BE1030925A1 - SOFT GUMMY - Google Patents

Abstract

The present invention relates to a soft gummy for therapeutic oral use, wherein the soft gummy comprises an outer shell encapsulating an inner liquid, the outer shell comprising: (i) a pectin; and (ii) honey in an amount of at least 25% by weight relative to the weight of the outer shell; wherein said inner liquid has a moisture content of at least 10% by weight as measured according to ISO 760:1978 and a viscosity of not more than 50.0 Pa s measured at 20°C, and wherein the soft gummy contains a hydrolyzable tannin or a source of hydrolyzable includes tannin. The invention also relates to a use of a soft gummy.

Description

1 BE2022/5782

SOFT GUMMY

FIELD OF 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

A cough medicine or cough and cold medicine is a medicine used for coughing and related conditions, especially associated with inflammation of the airways. This can also include liquid medications for daytime or nighttime relief from colds, flu, allergies, or insomnia.

Cough remedies usually include medicines with analgesic and fever-reducing properties, such as ibuprofen (IBU) or dextromethorphan (DXM), which is an antitussive in amounts up to 5% BW, but active substances of natural origin such as dry extracts of ivy willow are also 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.

Cough syrups do not have these swallowing problems. Cough 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, cough syrups are generally sticky liquids that are difficult to handle, difficult to dose accurately, and cannot be used discreetly.

2 BE2022/5782

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 composition is orally disintegrated 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.

3 BE2022/5782

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 dose control and single dose packaging, with the advantages of a syrup, i.e. application of a sweet syrup that can relieve cough symptoms.

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 cough 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 and third aspect, the present invention relates to a use according to claims 14 and 15 respectively. The therapeutic oral use of the soft gummy is suitable for preventing or reducing symptoms of coughing, such as those caused by many respiratory diseases. Furthermore, active ingredients can be absorbed into the inner liquid.

The soft gummy described herein provides a beneficial effect in the treatment or prevention of coughs or colds.

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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: “A,” “the,” and “it,” as used herein, include both singular and plural 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 here are synonymous with 'include', 'involving' 'entails' or 'containing', 'containing' 'contains' 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, not mentioned components, features, elements, parts, steps, which are well known in the art or described therein.

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

The expression 'weight%', 'weight percentage', 'wt. %', '%wt' or 'wt%', here and in the description, unless otherwise defined, refers to the relative weight of the respective component based on the 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.

The term 'honey' means the sweet, viscous liquid produced in the honey-producing canal of various bees. Bees can make honey from the nectar of flowers, from other soluble disaccharides, or from small oligosaccharide carbohydrates. 'Tannins' are widespread in plants and can be divided into 3 5 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.

In a first aspect, the invention relates to a soft gummy for therapeutic oral use, wherein the soft gummy comprises an outer shell encapsulating an inner liquid, the outer shell comprising: (i) a pectin; and (ij) honey.

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The inventors have found that the combination of pectin, honey and hydrolyzable tannin is suitable to form 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 placed in the mouth, the outer shell will burst and the inner liquid will be spread throughout the mouth.

The inner liquid, preferably a syrup, can form a thin layer in the throat, providing immediate relief to an irritated or sore throat. The soft gummy can be used to soothe an irritated 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 soft gummy dosage form that makes the inner liquid suitable for oral administration, wherein the inner liquid is provided as a liquid 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. 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.

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In one embodiment, honey is present in an amount of at least 25% by weight relative to the weight of the outer shell, preferably in an amount of at least 30% by weight, more preferably in an amount of at least 35% by weight. %, more preferably in an amount of at least 40% by weight, more preferably in an amount of at least 45% by weight, more preferably in an amount of at least 50% by weight, more preferably in an amount of at least 55% by weight, even more preferably in an amount of at least 60% by weight. In one embodiment, honey is present in an amount between 55-99% by weight relative to the weight of the outer shell, preferably in an amount between 60-99% by weight, more preferably between 60-97% by weight, with even more preferably between 60-90% by weight. The sugar and cellulose in honey lends itself favorably to cross-linking with pectin and tannic acid. Honey is advantageously well tolerated, gives a sweet taste, and has good antibacterial, anti-inflammatory and antimicrobial properties. Honey acts as an autolytic debridement agent on wounds, as an antitussive, an analgesic, a remedy for dyspepsia and a natural anticancer agent. Moreover, honey is biobased.

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, honey 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 liquid as measured according to ISO 760:1978, more preferably a moisture content of at least 15% by weight relative to the weight of the

8 BE2022/5782 inner liquid as measured according to ISO 760:1978, more preferably a moisture content of at least 16% by weight compared 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 the inner liquid as measured according to ISO 760:1978, most preferably the moisture content is a maximum of 20% by weight with respect 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

Pas 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 fluid 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

9 BE2022/5782 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.

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, especially when both mechanical and pharmaceutical modes of action are desired. Mechanical modes of operation generally require certain larger amounts 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

10 BE2022/5782 relative to the weight of the soft gummy, more preferably in an amount of maximum 80% by weight relative to the weight of the soft gummy, more preferably in an amount of maximum 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 maximum 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 amount of a maximum of 50% by weight relative to the weight of the soft gummy, more preferably in an amount of a maximum of 45% by weight relative to the weight of the soft gummy, more preferably in an amount of a maximum of 40% by weight. % with respect to the weight of the soft gummy, more preferably in an amount of up to 35% by weight with respect to the weight of the soft gummy, more preferably in an amount of up to 30% by weight with respect 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 to 1, more preferably 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

11 BE2022/5782 7 to 1, more preferably a maximum of 6 to 1, more preferably 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 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 comprises a hydrolyzable tannin or a source of 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 honey 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, suitable for holding 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 outer shell comprises 80-90% by weight honey and 0.5-3% by weight pectin. In one embodiment, the outer shell comprises 65-75% by weight honey and 2-4% by weight pectin. In one embodiment, the outer shell comprises 55-65% by weight honey and 5-10% by weight pectin. In one embodiment, the outer shell comprises 50-60% by weight honey and 5-10% by weight pectin. In one embodiment, the outer shell comprises 85-95% by weight honey and 0.5-3% by weight pectin. In one embodiment, the inner liquid comprises 80-90% by weight honey and 0.5-3% by weight hydrolyzable tannin. In

In an embodiment, the inner liquid comprises 65-75% by weight honey and 2-4% by weight hydrolyzable tannin.

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 (LM) pectins 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). It was found that HM pectin, together with honey, resulted in stronger gel strength compared to LM pectins or LMA pectins. 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 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

13 BE2022/5782 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, honey and a hydrolyzable tannin are at least partially cross-linked. In one embodiment, the pectin, honey and a hydrolyzable tannin are chemically cross-linked. In one embodiment, the pectin, honey 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.

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, said outer shell further comprises 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 with respect to the weight of the outer shell, more preferably in an amount

14 BE2022/5782 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 based on the weight of the outer shell.

In one embodiment, said inner liquid comprises honey. In a more preferred embodiment, the inner liquid comprises honey in an amount of at least 20% by weight relative to the weight of the inner liquid, more preferably the inner liquid comprises honey in an amount of at least 25% by weight relative to the weight of the inner liquid. weight of the inner liquid, more preferably the inner liquid comprises honey in an amount of at least 30% by weight with respect to the weight of the inner liquid, more preferably the inner liquid comprises honey in an amount of at least 40% by weight with respect to of the weight of the inner liquid, more preferably the inner liquid comprises honey in an amount of at least 50% by weight relative to the weight of the inner liquid, more preferably the inner liquid comprises honey in an amount of at least 60% by weight relative to the weight of the inner liquid, more preferably the inner liquid comprises honey in an amount of at least 65% by weight relative to the weight of the inner liquid, more preferably the inner liquid comprises honey in an amount of at least 70% by weight .% relative to the weight of the inner liquid, more preferably the inner liquid comprises honey in an amount of at least 75% by weight relative to the weight of the inner liquid, more preferably the inner liquid comprises honey in an amount of at least 80% by weight relative to the weight of the inner liquid, more preferably the inner liquid comprises honey in an amount of at least 85% by weight relative to the weight of the inner liquid, more preferably the inner liquid comprises honey in an amount of at least 90% by weight relative to the weight of the inner liquid. In one embodiment, said honey is clover honey, wildflower honey, acacia honey, alfalfa honey, buckwheat honey, manuka honey or eucalyptus honey. Honey, similar to other sweet syrups, provides instant relief from coughs and colds and has antibacterial and antimicrobial properties. Furthermore, honey in combination with a source of hydrolyzable tannin forms a suitable layer to soften the mucous membranes.

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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, said inner liquid comprises a pharmaceutically active ingredient (API).

In one embodiment, said inner fluid comprises at least one antibiotic. 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, 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, 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 respiratory tract, including the pharynx.

16 BE2022/5782

In one embodiment, the inner liquid includes a 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 rose hip flavor , a rosemary flavor, a passion fruit flavor, a licorice flavor, a ginger flavor, a honey flavor, tartar, malic acid, and citric acid, trisodium citrate. In one embodiment, the inner liquid comprises: 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 inner liquid includes: ginger, coffee, coffee bean, gotu kola root, gotu kola extract, kola nut, cacao, 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, cranberry, mint, cinnamon, cocoa, mint, spearmint (Mentha spicula), wild mint (Mentha arvensis), 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 (Valeriana 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 fluid comprises:

Black pepper, cinnamon, cumin, ginger, rose hips or any combination thereof. In one embodiment, the inner liquid comprises coltsfoot, mongoose, thyme leaf, wild cherry bark, quercetin, sundew, butterbur, grape seed extract, or any combination thereof.

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,

17 BE2022/5782 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, phenylmercuric nitrate, potassium benzoate, potassium sorbate, 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 metabisulfite, sodium thiosulfate, 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 carboxymethylcellulose, cellulose acetate, cellulose acetophthalate, ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate,

methacrylic acid copolymer, methylcellulose, 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 sulphate, sodium stearate, sorbitan monolaurate, sorbitan monooleate,

18 BE2022/5782 sorbitan monopalmitate, sorbitan monostearate, stearic acid, trolamine, emulsifying wax); filter aids (cellulose powder, purified silica); aromas and perfumes (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); 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, 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, 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,

10 BE2022/5782 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, 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, cottonseed oil, ethyl oleate, isopropyl myristate, isopropyl palmitate, myristyl alcohol, octyldodecanol, olive oil, peanut oil, persian oil, sesame oil, soy oil, squalane); solid carrier (sugar balls); sterile vehicle (bacteriostatic water for injection, bacteriostatic sodium chloride injection); viscosity increasing agent (See suspending 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 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 include tannins with 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 pressure within the soft gummy is greater than 1 atm, preferably between 1.01 and 1.10 atm.

20 BE2022/5782

In one embodiment, the soft gummy disintegrates orally within about 1-10 minutes after oral administration to a patient in need thereof, preferably within 1-5 minutes. The soft gummy has a faster disintegration time compared to most gelatin-based pharmaceutical formulations.

This can be particularly useful for the delivery of syrup and possibly an API to the pharynx and oral cavity.

The present invention includes a new product that benefits the respiratory tract. In particular, the novel herbal composition of this invention is useful in the prevention and/or treatment of cough. Coughing is a complicated process. Airway and/or airway disruption may have neurohumoral consequences that may ultimately lead to coughing. The cough reflex is truly 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.

In one embodiment, the present description relates to soft gummies formulated such that the final soft gummies have a palatable and non-bitter flavor profile. In some embodiments, the soft gummies are formulated to have a palatable and non-bitter flavor profile through the use of honey. The flavor and astringent mouthfeel of tannins limit their use. The addition of honey improves the

21 BE2022/5782 taste and mouthfeel. In some embodiments, the bitterness flavor profile of the soft gummy can be measured using a taste acceptability index (TAI).

As described herein, the Taste Acceptance Index (TAI) of a soft gummy of the present disclosure may be assigned by a panel of tasters. The TAI can be calculated by determining the presence and amount of bitterness of soft gummy by each taster, assigning each soft gummy a numerical value based on the degree of bitterness detected in the formulation, scaled from O (extreme bitter and unpalatable flavor profile) to 10 (no bitterness detected), and average the scores of each taster on the panel to identify the TAI of the particular soft gummy. In some embodiments, a TAI score of about 0 to about 4 indicates a soft gummy that has an extreme or high level of bitter and/or unpalatable flavor profiles. In some embodiments, a TAI score of about 5 to about 6 indicates a soft gummy that has moderate to low levels of bitter and/or unpalatable flavor profiles. In some embodiments, a score of about 7 to about 10 indicates a soft gummy that has little to no bitter and/or unpalatable flavor profiles. In some embodiments, the soft gummy may be formulated with a taste acceptance index (TAI) of about 6 to about 10. Soft gummies of the present disclosure may be formulated such that the product is not unpalatable, but at the same time does not have a flavor profile comparable to that of a candy. Additionally, the soft gummy can be formulated so that a slight bitter taste is noticeable, which may be preferable for some individuals.

Accordingly, in some embodiments, the soft gummy may be formulated with a taste acceptance index (TAI) of about 6 to about 8. In some embodiments, the soft gummy has a TAI of about 6 to about 10, about 6 to about 9, about 6 to about 8 , about 6 to about 7, about 7 to about 10, about 7 to about 9, about 7 to about 8, about 8 to about 10, about 8 to about 9, or about 9 to about 10. In some embodiments, the soft gummy has a TAI of about 6 to about 8, about 6 to about 7, or about 7 to about 8.

22 BE2022/5782

In one embodiment, the soft gummy has a chewable bite index (CBI) of about 2 to about 5. In one embodiment, the thickness of the outer shell is 0.3 to 1.2 mm.

In some embodiments, the soft gummy further comprises 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 some embodiments, the soft gummy further comprises one or more sweeteners. In some embodiments, 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 combination of them. 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 some embodiments, the soft gummy further comprises one or more colorants. In some embodiments, the one or more dyes are selected from FD&C Red 40, D&C Red 3, 22, 28, 33 and 36,

23 BE2022/5782

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 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 of aromas and perfumes, 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 one embodiment, the outer shell comprises: 25-99% by weight honey; 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 a second aspect, the invention relates to a use of a soft gummy according to the invention, for therapeutic oral use.

In a third aspect, the invention relates to a use of a soft gummy according to the invention, for therapeutic oral use, in the treatment or prevention of coughs or colds.

In one embodiment, one dosage is one soft gummy. For example, the dosage can be administered at least once a day, for example in five, four, three, two or one doses per day. In an illustrative example, the dose is administered once per day. In certain embodiments, administration of any composition described herein (e.g., for the treatment of respiratory inflammation, throat irritation, or coughing) is once per day. In other specific embodiments, administration (e.g., for the treatment of respiratory inflammation, throat irritation, or coughing) is twice daily. In yet other embodiments, administration (e.g., for the treatment of respiratory inflammation, throat irritation, or coughing) is three times daily. In another embodiment, administration (e.g., for the treatment of airway inflammation, throat irritation, or coughing) is four times daily. In another embodiment, the dose is administered at night. In another aspect, the dose becomes approx

24 BE2022/5782 administered 30 minutes before bedtime, without food or water being given after administration of the preparations herein. In another embodiment, the dose is administered before bedtime. In specific embodiments, a gummy comprising an API 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 up 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. For example, one or more dosage forms can be administered for 1, 2, 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.

Another embodiment described herein is a soft gummy suitable for chewing, sucking or buccal solution as described herein for treating, slowing the progression of, prophylaxis of, delaying the onset of, ameliorating, reducing the symptoms of , or promoting health, including but not limited to one or more of oral, buccal, respiratory or esophageal inflammation, eosinophilic esophagitis, oral lichen planus, odynophagia, acid reflux, dysphagia, cough, sore throat, common cold, viral infection such as a coronavirus (e.g. COVID-19), acute bronchitis, chronic bronchitis, pneumonia, flu, asthma, bronchitis, chronic obstructive airways disease (COAD), bacterial infections (e.g. tuberculosis), postnasal drip, laryngitis, RSV, bronchiectasis,

25 BE2022/5782 emphysema, unwanted side effects of other medicines, inhaling an irritant, allergies, whooping cough, acute sinusitis, bronchiolitis, reduced appetite or growth retardation. In another embodiment, the soft gummy described herein is suitable for reducing aches, coughs and pain.

In another embodiment, the soft gummy described herein is suitable for improving wound healing. The tannins can interact with the mucus layer, tightening damaged tissue. In another embodiment, the soft gummy described herein protects the intestinal mucosa.

Another embodiment described herein is a method for treating, slowing the progression of, prophylaxis of, delaying the onset of, ameliorating, reducing the symptoms of, or promoting the health of 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, pneumonia, influenza , asthma, bronchitis, chronic obstructive airways disease (COAD), bacterial infections (e.g. tuberculosis), postnasal drip, laryngitis, RSV, bronchiectasis, emphysema, unwanted side effects of other medicines, inhaling an irritant, allergies, whooping cough, acute sinusitis, bronchiolitis, loss of appetite or growth retardation, comprising administering to a patient in need thereof an oral soft gummy suitable for chewing, sucking or buccal solution 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, 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 of an irritant, allergies, whooping cough, acute sinusitis, bronchiolitis, decreased appetite or growth retardation, or postoperative inflammation.

26 BE2022/5782

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.

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.

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

27 BE2022/5782 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 temperature may 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 a further 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 honey 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 honey to said outer surface of the inner liquid, 2) allowing the liquid gelling composition to gel while in contact with the inner liquid, thereby 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 out of the outer concentric nozzle first, followed by inner liquid flow out of the

28 BE2022/5782 inner concentric nozzle, while the flow from the concentric nozzle of the outer shell 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 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 honey, it was discovered that the gel layer prevents significant moisture loss from the inner fluid. This results in an improved shelf life and a more attractive appearance during storage. The skilled person is aware that high concentrations of honey can be used, at least 25% by weight with respect to the weight of the outer shell, preferably even 50% by weight. 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.

29 BE2022/5782

Example 1:

Layer of soft gummy Ingredient (amount in wt% ee

Outer peel Honey (59) Aroma / Binder / er tee eee (mama er eee ee memes | Vemurendesier

Hydrolyzable tannin | Binder / Active (us PT ee

PO [rare (0.5) [Aroma

Inner liquid Honey (91) Aroma / Binder /

Too OT ee

Hydrolyzable tannin | Binder / Active a eee ee eee

LT | Famaarauur ss Acidifying Substance [Get [Emden

Example 2:

Part of soft | Ingredient mm (seen

Outer shell Honey (0.3 g) Aroma / Binder /

PTE Atamgesen [Buckles (0.08 9) Binding agent [We Wetting agent etc. | Acidifying substance

Inner liquid Honey (1.0 9) Aroma / Binder /

JTE (EEE ne

Hydrolyzable tannin | Binder / Active (a TU PTT [ennen (120 me) | Active Ingredient

30 BE2022/5782

PM CC CCD Ea

PC EU COQ

LT [Mon

Example 3:

Layer of soft | Ingredient (quantity in ms a

Outer peel Honey (75) Aroma / Binder /

PE Eee ete memes

LT (Becraiosets sea fabric

Hydrolyzable tannin (2) Binder / Active and

PQ (water repellent

Sodium carboxymethylcellulose | Coating agents etc

Inner liquid Honey (82) Aroma / Binder /

PTT EE ee

LT rroemaurs | Vernrendeser

LT |wetere Fighting Agent 1 |Pewieraet On Emalaator [Pentasa | Lubricants

LT mtscerteen emer

M CU CONS Ama

Examples 4-11

The effect of each component and the heating time of the outer shell were investigated. A needle prick test was used to obtain a combined indication of viscosity and gel strength. A weighted needle was placed on top of each composition and the time required for the needle to pass through the composition was determined. All samples were heated and then cooled prior to testing.

31 BE2022/5782

Comparative example 4 consisted of pure honey, heated at 105°C for 1 hour and then cooled.

Comparative example 5 includes 89% honey and 11% pectin. 25% water relative to the weight of honey and pectin was added. Honey and pectin were completely homogenized, which required high shear homogenization. The homogenized mixture was heated at 105°C for 1 hour and then cooled.

Comparative example 6 includes 89% honey and 11% pectin. 25% water relative to the weight of honey and pectin was added. Honey and pectin were completely homogenized, which required high shear homogenization. Citric acid was added at 1% by weight of the honey and pectin mixture. Trisodium citrate was added at 0.5% by weight of the honey and pectin. The homogenized mixture was heated at 105°C for 2 hours and then cooled.

Comparative example 7 includes 89% honey and 11% pectin. 25% water relative to the weight of honey and pectin was added. Honey and pectin were completely homogenized, which required high shear homogenization. Citric acid was added at 1% by weight of the honey and pectin mixture. Trisodium citrate was added at 0.5% by weight of the honey and pectin. The homogenized mixture was heated at 105°C for 3 hours and then cooled.

Comparative example 8 includes 89% honey and 11% pectin. 25% water relative to the weight of honey and pectin was added. Honey and pectin were completely homogenized, which required high shear homogenization. Citric acid was added at 1% by weight of the honey and pectin mixture. Trisodium citrate was added at 0.5% by weight of the honey and pectin. The homogenized mixture was heated at 105°C for 4 hours and then cooled.

Thus, the difference between Comparative Examples 6, 7 and 8 is the time spent at elevated temperatures. The results showed a decrease in both

32 BE2022/5782 moisture content as the volume. In addition, the formulations were darker compared to their original color, indicating that caramelization was taking place.

Comparative Example 9 did not include citric acid and trisodium citrate.

Comparative example 9 includes 89% honey and 11% pectin. 25% water relative to the weight of honey and pectin was added. Honey and pectin were completely homogenized, which required high shear homogenization. The homogenized mixture was heated at 105°C for 2 hours and then cooled.

Example 10 includes 89% honey and 11% pectin. 25% water relative to the weight of honey and pectin was added. Honey and pectin were completely homogenized, which required high shear homogenization.

Tannic acid, a hydrolyzable tannin, was added at 3% by weight of the honey and pectin.

The homogenized mixture was heated at 105°C for 2 hours and then cooled.

Example 11 includes 89% honey and 11% pectin. 25% water relative to the weight of honey and pectin was added. Honey and pectin were completely homogenized, which required high shear homogenization.

Citric acid was added at 1% by weight of the honey and pectin mixture. Trisodium citrate was added at 0.5% by weight of the honey and pectin. Tannic acid, a hydrolyzable tannin, was added at 3% by weight of the honey and pectin. The homogenized mixture was heated at 105°C for 2 hours and then cooled.

Table 1: Needle Penetration Test Results of Examples 4-11. travel distance (mm time (s) needle speed (mm/s

Comparative example 4 14.2 <1 > 14.2

Comparative example 5 15.6 wl 15.6

Comparative example 6 11.8 42 0.28

Comparative example 7 10.9 18 0.61

Comparative example 8 9.6 15 0.64

33 BE2022/5782

Comparative example 9 9.1 50 0.18

Example 10 11.9 1710 0.0070

Example 11 12.9 > 3600 < 0.0036

The results of the needle penetration tests are shown in Table 1.

The addition of a hydrolyzable source of tannin significantly increases the strength of the shell matrix, as shown in examples 10 and 11.

The combination of a polycarboxylic acid, in this case citric acid, and a source of hydrolyzable tannins, in this case tannic acid, appears to have a synergistic effect. The addition of citric acid in c. examples 6, 7 and 8 appear to reduce the strength of the honey-pectin mixtures compared to a composition without citric acid c. example 9. When a hydrolyzable source of tannin is added, the opposite is found to be true. The addition of citric acid significantly increased the matrix strength, as can be seen from the comparison of examples 10 and 11. The hydrolyzable tannin and polycarboxylic acid thus have a synergistic effect with regard to gel strength.

So it is clear that a hydrolyzable source of tannin is highly beneficial to greatly improve viscosity and gel strength. The effect can be further improved by the addition of a polycarboxylic acid, preferably dicarboxylic acid or tricarboxylic acid, such as citric acid.

Claims (15)

34 BE2022/5782 CONCLUSIONS A soft gummy for therapeutic oral use, wherein the soft gummy comprises an outer shell enclosing an inner liquid, the outer shell comprising: (i) a pectin; and (ii) honey in an amount of at least 25% by weight relative to the weight of the outer shell; wherein said inner liquid has a moisture content of at least 10% by weight as measured according to ISO 760:1978 and a viscosity of not more than 50.0 Pa s measured at 20°C, and wherein the soft gummy contains a hydrolyzable tannin or a source of hydrolyzable includes tannin. 2. Soft gummy according to claim 1, wherein the pectin is selected from the group of: high methoxyl pectin (HM), low methoxyl pectin (LM) or low methoxyl amidated pectin. LMA). Soft gummy according to any one of claims 1-2, wherein said pectin is high methoxyl pectin (HM), wherein said high methoxyl pectin (HM) has a degree of methoxylation (DM) of at least 50. 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 esterification (DE) of at least 60. Soft gummy according to any one of claims 1 to 4, wherein said pectin is high methoxyl (HM) pectin, said high methoxyl (HM) pectin is at least partially cross-linked, said cross-linking preferably being supported by said hydrolyzable tannin or source thereof . 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. Soft gummy according to any one of claims 1-6, wherein said inner liquid comprises honey, preferably in an amount of at least 25% by weight with respect to 35 BE2022/5782 of the weight of the inner liquid, more preferably at least 50% by weight of honey with respect to the weight of the inner liquid. A soft gummy according to any one of claims 1 to 7, wherein the outer shell comprises 1-10% by weight of (i) pectin relative to the weight of the outer shell; and 50-90% by weight of (ii) honey relative to the weight of the outer shell. A soft gummy according to any one of claims 1 to 8, wherein said inner liquid comprises said hydrolyzable tannin or source of hydrolyzable tannin, said hydrolyzable tannin being present in an amount of at least 0.5% by weight relative to the weight of the inner fluid. A soft gummy according to any one of claims 1 to 9, wherein said outer shell comprises said hydrolyzable tannin or source of hydrolyzable tannin, wherein the hydrolyzable tannin is present in an amount of at least 0.5% by weight relative to the weight of the outer shell. A soft gummy according to any one of claims 1 to 10, wherein said inner liquid comprises a hydrolyzable tannin or a source of hydrolyzable tannin in an amount of at least 0.5% by weight relative to the weight of the inner liquid. A soft gummy according to any one of claims 1 to 11, wherein said inner liquid comprises menthol or a mint extract. A soft gummy according to any one of claims 1 to 12, wherein said outer shell comprises at least 50% by weight of honey relative to the total weight of said outer shell, and wherein said inner liquid comprises at least 50% by weight of honey relative to the total weight of said inner fluid. Use of a soft gummy according to any one of claims 1-13, for therapeutic oral use. Use of a soft gummy according to any one of claims 1-13, for therapeutic oral use, in the treatment or prevention of coughs or colds.