotational treatment basis, where the treatment is given for a period of time and the patient is then taken off the drug for a period of time before resuming treatment. If the drug is discontinued, the patient may receive no treatment, treatment with a different drug, or treatment at a lower dose.

Another embodiment described herein involves administering one or more of the soft gummies described herein in combination with one or more additional active pharmaceutical ingredients. Another embodiment described herein involves administering one or more of the soft gummies described herein comprising two or more active pharmaceutical ingredients.

USE airways

The present invention includes a new product that benefits the respiratory tract. In particular, the novel composition of this invention is useful in the prevention and/or treatment of cough. Coughing is a complicated process.

35 BE2022/5913

Disruption of the respiratory and/or gastrointestinal tract may have neurohumoral consequences that may ultimately lead to coughing. The cough reflex is really a protective mechanism. However, with altered disease states, cough frequency and severity can increase dramatically and dramatically affect quality of life. Many patients have chronic cough due to a combination of multiple causes (e.g. gastroesophageal reflux, asthma, rhinitis, etc.). Other patients with chronic cough have no established etiology.

Regardless of the cause, the results of previous treatments remain dismal for a large number of patients with chronic cough. There are several ways in which the soft gummy of the invention can act to treat cough, e.g., 1) via central nervous system action; 2) via local anesthetic effect 3) as a demulcens (soothing effect); 4) as a surfactant; 5) as an expectorant; 6) as a mucolytic; 7) as an antispasmodic; 8) as an anti-inflammatory; 9) as an antioxidant; 10) as an antihistamine; or 11) as a decongestant. Indeed, it seems likely that combined effects of the soft gummy could have a greater chance of treatment success in a patient population in which no modality has worked before. There are many combination cough preparations commercially available around the world. However, the new soft gummy of the present invention provides a capsule with excellent inner liquid release.

Another embodiment described herein is a method of treating, slowing the progression of, prophylaxis of, delaying the onset of, ameliorating, reducing the symptoms of, or promoting the health of one or more esophageal , oral or buccal inflammation, eosinophilic esophagitis, oral lichen planus, aphthous stomatitis, odynophagia, acid reflux, dysphagia, oral, esophageal or peptic ulcers, heartburn, chest pain, abdominal pain, nausea, vomiting, cough, sore throat , decreased appetite or growth retardation, comprising administering to a patient in need thereof an oral soft gummy suitable for chewing, sucking or buccal dissolution as described herein.

Another embodiment described herein is a soft gummy suitable for chewing, sucking or buccal dissolution as described herein for treating a patient suffering from one or more of oral, buccal, inflammation of the airways or esophagus, eosinophilic esophagitis, oral lichen planus, odynophagia, acid reflux, dysphagia, cough, sore throat, common cold, viral infection such as coronavirus (e.g. COVID-19), acute bronchitis, chronic bronchitis,

36 BE2022/5913 pneumonia, flu, asthma, bronchitis, chronic obstructive airways disease (COAD), bacterial infections (e.g. tuberculosis), postnasal drip, laryngitis, RSV, bronchiectasis, emphysema, unwanted side effects of other medicines, inhalation from an irritant, allergies, whooping cough, acute sinusitis, bronchiolitis, loss of appetite or growth retardation, or postoperative inflammation.

Another embodiment described herein is a soft gummy suitable for treating a patient suffering from oral or respiratory inflammation, inflammatory bowel disease involving the pharynx, oral lichen planus, aphthous stomatitis or postoperative inflammation, including administering to the patient who needs it. This further relates to the use of an oral soft gummy suitable for chewing, sucking or buccal dissolution as described herein.

Another embodiment described herein is a method of treating a disease, allergic, idiopathic, immunogenic, traumatic, corrosive or general inflammation of the oral cavity, esophagus or upper gastrointestinal tract, or a symptom thereof, by administering a sufficient amount of a soft gummy suitable for chewing, sucking, or buccal dissolution as described herein to provide about 0.5 mg to about 5 mg API per day, about 0.5 mg to about 1 mg API per day, about 1 mg to about 2 mg API per day, about 2 mg to about 3 mg API per day, about 3 mg to about 4 mg API per day, or about 4 mg to about 5 mg

API per day to a person who needs it. method of production

In one embodiment, the inner liquid is produced by mixing all components, preferably at elevated temperature, until a homogeneous mixture is obtained, subjecting the homogeneous mixture to a vacuum to remove gas bubbles therefrom, and then cooling the homogeneous mixture. The mixture is then ready for use as an inner liquid in a soft gummy, preferably by concentric extrusion of the inner liquid and the outer shell.

In one embodiment, the outer shell is produced by mixing pectin in water at elevated temperature and high shear until homogeneous, followed by addition of all other components. Under mixing conditions the

37 BE2022/5913 temperature rise to at least 100°C. Heating is only stopped when the desired Brix values have been reached. Preferably the desired Brix value is at least 65 Brix, more preferably at least 70 Brix, more preferably at least 72 Brix, more preferably at least 74 Brix, more preferably at least 75 Brix, more preferably at least 76 Brix, more preferably minimum 77 Brix, more preferred minimum 78 Brix, more preferred minimum 79 Brix, more preferred minimum 80 Brix, more preferred minimum 81 Brix, more preferred minimum 82 Brix, more preferred minimum 83 Brix, more preferred minimum 84 Brix, more preferably at least 85 Brix.

In another embodiment, the soft gummy is produced by contacting an outer shell material with an inner liquid material in a nozzle comprising two openings. In one embodiment, the outer shell material is produced by heating a mixture of pectin and water to 70-90°C; add all other ingredients and then heat to 90-120°C; and cooling. In one embodiment, the inner liquid material is produced by heating honey to 35-65°C; adding hydrolyzable tannin; and cooling.

In one embodiment, the present invention provides a method of applying an outer shell around an inner liquid, comprising the steps of: 1) applying a liquid gelling composition comprising a pectin and other ingredients to said outer surface of the inner liquid, 2 ) allowing the liquid gelling composition to gel while in contact with the inner liquid, forming a gel layer that directly covers the inner liquid.

Preferably, the soft gummy is formed by encapsulating the inner liquid in the outer shell using concentric extrusion-drip techniques. In such methods, the outer shell flows from the outer concentric nozzle first, followed by inner liquid flow from the inner concentric nozzle, while the flow from the outer shell concentric nozzle continues. The inner fluid flow is stopped and then the outer shell flow is stopped. This sequence of fluid flows may be accompanied by a movement of the nozzle. Each sequence of liquid flows produces a single droplet, which upon cooling forms a stable soft gummy according to the first aspect of the present

38 BE2022/5913 invention. Advantageously, it is not necessary to contact the outer shell with gelling or fixing mixtures, such as a mixture containing calcium ions.

By adding pectin, it was discovered that the gel layer prevents significant moisture loss from the inner liquid. This results in an improved shelf life and a more attractive appearance during storage. The components of said soft gummy are preferably of food grade.

EXAMPLES

The invention is further described by the following non-limiting examples which further illustrate the invention and are not intended, nor should they be construed, to limit the scope of the invention.

Soft gummies with an inner liquid and outer shell as described in examples 1, 2 and 3 were produced. The weight ratio of outer shell to inner liquid was 1:1 in Example 1. In Example 3, the gummy comprised 35% by weight inner liquid to 65% by weight outer shell.

The outer shell was obtained after mixing all ingredients until homogeneous, heating to 100-110°C until a Brix value of at least 75 was obtained and then cooling. The inner liquid was obtained after dissolving all ingredients in water, mixing and heating to 40-65°C and then cooling.

Soft gummies were formed by concentric extrusion and dripping. The outer shell completely encapsulated the inner fluid, no leakage was detected. A soft gummy in which the inner liquid bursts after breaking the outer shell was obtained.

Example 1:

The soft gummy contains compounds suitable for improving the odor of breath (Table 1). The inner liquid includes a eucalyptol solution and the outer shell includes prebiotics. These prebiotics are suitable for restoring the healthy oral microbiome.

39 BE2022/5913

Table 1 composition of soft gummy suitable to prevent bad smelling breath.

Layer of soft gummy Ingredient (amount by weight.%

Lee

Outer shell Beta-glucan and inulin | Prebiotics rr [Peene Binder

LT | wæertss Combating agent [ear Acidifying substance

Hydrolyzable tannin | Binder / Active lessons [Tnet (05) [wax

Hydrolyzable tannin | Binder / Active (TE PTE har

PQ emmener ee [ee

LT | Famaarauur ss Acidifying Substance 1 Se emule

Example 2:

The soft gummy includes compounds suitable for preventing or reducing symptoms such as coughing caused by many respiratory diseases (Table 2). The inner liquid includes honey and

Acetaminophen and the outer shell includes honey.

Table 2 composition of a soft gummy suitable for preventing or reducing coughing

Part of soft | Ingredient mm (seen

Outer shell Honey (0.3 g) Aroma / Binder / ee (ER ee [Buckles (0.08 9) Binder [We Wetting agent

LT Wänstsenauur (5 Mon) | Acidifying Substance

40 BE2022/5913

Inner liquid Honey (1.0 9) Aroma / Binder /

JET (EEE ee

Hydrolyzable tannin | Binder / Active

La TT PTT [OO Réamimomhen (400 mon) | Active Ingredient

G [mr [GaGa [Sweeter [Geet (6.7 ma) Aroma

Example 3:

The soft gummy includes compounds suitable for preventing or reducing symptoms of energy dips (Table 3). This soft gummy provides an immediate energy boost and a long-lasting stimulating effect. One soft gummy contains 50-200 mg of caffeine.

Table 3 composition of soft gummy suitable for preventing or reducing symptoms of energy dips

Layer of soft | Ingredient (quantity in ps a

Outer shell Coconut (20) Binder / Active rr len

Chocolate (25) Binder / Active ee (ET re

LT (Porebedimen | Binder

Honey (24) Active Ingredient / ee fes PE [| drolysable tannin (9) | Sinking agent

Sodium carboxymethylcellulose | Coating agents etc

Inner liquid Concentrated water extract | Active ingredient of 1/3 coffee, 1/3 ginger and ee [OO EE [Aro

LT (Grroenauers | Acidifying substance

LT Feed (0.1) | Emulsifying oil (0.4) | Lubricants

41 BE2022/5913

Ginger (0.5) Aroma / Active

Example 4:

The soft gummy includes compounds suitable for preventing and treating symptoms of irritable bowel syndrome, diarrhea; constipation; inflammatory bowel disease (IBD); fungal infections; gingivitis; eczema (Table 4). Poor functioning of the gastrointestinal tract can be prevented and reduced with the help of this soft gummy.

Table 4 composition of soft gummy suitable to prevent or reduce symptoms associated with infections

Layer of soft | Ingredient (quantity in ps a

Outer shell Fructan, xylan, (75) Binder /

PE (EEE me ete memes

OO mess more

Hydrolyzable tannin (2) Binder / Active ee eee ee eee

Sodium carboxymethylcellulose | Coating agents etc

Inner liquid Kefir-based solution | Probiotic / Active consisting of Bifidobacterium | Ingredient and Saccharomyces (92) ee eee 1 |Peueemavenen | Emaester

LT Flantsardige all (0.4) | Lubricants

LT mtscerteen emer

M CU CONS Ama

Claims (15)

42 BE2022/5913 CONCLUSIONS 1. Soft gummy for oral use, wherein the soft gummy comprises an outer shell encapsulating an inner liquid, the outer shell comprising 0.5-25% by weight pectin relative to the weight of the outer shell and having a viscosity of 25-1000 Pa :s measured at 20°C and wherein said inner fluid has a moisture content of 5-99% by weight as measured according to ISO 760:1978 and a viscosity of 0.01-20 Pa:s measured at 20°C. The soft gummy of claim 1, wherein the soft gummy comprises a hydrolyzable tannin. 3. Soft gummy according to any of claims 1-2, wherein the pectin is selected from the group of: high methoxyl pectin (HM), low methoxyl pectin (LM) or low methoxyl amidated pectin (low methoxyl amidated pectin, LMA). Soft gummy according to any one of claims 1-3, wherein said pectin is high methoxyl pectin (HM), wherein said high methoxyl pectin (HM) has a degree of methoxylation (DM) of at least 50. A soft gummy according to any one of claims 1 to 4, wherein said pectin is high methoxyl pectin (HM), wherein said high methoxyl pectin (HM) is at least partially cross-linked. Soft gummy according to any one of claims 1-5, wherein the outer shell further comprises a dicarboxylic acid or a tricarboxylic acid, preferably citric acid. 7. Soft gummy according to any one of claims 1-6, wherein the outer shell and/or the inner liquid comprises a hydrolyzable tannin or a source of hydrolyzable tannin, the hydrolyzable tannin being present in an amount of 0.2-20% by weight compared to the weight of the soft gummy. 8. Soft gummy according to any one of claims 1-7, wherein the outer shell comprises 1-10% by weight pectin relative to the weight of the outer shell. 43 BE2022/5913 A soft gummy according to any one of claims 1 to 8, wherein the inner liquid comprises menthol or a mint extract. A soft gummy according to any one of claims 1 to 9, wherein the outer shell comprises: 1-10% by weight (i) pectin relative to the weight of the outer shell; 0.5-20% by weight of (ii) a hydrolyzable tannin or source of hydrolyzable tannin relative to the weight of the outer skin; and wherein said inner liquid comprises: 0.10-50% by weight (i) processed vegetable product with respect to the weight of the inner liquid, wherein the processed vegetable product is obtained by grinding or extraction of raspberries, cranberries, goji berries, mulberries , mint, oranges, tangerines, grapefruits or lemons; 5-89% by weight (ii) moisture relative to the weight of the inner liquid as measured according to ISO 760:1978; 0.5-20% by weight of (iii) a hydrolyzable tannin or source of hydrolyzable tannin relative to the weight of the inner liquid. A soft gummy according to any one of claims 1 to 9, wherein the outer shell comprises: 1-10% by weight (i) pectin relative to the weight of the outer shell; 0.5-20% by weight of (ii) a hydrolyzable tannin or source of hydrolyzable tannin relative to the weight of the outer skin; and wherein said inner liquid comprises: 0.00001-10% by weight of (i) an API relative to the weight of the inner liquid; 5-98% by weight of (ii) moisture as measured according to ISO 760:1978; 0.5-20% by weight of (iii) a hydrolyzable tannin or source of hydrolyzable tannin relative to the weight of the inner liquid. Soft gummy according to any one of claims 1-11, wherein the weight ratio of the outer shell to the inner liquid is a maximum of 100:1. A soft gummy according to any one of claims 1 to 12, wherein said inner liquid comprises 10-90% by weight of the total weight of said soft gummy. Use of a soft gummy according to any one of claims 1-13, for oral use. 44 BE2022/5913 A soft gummy according to any one of claims 1 to 13, for use in the treatment or prevention of cough, cold, bad breath, fatigue, pain, bacterial infection, viral infection, irritable bowel syndrome.