WO2018117855A1

WO2018117855A1 - Effervescent lozenge

Info

Publication number: WO2018117855A1
Application number: PCT/NO2017/050332
Authority: WO
Inventors: Roger BJØRKLI
Original assignee: X-Ing As
Priority date: 2016-12-20
Filing date: 2017-12-19
Publication date: 2018-06-28

Abstract

An effervescent lozenge comprising an effervescent mixture and at least one active substance, and the effervescent lozenge weighs more than 1.2 g, and the effervescent lozenge is formulated with a proportion of an acid to a base in an effervescent mixture that gives a disintegration time of between 2 minutes and 5 minutes when being sucked in an oral cavity.

Description

EFFERVESCENT LOZENGE

The invention relates to an effervescent lozenge. An effervescent tablet is known as a fizzy tablet. The invention specifically relates to an effervescent lozenge which is adapted in composition and size for oral administration as an intact tablet. The effer- 5 vescent effect of the tablet is achieved by a user positioning the lozenge on his/her tongue and sucking on the tablet. More specifically still, the invention relates to an effervescent lozenge that includes at least one active substance. The active substance may be a vitamin. The active substance may be an antioxidant, such as vitamin C. The active substance may be an antimicrobial agent. The active substance may be a i o pharmaceutical to be absorbed in an epithelial tissue in the back part of an oral cavity or in a throat. The effervescent lozenge may include a mixture of several active substances. The effervescent lozenge stimulates the saliva production in the user, and the saliva and the released contents of the lozenge form a mixture that feels foamy to the user. The user is stimulated to frequent swallowing, which carries the released con-

15 tents of the lozenge backwards to the user's back oral cavity and throat.

Fizzy tablets containing vitamin C are adapted for dissolving in water before the liquid vitamin-C mixture is drunk. The use of pharmaceuticals formulated as effervescent tablets is known as well. Such pharmaceuticals are administered by first dissolving the effervescent tablet in a suitable amount of water or aqueous liquid. The liquid with the 20 dissolved pharmaceutical is then administered orally by the liquid mixture being

drunk. Patent publication WO 2014/160872 teaches a fizzy tablet containing table salt. The dissolved mixture is then to be gargled, but preferably not swallowed. The tablet disintegrates in water in less than 120 seconds.

A beginning cold is felt by an itching or uncomfortable sensation in the oral cavity 25 and/or throat. The throat comprises the pharynx. Usually, the itching or the uncomfortable sensation is due to a viral infection, but it may also be due to a bacterial infection. Epithelial cells in the back part of the oral cavity and in the throat may be covered with a mucus that protects the epithelial cells. The mucus will also protect viruses and bacteria in or on the cells in the back part of the oral cavity and in the throat. The viral infection or the bacterial infection will also stimulate the cells to produce more mucus.

It is difficult to treat infections in the back part of the oral cavity and, in particular, infections in the throat by topically administering one or more active substances. The use of lozenges and drops with active substances against a cold is known, but such lozenges and drops only give a relieving effect or an effect experienced as relieving. Lozenges and drops have been formulated to be water-soluble as they are dissolved in saliva. The mucous layer in the oral cavity and throat protects the underlying cells from the active substances of such lozenges and drops, and the active substances do not reach the cells or viruses and bacteria that are on the outside of the cells.

Patent document AU2004242477 / US2011/0223115 discloses an effervescent tablet which is to be dissolved in the mouth to improve the absorption of a pharmaceutical compound across the mucous membranes. The tablet is held against the inside of the cheek, for example between the cheek and the gum, for buccal administration, under the tongue for sublingual administration or between the upper lip and gum for gingival administration. The size of the tablet may be between 4.7 mm (3/16") and 15.9 mm (5/8"). A tablet for buccal administration is described, the tablet weighing 100 mg. A tablet for sublingual administration is described as well, the tablet weighing 400 mg. In the examples, a tablet weighing 500 mg is described as well.

Patent document US2011/0014132 discloses an effervescent mixture that is to be dissolved in the mouth to achieve buccal, sublingual and/or gingival administration of a therapeutic agent. The mixture can be formulated as a tablet, a pill, a granule, a chewing gum or a drops.

Patent documents WO 2005/065318 and WO2005/065319 disclose effervescent oral dosage forms for achieving buccal, sublingual and/or gingival administration of a therapeutic agent. The dissolution time in the mouth is between 5 and 30 minutes, and preferably between 12 and 30 minutes. Suitable tablets may have a diameter of about 6.4 mm and a weight of 100 mg, or suitable tablets may have a diameter of about 7.9 mm and a weight of 200 mg.

Patent document EP2338495 discloses an effervescent tablet for the oral administration of iron bis-glycinate to patients suffering from coeliac disease. A suitable tablet weighs about 930 mg.

Patent document US 2013/0108745 discloses a coated effervescent tablet for the oral supply of omega-3 and omega-6 fatty acids. A suitable tablet according to one exem- plary embodiments weighs about 1.2 g. A suitable tablet according to another exemplary embodiment disintegrates within less than one minute.

Patent document WO2009/047321 discloses an effervescent tablet for the sublingual administration of progesterone. The tablet is to disintegrate in less than two minutes and preferably between 60 and 120 seconds. A suitable tablet has a weight of 665 mg and a diameter of 16 mm. The invention has for its object to remedy or reduce at least one of the drawbacks of the prior art or at least provide a useful alternative to the prior art.

The object is achieved through the features that are specified in the description below and in the claims that follow.

An effervescent mixture of an acid, especially an organic acid, and a base, especially a carbonate, produces CO2 gas when the acid and base react with water. An effervescent lozenge contains an effervescent mixture.

An effervescent lozenge, which is administered orally by it being inserted intact into an oral cavity for the user to suck and possibly chew on the effervescent lozenge, will emit CO2 gas when the effervescent mixture reacts with the saliva and possibly a mucus in the oral cavity.

It is an object of the invention to provide a formulation which continuously or frequently exposes the surfaces of the back parts of the oral cavity and of the throat to an active substance for a time long enough for the active substance to exert an effect. It is, in particular, an object for the formulation to expose these surfaces long enough for a possible mucous layer covering the surfaces to be affected by, for example, the pH of the mucous layer changing, the mucous layer coming loose from the underlying epithelial cells, or by the mucous membrane absorbing the active substance.

The invention achieves its object by an effervescent lozenge being disintegrated in the mouth by the effervescent lozenge being sucked on. The effervescent lozenge is preferably made to initially be placed on the top side (dorsum) of the tongue, that is to say between the top side of the tongue and the palate. As the lozenge disintegrates, it can be moved around in the mouth with the tongue. Preferably, the effervescent lozenge is further made to contain enough effervescent material to give a good stimulation of the saliva production. This leads to the saliva having to be swallowed frequently while the lozenge is disintegrating. The frequent swallowing leads to epithelial cells, mucus and mucous membranes in the back part of the oral cavity and of the throat being almost continuously exposed to a mixture of saliva, active substance, possibly a mixture of active substances and disintegrated substances from the effervescent lozenge. Preferably, the effervescent lozenge is further made to contain enough effervescent material and a proportion of an acid to a base that results in the disintegration time lasting longer than two minutes. Preferably, the disintegration time lasts for more than three minutes. More preferably, the disintegration time lasts for more than four minutes. Preferably, the disintegration time is to be shorter than five minutes.

The invention also relates to the effervescent reaction not running to completion while the lozenge is positioned on the top side of the tongue. The effervescent reaction continues between the acid and the base of the effervescent mixture when they have been dissolved in the saliva, so that some of the effervescent reaction continues in the back part of the oral cavity and in the throat. The saliva with the dissolved active substances, other components of the lozenge, released CO2, and any remnants of the effervescent mixture form a foamy solution or a solution which feels foamy to a user. The foamy solution is carried backwards in the oral cavity and partly into the throat. The foamy solution stimulates swallowing.

The invention differs from other oral effervescent formulations in that the effervescent lozenge is larger than preparations for buccal, sublingual or gingival administration. The effervescent tablet according to the invention thereby leads to greater saliva secretion than other oral effervescent formulations. The invention differs from other oral effervescent formulations in that the effervescent lozenge disintegrates more quickly than many preparations for buccal, sublingual or gingival administration. The invention has for its object to affect surfaces in the back part of the oral cavity and in the throat and not tissues / epithelial cells under the tongue, in the gum or on the inside of the cheek. The invention does not have for its object to improve the absorption of active substances across tissues / epithelial cells under the tongue, in the gum and/or on the inside of the cheek. An effervescent lozenge according to the invention is larger than effervescent tablets that have been produced for the buccal, sublingual or gingival administration of an active substance. For a user, the effervescent tablet will be experienced as too large for buccal, sublingual or gingival positioning in the oral cavity.

The inventor does not want to be bound by the following as theory: The moisture of the mucus layer reacting with the effervescent mixture that is dissolved in the saliva will be drawn out of the mucus layer, and the mucus layer may become weakened thereby. The mucus layer may also come loose from the underlying cells because of the CO2 gas that is being released and that will have a mechanical effect on the mucus layer. The effervescent tablet that is sucked in the oral cavity includes one or more active substances. The active substance or active substances will typically come into topical contact with the cells under the mucus layer where the mucus layer has been weakened or come loose. An active substance which is effective against a virus, a bacterium or which is effective against viruses and bacteria may have an increased effect 5 against viruses and bacteria on the outside of the cells as these viruses and bacteria will be directly exposed to the active substance. The cells may also absorb the active substance across the cell membrane.

Known fizzy tablets that include an active substance and that are dissolved in water or an aqueous liquid before oral administration will not give the same effect as an effer- i o vescent lozenge that is disintegrated in the oral cavity according to the invention. The liquid that is drunk will not affect the moisture of the mucus layer in the oral cavity and throat. The effervescent mixtures of the known fizzy tablets will react with the water in the liquid. This water is freely available as opposed to the water in a moist mucus layer. The form of oral administration according to the present invention is

15 therefore substantially different from the form of oral administration in which the

preparation is first disintegrated in water or an aqueous liquid and then drunk. Known fizzy tablets have a disintegration time in water of about 1 minute to 1.5 minutes. The disintegration time is relatively quick for the user not having to wait so long before the solution is ready for use.

20 The active substance may be a vitamin. The vitamin may be a vitamin C. The active substance may be an antioxidant. The active substance may be an antibiotic. The active substance may be an antiviral agent. The effervescent lozenge may contain a mixture of a plurality of active substances.

It is mentioned as an example that a known fizzy tablet containing vitamin C will form 25 a drinkable fluid when the fizzy tablet is disintegrated in water or an aqueous liquid.

The vitamin C will be dissolved in the water or liquid. Viruses and bacteria in the oral cavity and throat will not be directly affected by the vitamin C in the water or in the liquid when the water or liquid is administered orally.

The effervescent lozenge in accordance with the invention is formulated in such a way 30 that the user experiences an acceptable oral sensation when the user sucks on the intact effervescent tablet.

By an intact effervescent lozenge is meant that the lozenge has not been exposed to water or an aqueous liquid before oral administration. The effervescent lozenge may be provided with a notch for a user to be able to divide the effervescent lozenge into smaller pieces. Such smaller pieces also constitute an intact lozenge. In other words, by an intact lozenge is meant that the lozenge is dry when the lozenge, or pieces of the lozenge, is/are being inserted into the mouth.

The invention is defined by the independent claim. The dependent claims define ad- 5 vantageous embodiments of the invention.

In a first aspect, the invention relates more specifically to an effervescent lozenge including an effervescent mixture and an active substance or a combination of active substances, and the effervescent lozenge weighs more than 1.2 g, and the effervescent lozenge is formulated with a proportion of an acid to a base that gives a disinte- i o gration time of between 2 minutes and 5 minutes.

The disintegration time of the effervescent lozenge in an oral cavity may be between 2.5 minutes and 4.5 minutes. The disintegration time of the effervescent lozenge in an oral cavity may be between 3 minutes and 4.5 minutes. The disintegration time of the effervescent lozenge in an oral cavity may be between 3 minutes and 4 minutes. The

15 disintegration time of the effervescent lozenge in an oral cavity may be at least 2

minutes, preferably at least 2.5 minutes, preferably at least 3 minutes, preferably at least 3.5 minutes and preferably at least 4 minutes. The disintegration time of the effervescent lozenge in an oral cavity may be 5 minutes maximum, preferably 4.5 minutes maximum, preferably 4 minutes maximum, preferably 3.5 minutes maximum

20 and preferably 3 minutes maximum. The disintegration time of the effervescent lozenge in an oral cavity may be a combination of the minimum disintegration times and the indicated maximum disintegration times.

The active substance may be ascorbic acid or a pharmaceutically acceptable compound of ascorbic acid. The ascorbic acid or the pharmaceutically acceptable ascorbic- 25 acid compound may constitute from 10 per cent by weight to 50 per cent by weight of the effervescent lozenge.

The effervescent lozenge may include a pharmaceutically acceptable mixture of an acid and a base. The acid may include a pharmaceutically acceptable organic acid or a pharmaceutically acceptable compound of the pharmaceutically acceptable organic 30 acid. The base may be a carbonate base. The carbonate base may comprise at least sodium bicarbonate. The quantitative proportion (weight/weight) of the organic acid or the pharmaceutically acceptable compound of the pharmaceutically acceptable organic acid to sodium bicarbonate may be from 1 : 2 to 2 : 1.

The active substance may comprise an antioxidant. The active substance may com- prise an antibiotic. The active substance may comprise an antiviral agent.

An acid in the effervescent lozenge may comprise ascorbic acid or a pharmaceutically acceptable compound of ascorbic acid. An acid in the effervescent lozenge may comprise citric acid or a pharmaceutically acceptable compound of citric acid.

The effervescent lozenge may have a diameter of 18 mm. Preferably, the effervescent lozenge may have a diameter of 20 mm. Preferably, the effervescent lozenge may have a diameter of 22 mm. Preferably, the effervescent lozenge may have a diameter of 25 mm. Preferably, the effervescent lozenge may have a diameter of 30 mm. The effervescent tablet may also be produced with other diameters of between 20 mm and 35 mm. The effervescent lozenge may have a thickness which may be adapted to the diameter, so that amount of effervescent mixture in the lozenge is adapted for stimulating the desired amount of saliva production.

The effervescent lozenge contains an organic acid which may acidify the surfaces in the back part of the oral cavity and the surfaces of the throat when the effervescent lozenge is being disintegrated in the oral cavity.

According to the invention, a use of an effervescent mixture for the production of an intact effervescent lozenge is described as well, the intact effervescent lozenge containing an active substance or a combination of two or more active substances, and the intact effervescent lozenge being administered orally. The effervescent mixture may include a pharmaceutically acceptable mixture of an acid and a base. The acid may comprise a pharmaceutically acceptable organic acid or a pharmaceutically acceptable compound of the pharmaceutically acceptable organic acid. The base may be a carbonate base. The carbonate base may comprise at least sodium bicarbonate. The quantitative proportion (weight/weight) of the organic acid or the pharmaceutically acceptable compound of the pharmaceutically acceptable organic acid to sodium bicarbonate may be from 1 : 2 to 2: 1.

The active substance may comprise an ascorbic acid or a pharmaceutically acceptable compound of ascorbic acid for the prevention or relief of an itchy throat. The active substance may comprise an ascorbic acid or a pharmaceutically acceptable compound of ascorbic acid for the prevention or relief of a sore throat. The active substance may comprise an ascorbic acid or a pharmaceutically acceptable compound of ascorbic acid for prophylaxis or relief of an itchy throat. The active substance may comprise an ascorbic acid or a pharmaceutically acceptable compound of ascorbic acid for the relief of a sore throat. The active substance may comprise an ascorbic acid or a pharma- ceutically acceptable compound of ascorbic acid for the relief of a sore throat.

The ascorbic acid or the pharmaceutically acceptable compound of the ascorbic acid may make up from 10 per cent by weight to 50 per cent by weight of the intact effervescent lozenge.

The active substance may comprise an antioxidant. The active substance may comprise an antibiotic. The active substance may comprise an antiviral agent.

An acid in the effervescent mixture may comprise ascorbic acid or a pharmaceutically acceptable compound of ascorbic acid. An acid in the effervescent mixture may comprise citric acid or a pharmaceutically acceptable compound of citric acid.

Example 1

A composition of an effervescent lozenge according to the invention. The tablet contains 1000 mg of ascorbic acid.

Tablet weight 4.3 g

Tablet size (diameter) 25 mm

Acid : L-ascorbic acid CeHsOe

Citric acid CeHsOy

pH regulator: Sodium hydrogen carbonate Na HCOs

Moisture-preserving

agent: Sorbitol CeHwOe

Additive Maltodextrin C6nH(10n+2)O(5n+l) pH regulator Sodium carbonate Na₂C0₃

Substitute substance Inulin C6nH(10n+2)O(5n+l)

Anti-caking agent Tricalcium phosphate Ca₃(P0₄)2

Additive Starch (CeHloOsJn

Flavouring Orange

Sweetener Sucralose C12H19CI3O8

Additive Beetroot-juice powder (maltodextrin, beetroot-juice powder)

Colouring Riboflavin 5'-phosphate sodium C17H21N4O9P (Na)

Example 2

Tablet weight 4.2 g Tablet size (diameter) 25 mm

Sodium hydrogen carbonate 1050 mg

Citric acid 630 mg

L-ascorbic acid 1000 mg

Maltodextrin 924 mg

Sweetener

(sorbitol, natural sugar from fruits and be 430 mg

Colouring, flavouring 176 mg

A whole lozenge that weighs about 4.2 g disintegrates in the mouth within about 3 to 3.5 minutes when not chewed. Half a lozenge, weighing about 2.1 g, disintegrates in

5 the mouth within about 3 to 3.5 minutes when not chewed. A quarter of a lozenge, weighing about 1 g, disintegrates in the mouth within about 3 to 3.5 minutes when not chewed. The size of the lozenge is thus not very important for the disintegration time, as the disintegration time depends on the composition of the effervescent mixture. A whole lozenge that weighs about 4.2 g and half a lozenge, weighing 2.1 g, i o gave a satisfactory secretion of saliva for regular swallowing and thereby regular exposure of the surfaces at the back oral cavity and throat. A quarter of a lozenge, which weighs about 1 g, was considered to give too little saliva secretion in relation to the purpose.

Example 3

15 Comparison with a commercial product A

Product A is a commercially available fizzy tablet containing vitamin C. The fizzy tablet is first to be disintegrated in water, and the solution is then to be drunk. Each fizzy tablet contains 200 mg of vitamin C. According to the manufacturer's information, each tablet contains an acidity regulator (citric acid, sodium hydrogen carbonate), vit- 20 amin C ester C (calcium ascorbate), inulin (chicory root fibre), aroma (orange), colouring (beetroot powder, beta carotene) and sweetener (saccharin). Each tablet weighs about 4.5 g and has a diameter of about 25 mm. The tablet disintegrates completely in cold water over a period of about 70 seconds.

Comparison with a commercial product B

25 Product B is a commercially available fizzy tablet containing vitamin C. The fizzy tablet is first to be disintegrated in water, and the solution is then to be drunk. Each fizzy tablet contains 1000 mg of ascorbic acid (vitamin C). According to the manufacturer's information, each tablet contains 580 mg sodium hydrogen carbonate, 217 mg water- free sodium carbonate, water-free citric acid, rice starch, sodium citrate dihydrate, 25 mg mannitol, sweetener (sodium cyclamate, saccharin sodium), colourings (riboflavin sodium phosphate, beetroot extract, maltodextrin) and flavourings (sorbitol, mannitol, orange/mandarin oil). Each tablet weighs about 3.5 g and has a diameter of about 25 mm. The tablet disintegrates completely in cold water over a period of about 80 seconds.

It should be noted that all the above-mentioned embodiments illustrate the invention, but do not limit it, and persons skilled in the art may design many alternative embodiments without departing from the scope of the attached claims. In the claims, reference numbers in brackets are not to be regarded as restrictive.

The use of the verb "to comprise" and its different forms does not exclude the presence of elements or steps that are not mentioned in the claims. The indefinite article "a" or "an" before an element does not exclude the presence of several such elements.

The fact that some features are indicated in mutually different dependent claims does not indicate that a combination of these features cannot be used with advantage.

Claims

C l a i m s

An effervescent lozenge comprising an effervescent mixture and at least one active substance, c h a r a c t e r i z e d i n that the effervescent lozenge weighs more than 1.2 g and the effervescent lozenge has been formulated with a proportion of an acid to a base in an effervescent mixture that gives a disintegration time of between 2 minutes and 5 minutes.

The effervescent lozenge according to claim 1, wherein the disintegration time is between 3 and 4.5 minutes.

The effervescent lozenge according to claim 2, wherein the disintegration time is between 3 and 4 minutes.

The effervescent lozenge according to any one of the preceding claims, wherein the active substance is ascorbic acid or a pharmaceutically acceptable compound of ascorbic acid.

The effervescent lozenge according to any one of the preceding claims, wherein ascorbic acid or a pharmaceutically acceptable compound of ascorbic acid constitutes from 10 per cent to 50 per cent of the effervescent lozenge.