WO2015189479A1

WO2015189479A1 - Composition containing cysteine or a derivative thereof for the treatment or prevention of acute hypersensitivities

Info

Publication number: WO2015189479A1
Application number: PCT/FI2015/050430
Authority: WO
Inventors: Osmo Suovaniemi
Original assignee: Biohit Oyj
Priority date: 2014-06-13
Filing date: 2015-06-15
Publication date: 2015-12-17

Abstract

The present invention concerns a pharmaceutically acceptable composition containing one or more cysteine compounds selected from L-cysteine, D-cysteine and N-acetylcysteine, as active agent(s), most suitably formulated for controlled release, for use in treating acute hypersensitivities, when administered in a single dose of 300 to 1500 mg of said cysteine. The invention also concerns a pharmaceutically acceptable composition containing said cysteine compound(s), most suitably formulated for controlled release, for use in preventing the onset of said acute hypersensitivities, when administered to give a daily dose of cysteine of 200 to 3000 mg. Optionally, these cysteine compound(s) can be administered in combination with one or more β2 agonists or one or more corticosteroids, or both.

Description

COMPOSITION CONTAINING CYSTEINE OR A DERIVATIVE THEREOF FOR THE TREATMENT OR PREVENTION OF ACUTE HYPERSENSITIVITIES

FIELD

The present invention concerns a pharmaceutically acceptable composition containing at least one cysteine compound, in the form of L- or D-cysteine or N-acetyl cysteine, most suitably in the form of the sustained-release preparation Acetium®, for use either in the treatment of acute hypersensitivities (such as asthma attacks) or in preventing onset of said acute conditions, using specific dosage regimens, optionally by administering the composition in combination with one or more corticosteroids, or in combination with one or more β2 agonists.

BACKGROUND

Asthma is a common chronic inflammatory disease of the airways, commonly included in the group of hypersensitivities, although both allergic and non-allergic asthma exist.

Asthma is characterized by variable and recurring symptoms, reversible airflow

obstruction, and bronchospasms. Common symptoms include wheezing, coughing, chest tightness, and shortness of breath.

Globally, over 300 million people are presently affected by bronchial asthma, with some 250,000 annual deaths. Thanks to the recent developments of more effective therapies, asthma mortality has decreased substantially. Meanwhile, however, allergic diseases have markedly increased in the past half century, and children today have the highest prevalence of asthma compared with the older generations. Unfortunately, it is anticipated that the number of asthma patients will increase from these numbers by more than 100 million until

2025.

Asthma is thought to be caused by a combination of genetic and environmental factors. These environmental factors include allergens, air pollution, and other environmental chemicals. Smoking in general, or particularly during pregnancy and after delivery, is associated with a greater risk of asthma-like symptoms. Also low air quality in general, from factors such as traffic pollution or high ozone levels, has been associated with both asthma development and increased asthma severity. Exposure to indoor volatile organic compounds may be a trigger for asthma; formaldehyde exposure, for example, or exposure to other aldehydes. These aldehydes particularly play a role in the triggering of

occupational asthma.

Further, an aldehyde present in, for example tobacco smoke, acetaldehyde, has recently been considered to have a particular effect as a trigger. This acetaldehyde can be found also in other sources, and can be formed from, for example alcohol. For example in one study (Linneberg A, Gonzalez-Quintela A, Vidal C, Jorgensen T, Fenger M, Hansen T, Pedersen O, Husemoen LL.; Clin Exp Allergy. 2010 Jan; 40(1): 123-30), alcohol drinkers with a genetically determined fast metabolism of ethanol, i.e. a fast conversion into acetaldehyde, have an increased risk of alcohol-induced hypersensitivity reactions. In pathogenesis of asthma, histamine (and other mediators) plays a key role in the development of the three clinical hallmarks of full-blown asthma; 1) airway inflammation, 2) bronchial hyper-reactivity, and 3) obstruction. Most histamine in the human body is generated in granules of the mast cells. Mast cells, in turn, are especially numerous at sites of potential injury, including the nose and other airways, the mouth, the gastrointestinal tract (the GI tract), the skin, as well as the blood vessels. Histamine is also stored and released in the enterochromaffin-like cells of the gastric corpus.

At tissue level, said mast-cell mediators, i.e. the histamine, induce i) vasodilation, ii) contraction of the bronchial smooth muscle, and iii) mucous secretion by the bronchial mucous glands. At molecular level, histamine is a potent trigger of epithelium-derived oxidative stress.

The mechanism of the effect acetaldehyde has in triggering asthma has been described in many publications, including the publications by Chrostek et al. (Chrostek L, Cylwik B, Szmitkowski M.; Pol Merkur Lekarski. 2007 Sep; 23(135):225-30), as well as by Matsuse et al. (Matsuse H, Fukushima C, Shimoda T, Sadahiro A, Kohno S.; Novartis Found Symp. 2007; 285:97-106; discussion 106-9, 198-9). Based on these publications, increased blood acetaldehyde levels can release histamine from mast cells and basophiles, which induces hypersensitivity reactions, such as asthma-related symptoms. Thus, acetaldehyde causes the release of histamine from said mast cells at those sites of the body of a subject that it is capable of reaching, including the airways and the GI tract.

As acetaldehyde is known to be carried to the body, or to be formed in the body, following alcohol consumption or smoking, these events are particular triggers of asthma.

Based on a survey of asthmatics conducted by Vally and Thompson (Vally H, Thompson PJ.; Addict Biol. 2003 Mar; 8(1):3-11), over 40% of the subjects taking part in the survey reported the triggering of allergic or allergic- like symptoms following alcoholic drink consumption and 30-35% reported worsening of their asthma.

In mild cases of asthma, the common treatment plan includes as its most important step an identification of the triggers and subsequently avoiding these triggers. Thus, a lifestyle modification is essential, such as quitting smoking. This is, however, not always sufficient. Some medication, such as bronchodilators, can be used in also these mild cases.

In acute asthma attacks, medication is always relied on, often by administering a beta₂ (or β2) agonists or corticosteroids, or a combination of these. The beta₂ agonists are examples of bronchodilators, while the corticosteroids belong to the class of steroids. These medications, however, have undesirable side-effects, particularly when used in large amounts. Therefore, there is a need for mild treatment plans for acute asthma attacks, particularly for patients who experience frequent attacks, to enable them to at least reduce the required doses of these bronchodilators and corticosteroids. This is particularly important in patients suffering from an achlorhydric stomach, which is commonly caused by certain medication or by atrophic gastritis (AG). The absorption of several drugs is impaired in an achlorhydric stomach. Further, several of the microbes formed in the stomach as a result of achlorhydria (e.g. due to AG) are able to produce significant amounts of acetaldehyde, particularly by oxidation from ingested alcohol.

Under anaerobic conditions, such as in the stomach, these microbes are able to produce acetaldehyde also from glucose, such as the glucose carried to the stomach with food products. US 2009/192227 relates to N-acetylcysteine compositions and methods for treating inflammation and redox imbalance in acute exacerbations of inflammatory lung disease. The US-application is based on the antioxidative effect of N-acetylcysteine. However, the connection between acute hypersensitivities and histamine is not disclosed, nor a pharmaceutical composition, which is able to bind acetaldehyde and thereby affect to the release of histamine.

Many traditional asthma medications are also administered by inhalation. In such a case, the medication ends up in the respiratory system, whereas for example a significant amount of mast cells (responsible for histamine release) are located elsewhere, and a significant amount of the histamine-release-inducing acetaldehyde is formed elsewhere.

Thus, there is a need for novel dosage regimens, particularly focused on the oral administration of medications, which dosage regimens would be capable of targeting and treating asthma that has been induced by the histamine released with the help of acetaldehyde. Such an induction and asthma triggering can take place at any time and for various reasons. Particularly, treatments using mild and harmless substances would be beneficial. One option for eliminating the histamine-release inducing compound acetaldehyde from saliva or the stomach, for example after alcohol intake and during smoking, is to use a semi-essential amino acid, cysteine. It has been shown that a formulation releasing cysteine in a controlled manner (e.g. the formulation known as Acetium^®) can be used to decrease the acetaldehyde concentration formed during alcohol exposure, thus minimizing the exposure to acetaldehyde (as described in EP 1339394). However, this decrease of acetaldehyde concentration is targeted only to the time period during alcohol exposure, whereby the effect is short-term (a couple of hours in an optimal situation), and the dose is designed only for this immediate need. Thus, there is also a need for dosage regimens, utilizing the beneficial effect of cysteines, which would be specifically designed for asthma patients or patients with other

hypersensitivities . SUMMARY OF THE INVENTION

It is an objective of the present invention to develop a harmless pharmaceutical composition to be administered in a dosage regimen effective for treating acute asthma attacks.

Another objective of the present invention is to develop a harmless pharmaceutical composition to be administered in a dosage regimen effective in preventing onset of asthma attacks.

These and other objectives, together with the advantages thereof over known compositions and dosage regimens, are achieved by the present invention, as described and claimed hereinafter. This invention is based on the finding that a semi-essential amino acid, cysteine, in the form of either L- or D-cysteine (or as N-acetylcysteine), by preventing the release of histamine, is capable of preventing (or inducing recovery from) asthma attacks, when used according to a suitable dosage regimen and in a suitable dosage form. An asthma attack (or an acute asthma exacerbation) can be recognized from classic symptoms, such as shortness of breath, wheezing and chest tightness, ranging in severity from mere coughing to significantly impaired air motion, which can even lead to the subject experiencing a lack of oxygen. In addition to subjects suffering from asthma, the present invention is useful for any subjects suffering from allergies or other histamine-induced hypersensitivities (e.g. edema or itching).

The administration preferably takes place using compositions formulated to act locally either in the mouth or in the stomach, preferably by sustained release, and optionally in combination with other formulations, such as inhalers.

When the acetaldehyde, which enters the body through smoking or through the consumption of alcohol or certain food products, is bound into a harmless form in the early parts of the gastrointestinal tract, the acetaldehyde will not reach the mast cells of the body in any significant amounts, and the histamine-release from these mast cells, which generally causes the acetaldehyde-induced hypersensitivities (e.g. asthma attacks), will not take place (or will at least be remarkably reduced).

Thus, the present invention concerns pharmaceutically acceptable compositions containing at least one cysteine compound, in the form of L- or D-cysteine or N-acetyl cysteine, optionally administered in a synergistic combination with one or more corticosteroids or beta2 (or β2) agonists, or both, (and possibly further active agent(s)), for use either in the treatment of acute attacks of asthma or allergies, or in preventing the onset of such attacks, using specific dosage regimens.

The compositions of the invention can also be used to prevent exercise-triggered bronchoconstriction, where beta2 agonists often fail to dilate the bronchial passages. In this case, the composition containing the cysteine compound(s) is preferably administered to the subject prior to the subject exercising, preferably within 15 minutes, most suitably within 5 minutes, before starting the exercising, optionally in a synergistic combination with one or more corticosteroids or β2 agonists, or both (and possibly further active agent(s)).

Such an administration (i.e. prior to exercising) is suitable particularly for subjects suffering from asthma, since exercise can trigger their asthma attacks, especially in combination with the effect of any acetaldehyde present in the body of the subject. Particularly, however, the present invention concerns a pharmaceutically acceptable composition containing one or more cysteines (selected among L-cysteine, D-cysteine and N-acetylcysteine), for use in treating acute asthma attacks, when administered in a single dose of 300 to 1500 mg, using one or more units of the composition, after onset of the attack.

When used in preventing the onset of asthma attacks, a daily dose of 200 to 3000 mg of cysteine(s) is preferred. The cysteine is preferably administered in the form of a composition including, in addition to the cysteine compound(s), one or more carriers capable of providing controlled

(typically sustained) release of the cysteine. One such suitable composition is known as Acetium®.

More specifically, the pharmaceutically acceptable composition of the present invention and the uses and dosage regimes thereof are characterized by what is stated in the characterizing parts of Claims 1 and 3. The described compositions can also be used in methods for treating asthma or other hypersensitivities, in which methods the described dosage regimes, and preferably also one or more of the described further active agents, are used.

Considerable advantages are obtained by means of the invention. Particularly it provides an effective, but gentle, treatment of asthma attacks or prevention of the onset of such attacks.

Further, the said composition in the used dose has the advantage of being completely harmless to the subject. Therefore, even if the cysteine compounds of the invention are used in combination with conventional asthma medication, the amounts of such conventional medications can be reduced significantly.

Due to early warning signs of an asthma attack, such as physical changes in feelings or in regular health conditions that an asthmatic person has before an attack (including frequent coughing, easy loss of breath, weakness and tiredness, as well as symptoms of a cold), the present treatment sequences (dosage regimes) can even be used to prevent asthma attacks just before they occur, or at least to keep its severity under control.

Next, the present technology will be described more closely with reference to certain embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the results of a dissolution test using capsules prepared from the composition used according to the present invention, the capsules containing L-cysteine that is released at a controlled rate, yet fast enough to have time to react with acetaldehyde before leaving the stomach.

Figure 2 shows the effect of administration of cysteine-containing capsules (or placebo administration) on acetaldehyde levels.

Figure 3 shows the mean cysteine concentrations in the gastric juice of volunteers after the administration of study formulations containing L-cysteine.

EMBODIMENTS

The present invention concerns a pharmaceutically acceptable composition containing one or more semi-essential amino acids, preferably one or more cysteine compounds, particularly selected from L-cysteine, D-cysteine and N-acetylcysteine, as active agent(s), and most suitably formulated for controlled release. This composition is for use in treating acute hypersensitivities (e.g. allergy or asthma attacks) in a subject with a single dose of 300 to 1500 mg, for use in combination with one or more corticosteroids (e.g.

glucocorticosteroids) or one or more β2 agonists, or both, in a recommended dose. Further, the present invention concerns a pharmaceutically acceptable composition containing one or more semi-essential amino acids, preferably one or more cysteines, particularly selected from L-cysteine, D-cysteine and N-acetylcysteine, as active agent(s), and most suitably formulated for controlled release. This composition is for use in preventing onset of acute hypersensitivities (e.g. allergy or asthma attacks), with a daily dose of 200 to 3000 mg of cysteine(s), optionally for use in combination with one or more corticosteroids (e.g. glucocorticosteroids) or one or more β2 agonists, or both, in a recommended dose. In the case of using two cysteines, it is particularly preferred to select a combination of L- cysteine and N-acetylcysteine.

According to an embodiment of the invention, the composition consists of one or more cysteine compounds, one or more carriers and one or more further additives. According to this embodiment, the composition is formulated into a suitable preparation for oral administration, particularly for controlled release in the mouth or in the stomach, and is optionally administered in combination with one or more corticosteroids (e.g.

glucocorticosteroids) or one or more β2 agonists, formulated in a conventional manner using recommended doses.

A particularly suitable controlled-release cysteine- containing composition is in the form of the preparation Acetium®, which contains L-cysteine. Preferably, the daily dose of cysteine compound(s) is achieved by administration in 4-10 equal single doses, such as 6-8 single doses, spread out to different times of the day, for example by administering one single dose before breakfast, further single doses during the midday - afternoon at for example 2- to 3-hour intervals, and the last single dose before bedtime. In case of the subject exercising during the day, one dose is preferably

administered before said exercise, more preferably within 15 minutes before beginning the exercise, and most suitable within 5 minutes before beginning said exercise.

According to a preferred embodiment of the invention, the above mentioned daily dose is obtained by administering the units or formulations containing the composition using a dose of 50 to 300 mg of cysteine compound(s), at regular intervals, such as at 2- to 4-hour intervals, preferably at 2- to 3-hour intervals, 4-10 times a day, preferably 6-8 times a day, most suitably to an empty stomach, e.g. at least 1 hour, after the previous meal.

The terms "unit" and "preparation" are both intended to encompass a single unit of any dosage forms, such as tablets, capsules or inhaler-doses, whereas the term "formulation" is intended to describe the type of dosage form, such as tablet, capsule or inhaler-aerosol.

According to another alternative, the sizes of the doses of the cysteine-containing composition of the present invention are varied along the day, e.g. by administering the last dose of the day, the dose administered prior to bedtime, as a larger single dose, e.g. as a dose of 300-500 mg of cysteine, to provide an increased effect of the active agent(s) while the subject is asleep, and to prevent asthma attacks in the early morning when such asthma attacks generally are frequent.

The corticosteroids or β2 agonists, in turn, are preferably administered in 1-4 equal single doses, as needed, which doses most suitably are selected to be administered essentially simultaneously with administration of doses of cysteine-containing composition. The term "essentially simultaneously" is here intended to mean administration of both compositions or all active agents within a time frame of about 5 minutes, whereby a synergistic effect is achieved.

The active agents mentioned herein, used in the context of the present invention, are mainly described as their free bases, but the present invention encompasses these agents also in the form of conventional pharmaceutically acceptable salts, such as acetates, citrates, decanoates (or caprates), fumarates, halogenates, maleates, nitrates, phosphates, propionates, salicylates, succinates, sulphates and tartrates, as well as in the form of their hydrates and hydrochlorides. As stated above, the cysteine compound can be selected from L- or D-cysteine or from a derivative or a salt of these cysteines. A particularly suitable derivative of cysteine is N- acetyl cysteine. A particularly preferred cysteine compound for use as active agent in the present invention is L-cysteine, used alone or mixed with another cysteine compound, such as N-acetyl cysteine. The cysteine compound(s) is/are used as components of

compositions, preferably formulated for controlled release, most suitably sustained release, since the cysteine compounds, alone, will not provide the desired effect.

Said subjects are preferably human subjects suffering from asthma, although the invention is useful also for subjects suffering from allergies or other histamine-induced

hypersensitivities. The doses described herein are intended for adult human subjects. For children, these doses can be, for example, halved.

Also β2 agonists and corticosteroids, for example in the below described recommended doses, can be used in treating these acute hypersensitivities, such as asthma attacks, as they occur, or in preventing exercise-induced asthma attacks. However, these further active agents are particularly useful as prophylactics, in combination with the cysteine(s) of the composition of the invention. Thus, in addition to the above described cysteine compound(s) of the composition, one or more inhaled β2 agonists or one or more corticosteroids, e.g. in the form of inhaled corticosteroids (ICS), are particularly useful in the dosage regimens of the present invention, administered as needed, in a first step of treating the subject while maintaining the low doses mentioned in the following paragraph, but in increased doses (such as the doses in the parentheses of the following paragraph) if these low doses are not sufficient.

Of these additional active agents, β2 agonists are generally preferred in the mildest cases of asthma or other hypersensitivities, or as a first treatment step for a subject, while they are replaced with corticosteroids if the treatment using the β2 agonists is insufficient, and are used in combination if the corticosteroids (as the only additional active agent) are insufficient.

Suitable inhaled β2 agonists for use according to the present invention include formoterol, salbutamol, salmeterol and terbutaline. The recommended doses of these are:

- for formoterol: 6-24μg/day, typically administered in one or two equal doses (can be increased to a total of 48 μg/day),

for salbutamol: 100-400μg/day, typically administered in a single daily dose (can be increased to 400-1600μg/day, preferably administered in 3-4 equal doses), for salmeterol: 50-100μg/day, typically administered in one or two equal doses (can be increased to 100-200μg/day),

for terbutaline: 250-500μg/dose, administered when needed (the dose can be increased to 1500μg), maintaining a maximum daily dose of <6mg.

Suitable inhaled corticosteroids for use according to the present invention include beclomethasone, budesonide, ciclesonide and fluticasone. The recommended (low) doses of these are:

for beclomethasone: 100-200μg/day, typically administered in up to two equal doses (can be increased to a total of 800μg/day), for budesonide: 200-80(^g/day, typically administered in one or two doses (can be increased to 160(^g/day, when administered in two or more doses),

for ciclesonide: 80-16(^g/day, typically administered in a single daily dose, and for fluticasone: 200-200(^g/day, typically administered in up to two equal doses (can be increased to 400(^g/day).

These inhaled agents represent the basis for the conventional treatments of asthma attacks, as well as the asthma prophylaxis.

Thus, according to a particularly preferred embodiment of the invention, the present composition is used in treating acute hypersensitivities by administering the cysteine- containing composition using one of the following options, starting from the first option and continuing to the following option when the previous one has been insufficient:

1) administering the cysteine-containing composition without additional active agents,

2) administering the cysteine-containing composition in synergistic combination with one or more β2 agonist (particularly rapid-acting inhaled β2 agonist),

3) administering the cysteine-containing composition in synergistic combination with one or more corticosteroid (particularly in low doses), or

4) administering the cysteine-containing composition in synergistic combination with both one or more β2 agonists (here particularly long-acting agonists) and one or more corticosteroids (here possibly in the described increased doses).

According to another particularly preferred embodiment of the invention, the present composition is used in preventing the onset of acute hypersensitivities by administering the cysteine-containing composition using one of the following options, starting from the first option and continuing to the following option when the previous one has been insufficient:

4) administering the cysteine-containing composition in synergistic combination with both one or more β2 agonists (here particularly long-acting agonists) and one or more corticosteroids (here possibly in the described increased doses). The preferred corticosteroid-P2-agonist combinations (to be used in a synergistic combination with the cysteine compound(s) of the invention) are generally administered by inhalation. Typical examples of these are a combination of budesonide and formoterol (preferably dosed in a 17: 1-35: 1 ratio, most suitably in doses of 80/4^g-320^g, when administered 1-4 times per day, which in severe cases can be increased to 8 times per day), as well as a combination of fluticasone and salmeterol (preferably dosed in a 2: 1-10: 1 ratio, most suitably in a daily dose of 200/100-1000/100μg, when administered 1-2 times per day). According to a preferred embodiment of the invention, if the used regimens have been successful, the daily dose of β2 agonists or corticosteroids is reduced by 25% within the first 6 months of use of the dosage regimen of the present invention, and by a further 25% within the following 6 months, optionally continuing the reduction at said pace (of 25% each half year) after the first year. Thus, the overall use of inhalers can be reduced in the course of time using the present invention.

Since asthma is an incurable disease, it is, however, preferred to continue the preventive treatment (with the dosage regimen of the invention) as a prophylactic even when the hypersensitivity attacks (such as the asthma attacks) appear to have stopped occurring, possibly with a declining cysteine dose, for example starting with a dose of 200 to 900mg per day, after the first year has passed from the last attack, and optionally reducing it further to 100 to 400mg per day, after the second year has passed.

It is also preferred to continue administering the cysteine-containing composition using a single dose of 100 to 200mg of the active cysteine compound prior to drinking any alcoholic drink and prior to smoking (or otherwise using a tobacco product) even after reducing the daily dose, as described above.

In addition to the cysteine compound(s) and the optional additional active agents, i.e. the β2 agonists and the corticosteroids (preferably in inhaled form), the preparation or the combined preparations containing the cysteine-containing composition of the invention can include one or more further active agents. Further active agents that may be added to the preparation include:

antihistamines (e.g. cetirizine, levocetirizine, loratadine, desloratadine or fexofenadine),

leukotriene modifiers (e.g. montelukast or zafirlukast),

- immunoglobulin E (e.g. omalizumab),

- theophylline, and

oral corticosteroids (e.g. hydrocortisone, prednisolone, prednisone, dexamethasone, methylprednisolone or fludrocortisone acetate). Said antihistamines are commonly used and are therefore among the preferred options. These antihistamines function mainly by reducing allergic symptoms and other

hypersensitivity reactions. These symptoms, however, often occur along with asthma, whereby their administration in combination with asthma medication is of advantage. The recommended daily dose for these can vary. For cetirizine, a daily dose of 5-20 mg is used for adults, preferably about lOmg. For levocetirizine, a daily dose of 2-1 Omg is used for adults, preferably about 5mg. For loratidine, a daily dose of 5-20 mg is used for adults, preferably about lOmg. For desloratidine, a daily dose of 2-1 Omg is used for adults, preferably about 5mg. For fexofenadine, a daily dose of 100-150mg is used for adults, preferably about 120 mg.

These antihistamines are generally administered orally as tablets or liquids, preferably in 1-4 single doses per day.

Orally administered alternatives for use as further active agents instead of the inhaled agents include the above mentioned oral corticosteroids, oral bronchodilators (e.g.

salbutamol) and theophylline (particularly slow release theophylline). It is, however, preferred to administer these only in severe cases (particularly, in cases of frequently occurring acute asthma attacks). Conventionally used doses can be applied. A widely accepted classification of asthma by severity is: i) intermittent, ii) mild persistent, iii) moderate persistent and iv) severe persistent. A more clinical approach focuses on asthma control, and provides the following classification: i) controlled, ii) partly controlled, and iii) uncontrolled. The commonly recommended asthma treatments (according to the Global Initiative for Asthma, or GINA) follow the latter approach: Step 1 (or more accurately, Option 1) is the use, as needed, of a rapid-acting inhaled β2 agonist. The other 4 treatment steps (or options) range from the use of low-dose inhaled corticosteroids (ICSs) as the preferred treatment option of Step 2, to the use of high-dose ICSs plus long-acting inhaled β2 agonist combinations together with oral corticosteroids at Step 5. Thus, Step 2 is the use of low- dose inhaled corticosteroids (ICSs), Step 3 is the combined use of ICSs and long-acting inhaled β2 agonists (LABAs), Step 4 is the use of increased doses of the ICS/LABA combination, and the final Step 5 is the use of said ICS/LABA combination together with oral cortico steroids .

Once the level of asthma control has been established, i.e. the above mentioned level i), consideration should be given to reducing the amount of administered medication according to the treatment step or option. By contrast, if asthma is uncontrolled, treatment needs to be increased to the next step. Generally, a dose reduction or a step down to the previous milder treatment option can be attempted, for example every 3 months.

The present invention introduces a new Step 1, i.e. the administration of only the present cysteine-containing composition.

The following steps are similar to the mentioned prior steps, i.e. with new Step 2 including the administration of the present cysteine-containing composition in combination with the rapid-acting inhaled β2 agonist, used as needed. The benefits obtained by replacing the prior Step 1 with the present Step 1 and Step 2 include the possibility to decrease the frequency of dosing of the β2 agonist.

Step 3 according to the present invention includes the administration of the present cysteine-containing composition in combination with a low-dose inhaled corticosteroid (ICS). The benefits obtained by replacing the common Step 2 with the present Step 3 include the possibility to decrease the frequency of dosing of the ICS.

The further treatment steps are modified accordingly, i.e. by introducing the present cysteine-containing composition as an additional treatment component. The cysteine compound(s) and the additional active agent(s) of the invention can be formulated into a single preparation (in case they are all suitable for oral administration), or they can be administered separately. Preferably, they are, however, administered separately. In this latter case, the separate preparations are still administered

simultaneously or at least within a time frame that provides an overlap between the active periods of these active agents, thus providing synergy in the treatment or prophylaxis of acute hypersensitivities. Thus, also inhalers can be used, containing e.g. the corticosteroids.

According to a preferred embodiment of the invention, the cysteine compound(s) and the β2 agonists or corticosteroids (or further active agent(s)) are administered as separate preparations, but essentially simultaneously, thus facilitating the above described advantageous reduction in the amount of β2 agonists or corticosteroids, since the same units containing the cysteine compound(s) can be administered while the amount of additional active agents is reduced in the separate unit.

The cysteine compound(s) are preferably formulated into units intended for oral administration, such as monolithic or multi-particular tablets, capsules, lozenges, chewing gums, or granules (contained in capsules or used as such), or into the physical structure of a gel. Preferably, these formulations include one or more carriers to facilitate controlled release of the active agent(s).

Such a formulation intended for oral administration can be formulated for swallowing by the subject, or it can be formulated to be kept in the mouth by the subject. A formulation intended to be swallowed by the subject is suitably in the form of a tablet or a capsule, particularly comprising a mixture of powder or granules. Most preferably, it is in the form of capsules comprising granules.

A formulation intended to be kept in the mouth, in turn, is suitably in the form of a lozenge or a sublingual tablet. These types of formulations can optionally include coatings to provide a further controlled release of the active agent(s).

According to a preferred embodiment of the invention, the composition containing the cysteine compound is formulated to be swallowed by the subject, i.e. as tablets or capsules. For smokers (or frequent passive smokers), it is, however, preferred to administer the composition as a formulation to be kept in the mouth, e.g. a lozenge, a sublingual tablet or a chewing gum, either to replace or to be used along with the preferred tablet(s) or capsule(s). In this manner, the evaporation of the acetaldehyde, which is a highly volatile compound, can be prevented, whereby it does not end up directly in the respiratory system. Such formulations to be kept in the mouth can optionally contain also xylitol, which is capable of further facilitating the action of the cysteine compound.

Primarily, the formulation including the cysteine compound(s) is intended to provide a local action by delivering the active agent(s) to its/their desired site of action, i.e., the mouth or the stomach, or both. Further, a controlled release of the active agents in the conditions of the desired target area is preferred in order to ensure said local action. Thus, at least one of the carriers of the composition will be selected among those known to facilitate controlled and particularly sustained release, of the active agent(s). Without these carriers, the cysteine would be carried directly to the blood stream before any effect can be achieved, whereby the effect would not be local. In the mouth, this controlled release can be achieved for example using gum base or a poorly dissolving coating, and in the stomach this can be achieved for example using a coating or a filler containing an enteric polymer. The term "carrier" here includes fillers and binders, as well as any other additives that facilitate controlled release of the active agent(s).

Thus, according to one embodiment of the invention, one or more carriers of this formulation are selected among those capable of maintaining an effective concentration of the pharmaceutically active agent(s) in the stomach during a period of at least 30 minutes using one unit dose.

More preferably, the used carriers are selected from those capable of controlling the releasing speed of the active agent(s) so that these compounds are released, locally, in the stomach during a period of 60-120 minutes.

Examples of such carriers are substances, which are selected from the group of chitosans, alginates, such as sodium alginate, aluminium hydroxide, sodium carboxymethyl cellulose, sodium hydrogen carbonate, and enteric polymers, preferably from enteric polymers. Such carriers may be used either alone, particularly when the intended release time is 30-60 minutes, or as combinations of two or more substances, in cases when the intended release times exceed 60 minutes.

The enteric polymers are preferably selected from methacrylate derivatives, or

hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate or hydroxypropyl methylcellulose acetate-succinate. Commonly used enteric polymers are the Eudragit polymers.

The enteric polymers can be divided into two groups, depending on their end-use. Thus, for example Eudragit RL, RS, and NE are used for controlled release or sustained release formulations (or selected tablet layers), and function at least partly based on their insolubility and by swelling, whereas for example Eudragit L and S are used for colon or intestine targeted formulations (or selected tablet layers), since they are pH dependent. Therefore, Eudragit RL, RS and NE are particularly suitable for use in formulating the compositions of the present invention. An example of these is Eudragit RS-PO.

The amount of enteric polymer in the formulation intended to release the active agent(s) in the stomach is preferably 2-5%, most preferably 3-4% of the weight of the entire formulation.

Such a formulation for release of the active agent(s) in the stomach preferably contains also a filler in the form of calcium hydrogen phosphate (CaHP0₄), which has the advantage of i) not swelling in the stomach content and ii) being suitable for direct compression. The amount of such a filler in the formulation is preferably 30-70%, most suitably 40-60% by weight of the formulation.

Such a formulation can also contain other conventional additives, such as fillers, binders, pigments and lubricants, e.g. the pigment titanium dioxide, preferably in minor amounts of 2-5% by weight of the entire formulation.

It is also possible to use carrier polymers, whereby it is particularly preferred to mix the carrier polymer(s), or the active agent(s), with 10-30%), preferably 20%> of sodium hydrogen carbonate of the weight of the polymer(s). The total amount of polymers in the formulation in this case is, generally, 10-50%, preferably 15-40%), and most preferably 20- 30% of the total weight of the formulation.

In case of the formulation being in the form of, or containing, granules (for example contained in capsules), it is preferred to formulate these granules to separately contain binders, preferably selected from enteric polymers of poor solubility, e.g. methacrylate derivatives, a suitable alternative being Eudragit RS. The total amount of such granule binders is preferably 2-5%, preferably 3-4% by weight of the granules. According to a preferred embodiment of the invention, the composition for release of the active agent(s) in the stomach is formulated into an encapsulated composition comprising a mixture of powder or granules that form a gel in the stomach. In addition to cysteine(s), the composition comprises one or more, preferably two or more, polymers for controlling the release of the active agent(s), preferably in an amount of 10-50%, more preferably 15-40%, and most preferably 20-30%), as well as optional further additives. This encapsulated composition is generally formulated to be swallowed by the subject.

According to one preferred option for manufacturing the above described formulation, the cysteine(s) of the present cysteine-containing composition are mixed with the fillers needed and, after that, granulated by using enteric polymers as binders. According to this option, the granules can, for example be added into an HPMC capsule, the granules containing a suitable filler and a suitable binder, as well as, optionally, further conventional pharmaceutical additives (such as pigments). An exemplary granulated composition might contain:

L- or D-Cysteine or N-acetylcysteine 100 mg

Calcium hydrogen phosphate (filler) 30-50 mg

Eudragit RS-PO (binder) 40-60 mg

titanium dioxide (further additive) 5-10 mg

According to another embodiment of the invention, one or more carriers added to the cysteine-containing composition are selected among those capable of maintaining an effective concentration of the pharmaceutically active agent(s) in the mouth during a period of at least 5 minutes using one single dose. More preferably, the used carriers are selected from those capable of controlling the releasing speed of the active agent(s) so that these compounds are released, locally, in the mouth during a period of 5-20 minutes. Examples of such carriers are gum base, various chitosans, alginates, such as sodium alginate, aluminium hydroxide, sodium carboxymethyl cellulose, and sodium hydrogen carbonate. Such carriers may be used either alone, particularly when the intended release time is 5-10 minutes, or as combinations of two or more substances, in cases when the intended release times exceed 10 minutes. In case of using two or more carrier substances, at least one of them preferably forms a coating.

According to a preferred embodiment of the invention, the composition intended to release the active agent(s) in the mouth, contains at least one - preferably two or more - polymers for controlling the release of the active agent(s) in the mouth, preferably for five minutes minimum, for example by forming a gel that adheres to the mucous membranes, or by binding the active agents to the polymer.

Such a composition is preferably formulated into a sublingual tablet, lozenge or chewing gum, most suitably to be kept in the mouth for a prolonged time by the subject placing it under the tongue, sucking on it or chewing on it. In addition to the active agent(s), such a formulation comprises the said polymers (e.g. polymeric binders) and optional further additives. The amount of polymers in this formulation is 10-50%, preferably 15-40%, and most preferably 20-30%). A single unit, or formulation, of the cysteine-containing composition preferably comprises 50-500mg, more preferably 50-300mg, and most suitably 100-200mg of the cysteine(s), whereby the required daily dose of cysteine(s) can be provided using one or more units or formulations, preferably 3-10 units or formulations per day. In this context, the "unit" or "formulation" may implicate one tablet, capsule, lozenge or chewing gum, or one measurable unit of a gel or a gel-forming liquid.

When the optional further active agent(s) (such as antihistamines, leukotriene modifiers, theophylline, and oral corticosteroids) are added to the same formulation as the cysteine compound(s), they are generally used in contents of 1 to 50 weight-% of the total amount of active agent(s), preferably 1 to 30 weight-%, most suitably 5 to 20 weight-%).

Generally, the formulation prepared according to the present invention is intended to be administered to patients (subjects) suffering from asthma, allergies or other histamine- induced hypersensitivities. Using the said composition, a long-term treatment is possible and large doses can be used without harmful side effects, because the cysteine-containing composition of the invention contains no substances that even in large concentrations are harmful or toxic.

Using the present cysteine-containing composition, the amounts of administered conventional asthma medicaments can also be reduced over time.

The present invention thus also introduces a novel method of treating subjects suffering from asthma, allergies or other histamine-induced hypersensitivities, by administering to the said subjects, one or more units of the composition of the present invention, with a daily dose of 500 to 3000mg of cysteine(s), or a single dose of 300 to 1500mg of cysteine(s), using the composition as described above, optionally in combination with a recommended dose of antihistamine(s), and optionally by reducing the doses of these active agents after the hypersensitivity attacks have stopped occurring.

The following non-limiting examples are intended merely to illustrate the advantages obtained with certain embodiments of the present invention.

EXAMPLES

Example 1 - preparation of capsules according to the present invention

The capsules were prepared by mixing 500 g of L-cysteine (Gonmisol S.A., Spain), 500 g of Eudragit RS-PO, forming a matrix structure (Evonik Rohm GmbH, Germany), and 1 kg of calcium hydrogen phosphate (Emcompress® Anhydrous; Mendell a Penwest Company, Lakeville, MN) in a Turbula Powder Blender (Glen Mills Inc., Clifton, NJ) for 10 minutes. The mixture was wet-granulated using ethanol. The obtained wet granules were sieved using a 2-mm sieve, and thereafter allowed to dry at room temperature in a fume hood for 24 hours. The dried granules were sieved using a 1.68 mm and 1.18 mm sieves, and the obtained middle fraction was collected for capsulation.

Simultaneously, a placebo formulation, where the L-cysteine was replaced by the same amount of CaHP0₄, was prepared following the exact same procedure.

The obtained matrix granules were weighed into HPMC capsules so that the desired amount of cysteine per capsule was obtained. The L-cysteine concentration of the granules was determined using a capillary method (400 mg of granules contained 98 mg of L- cysteine). The amount of L-cysteine per capsule was left at 50 mg in order to ease the selection of a suitable dosage (for a dosage of 100 mg or 200 mg of L-cysteine, 2 or 4 capsules were administered at essentially the same time to the subject).

Similar capsules containing also titanium dioxide were prepared, and this excipient was found not to have an effect on the desired function of the capsule (results not shown).

Example 2 - dissolution test for the capsules

Dissolution tests were carried out on the capsules of Example 1 according to the USP I method (USP 24) (The United States Pharmacopeia 2001). A standard curve was prepared between 0.01 and 0.6 mg/ml (y = 2.196 + 0.0016, r² = 0.9999). The medium used was 500 ml of pH 1.2 HC1 buffer. The rotation rate of the baskets was 100 rpm, and the temperature of the medium was +37°C (± 0.5). Samples were taken at 5-minute intervals for the first half hour and thereafter at 10-minute intervals for the remaining 2 hours. L-cysteine was detected in flow-through cells (10 mm) at a wavelength of 213 nm. The results were calculated by using dissolution software. The system was equipped with a bath and a pump (Sotax AT7 UV Dissolution System, Stax, Allschwil, Switzerland) and a spectrophotometer (PerkinElmer, Lambda 25, PerkinElmer, Inc., Waltham, MA), the software used for the test and for calculating the results was WinSotax (Sotax).

This dissolution test showed that the formulation released L-cysteine at a controlled rate, yet fast enough to have time to react with acetaldehyde before leaving the stomach. These results are shown in Fig. 1. When not granulated and formulated as above, the L-cysteine was dissolved rapidly (100 % in 5 minutes).

Example 3 - Acetaldehyde-binding

Study procedure:

Seven volunteers (2 men, 5 women) with achlorhydric atrophic gastritis participated in the study. Their mean age ± SD was 57 ±7 years and mean body weight 75 ± 22 kg. All volunteers were non-smokers and normal social drinkers, with an average consumption of 50 g or less of ethanol per week.

A randomized double-blinded placebo-controlled study design was used, and each participant served as his/her own control. The 2 study days were separated by at least a 3- day interval. The volunteers were told to refrain from alcohol intake for 24 hours and food intake for 12 hours prior to the study.

A nasogastric tube (Duodenal tube Levin, CHIO, Unomedical, Denmark) was inserted into the subjects to a depth of 55 cm at the beginning of each study day. The tube was lubricated with Xylocain gel (AstraZeneca, Sodertalje, Sweden) containing no ethanol. During the tube placement, the volunteers were given 100 ml of water to facilitate swallowing of the tube.

The subjects were given four capsules, containing either cysteine (50 mg in each capsule) or placebo, as prepared according to Example 1 , orally double blindly with 200 ml of water. Immediately thereafter, ethanol (0.3 g/kg body weight) diluted in water to 15 vol%, was infused via the nasogastric tube into the stomach of the volunteers.

Samples of gastric juice (5 ml) were aspirated through the tube at 5-minute intervals up to 60 minutes after the ethanol infusion or until the stomach had emptied, as indicated by unsuccessful aspiration. The samples were analyzed for pH and acetaldehyde, ethanol and cysteine concentrations. Analysis:

To measure the acetaldehyde concentration, 450 μΐ of gastric juice was immediately transferred into a headspace vial containing 50 μΐ of 6 mol/1 perchloric acid. Perchloric acid does not hydrolyze the cysteine-acetaldehyde bond.

For the ethanol analysis, the gastric juice was diluted 10-fold in purified water, and 500 μΐ of diluted gastric juice was transferred into a headspace vial. Two parallel samples were used for the measurements, and the mean value was calculated. The levels of acetaldehyde and ethanol were analyzed by headspace gas chromatography.

L-cysteine concentration of the gastric juice samples were determined by using an HPLC method. A standard curve was prepared between concentrations of 0.0625 and 2.0 mg/ml (y = 851.06x + 8.52, r² = 0.9704). Two parallel samples were again prepared. 60 μΐ of gastric juice was measured into a test tube, and 30 μΐ of pH 7.4 phosphate-buffered saline solution and 30 μΐ of 20 vol-% tri-n-butyl phosphine in dimethylformamide were added. The samples were incubated for 30 minutes at +4°C, after which 90 μΐ of cold 10% trichloroacetic acid containing 1 mM Na₂EDTA was added, and the samples were vortexed for 2 minutes and then centrifuged for 10 minutes at 4500 rpm. 50 μΐ of supernatant was pipette into a test tube containing 125 μΐ of pH 9.5 borate buffer with 4mM Na₂EDTA, 10 μΐ of 1.55 M sodium hydroxide, and 50 μΐ of 2 mg/ml 4-fluoro-7-sulfobenzofurazan, ammonium salt (SBD-F) solution in borate buffer. The samples were incubated for 60 minutes at +60°C so that a yellow derivate was formed. Thereafter, 150 μΐ of the solution was pipette into HPLC inserts, and used for the measurements. The isocratic mobile phase was pH 7.0 phosphate buffer and methanol (95 :5). The flow rate was 1 ml/min and the retention time was 6 minutes. The L-cysteine concentration was determined using a fluorescence detector (excitation 385 nm, emission 515 nm). Results:

Fig. 2 shows the effect of the L-cysteine administration (or the placebo administration) on the acetaldehyde levels. In all measurements, the average acetaldehyde concentration of the gastric juice was 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 volunteers after the administration of study formulations containing L-cysteine. The mean cysteine concentrations are represented in Fig. 3. After administration of placebo formulations, no L-cysteine was detected.

Example 4 - preparation of sucking tablets

A sucking tablet was prepared, comprising:

L-cysteine 20 mg

Flavouring (including xylitol) q.s.

Magnesium stearate lO mg

The composition was prepared by mixing the cysteine and most of the remaining ingredients into a powdery mass and compressing it into sucking tablets, which were coated with the xylitol.

Example 5 - preparation of sublingual tablets

A sublingual tablet was prepared, comprising:

L-cysteine lO mg

Flavouring (including xylitol) q.s.

Magnesium stearate 5 mg

The composition was prepared by mixing the cysteine and most of the remaining ingredients into a powdery mass and compressing it into sublingual tablets, which were coated with the xylitol. Example 6 - Acetaldehyde binding

Two individuals tested the preparation prepared according to Example 4. The salivary acetaldehyde contents of the testees were measured before smoking and then after 5 minutes during smoking, i.e., Omin, 5min, lOmin, and 15min after the testees started smoking. Each testee smoked one cigarette and, at the same time, saliva was collected from their mouths, as they sucked placebo tablets. Smoking lasted for 5min. In another test, the testees repeated the study by sucking tablets containing 20 mg of cysteine. Before smoking, the salivary acetaldehyde content of each testee was very low. In the second test, the acetaldehyde content had reduced to a non-measurable level already after the first 5 minutes.

Example 7 - Acetaldehyde binding

Five smokers (of the age of 29 ± 2.8) participated in the study, in which three cigarettes were smoked (with cleaning periods in between). While smoking each cigarette (in 5 minutes time), the voluntaries sucked tablets blindfold, containing a placebo, 1.25 mg, 2.5 mg, 5 mg, 10 mg or 20 mg of L-cysteine, prepared according to Example 4. The acetaldehyde in the saliva samples was analysed by gas chromatography after 0, 5, 10, 20 minutes from starting to smoke.

The L-cysteine tablets (5 mg, 10 and 20 mg) removed from the saliva all of the acetaldehyde originating from tobacco. The average salivary acetaldehyde contents immediately after smoking were 191.2 ± 48.5 μΜ, 0 μΜ, 0 μΜ, 0 μΜ with the placebo and the 5 mg, 10 mg, and 20 mg L-cysteine tablets, respectively.

The study showed that even 5 mg of L-cysteine, when delivered with a melting tablet, completely inactivated the carcinogenic acetaldehyde in the saliva during smoking. The L- cysteine tablet of 1.25 mg reduced the amount of acetaldehyde by about two thirds compared with the placebo. Example 8 - Cysteine in treating asthma

Study design: A double-blind, randomized placebo-controlled clinical trial is carried out, comparing Acetium capsules (lOOmg L-cysteine, twice a day) and placebo (preparation with design and package identical to the test preparation) in control of asthma during a 3-month trial period. A cohort of 200 voluntary subjects (both genders) are invited to participate in the study. To be eligible, the subjects are required to: i) have partly controlled or uncontrolled asthma, ii) have their asthma diagnosed for at least 12 months, iii) have the onset of their asthma before 50 years of age, iv) be between 18 and 65 years of age, and v) have a minimum of co -morbidity.

Methods:

A 3 -month retrospective history and 1 -month prospective baseline (run-in) period is used to assess the baseline asthma control (attach frequency). Parallel group design instead of cross-over design is used. Randomization is performed after the 1 -month prospective run- in time, using a random number generator, with blocks size of 4, and creating unique randomization codes for each subject. To control for gender differences, a stratified randomization is used, gender as the stratification variable. The treatment period in both study arms is 3 months. All patients should continue their regular treatment tailored according to the level of asthma control, including their usual symptomatic or acute treatment. During the 3 -month treatment period, participants are evaluated at monthly intervals. In addition to the baseline assessment of asthma control (by 1 -month diary, spirometry), each subject are requested to fill in a structured Questionnaire recoding their detailed asthma history and other pertinent data on potential triggers, to be used as covariates in multivariate analysis. The asthma diary is the main research tool used to monitor the efficacy of the test preparations, recording all predefined assessment measures (efficacy, tolerability and safety). These diaries also include the daily records of daytime asthma symptom scores and nocturnal awakenings, as well as the peak expiratory flow rate (PEFR) measurement twice a day (morning and evening). In addition, asthma control is monitored at baseline, randomization, and at 1 -month intervals by spirometry as well as using three internationally validated classification tools: the Asthma Control Test™ (ACT), the GINA guidelines, and the (adult) Asthma Therapy Assessment Questionnaire (ATAQ).

Interpretations:

The pre-specified primary efficacy endpoint is the percentage of asthma exacerbation days, defined as the days when any of the following occur: i) awake all night (awake all night or recurrent episodes of awakening)(nocturnal scale), ii) increase of >50% from baseline in the symptom score (daytime scale), iii) increase from baseline in β-agonist use of >70% (minimum increase 2 puffs/day), iv) decrease from baseline of >20% in the morning PEFR, v) morning PEFR <180 1/min, or vi) an asthma attack (i.e., unscheduled medical care for asthma).

The treatment efficacy is also analysed for a series of secondary efficacy endpoints, of which the number of asthma-free days is the most relevant. An asthma-free day is defined as a day when all of the following occur: i) no nocturnal waking, ii) use of two puffs or less of β-agonist, iii) no use of oral corticosteroids, and iv) no unscheduled use of medical care for asthma (=no asthma attack).

Claims

1. A pharmaceutically acceptable composition containing one or more cysteine compounds selected from L-cysteine, D-cysteine and N-acetylcysteine, as active agent(s), for use in treatment of acute hypersensitivities, with a single dose of 300 to 1500 mg of cysteine(s), optionally for use in combination with one or more β2 agonists or one or more corticosteroids, or both, and further containing one or more carriers selected among carriers that are capable of maintaining an effective concentration of the pharmaceutically active agent(s) in the stomach contents for at least 30 minutes.

2. The composition according to Claim 1, characterized in that it is formulated for use in single doses for acute conditions, using a daily dose containing 500 to 3000 mg of cysteine compound(s), in combination with a recommended dose of β2 agonists or corticosteroid(s).

3. A pharmaceutically acceptable composition containing one or more cysteine compounds selected from L-cysteine, D-cysteine and N-acetylcysteine, as active agent(s), for use in preventing onset of acute hypersensitivities, with a daily dose of 200 to 3000 mg of cysteine(s), optionally for use in combination with one or more β2 agonists or one or more corticosteroids, or both.

4. The composition according to any preceding claim, characterized in that the acute hypersensitivity is an asthma attack, an acute allergy or another acute histamine-induced hypersensitivity, most suitably being an asthma attack.

5. The composition according to any preceding claim, characterized in that it is formulated for daily use at 4-hour intervals, particularly 6 times a day, preferably to an empty stomach at least 1 hour, more preferably 2-5 hours after the previous meal.

6. The composition according to any of claims 1 to 5, characterized in further containing one or more carriers selected among the carriers that are capable of maintaining an effective concentration of the pharmaceutically active agent(s) in the stomach contents during a period of 30-120 minutes, more preferably within 60-120 minutes, by using one unit dose.

7. The composition according to any of claims 1 to 5, characterized in further containing one or more carriers selected among the carriers that are capable of maintaining an effective concentration of the pharmaceutically active agent(s) in the saliva for at least 5 minutes using one unit dose.

8. The composition according to any of claims 1 to 7, characterized in containing one or more carriers selected from chitosans, alginates, e.g. sodium alginate, aluminium hydroxide, cellulose derivatives, e.g. sodium carboxymethyl cellulose, and sodium hydrogen carbonate, as well as enteric polymers.

9. The composition according to any of claims 1 to 7, characterized in containing one or more polymeric carriers selected from chitosans, alginates, e.g. sodium alginate, cellulose derivatives, e.g. sodium carboxymethyl cellulose, and enteric polymers, e.g. methacrylate copolymers, hydroxypropyl methylcellulose acetate succinates and cellulose acetate phthalate.

10. The composition according to claim 9, characterized in that the composition comprises 10-30%, preferably 20% sodium hydrogen carbonate of the weight of the polymers.

11. The composition according to any of claims 8 to 10, characterized in containing a total amount of polymers adjusted to 10-50%), preferably 15-40%), and most preferably 20- 30% of the weight.

12. The composition according to any of claims 1 to 11, characterized in that it comprises granules, preferably containing binders, which can be selected for example from enteric polymers, preferably methacrylate derivatives, more preferably being Eudragit RS, and most suitably in a total weight of 2-5%, preferably 3-4%, of the composition.

13. The composition according to any of claims 1 to 12, characterized in that it is in the form of monolithic or multi-particular tablets or capsules, or granules as such, or it has the physical structure of a gel, preferably a tablet or a capsule comprising a mixture of powder or granules.

14. The composition according to any of claims 1 to 13, characterized in that it is in the form of capsules containing granules.

15. The composition according to any of claims 1 to 11, characterized in that it is in the form of sublingual tablets, lozenges or chewing gums.

16. The composition according to any of claims 1 to 15, characterized in that it is administered in combination with one or more β2 agonists, which are selected from formoterol, salbutamol, salmeterol and terbutaline.

17. The composition according to claim 16, characterized in that the recommended doses in adult subjects are, for formoterol: 6-24μg/day typically administered in one or two equal doses, for salbutamol: 100-400μg/day typically administered in a single daily dose, for salmeterol: 50-100μg/day typically administered in one or two equal doses, for terbutaline: 250-500μg/dose administered when needed while maintaining a maximum daily dose of <6mg.

18. The composition according to any of claims 1 to 17, characterized in that it is administered in combination with one or more corticosteroids, which are selected from inhaled corticosteroids, such as beclomethasone, budesonide, ciclesonide and fluticasone.

19. The composition according to claim 18, characterized in that the recommended daily dose in adult subjects is, for beclomethasone: 100-200μg/day, typically administered in two equal doses, for budesonide: 200-800μg/day, typically administered in one or two doses, for ciclesonide: 80-160μg/day, typically administered in a single daily dose, and for fluticasone: 200-2000μg/day, typically administered in two equal doses (can be increased to 4000μg/day).

20. The composition according to any of claims 1 to 19 for use in treating acute

hypersensitivities, including administering to a subject said composition, containing at least one cysteine compound, selected from L,-D-, and N-acetylcysteine, as active agent(s), and using a daily dose of 200 to 3000 mg of said cysteine compound(s).