Field of the invention

The present invention relates to a composition for oral administration for simultaneously binding both aldehydes and free radicals, particularly oxygen radicals, present in the gastrointestinal tract of a human subject, or specifically in the mouth and in the stomach of the subject, in order to decrease the risk of cancer in said areas.

The invention also relates to methods for decreasing the risk of developing cancer in said areas of the subject, caused by the joint effect of aldehydes and free radicals. Description of related art

An inflammation can have many causes, including infections, mechanical irritation, autoimmune responses, foreign material, etc. One common response is invasion of the inflamed area of tissue by white blood cells, viz. granulocytes and macrophages. These inflammatory cells have a specific means of incapacitating and/or destroying the foreign material. After stimulation of these cells an NADPH oxidase in their cell membrane is activated and reduces large amounts of 0 ₂ to superoxide (called the "respiratory burst" even though it has nothing to do with cell respiration), most of which is ejected into the extracellular space. Although this is an effective means of killing invading bacteria, the response is somewhat indiscriminating and also affects the surrounding healthy tissues. In autoimmune responses, e.g. in rheumatoid arthritis, the mechanism has gone out of control and bombards healthy tissue with superoxide radical despite the absence of microorganisms. Despite the key importance of oxygen (0 ₂ ) to sustain life, it has also important toxic properties. Oxygen toxicity arises from the products of its reduction. One-electron reduction of 0 ₂ gives rise to 0 ₂ ^'~ , the superoxide free radical, and two-electron reduction (plus two protons) yields hydrogen peroxide (H ₂ 0 ₂ ) in neutral aqueous solutions. Three- electron reduction causes scission of the 0-0 bond yielding two products, namely the OH ^" hydroxyl anion (or water after protonation), and the OH ^' radical. One-electron reduction of the latter (plus a proton) yields a second water molecule. This leads to the following scheme in which each arrow implies the addition of one electron.

0 ₂ → 0 ₂ ^" → H ₂ 0 ₂ → OH → H ₂ 0 (eqnl)

It is noteworthy that atmospheric oxygen is itself a free radical, in fact a double radical, occurring in the so-called triplet state. 0 ₂ is fortunately quite unreactive at ambient temperatures. If it were not, no life would exist on Earth since all hydrocarbons would spontaneously burn. In most cases in biology oxygen requires chemical activation to react, as is the case for example in cellular respiration. Nevertheless, 0 ₂ is not entirely unreactive but does react with highly reduced biological substances. These side reactions usually occur at relatively low rates, but the products (primarily superoxide and peroxide) must be quickly disposed of to prevent oxygen toxicity.

Such oxygen detoxification is catalyzed by an array of enzymes, e.g. the superoxide dismutases, peroxidases and catalase. Several biological substances, e.g. antioxidants such as vitamins C and E and ubiquinol, are moreover able to inactivate superoxide.

Superoxide and peroxide are not particularly toxic by themselves, but when superoxide is formed, hydrogen peroxide is always formed as well due to the dismutation reaction

0 ₂ - + 0 ₂ - (+ 2H ⁺ )→ 0 ₂ + H ₂ 0 ₂ (eqn 2) where one superoxide molecule donates an electron to the other so that the first superoxide becomes a dioxygen molecule and the second becomes peroxide. The dismutation is spontaneous, but it is further greatly accelerated in organisms such as human beings by superoxide dismutase enzymes that are found both intra- and extracellularly, and also in the mitochondria of cells.

When superoxide and peroxide are thus present simultaneously, they react with one another 0 ₂ ^~ + H ₂ 0 ₂ → 0 ₂ + OH + OH ^" (eqn 3) so that superoxide donates an electron to peroxide (see eqn 1) becoming 0 ₂ itself and splitting the 0-0 bond of the peroxide forming hydroxyl radical and water (hydroxide). In biological systems this reaction is catalyzed by heavy transition metals such as iron and copper that are always present in biological systems.

It is mainly the hydroxyl radical that is responsible for the toxicity of oxygen. The OH radical reacts in microseconds with nearly any biological material, causing its oxidation and destruction. For example, OH radical attack on DNA leads to mutations which can cause several diseases including cancer. Therefore, radical formation as a response to an inflammation can have serious consequences.

Gastritis is an inflammation of the stomach, often caused by bacterial H. pylori infection. When chronic it may develop into atrophic gastritis where much of the stomach lining is destroyed, acidic conditions can no longer be maintained, and secondary infections are common. On the basis of the above summary, treatment with a substance that traps superoxide (that is likely to be generated in large quantities as a response to the stomach inflammation) would be beneficial.

Further, it is well known that H. pylori infection is the foremost risk factor for stomach cancer, and it has been estimated that a significant part of this risk is mediated by reactive oxygen species formed mainly from white blood cells due to the inflammation. Cysteine is the only one of the naturally occurring 20 amino acids that has a chemically reactive thiol group (-SH) in its side chain. Due to the reactive thiol group, cysteine reacts well with superoxide and hydrogen peroxide (1) and is thus an effective antioxidant. The thiol group also reacts with acetaldehyde, which is produced by bacteria invading the stomach as a result of the anacidic conditions generated in an H. pylori -infected stomach. Since acetaldehyde has also been found to cause cancer, in a similar manner as said radicals (Salaspuro, 2009; Seitz and Stickel, 2010), acetaldehyde present in alcoholic beverages and formed endogenously from ethanol was recently classified as carcinogenic to humans (group 1) by the International Agency for Research on Cancer (IARC) (Secretan et al. 2009).

Alcohol is evenly distributed in the liquid phase of the organs. Hence, after consuming alcohol, and as long as there is alcohol in the organs, the alcohol content in the blood, saliva, gastric juice and the contents of the intestine is the same. In that case, the microbes in the digestive tract are capable of oxidizing the alcohol to acetaldehyde. For example, even after a moderate dose of ethanol (0.5 g/kg), high acetaldehyde contents of a microbial origin (18-143μΜ) have been found in human saliva; in other words, acetaldehyde builds up in saliva as an intermediate product of the microbial metabolism (Homann et al, 1997).

Acetaldehyde is also formed (particularly in the mouth, the pharynx, and the upper airways) as a consequence of smoking, and exposure to air contamination. It has been proven that chronic smoking significantly increases the acetaldehyde production of saliva originated in microbes. In fact, it has been demonstrated that the cancer risk associated with cigarette smoking is not only caused by the commonly known polycyclic aromatic hydrocarbons (PAH), but to a significant degree (up to 40%) by aldehydes, particularly by acetaldehyde and formaldehyde, whereas acrylic aldehyde causes up to 88.5% of the other toxic effects.

On the other hand, carcinogenic acetaldehyde can be produced also endogenously by the oral microbes from various foodstuffs with high sugar or carbohydrate content, especially in an achlorhydric stomach. The formation of acetaldehyde in the organism mainly takes place in the mouth, particularly in the saliva, and is carried with the saliva from the mouth to the stomach. The average amount of saliva secreted by a human is 2.5 litres per day. The areas of influence of the acetaldehyde contained in this saliva include the mouth, the pharynx, the oesophagus and the stomach. Consequently, the effects of acetaldehyde may extend to the whole upper digestive tract area.

The prior art discloses pharmaceutical compositions which contain compounds that bind acetaldehyde, such as ascorbic acid, thiamine, cysteine or cysteic acid, and flavonoids or flavonoid complexes, their effect being based on the reaction of the effective substances with the acetaldehyde inside blood and/or cells, for example, US 5 202 354, US 4 496 548, US 4 528 295, US 5 922 346. In fact, when swallowed, the effective substances of these publications travel via the stomach directly to the small intestine and from there into the blood circulation. This is based on the solubility of e.g. cysteine, and on the lack of suitable additives in the formulations of the publications capable of sustaining the release of the used active agents and capable of targeting their release to give a local effect.

WO 02/36098 suggests the use of compounds containing a free sulfhydryl and/or amino group for a local and long-term binding of acetaldehyde from saliva, the stomach or the colon. The compounds were mixed with a substance that enabled them to be released for at least 30 minutes in the conditions of the mouth, the stomach or the colon. However, only acetaldehyde was targeted, and each type of preparation gave an effect in only one of these areas. In addition, the publication does not disclose a composition, wherein the active cysteine compounds are added in two or more separate layers, which are formulated to provide an inner controlled-release layer and an outer quick-release layer.

Similarly, WO 2006/037848 suggests a composition comprising one or more free sulfhydryl and/or amino groups for removing or decreasing the aldehyde content of the saliva during smoking, whereby, again, only the aldehyde was targeted, and an effect was obtained only in one single area of the gastrointestinal tract.

WO 2009/137827 provides a controlled-release composition composed of two or more layers, which provides a therapeutically effective plasma concentration of N-acetylcysteine over prolonged period of time for reduction of vascular inflammation in a patient. The compositions provide sustained systemic blood concentration of N-acetylcysteine and inhibit systemic, organ-specific, and/or vascular inflammation continuously. Application fails to mention binding of aldehydes and free radicals simultaneously. US 2007/099843 relates to compositions for enhancing the health of the liver with the synergistic effect of N-acetylcysteine, glutathione, vitamin C and vitamin E. Thus, the composition is coated/formulated so that the prevention of toxic effect of analgesics (such as acetaminophen) takes place locally on the liver. Nothing is mentioned about inactivating aldehydes and free radicals in the mouth and in the stomach.

As a conclusion, both aldehydes and free radicals play a considerable part in the pathogenesis of stomach cancers, in particular in people having an achlorhydric stomach. There is thus a need to find alternative ways to inactivate both of these in the stomach, or already in the mouth, before they reach the stomach.

Brief description of the invention

It is an aim of the present invention to provide new compositions, which can be used to reduce both the content of free radicals and of aldehydes in the mouth and the stomach of a subject using a single formulation. It is also an aim of the invention to provide new methods for binding these radicals and aldehydes in said areas.

Further, it is an aim of the present invention to provide new compositions, which contain the components capable of protecting the active compound(s), for example to mask their taste or to prevent their early release from a formulation. These and other objects, together with the advantages thereof over known compositions and methods are achieved by the present invention, as hereinafter described and claimed.

Thus, the present invention concerns a non-toxic composition for oral administration containing one or more different cysteine compounds, preferably formulated for two or more different release rates, for decreasing the amount of aldehydes and free radicals in the gastrointestinal tract (the GI tract), or specifically in the mouth and the stomach, which consequently also reduces the risk of the subject contracting cancer of said areas.

The composition comprises one or more different cysteine compounds, preferably bound to such non-toxic additives that effect sustained release of said active compounds specifically into the desired part(s) of the gastrointestinal tract, following at least two different release profiles. Particularly, the composition according to the invention is characterized by what is stated in the characterizing part of claim 1.

The invention provides considerable advantages. The compositions of the invention can be used to reduce the risk of developing cancer of the mouth and of the stomach, as well as indirectly of the small intestine and the colon, of people having increased risk for cancer in these areas, for example due to atrophic gastritis or an achlorhydric stomach.

Likewise, the compositions can be used to prevent other serious complications associated with inflammatory conditions of the upper GI tract.

By the compositions and methods of the invention can be treated in particular people suffering from atrophic gastritis, achlorhydric and low acid stomach, since these are most susceptible to said risks as well as to the formation of free radicals and to high aldehyde contents.

Consuming the compositions according to the invention mainly causes the binding of the free radicals and aldehydes locally, due to the local release of the contents of the composition in the desired areas of the gastrointestinal tract, but this also gives a systemic effect, particularly when using large (> 1 equivalent) doses of the compositions and the active agents.

Through the local binding of said free radicals and aldehydes in the gastrointestinal tract, the compositions of the present invention will have a significant effect on the overall health of the subject, since these radicals and aldehydes otherwise would contribute in the cause of many diseases and conditions, including cancer and inflammatory conditions of the gastrointestinal tract.

Likewise, through the above-mentioned systemic effect, the compositions of the invention will be helpful also in treating conditions of other areas of the body, which free radicals typically are considered to have an influence on, such as atherosclerosis, rheumatoid arthritis, heart diseases, lung diseases (particularly acute respiratory distress syndrome, i.e. ARDS), neurological disorders, cerebral trauma or ischemia, or other age-related diseases or disorders.

Brief description of the drawings

Figure 1 shows the effect of administration of a composition containing L-cysteine (or placebo administration) on acetaldehyde levels.

Figure 2 shows the mean cysteine concentrations in the gastric juice of volunteers after the administration of study formulations containing L-cysteine.

Detailed description of embodiments of the invention

The present invention concerns a non-toxic composition containing one or more cysteine compounds, for decreasing the risk of a subject contracting cancer of the mouth and the stomach, and indirectly cancer of the small intestine and the colon, by locally binding both the free radicals and the aldehydes present in the mouth and the stomach using a single formulation. The same composition can, however, also be used for treating inflammations of the gastrointestinal tract.

The "binding of radicals" refers to the inactivation of the radicals by forming non-toxic (harmless) molecules.

The "binding of aldehyde", in turn, refers to a chemical reaction between the aldehyde and the free sulphhydryl or amino group or both of the cysteine (or similar compound), wherein the aldehyde jointly with the "aldehyde-binding compound" forms a larger molecule. In the reaction with cysteine, for example acetaldehyde binds itself to the sulphhydryl and the amino group of the cysteine, and forms 2-methyl-L-thiazolidine-4- carboxylic acid (and water). To achieve the sufficiently large and targeted effect, the composition is formulated for controlled release of the cysteine compounds with the help of two or more additives into capsules or into tablets, which optionally are coated. These units, i.e. tablets or capsules, contain one or more inner controlled release layer including at least one additive selected from cationic and gel- forming polymers and at least one cysteine compound, as well as an outer quick-release layer including at least one additive selected from water-soluble pharmaceutically accepted additives and at least one cysteine compound.

According to one option, at least one cysteine compound in the unit or formulation is in granulated form, preferably granulated with the help of one or more additives, such as a binder, whereby at least one remaining cysteine compound in the unit is in ungranulated form. The granulated form is preferably surrounded by a matrix containing the ungranulated cysteine compound(s), which in turn is optionally mixed with one or more additives, such as filler, before pressing the total mixture into tablets or adding it into capsules. The partially granulated composition thus provides a formulation containing different layers (granules and surrounding matrix).

The granulation causes a delay in the release of the contents of the granules, which delay can be further prolonged using suitable additives, as described below. Thus, the entire partially granulated composition includes at least one cysteine compound for quick-release as well as at least one cysteine compound for sustained-release.

According to another option, the cysteine compounds are formulated into two or more different layers in a tablet, whereby any inner layer(s), or inner structure(s), preferably in the form of granules, mini tablets, medium-sized core tablets, pellets or cross-linked matrix structures, release their contents in the stomach after an outer layer has released its contents in the mouth or the stomach. Each layer contains at least one additive, among others for guiding the release to the desired area and for providing the desired release rate. Thus, also this option provides a composition including at least one cysteine compound for quick-release as well as at least one cysteine compound for sustained-release.

According to a preferred embodiment of the invention, the composition is formulated into a two-layered tablet, which is intended to first be sucked in the mouth by the subject, whereby the outer layer will dissolve, whereby the inner layer can be swallowed by the subject to provide the desired effect also in the stomach. The inner layer preferably contains one or more additives selected from cationic and gel-forming polymers, for achieving release of the contents of said layer in the stomach. An optional coating can also be added on said inner layer, preferably a coating made of a polymeric film. The outer layer preferably contains one or more additives, e.g. in the form of a water-soluble coating, for achieving an essentially immediate release of the contents of said layer in the mouth.

The cysteine compounds are selected from L-cysteine, D-cysteine, and N-acetylcysteine, whereby a preferred alternative is to use a combination of two or more different cysteine compounds, added into different layers of the formulation. For example, one suitable combination is formed from L-cysteine and N-acetylcysteine.

Thus, according to a preferred embodiment of the invention, the cysteine compounds of the present composition are selected from the following combinations:

L-cysteine in granulated form and L-cysteine in a surrounding matrix,

L-cysteine in granulated form and N-acetylcysteine in a surrounding matrix, and - N-acetylcysteine in granulated form and L-cysteine in a surrounding matrix. In the following, the complete unit is called a tablet or a capsule, while the term "inner layer" is used to refer to a pellet or granules or another form of core unit.

The separate layers or forms of the tablets or capsules are provided with different release profiles by varying their solubilities by providing the outer layer with a higher solubility in aqueous solutions compared to the inner layer(s) or by varying the release rate of the separate layers, essentially by providing a quick-release outer layer and sustained-release inner layer.

The cysteine compounds are used in a pharmaceutically effective amount, which means a combined amount of cysteine compounds that is capable of binding or inactivating the amount of aldehyde and oxygen radical carried to or formed in the mouth and stomach of a subject. Typically, a single unit, or formulation, of the composition comprises a total of 5-300mg, preferably 10-250mg, more preferably 50-200mg, and most suitably 50-1 OOmg of cysteine compound(s). However, 1-2 of these units can be administered at once if a larger dose is desired.

Preferably, the total content of the cysteine compounds is then 1 to 40 w- %, more preferably 5 to 40, and even more preferably 10 to 30 w- %. Typically the content is 20 to 25 w-%. Further, the composition of the invention typically comprises at least one non-toxic additive that masks the taste of the tablet or capsule or its contents, preferably in the form of a coating, such as a coating of an aromatic agent or a flavouring, e.g. a carbohydrate (or sugar) coating, applied onto the outer layer of the tablet, or in the form of the encapsulating material of the capsule. Such an aromatic agent can even improve the taste of the unit.

Typical aromatic agents include carbohydrates (or sugars), such as glucose, sorbitol, eucalyptol, thymol, sucrose, sodium saccharine, methyl salicylate, menthol and xylitol, and are preferably selected from glucose, sorbitol, sucrose and xylitol. The composition of the invention also comprises at least one non-toxic additive added to the inner layer(s) of the tablet, preferably in the form of a binder or a filler, and most suitably as a combination thereof, which causes sustained release of the cysteine compound(s) in said layer(s) in the stomach. Sustained release here means the release of said cysteine compound(s) for at least 30 minutes in the conditions of the stomach. Preferably the compound(s) are released in the stomach during 0.5 to 8 hours, more preferably 2 to 6 hours, most preferably 2 to 4 hours. The optional coating and also optional large size of the pellet, core or granules already cause some delay in the release. However, it is preferred to additionally use separate additives further delaying the release of the active compound(s).

The term "additive" here includes carriers, fillers, binders and coatings, as well as aromatic agents, colorants and non- functional additives. These additives are non-toxic, and preferably at least a portion of them function by controlling the release of the cysteine compound(s) to take place specifically in the stomach, most suitably in a sustained manner. Another objective of using additive(s) is to protect the cysteine compound(s), among others to mask their taste or provide an improved taste.

Preferably, at least a portion of the additives of the inner layer are selected to achieve the release of the cysteine compound(s) in the conditions of the stomach in an amount of 40- 80mg in an hour. The controlled release is essential in order to achieve the local effect in the gastrointestinal tract. For example, two free L-cysteine molecules readily react with each other to form cystine (by dimerizing) that is not able to effectively bind and inactivate the aldehyde present in the stomach. Further, cysteine is highly soluble, and is, in free form, readily carried past the mouth and the stomach, and absorbed from the small intestine into the blood stream before a reaction can take place to a detectable degree. However, the present invention provides a dosage form (particularly a large coated tablet or capsule to be swallowed by the subject) that prevents said dimerization at least to a significant degree, and gives a local and long-term effect by providing a sustained source of L-cysteine over the expected time of acetaldehyde exposure.

Preferably, the used additive(s) of the inner layer are selected from those capable of controlling the release of the active compounds locally in the stomach during a time of more than 30 minutes, preferably 0.5-8 hours, most suitably in 2-4 hours. According to a preferred embodiment of the present invention, the composition is intended to be administered in connection with eating, i.e. just before, during or just after eating, or in connection with consuming alcohol, i.e. just before, during or after consuming a dose of alcohol. According to another preferred embodiment of the invention, the composition is intended to be administered in connection with smoking or other use of tobacco, i.e. just before, during or just after smoking (or other use of tobacco). "Smoking" refers to the smoking of any tobacco product, using snuff, chewing tobacco, or any other use of a tobacco product, wherein the tobacco product or a part thereof is placed in the mouth or in close vicinity to the oral cavities. The tobacco product can thus be a cigarette, a cigar, snuff, chewing tobacco or pipe tobacco. However, the present invention is particularly beneficial when the composition is used to prevent the harm caused by tobacco smoke, whereby its use in connection with smoking a cigarette, a cigar or pipe tobacco is particularly preferred.

A further advantageous option is to administer one dose (e.g. one unit) of the composition just before and another dose just after eating, drinking or smoking, thus targeting particularly the acetaldehyde formed in these situations most effectively.

The terms "just before" and "just after" mean a time frame of up to 5 minutes before or after eating, consuming alcohol or smoking (or otherwise using tobacco), preferably a time frame of <2 minutes, more preferably a time frame of <1 minute, and most suitably a time frame of <0.5 minutes before or after eating, or consuming alcohol, and over the entire duration of smoking.

However, the compositions can also be used in a more continuous way, for example by administering a dose every 10 minutes. According to a preferred embodiment of the invention the dosage is renewed at 5- to 15-minute intervals, preferably at 5- to 10-minute intervals, if alcohol consumption or smoking is continued for a time period longer than said interval. It is, however, sufficient for achieving a continuous or at least essentially continuous effect to administer the composition at 4- to 10-hour intervals, preferably at 6- to 8-hour intervals, e.g. in connection with eating.

According to the invention, the compounds obtained from aldehydes and free radicals by chemical binding with cysteine, or a derivative or salt thereof, are safe for the subject. In contrast, the free radicals and the aldehydes (in free form) are not safe for the subject. For example, a harmful/carcinogenic content of acetaldehyde in e.g. the human mouth is roughly 20 to 800 μιηοΐ/ΐ of saliva, and a content of as low as about 20 to 50μΜ causes carcinogenic DNA adducts on the cell level. Generally, levels of above 40 to ΙΟΟμΜ are considered mutagenic. Further, formaldehyde is responsible for some carcinogenic effect, while acrolein causes other toxic effects. Since the saliva that is carried to the stomach is also the main cause of the aldehyde-contents of the stomach, similar values are valid also for the stomach. By using the present invention, the aldehyde content, particularly in the mouth and the stomach of the subject, can be kept at a level that is at least 20% lower, preferably >40% lower, and most suitably >60% lower than in a corresponding situation without using the composition according to the invention.

Such a harmful or carcinogenic content of aldehyde in the human stomach, as well as in the other parts of the gastrointestinal tract, can be caused by consuming alcoholic drinks, particularly strong alcoholic drinks, or foodstuffs containing alcohol, or as a consequence of smoking, or when consuming products (e.g. foodstuffs) containing aldehyde.

The ethanol can generate aldehydes with the help of oral microbes. Both these microbes and the formed aldehydes are constantly carried also to the stomach with the saliva, particularly as the subject swallows, whereby the harmful effect is spread also to the lower parts of the gastrointestinal tract.

"Aldehyde-containing foodstuffs" refers to foodstuffs containing aldehyde even prior to consumption (i.e. in contrast to the aldehyde formed in the mouth of a subject consuming said foodstuff). In certain foodstuffs, such as some dairy products, acetaldehyde is used for preservation purposes and to add flavor.

"Alcoholic drinks" are ethanol-containing drinks, their ethanol content varying between 0.7% by volume and 84% by volume."

"Alcoholic foodstuffs" refer to foodstuffs containing at least 0.7% by weight of ethanol. Such foodstuffs can be, for example, fermented juices, yoghurts, any pickled food or other kind of preserves, or foodstuffs preserved with small amounts of alcohol, pastries, jellies, and mousse seasoned with liqueur or corresponding products containing alcohol. The additives in the present composition are selected from a combination of substances, which can function for example as carriers, fillers, binders, coatings, aromatic agents, and other types of additives. According to an alternative of the invention, the composition is formulated into a coated tablet, with at least one additive forming said coating (e.g. a polymeric or inorganic film coating or sugar coating). Preferably, such a tablet is compressed from the constituents of the composition (excluding the coating additive), which constituents include the above described inner layer, which can optionally be covered with a further polymeric film, and the described outer layer.

In case of the inner layer being in the form of granules, they can be prepared by moisturing a dry mixture of the desired granule contents, and granulating it using enteric polymers as binders and by using methods and devices that are well-known in the pharmaceutical industry. The enteric polymers are preferably selected from polymers with a solution pH of 6-7, and most preferably from methacrylate derivatives, which are known by the trade names Eudragit L, Eudragit S, and Eudragit RS. The amount of enteric polymer in the preparation is preferably 2-5%, most preferably 3-4%. An inner tablet (core tablet) or pellet can be prepared by compressing, also using methods and devices that are well-known in the pharmaceutical industry.

The tablets and the pellets can be shaped as discs or as capsules, or they can be round or oval shaped.

It is of advantage if the composition is formulated into a large tablet (the complete unit), the diameter of which is at least 7 mm, preferably 8 to 15 mm, more preferably 11 to 15 mm. For an oval or capsule shaped tablet, the length can, in turn, be as high as 20 mm. The unit comprises an outer layer, which surrounds the inner layer e.g. by forming a coating layer on the inner tablet, pellet or granule structure. Such a coating layer preferably has a thickness of only 1 to 3 mm, most suitably 1 to 2 mm. Thus, the inner layer can have a diameter of up to 14 mm. The large diameter of the inner layer delays its dissolution in the stomach. However, the composition can also be formulated into a small tablet or a lozenge-like structure, having a diameter of <5mm, preferably 2 to 4mm, most suitably 2 to 3mm. Such a formulation is particularly suitable for use with small amounts of cysteine compounds, such as <100mg, preferably <80mg, and most suitably <50mg. Due to the small size of such tablets, they can easily be administered in amounts of >1 tablet per dose. However, even one tablet will be sufficient for binding an essential portion of the acetaldehydes in the mouth and the stomach, particularly if a major portion (>50w-%) of the cysteine compounds is included in the inner layer. Said small tablets have the advantage of being easy to swallow, and can even be mixed with food to provide a particularly suitable time of administration.

According to another alternative of the invention, the composition is encapsulated, preferably by adding a mixture of the different layers into a hydroxypropyl methyl cellulose capsule (an HPMC capsule).

According to an embodiment of the invention, the composition comprises at least one additive that causes the quick (or even immediate) release of a first portion of the cysteine compounds in the mouth, and at least one additive that delays the release of a second portion of the cysteine compounds to take place in the stomach. The quick release can be provided, for example with the help of any common water-soluble tablet coating (including coatings made of carbohydrates, inorganic salts and water-soluble polymers).

According to a preferred embodiment of the invention, the composition comprises at least one additive that does not dissolve or dissolves only poorly in the stomach. One option for achieving this is to cover the inner layer with an essentially water-insoluble film.

According to another preferred embodiment of the invention, the composition comprises at least one additive selected from those that form a gel in the conditions of the stomach, which gel then helps to maintain the formulation floating in the contents of the stomach for a prolonged time. Such a gel-forming additive can be added into a dry mixture to be granulated, or into a mixture to be compressed to form another type of inner layer (e.g. a core tablet). Suitable additives not dissolving in the stomach include polymers, such as hydroxypropylmethyl cellulose, polypropylene, Carbopol, or a metacrylate polymer, for example Eudragit RL, RS, NE or S, or ethyl cellulose. Additives for use in achieving a gel are various chitosans, alginates, such as sodium alginate, aluminium hydroxide, sodium hydrogen carbonate, sodium carboxymethyl cellulose, and sodium hydrogen carbonate as described in WO 02/36098.

It is particularly preferred to achieve a formulation that floats in the contents of the stomach by using polymers, such as alginic acid, as additives, which form a gel, and by adding to the formulation sodium hydrogen carbonate, which under the influence of gastric acid releases carbon dioxide, which in turn forms gas bubbles inside the gel.

A gel that floats in the stomach can also be prepared from sodium alginate, aluminium hydroxide, sodium hydrogen carbonate, and water, to which the cysteine compound(s) can be added.

A corresponding gel can also be obtained by adding the cysteine compound(s) to an aqueous dispersion of chitosan. The total content of said polymers, or other gel-forming agents, in the composition is preferably 10 to 50 w-%, more preferably 20 to 40 w-%, and most suitably 20 to 30 w-%.

The additives of the composition can also include one or more inert bulking agents or fillers, preferably selected from dicalcium hydrogen phosphate, microcrystalline cellulose (MCC), lactose, or other corresponding bulking agents that are either water-soluble or non- soluble in water. Particularly, the bulking agents are selected from non-swelling agents, such as said dicalcium hydrogen phosphate.

The content of such optional bulking agents in the composition is preferably 20-70 w-%, more preferably 40 to 60 w-%, and most suitably about 50 w-%>.

To facilitate retaining the tablet in the mouth, it is preferred to include at least one binder or adhesive agent in the composition, preferably selected from adhesive polymers, such as cellulose derivatives, chitosanes, alginates, polyethylene glycols, carbomers or polycarbophils, most suitably selected from hydroxypropyl methyl cellulose or its derivative or a Carbopol grade of a carbomer. Such adhesive agents are preferably added to coatings on the outer layer of the tablet, to facilitate the adhesion of the unit dose to the mucous membranes of the mouth. For this purpose, a polymer that forms a gel in the conditions of the mouth is particularly preferred. Such gel-forming polymers include the above mentioned binders. The portion of this optional adhesive agent in the composition is preferably l-50w-%, more preferably 5-40w-% and most suitably 10-30w-%.

As stated above, a coating formed of an aromatic agent can be used to mask or even improve the taste of the contents of the unit or formulation. Other typical coating materials are polymeric film coatings. These can be formed, for example using water-soluble polymers, such as hydroxypropyl methyl cellulose, particularly for coating the outer layer of the tablet, or using porous film forming agents, such as ethyl cellulose (EC) or a combination of EC and hydroxypropyl methylcellulose (HPMC), particularly for coating the inner layer of the tablet. Preferably a mixture of these is used, more preferably a mixture, where the relative amount of EC to HPMC is from 1/1 to 5/1, particularly from 2/1 to 5/1, and most suitably from 3/2 to 7/3. Such a mixture has advantageous dissolution properties due to the different characters of the constituents, as HPMC is a water-soluble polymer and EC is a water-insoluble polymer. In the conditions of the stomach the water- soluble polymer dissolves and pores are formed to the water insoluble polymer. In such a case, the release of the water-soluble cysteine compounds is based on their diffusion from the pores formed to the film. The film-forming substances also effectively mask the taste of the cysteine compounds, whereby this main dose of cysteine compounds will not cause an unpleasant taste before the subject swallows it. Based on the above, a typical inner layer of the tablet (such as a pellet) can comprise for example:

Cysteine compounds 5 to 40 w-% (preferably 25 w-% )

Polymer not dissolving in stomach 10 to 50 w-% (preferably 20 to 30 w-% ) Inert bulking agent 20 to 70 w-% (preferably 40 to 60 w-% )

Ethanol q.s.

In such a pellet, the release of the cysteine compound(s) is mainly based on the diffusion of the water-soluble cysteine compound(s) from the pores formed to the pellet matrix. In case the pellet is coated, this can be carried out separately, preferably using a water-soluble polymer, such as hydroxypropyl methyl cellulose (HPMC), and a water-insoluble polymer, such as ethyl cellulose (EC). In the conditions of the stomach the water-soluble polymer dissolves, whereby pores are formed to the water insoluble polymer.

In addition to the above cysteine compounds and additives, it is of advantage to add to the compositions of the present invention at least one of the substances selected from the group comprising compounds assisting in the decrease of the content of aldehydes, functioning e.g. by limiting the harmful effect of microbes in the mouth, such as xylitol or sulphites, or further beneficial agents, such as chromium, vitamin B12, vitamins A, D, E and C, niacin, biotin, thiamine, vitamins B2, B5 and B6, and folic acid, as well as trace elements, such as chromium, manganese, selenium, zink and iron.

Further, according to one preferred embodiment of the invention, the composition is administered to people having an achlorhydric stomach in connection with administering medication that causes said achlorhydric stomach, such as proton pump inhibitors, including:

• Dexlansoprazol

• Esomeprazol

• Lansoprazol

• Omeprazol

• Pantoprazol

• Rabeprazol

• Tenatoprazol

The following non-limiting example demonstrate the advantages obtained by using the preferred embodiments of the invention. Example - Acetaldehyde-binding

An analysis was carried out after administering L-cysteine (in a total of 200 mg) or placebo, orally to human subjects. This cysteine or placebo was formulated into film- coated tablets as described above, with a major portion of the cysteine or the placebo in granules together with a polymer not dissolving in the stomach and an inert bulking agent, and a remaining part in the tablet matrix surrounding the granules. The subjects swallowed said tablets with 200 ml of water. Immediately thereafter they were given ethanol (0.3 g/kg body weight) diluted in water to 15 vol%.

Gastric juice samples were collected, and their L-cysteine concentrations were determined using HPLC, and two parallel samples.

Fig. 1 shows the effect of the L-cysteine administration (or the placebo administration) on the acetaldehyde levels in the stomach of the subjects. In all measurements, the average acetaldehyde concentration of the gastric juice was around 2.6 times higher with placebo than with cysteine. No significant differences existed in ethanol concentrations between cysteine and placebo treatments. The average ethanol concentration in the gastric juice was 5.0 vol-% in the first sample, declining to 0.9 vol-% in the 40-minute sample. A positive correlation emerged between the acetaldehyde concentration and the ethanol concentration.

L-cysteine was detected in the gastric juice of all subjects after the administration of study formulations containing L-cysteine. The mean cysteine concentrations are presented in Fig. 2. After administration of placebo formulations, no L-cysteine was detected. No significant correlation was found between the cysteine concentration and the acetaldehyde concentration. Literature

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