Optimised pharmaceutical formula for the treatment of inflammatory changes of the esophagus

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DESCRIPTION

Pharmaceutical formulation optimized for the treatment of esophageal inflammatory modifications

For the treatment of inflammatory esophageal processes and modifications, such as eosinophilic esophagitis, a drug form is required, which after oral application allows the local availability of the active substance budesonide in a sufficiently high concentration at the site. of inflammation. This concept referred to as focusing on the esophagus cannot be done with the oral application of a simple active ingredient solution, since there is a high risk that the active substance will then be swallowed quickly and almost quantitatively in the stomach. The objective of focusing on the esophagus must therefore be achieved preferably because a slow sliding of the active principle is possible through the esophageal mucosa together with a complete surface wetting, as well! as to an adhesion of the active substance. This type of application takes the active principle precisely to the place of actuation. It should also be taken into account that the therapeutic treatment of the esophagus ideally requires additional special requirements as far as the drug form is concerned, depending on which patient population is to be treated. The present invention is particularly suitable for making available an age-appropriate drug form, which can be used easily and reliably in adult patients and thus attains a high level of compliance with the prescribed daily dose ("compliance"). .

Eosinophilic esophagitis is a chronic inflammatory disease of the esophagus, which entails a limitation of the functioning of the esophagus and is characterized by an infiltration of the esophageal epithelium with eosinophilic granulocytes. Since the end of the decade of the seventies, eosinophilic esophagitis has been described as chaslastic and since the end of the decade of the nineties it has been increasingly diagnosed. There seems to be a response transmitted by Th2 cells to airborne or assimilated allergens through food, which leads to a discharge of IL-13, IL-15 and increased production of Eotaxin-3. Because of this, eosinophilic granulocytes are attracted. Only a dysphagia often of prolonged existence occurs in the foreground as well! as a bolus impaction. The diagnosis requires, according to the standard, the detection of> 15 eosinophils per field of large increase in the esophagus in patients with symptoms of an esophageal dysfunction. In the case of some patients, only mucosal modifications are observed that are easy to ignore. Eosinophilic esophagitis often affects men and often appears both during childhood, as well as at young adulthood.

WO 2009/064417 discloses compounds for the treatment of gastrointestinal inflammations. The compounds that all! described comprise a corticosteroid and at least one additional agent for the treatment of inflammation. WO 2009/064457 discloses corticosteroid-containing compounds, which are suitable for the treatment of inflammations of the gastrointestinal tract.

US 2007/0111978 describes procedures for alleviating inflammatory diseases of the gastrointestinal tract. In this case, the preparation of a highly viscous solution from a budesonide suspension with a very high sucralose concentration is proposed. US 2009/0264392 describes procedures and compounds that are suitable for the treatment of eosinophilic esophagitis. In the case of this method of treatment a steroid and an agent that adheres to the mucosa are used.

EP 2 151 235 A1 discloses pharmaceutical formulations, in particular effervescent budesonide tablets, however not orodispersible tablets.

US 2007/0020330 refers to pharmaceutical compounds, which always contain azelastine and one or more steroids as an antihistamine or antihistamine agent.

It is a task of the present invention to make pharmaceutical formulations available, which on the one hand entail advantages in the application and on the other hand can be well prepared and made available in a stable manner during storage.

The present invention relates to pharmaceutical formulations, in particular an effervescent tablet for orodispersible use, which comprises as a pharmaceutical active ingredient budesonide or a pharmaceutically acceptable salt or derivative thereof and which is preferably used in adults for the treatment of inflammatory diseases of the esophagus.

The type of use of effervescent tablets is generally known, which after dissolution in water are used as a drinking solution or as a rinse. This use of the active principle has different disadvantages for the described indication, such as the use of a large volume of water (usually 250 ml) and the dilution that this entails of the active principle or the distribution of the active principle in the entire cavity Buccal, ace! like the one usually practiced quickly swallowed from the solution to the stomach. The use of budesonide in eosinophilic esophagitis is also known (Straumann et al., Gastroenterology, 2010, p. 1526-1537). In this study, however, liquid ampoules were used, the so-called "respules", whose intended use is inhalation, introducing the contents of the ampoule previously into an atomizer and then inhaling. Deviating from this intended use was used in

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The study cited the budesonide suspension of the vial as a solution for drinking.

The effervescent tablet according to the invention on the other hand does not dissolve in water before use and thus clearly differs from the usual mode of use of effervescent tablets. The effervescent tablet according to the invention is not used for the preparation of a solution for drinking, but is used orally and is placed for example on the tongue, preferably the tip of the tongue, and slowly dissolves under the influence of saliva in mouth. Therefore, the orodispersible effervescent tablet according to the invention clearly differs from previously known formulations in terms of composition and form.

The orodispersible effervescent tablet according to the invention can also be referred to as the lingual effervescent tablet, since during application it is preferably to be in contact with the tongue. The formulation form can also be abbreviated as BUL (from German Budesonid-haltige linguale Brausetablette, effervescent lingual tablet containing budesonide).

The orodispersible use of the effervescent tablet is a form of special use, in which case the tablet is used as such orally and is arranged for example on the tongue, preferably the tip of the tongue, and after closing the mouth it is pressed slightly against the palate . In this way the effervescent reaction is started and the saliva flow is activated after approximately 5-15 seconds. The tablet components begin to dissolve in saliva. By means of the natural swallowing reflex, the saliva is then swallowed in portions and continuously moisturizes the esophagus, so that an adhesion of budesonide to the mucosa is given. During the decomposition of the effervescent tablet, the patient swallows on average 5-10 times, so that the esophagus is permanently moistened with saliva fluid containing active substance. The effervescent tablet completely undoes and there are no detectable residual parts. It will not be necessary to drink liquid later, since no stimulation is caused to drink. An advantage of the optimized formulation is therefore precisely that no liquid should be drunk afterwards, and thus a sufficiently long residence time of the therapeutically budesonide active substance in the affected areas of the esophagus is guaranteed. The application ends after 1.5 to 2 minutes and allows a concentrated distribution of budesonide in the esophagus. The distribution of the active substance within the esophagus on the esophageal mucosa occurs in this case only with saliva. A wide distribution of budesonide is already avoided in the oral cavity. The orodispersible effervescent tablet according to the invention can be taken very comfortably by patients at appropriate times.

The orodispersible effervescent tablet according to the invention is administered with the use in the oral cavity of the patient, where it quickly dissolves into a plurality of small particles. The orodispersible effervescent tablet according to the invention advantageously not only has the ability to quickly discard in a small amount of liquid, preferably therefore without additional drinking of water. Another advantage is an acceptable taste and a good mouthfeel when used. Sufficient tear strength and high storage stability are also advantageous also in conditions with high temperature and high humidity, as well! as the possibility of a large load with the active substance budesonide. The orodispersible effervescent tablet according to the invention has a high mechanical stability, due to which subsequent processing, packaging and transport are not problematic. It should be noted in particular that the orodispersible effervescent tablets according to the invention have, in comparison with the pharmaceutical preparations known above, an improved long-term stability, which is shown, for example, by tables 2 and 3.

The use according to the invention of the effervescent tablet clearly reduces the risk of an undesired absorption of budesonide in systemic circulation. In this way there is no oral or sublingual use of the drug form. In addition, relevant amounts of budesonide are not absorbed through the oral mucosa in case of the intended use. With respect to the flux tablets, which are also used in a bucodispersible manner, there is a clear advantage that the disintegration of the effervescent tablets allows a continuous release lasting from 1.5 to 2 minutes and thus topical application of the active ingredient on the mucosa of the esophagus. The flux tablets have the disadvantage that they disintegrate directly and, for this reason, can only be taken at one drink. In addition, effervescent tablets are easier to manufacture industrially compared to flux tablets. Therefore, orodispersible effervescent tablets containing from 0.25 mg to 5 mg of budesonide, preferably from 0.3 to 4 mg, particularly preferably from 0.4 to 3 mg and very particularly preferably, are object of the present invention. 0.5 to 2.0 mg budesonide according to the claims. The budesonide used can be used in any pharmaceutically acceptable form. The amount indicated represents the total amount of budesonide active ingredient in an orodispersible effervescent tablet. In a preferred embodiment, the orodispersible effervescent tablet according to the invention does not contain any additional pharmaceutical active substance.

An essential component of the orodispersible effervescent tablet is a system, which in the presence of saliva can develop gas, in order to achieve the effervescent effect. It is an indispensable requirement that this gas development system be pharmaceutically compatible. A gas development system of this type consists on the one hand of a weak acid or a salt of a weak acid. In the presence of water, acid results from it.

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weak free. The acid must not be too strong, however, to avoid negative health influences. In this case, it may be tartaric acid, acetic acid, lactic acid, and particularly preferably citric acid. Usually acid salts are used, that is, for example, sodium, magnesium or calcium salts. The other component of the gas development system consists of a salt of an acid, which in interaction with an additional acid can release a gas. Preferably these are salts of carbonic acid. In this case it may be carbonates or bicarbonates, such as sodium or potassium carbonate or sodium or potassium bicarbonates or calcium carbonates, as well! as mixtures of these salts. It is essential that a harmless gas for health, specifically CO2, be released in small quantities when the effervescent tablet is used. The gas is released through the interaction of the gas generating components with saliva.

An orodispersible effervescent tablet according to the invention has a mass, which is between 100 mg and 200 mg, orodispersible effervescent tablets preferably have a mass of 120 mg to 160 mg. Very particularly preferred embodiments of the orodispersible effervescent tablets have a mass of 133 mg to 147 mg.

The dimensions of the effervescent tablet according to the invention are equally essential. Effervescent tablets preferably have a diameter, which is between 5 and 10 mm. It is preferred that the effervescent tablets are round, however, a completely round shape is not necessarily necessary. Deviations of the round shape can be chosen. The effervescent tablets are preferably biplanes, the diameter preferably being between 6.0 and 8.0 mm and particularly preferably between 6.9 and 7.3 mm. The height of the orodispersible effervescent tablet is preferably between 1.5 and 3.0 mm, particularly preferably between 1.6 and 2.8 mm and very particularly preferably between 1.8 and 2.6 mm.

As regards the mechanical properties of the orodispersible effervescent tablet, these are essential. The breaking strength of the effervescent tablet is preferably between a value of 10 and 100 N, particularly preferably between 20 N and 70 N and is preferably determined according to the European Pharmacopoeia according to monograph 2.9.8.

In the test of mechanical resistance of tablets the solid test unit is held between two males

0 A male and a surface. A force is then allowed to act on the test unit (compressed) and the force is determined, which is necessary to give rise to a break in the tablet. The determination of the breaking strength of the orodispersible effervescent tablet according to the invention can be carried out, for example, with fully automatic test devices. These test systems are made available for example by the Pharmatest company under the trade name WHT 3ME. Of course similar test devices can also be used.

The resistance to the preferential breakage makes possible on the one hand a good and reproducible industrial production, but also a sufficient mechanical stability. According to the invention, orodispersible effervescent tablets have a friability (abrasion resistance) of a maximum of 5%, preferably a maximum of

one %. Friability (abrasion resistance) is preferably determined according to the European Pharmacopoeia according to monograph 2.9.7.

The shape, consistency and mechanical properties of the orodispersible effervescent tablet are essential, given that the size and shape make it possible on the one hand the continuous and relatively uniform disintegration in the presence of saliva. On the other hand they allow sufficient mechanical stability, so that the effervescent tablet during the intended use does not disintegrate in advance in partial parts and due to this it no longer allows a use according to the invention. The properties of the orodispersible effervescent tablet have the consequence that a foreign body sensation is no longer in the mouth, and thus the use is perceived by the patient as subjectively pleasant.

The effervescent tablet properties described in the particularly preferred embodiment allow the administration of individual variable dose of budesonide in an amount of preferably 0.5 to 3 mg of budesonide. The amount of active ingredient processed in this case has no influence on the quality parameters described and relevant for use, such as size, shape and mechanical stability. A division of the tablet is not necessary, rather a tablet corresponds to a dose of use.

The lower the dose of budesonide in the tablet, the higher the requirements regarding the selection of suitable excipients to ensure sufficient long-term stability of the drug form. An undesired degradation of the active ingredient would be particularly undesirable when low dosages are administered, since then a sufficient pharmaceutical amount of the active ingredient will no longer be present in the tablets. Surprisingly, it has been shown that the physical-chemical stability of budesonide in the effervescent tablet is possible only due to the composition according to the invention. Even if individual excipients are part of the state of the art of effervescent tablets, it is preferably possible only with exactly the qualitative and quantitative composition according to the invention a long-term stability of the drug form of up to 36 months for all dosages of one tablet

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Effervescent budesonide for orodispersible use. Effervescent tablets according to the invention can be stored at room temperature.

In a preferred embodiment, an effervescent tablet according to the invention contains a polyvinyl pyrrolidone. In this case, these are polymerization products of vinyl pyrrolidone. Low molecular weight polyvinylpyrrolidones are hygroscopic, particularly preferably povidone K25 is used according to the invention. It is also possible to use polyvinylpyrrolidone derivatives known in the field. The amount of polyvinylpyrrolidone used (for example, povidone K25) is preferably 1 to 10, particularly preferably 1.5 to 3.5% by weight based on the finished tablet.

It is necessary that the orodispersible effervescent tablet according to the invention present a pleasant taste. A substance is therefore added, which leaves a sweet taste when dissolved in the mouth. Since the use of sucrose can be disadvantageous, an alternative sweetener is used. This is sucralose. In the case of sucralose, it is sucrose, with hydroxyl radicals substituted by chlorine atoms. Sucralose is compared to sucrose clearly more sweet. However, the conditions of preparation and the other components of the orodispersible effervescent tablet must be adjusted in such a way that there is no disintegration of sucralose, which could lead to unwanted colorations. In the orodispersible effervescent tablet the proportion of sucralose is preferably between 0.1 and 1.0% by weight, particularly preferably between 0.2 and 0.6% by weight, based on the finished tablet.

Another component preferably used of the orodispersible effervescent tablet is sodium docusate. In this case it is a white wax substance, which is used as a solubilizing agent and emulsifying agent in particular for the active ingredient budesonide. The amount of sodium docusate is preferably between 0.01 and 0.2% by weight, particularly preferably between 0.02 to 0.15% by weight based on the finished tablet.

Another excipient preferably used is mannitol. In the case of the mannitol used according to the invention, it is treated in a preferred embodiment of a solid polymorphic crystalline substance. The two most common characteristic modifications are p- and a-mannitol, which are also referred to as modifications I and II. As an additional modification, 5-mannitol has also been described. For the preparation of orodispersible effervescent tablets according to the invention, the properties of the excipients, in particular of mannitol, must meet particular requirements. On the one hand it is necessary that the powder mixtures have a good flow capacity in the preparation, on the other hand optimal compatibility is essential, that is, the ability to form tablets with high resistance in case of reduced pressure force. The distribution of particle size of individual mannitol crystals may be central in this case. According to the invention, an amount of 2.0 to 10.0% by weight is preferably used, particularly preferably 4.0 to 7.0% by weight of mannitol based on the finished tablet.

Another important excipient, which is preferably used according to the invention, are polyethylene glycols. In a preferred embodiment, macrogol 6000 is used in an amount of 1.0 to 10% by weight, preferably 2.0 to 7.0% by weight based on the finished tablet.

Another preferred excipient component is magnesium stearate, which is preferably used in an amount of 0.01 to 0.5% by weight, particularly preferably in an amount of 0.05 to 0.15% by weight.

The components, which achieve the effervescent effect, represent in terms of weight the main part of the orodispersible effervescent tablet. In this case it is treated in a preferred embodiment of a mixture of disodium citrate, monosodium citrate, as! like baking soda. This effervescent mixture represents a weight ratio of about 70 to 95% by weight, preferably 85 to 92% by weight, based on the finished orodispersible effervescent tablet. The particle form of the components of the effervescent mixture is decisive above all for the mechanical properties of the orodispersible effervescent tablet. Therefore, from among the qualities of the individual components available on the market, those that can be compressed when interacting with the other excipients and with the pharmaceutically active ingredient budesonide must be selected, so that the properties of the finished bucodispersible effervescent tablet can be achieved , in particular the breaking strength and friability required.

Naturally, all components of the orodispersible effervescent tablet must be 100% by weight when added.

The orodispersible effervescent tablet according to the invention can preferably be used for therapy, but also for the prevention of inflammatory modifications of the esophagus. The formulation according to the invention enables a continuous active ingredient release pleasant for the patient, which is distributed particularly evenly over the esophagus. The active substance budesonide is therefore carried precisely and efficiently topically to the inflamed places of the esophagus. Particularly preferred orodispersible effervescent tablets are used according to the invention for the therapy of eosinophilic esophagitis.

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Preferred embodiments of the present invention are clarified by the following examples.

Example 1:

It has been surprisingly seen that physical-chemical stability of effervescent budesonide tablets of up to 36 months can be achieved, as well! as the quality parameters relevant to the use of the effervescent tablet, such as size, shape and mechanical stability, by means of the qualitative and quantitative compound indicated in table 1.

Particularly preferred concentration indications of the components preferably used according to the invention are reproduced in Table 1. The values ​​indicated in the table must not be kept completely accurate. However, the essential components and the proportions of the individual components are decisive for the advantageous properties of budesonide effervescent tablets orodispersible according to the invention.

Table 1: Composition of preferred orodispersible budesonide effervescent tablets

Composition [mg]

Budesonide 0.5 mg Budesonide 1 mg Budesonide 2 mg

compressed compressed tablet

effervescent effervescent effervescent

Granulated

Budesonide 0.501,002.00

Disodium citrate67,0067,0067.00

Monosodium citrate15,0015,0015.00

Baking Soda45,0045,0045.00

Povidone K252,002,002.00

Sucralose0,300,300.30

Sodium docusate 0.050.0550

Sum129,85130.35131.35

Final mix

Mannitol5,955,955.95

Macrogol 60005,005,005.00

Magnesium stearate0,100,100.10

Sum140,90141.40142.40

Example 2:

The results of the durability tests of effervescent tablets of budesonide 1 mg in different storage conditions are shown in Table 2. Compared to the initial values, it was not possible to see relevant modifications even in case of storage under load test conditions. .

Table 2: stability results of budesonide effervescent tablets 1 mg

Storage period at 25 ° C / 60% relative humidity in months

Initial369121824

Breaking strength [N] 36333535363635

Water disintegration [minutes] 1.31.41.31.81.51.42.9

Budesonide content [%] 101,499,5100,0100,799,599,998.0

Total impurities [%] <0.10,130,110,120,130,190.22

Storage period at 30 ° C / 65% relative humidity in months

Initial3691218

Breaking strength [N] 363734363428

Water disintegration [minutes] 1.31.71.51.71.72.9

Budesonide content [%] 101,4100,599,6100,098,197.3

Total impurities [%] <0.10,130,120,150,180.40

Storage period at 40 ° C / 75% relative humidity in months

Initial123

Breaking strength [N] 36213638

Water disintegration [minutes] 1,30,91,71.8

Budesonide content [%] 101,4100,2100,699.5

Sum of total impurities [%] <0.10,140,270.39

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Example 3

In comparison with the starting values, above all, no relevant modifications are shown in case of storage under the conditions of the climatic zone 2. On the contrary, the results of table 3 have shown that with only a minimum deviation of this formulation (for example , replacement of 0.40 mg of sucralose with 1.0 mg of aspartame) The long-term stability of effervescent tablets of budesonide of 1 mg is no longer given. As the failed test clarifies in a shocking way, the degradation of budesonide increases after a comparatively long storage period at the rate of, for example, a factor of for example 7. Since this degradation is clearer even in case of dosages of less than 1 mg budesonide, the physical-chemical stability of the effervescent tablet is preferably given with the qualitative and quantitative composition indicated in Table 1. In case of less than 1 mg of budesonide per effervescent orodispersible tablet the instability is even clearer.

Table 3: missing stability of budesonide effervescent tablets of 1 mg orodispersible with modified composition

Storage period at 25 ° C / 60% relative humidity in months

Initial369121827

Budesonide content [%] 98,699,7101,199,898,996,895.7

Sum of total impurities [% 1 <0.10,310,660,860,811,051.63

Storage period at 30 ° C / 65% relative humidity in months

Initial36912

Budesonide content [% 198,6100,1100,499,498.2

Sum of total impurities [% 1 <0.1 <0.10,911,011.31

In this test, 0.4 mg of sucralose was replaced by 1.0 mg of aspartame.

Example 4:

Clinical data: In a placebo-controlled, randomized, double-blind, multicenter phase II study of 4 branches, effervescent budesonide tablets of 2 x 1 mg / dla or 2 x 2 mg / dla were compared with a budesonide suspension 2 x 2 mg / dla oral viscose or placebo in the treatment of active eosinophilic esophagitis. Blinding was guaranteed by using the double simulation method. The objective of the study was to show the superiority of budesonide formulations over placebo. The first primary partial endpoint of this study was the rate of histological remission, and the average eosinophils (eos) of patients in remission must reach an average of <16 eos / mm2 hpf (high power field) increase, that is, the field visible in the microscope with an increase of 400x) after two weeks of treatment. As the second primary partial endpoint, the difference in the average eos / mm2 hpf between the start of the study and the end of treatment was measured. Both described efficacy parameters were confirmed in a closed test procedure, to enable a comparison of the three study groups. The design of this study, including the described endpoints, is almost identical to the study described in the Straumann publication, 2010, already indicated.

Surprisingly, the results of the three test formulations were not only significantly better than in the case of placebo, but also better than in the case of budesonide formula, which is described in the work of Straumann et al., 2010, and indicated, with the dosage 2 x 1 mg / dla this result is significant.

Table 4 shows the results of histological remission, defined as an average of patients <16 eos / mm2 hpf, who completed the study prematurely, without having produced a subsequent histological study, analyzed as patients who are not in remission. In a sensitivity analysis, only those patients who completed the study were analyzed.

Table 4: Histological remission

Number (%) of patients, who have a histological remission

BUU-2 / EEAStraumann (2010 already mentioned)

Budesonide Budesonide PlaceboBudesonide Placebo

2x1 mg 2x2 mg2x1 mg

compressed tablets

FAS

At wk 12 **

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(LOCF) ITT ((last observation made) intention of 19/19 (100%) 18/19 (95%) 0/19 (0%) 13/18 (72%) 2/18 (11%)

treat) [95% RCI] [64.7%; 100 [57.6%; 99.5NA

%]%]

I P value * <0.0001 <0.0001— <0.0001—

PPAt wk 12 ** (LOCF) ITT19 / 19 (100%) 17/17 (100%) 0/17 (0%)

[95% RCI] [63.1%; 100 [61.3%; 100 ---------

%]%]

P value * <0.0001 <0.0001 ---------

Histological remission defined as <5 eos / hpf (corresponding to <16 eos / mm2 hpf)

FAS, Full Analyze Set (complete analysis group); PP, Per-Protokoll Analyze Set (protocol analysis group); RCI, repeated reliability interval (for the difference between study group and placebo)

* for superiority of the study group with respect to placebo

** At wk 12, in 12 weeks_______________________________________________________________

Also for the co-primary endpoint analysis, superiority could be shown compared to placebo (Table 5). (Comparison with Straumann is not possible, since this endpoint was not evaluated in the case of Straumann).

Table 5: difference in average eos / mm2 hpf (FAS)

Budesonide 1 mg tablet (n = 19) Budesonide 2 mg tablet (n = 19) Budesonide 2 mg suspension (n = 19) Placebo (n = 19)

Average (SD) -119,919 (79,275) -128,120 (78,457) -96,665 (124,253) -7,882 (157,939)

nn = 19n = 18n = 18n = 19

P-value * 0.00060,00050.0041—

* For superiority of study group with respect to placebo

Additionally, it could be shown for all study groups that the eosinophilic load could be almost completely eliminated in all esophageal segments (in a range of 0.2-2.7 eos / mm2 hpf). This result confirms that the pharmaceutical formulation according to the invention distributes the specific active ingredient of esophagus throughout the esophagus. This is represented in figure 1.

Figure 1 shows the average eosinophilic load in the corresponding esophageal segment. The esophagus was divided into proximal, central (mid) and distal. The amount of those syphilophils / mm2 hpf averaged was indicated. The abbreviation EOT stands for "End of Treatment."

Example 5:

In addition to the effectiveness described in the histology, it could be demonstrated that a two-week treatment with the formula according to the invention also leads to a statistically significant and clinically relevant improvement of eosinophilic esophagitis in relation to the endoscopic image. This is represented in figure 2.

An average endoscopic activity result is reproduced in Figure 2. The abbreviation BUET means effervescent tablet with budesonide orodispersible content (from German Budesonid enthaltende Brausetablette). The abbreviation 2x1 mg means double administration of respectively one tablet with 1 mg of active ingredient. The abbreviation 2x2 mg means the double daily administration of an orodispersible tablet with 2 mg of active substance. Baseline means initial situation, EOT means “End of Treatment”. In this case Baseline means the first visit of the patient, in which it begins with the treatment and EOT is the last visit of the treatment. Since the LOCF principle is always used (from English last observation carried forward, last observation made), the EOT visit can occur at different times, but always with all the test parameters of the last visit according to the patient's protocol.

Example 6:

The orodispersible effervescent tablets according to the invention with 2 mg budesonide per tablet were administered in a study to a group of patients aged between 20 and 50 years. Patients were treated in a test group with a budesonide table of 2 mg per day. The control group obtained an orodispersible effervescent tablet with no active substance (placebo). During a 15-day treatment it was found that the effervescent tablet with orodispersible budesonide content was well tolerated and that

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markedly improved histological and clinical parameters, unlike the placebo group. The orodispersible effervescent tablet was evaluated by all test subjects as positive in relation to its use.

Example 7:

In additional tests, seric markers / biomarkers were identified for the supervision and verification of the response to therapy of a drug treatment of eosinophilic esophagitis (EoE). EoE patients were included in the clinical study, who had obtained a topical steroid treatment (the orodispersible effervescent tablet according to the patent). Different seric markers were checked in relation to their suitability, to verify to what extent the response to therapy and the success of the therapy were correlated with differences of these seric markers. The sample material for the serial samples is based on the clinical study described in the patent application (example 4).

The "cationic protein of the eosinophil ECP" has been particularly suitable as a marker. In this case it is a cytocyclic protein, which is released from the eosinophilic granulocyte activated in the granulate (Rothenberg, Gastroenterology 2009, 1238-1249). It is known that this protein appears to be suitable for the control of the response to therapy under Fluticason topico (Schlag et al., J Clin Gastroenterol. 2014, 600-606).

It has been surprisingly seen that the EPC not only reflects the clinical results. In addition to the clear correlation between the histological remission and the broth of the ECP seric level during the 2-week treatment with 1 or 2 mg of budesonide effervescent tablets orodispersible, a long-term success in the therapy could also be seen after the end of the 2-week treatment . This is represented in Figure 3 (right image relative to “Follow-up Phase, FU”, follow-up phase; duration of FU: 2 weeks).

An additional effect follows from the experiments carried out. The formulation according to the invention is also suitable for effective treatment, also to achieve a lasting clinical effect after the end of therapy. There is no rebound effect often observed when a medication therapy measure ends.

Example 8:

Concretion of the long lasting effect

Based on additional tests, the lasting clinical effect can be shown by representing the result of dysphagia at the time of subsequent observation free of treatment. This instrument, the so-called result reported by the patient, documents the frequency of dysphagia episodes from 0 (no episode) to 4 (several episodes a day), as! such as the intensity of these episodes from 0 (without swallowing difficulties) to 5 (long-term complete obstruction that requires endoscopic intervention). The results of the BUU2 study show for this result that the treatment effect, measured as mean modification (in%), between the last treatment and the end of the subsequent observation time in the test groups (1 mg and 2 mg budesonide ) it keeps. In both groups this modification is negative, that is, the result has improved from a higher value to a lower one. In the placebo group this value has clearly worsened with +25%. The results of these tests are gathered in Figure 4.