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

Description For the treatment of inflammatory processes and changes in the esophagus, such as eosinophilic esophagitis, a pharmaceutical form is required, which after oral administration allows the local availability of the active substance budesonide in a sufficiently high concentration at the site of inflammation. This concept, which is called targeted release in the esophagus or. esophagus, is not possible by oral administration of a simple solution of the active substance because there is a high risk that the active substance is swallowed rapidly and approximately quantitatively so that it reaches the stomach. Targeted release in the esophagus or. the esophagus should therefore be achieved by allowing the active substance to slide slowly down the esophageal mucosa associated with complete wetting of the surface as well as adhesion of the active substance. This method of administration deliberately brings the active substance to the site of action. Furthermore, it should be taken into account that the therapeutic treatment of esophagus requires additional conditions in terms of pharmaceutical form, depending on which patient population needs to be treated. The present invention is particularly suitable for providing an age-appropriate pharmaceutical form which can be administered simply and reliably to adult patients and thus achieves a high quota for adherence to the prescribed daily dose ("Compliance").

Eosinophilic esophagitis is a chronic, inflammatory disease of the esophagus with limited esophageal function (esophagus) and characterized by infiltration of the esophageal epithelium with eosinophilic granulocytes. Eosinophilic esophagitis has been rarely described since the late 1970s, and has been increasingly diagnosed in the late 1990s. There appears to be a Th2-cell-mediated response to aerogens and induced allergens, leading to the distribution of IL-13, IL-5, and subsequently increased eotaxin-3 production. In this way, eosinophilic granulocytes are attracted. Clinically, long-term dysphagia, as well as bolus impaction, often come to the fore. Diagnosis normally requires confirmation of> 15 eosinophils / high power field in the esophagus in patients who have symptoms of impaired esophageal function. In some patients, only changes in the mucosa can be noticed that are easy to overlook. Eosinophilic esophagitis mainly affects men, and it occurs more often in both children and young adults.

WO 2009/064417 discloses compositions for the treatment of gastrointestinal inflammation. The compositions described therein include a corticosteroid and at least one additional agent for treating inflammation. WO 2009/064457 discloses compositions comprising a corticosteroid, which are suitable for the treatment of inflammation of the gastrointestinal tract.

US 2007/0111978 describes a method for alleviating inflammatory diseases of the gastrointestinal tract. The production of a highly viscous solution from a suspension of budesonide with a very high concentration of sucralose is proposed. US 2009/0264392 describes a method and compositions, which are suitable for the treatment of eosinophilic esophagitis. This method uses a steroid and an agent that adheres to the mucous membrane.

EP 2 151 235 A1 discloses pharmaceutical formulations, namely effervescent budesonide tablets but not orodispersible tablets.

US 2007/0020330 relates to pharmaceutical compositions, which always contain azelastine and one or more steroids as antihistamines and antiasthmatics.

58112 The object of the present invention is to provide pharmaceutical formulations which, on the one hand, have an advantage in administration and, on the other hand, can be well manufactured and provided in a form which is stable for storage.

The present invention relates to pharmaceutical formulations, in particular effervescent tablets for orodispersible administration, which comprise as a pharmaceutically active substance budesonide or a pharmaceutically acceptable salt or derivative thereof and is preferably administered to adults for the treatment of inflammatory diseases of the esophagus.

It is generally known to administer effervescent tablets, which, after dissolving in water, are used as a solution for drinking or rinsing. This application of the active substance in the described indication has various disadvantages, such as the use of a larger volume of water (usually 250 ml) and the associated dilution of the active substance or. distribution of the total active substance in the entire oral cavity, as well as rapid ingestion of the solution into the stomach, which is usually practiced. The use of budesonide in eosinophilic esophagitis is also known (Straumann et al., Gastroenterology, 2010, pp. 1526-1537). However, liquid ampoules, so-called "respules", are destined to be used in inhalation in this study, where the contents of the ampoule are pre-filled into a nebulizer and then inhaled. Deviation from this intended use was applied in the cited study in which a suspension of budesonide in an ampoule was used as a drinking solution.

The effervescent tablet according to the invention does not dissolve in water before administration and is therefore clearly different from the usual route of administration of effervescent tablets. The sum 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 on the tip of the tongue, and dissolves slightly under the influence of saliva in the mouth. Thus, the orodispersible effervescent tablet according to the invention clearly differs from the known formulations in terms of composition and shape.

The orodispersible effervescent tablet according to the invention may also be called a lingual effervescent tablet, since it should preferably come into contact with the tongue when administered. The abbreviated form of the formulation can also be called BUL (= lingual effervescent tablet containing budesonide).

Orodispersible administration of an effervescent tablet is a special form of administration, in which the tablet as such is administered orally and placed on the tongue, preferably on the tip of the tongue, and after closing the mouth lightly rests on the entire palate. In this way, an effervescent reaction is initiated and the flow is accelerated within 5-15 seconds. The components of the tablet begin to dissolve in the saliva. With the natural swallowing reflex, the saliva is then partially swallowed and the esophagus is constantly moistened, so that in this way budesonide adheres to the mucous membrane. During the disintegration of the effervescent tablet, the patient swallows an average of 5-10 times, so that the esophagus is constantly moistened with saliva that contains the active substance. The effervescent tablet completely disintegrates and no noticeable parts remain. It is not necessary to drink additional liquids because it does not cause drinking irritation. The advantage of the optimized formulation is therefore that it is not necessary to drink additional fluid, and thus ensures a sufficiently long survival of the therapeutically active substance budesonide in the relevant parts of the esophagus. The administration is completed after 1.5 to 2 minutes and allows a concentrated distribution of budsonide per unit. The distribution of the active substance within the esophagus on the esophageal mucosa is done exclusively by saliva. The wide spread of budesonide inside the oral cavity is also avoided. The orodispersible effervescent tablet according to the invention can very easily be taken by the patient at appropriate intervals.

The orodispersible effervescent tablet according to the invention is administered during administration to the patient's oral cavity, where it disintegrates very rapidly into a large number of small particles. The orodispersible effervescent tablet according to the invention preferably does not only have the ability to disintegrate rapidly with a small amount of liquid, preferably without additional liquid consumption. An additional advantage is the acceptable taste and good feeling

58112 Β1 by mouth during application. Sufficient strength and high stability during storage, even at high temperatures with high humidity, are also desirable, as well as the possibility of giving larger amounts of the active substance budesonide. The orodispersible effervescent tablet according to the invention has a high mechanical stability, which is why subsequent processing, packaging and transport are not a problem. In particular, it should be noted that the orodispersible effervescent tablets according to the invention have improved long-term stability compared to known pharmaceutical formulations, as evidenced in Tables 2 and 3.

The use of an effervescent tablet according to the invention significantly reduces the risk of unwanted budesonide entering the systemic circulation. So that no buccal or sublingual administration of the pharmaceutical form is performed. In the case of predetermined use, the relevant amounts of budesonide are not taken over the oral mucosa. In relation to lozenges, which are also applied orodispersibly, the clear advantage is that the disintegration of the effervescent tablet allows continuous release of the active substance for 1.5 to 2 minutes and thus topical application to the mucous membrane of the esophagus. Lozenges for application have the disadvantage that they disintegrate immediately and can therefore be taken in one gulp. At the same time, effervescent tablets are easier to produce industrially. The present invention therefore relates to orodispersible effervescent tablets containing 0.25 to 5 mg of budesonide, preferably 0.3 to 4 mg, particularly preferably 0.4 to 3 mg and particularly preferably 0.5 to 2.0 mg of budesonide according to the patent requirements. The budesonide used can be used in any pharmaceutically acceptable form. The indicated amount shows the total amount of the active substance budesonide in the orodispersible effervescent tablet. In a preferred embodiment, the orodispersible effervescent tablet according to the invention does not contain an additional pharmaceutically active substance.

An essential component of an orodispersible effervescent tablet is a system that generates gas in the presence of saliva, in order to achieve an effervescent effect. It is assumed that this gas generating system is pharmaceutically acceptable. Such a gas-generating system consists on the one hand of a weak acid or. weak acid salts. In the presence of water, free weak acid is formed from it. However, the acid should not be too strict, in order to avoid health consequences. This can be tartaric acid, acetic acid, lactic acid, and especially preferably citric acid. Acid salts are usually used, ie salts of sodium, magnesium and calcium. Another component of the gas-generating system consists of acid salts, which in conjunction with additional acid can release gas. These are preferably salts of carbonic acid. These are hydrogen carbonates or carbonates, such as, for example, sodium or potassium carbonate or sodium or potassium bicarbonate or calcium carbonate, as well as mixtures of these salts. The essence is to be a health-safe gas, namely CO₂, releases in small amounts when taking an effervescent tablet. Gas is released by the interaction of gas-producing components and saliva.

The orodispersible effervescent tablet according to the invention has a weight of between 100 mg and 200 mg, preferably the orodispersible tablets have a weight of 120 mg to 160 mg. Particularly preferred embodiments of the orodispersible tablet have a weight of 133 mg to 147 mg.

Dimensions of the effervescent tablet according to the invention are also important. Preferably the effervescent tablets have a diameter of between 5 and 10 mm. It is desirable that the effervescent tablets are round, and it is not necessarily necessary for them to be completely circular. Deviations from the circular shape can also be selected. Effervescent biplan tablets are preferred, with a diameter preferably between 6.0 and 8.0 mm and 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 particularly particularly between 1.8 and 2.6 mm.

58112 00 As for the mechanical properties of orodispersible effervescent tablets, they are essential. The crushing resistance preferably lies between values ​​of 10 and 100 N, particularly preferably between 20 N and 70 N and is preferably determined by the European Pharmacopoeia in accordance with monograph 2.9.8.

When checking the mechanical strength of the tablets, a solid sample is stretched between two hammers or between a hammer and an anvil. Then a force is applied to the sample (tablet) and the force necessary to achieve the crushing of the tablet is determined. Determination of the crushing resistance of orodispersible effervescent tablets can be performed with fully automatic test devices. Such test systems are offered, for example, by the company Pharmatest under the name WHT ZME. Of course, the same test devices can be used.

The desired resistance to crushing on the one hand allows good reproducible industrial production but also sufficient mechanical stability. According to the invention, orodispersible effervescent tablets have a friability (abrasive strength) of a maximum of 5%, preferably a maximum of 1%. Friability (abrasive strength) is preferably determined according to the European Pharmacopoeia in accordance with monograph 2.9.7.

The shape, consistency and mechanical properties of the orodispersible effervescent tablet are essential because the size and shape on the one hand allow for continuous and relatively even disintegration in the presence of saliva. On the other hand, they allow sufficient mechanical stability, so that the effervescent tablet does not crumble prematurely during the intended application and thus does not prevent the application according to the invention. The properties of orodispersible tablets have the consequence that there is no feeling of a foreign body in the mouth, and that the patient subjectively perceives the application as pleasant.

The effervescent tablet features described in the preferred embodiment allow for variable administration of individual doses of budesonide in an amount of preferably 0.5 to 3 mg of budesonide. The processed amount of active substance does not affect the quality parameters, which are described and relevant for the application, such as size, shape and mechanical stability. It is not necessary to divide the tablet, but one tablet corresponds to one dose.

The lower the dose of budesonide in the effervescent tablet, the greater the requirements for selecting appropriate excipients to ensure sufficient long-term stability of the drug. Adverse drug degradation would be particularly undesirable if low doses are given because then there would not be a sufficiently pharmaceutically sufficient amount of the active substance in the tablets. It has surprisingly been shown that the physicochemical stability of budesonide in an effervescent tablet can only be achieved with the compounds of the invention. Even when the individual excipients belong to the prior art effervescent tablets, long-term drug stability of up to 36 months is possible only with the qualitative and quantitative composition according to the invention for all dosage doses of budesonide effervescent tablets for orodispersible administration. The co-tablets according to the invention can be stored at room temperature.

In a preferred embodiment, the orodispersible effervescent tablet according to the invention comprises polyvinylpyrrolidone. These are vinylpyrrolidone polymerization products. Low molecular weight polyvinylpyrrolidones are hygroscopic, povidone K25 is particularly preferably used according to the invention. It is also possible to use known polyvinylpyrrolidone derivatives in the field. The amount of polyvinylpyrrolidone used (for example povidone K25) is preferably 1 to 10, particularly preferably 1.5 to 3.5 weight percent relative to the finished tablet.

Preferably, the orodispersible effervescent tablet according to the invention has a pleasant taste. Therefore, a substance is added that has a sweet taste in the mouth during dissolution. Since the use of sucrose can have disadvantages, an alternative sweetener is used. It's called sucralose. Sucralose is sucrose, where hydroxyl residues are replaced by chlorine atoms. Sucralose is much sweeter than sucrose. However, the conditions during production and other components of the orodispersible tablet must

58112 Β1 be adjusted so as not to degrade sucralose which could lead to unwanted discolorations. In the orodispersible effervescent tablet, the proportion of sucralose is preferably between 0.1 and 1.0 weight percent, particularly preferably between 0.2 and 0.6 weight percent, relative to the finished tablet.

Another component of the orodispersible effervescent tablet, which is preferably used, is sodium docusate. This is a white wax-like substance, which is used as a solubilizer and emulsifier, especially for the active substance budesonide. The amount of sodium docusate is preferably between 0.01 and 0.2 weight percent, particularly preferably 0.02 to 0.15 weight percent relative to the finished tablet.

Another preferred excipient is mannitol. The mannitol used according to the invention is, in a preferred embodiment, a polymorphite crystalline solid. The two most common modifications are β- and α-mannitol, which are also referred to as modifications I and II. B-mannitol has already been described as an additional modification. For the production of orodispersible effervescent tablets according to the invention, the properties of excipients, in particular mannitol, must meet special requirements. On the one hand, it is necessary that the powder mixtures have a good ability to flow, and on the other hand, optimal compatibility is important, ie the ability to form tablets with minimal pressure. The particle size of individual mannitol crystals can play a central role here. According to the invention, an amount of 2.0 to 10.0 weight percent is preferably used, particularly preferably 4.0 to 7 weight percent mannitol relative to the finished tablet.

An additional essential excipient, which is preferably used, is polyethylene glycols. In a preferred embodiment, Macrogol 6000 is used in an amount of 1.0 to 10 weight percent, preferably 2.0 to 7.0 weight percent relative to the finished tablet.

One additional preferred auxiliary component is magnesium stearate, which is preferably used in an amount of 0.01 to 0.5 weight percent, particularly preferably in an amount of 0.05 to 0.15 weight percent.

The components that achieve the effervescent effect are, in terms of weight, the main part of the orodispersible effervescent tablet. Here, in a preferred embodiment, it is a mixture of disodium citrate, monosodium citrate as well as sodium hydrogen carbonate. This effervescent mixture represents a weight fraction of about 70 to 95 weight percent, preferably 85 to 92 weight percent relative to the finished orodispersible effervescent tablet. First of all, the particle shape of the components of the effervescent mixture is important for the properties of the orodispersible tablet. Therefore, the commercially available qualities of the individual components must be selected, which in combination with other excipients and the pharmaceutically active substance budesonide will be able to be compressed to achieve the properties of the finished orodispersible tablet, in particular the desired crushing strength and friability.

Of course, all components of the orodispersible tablet must be pooled to give 100 weight percent.

The orodispersible effervescent tablet according to the invention can preferably be used for the therapy but also for the prevention of inflammatory changes of the esophagus. The formulation according to the invention allows the patient to pleasantly continuously release the active substance, which is relatively evenly distributed on the esophagus. The active substance budesonide is thus applied in a targeted and effective manner to the inflamed parts of the esophagus. Particularly preferably, the orodispersible tablets of the invention are used in the treatment of eosinophilic esophagitis.

Preferred embodiments of the present invention are illustrated in the following examples.

58112 ΒΙ

Primer 1:

Surprisingly, it has been found that the physicochemical stability of budesonide effervescent tablets up to 36 months, as well as qualitative parameters for the effervescent tablet application such as size, shape and mechanical stability can be achieved by the qualitative and quantitative composition shown in Table 1.

Table 1 shows particularly preferred data on the concentration of components used according to the invention. The values ​​shown in the table do not necessarily have to be observed. The essential components and the interrelationships of the individual components are, however, essential to the desirable properties of the budesonide orodispersible effervescent tablet according to the invention.

Table 1: Composition of preferred orodispersible effervescent budesonide tablets

<td colspan="4">Composition [mg]</td>

<td></td><td>Budesonide 0.5 mg Suspended tablet</td><td>Budesonide 1 mg Suspended tablet</td><td>Budesonide 2 mg Suspended tablet</td>

<td colspan="4">granules</td>

<td>Budesonid</td><td> 0,50</td><td> 1,00</td><td> 2,00</td>

<td>Dinatrijumcitrat</td><td> 67,00</td><td> 67,00</td><td> 67,00</td>

<td>Mononatrij umcitrat</td><td> 15,00</td><td> 15,00</td><td> 15,00</td>

<td>N sodium hydrocarbonate</td><td> 45,00</td><td> 45,00</td><td> 45,00</td>

<td>Povidone K25</td><td> 2,00</td><td> 2,00</td><td> 2,00</td>

<td>Sukraloza</td><td> 0,30</td><td> 0,30</td><td> 0,30</td>

<td>Dokusat-sodium mind</td><td> 0,05</td><td> 0,05</td><td> 0,05</td>

<td>Sum</td><td> 129,85</td><td> 130,35</td><td> 131,35</td>

<td colspan="4">The final mixture</td>

<td>Manitol</td><td> 5,95</td><td> 5,95</td><td> 5,95</td>

<td>Macrogol 6000</td><td> 5,00</td><td> 5,00</td><td> 5,00</td>

<td>Magnesium umstearate</td><td> 0,10</td><td> 0,10</td><td> 0,10</td>

<td>Sum</td><td> 140,90</td><td> 141,40</td><td> 142,40</td>

Primer 2:

The results of the study regarding the shelf life of effervescent tablets with 1 mg budesonide in different storage conditions are shown in Table 2. Compared to the initial values, even when stored under adverse conditions, no relevant changes were shown.

58112 ΒΙ

Table 2: Stability results for effervescent tablets with 1 mg budesonide

<img file="RS58112B1_D0001.tif" />

Primer 3:

Compared to the initial values, especially during storage in the conditions of climate zone II, no relevant changes are shown. In contrast, the results in Table 3 showed that even with minimal deviation from this formulation (e.g., replacement of 0.40 mg of sucralose with aspartame 1.0), the long-term stability of effervescent tablets with 1 mg of budesonide was no longer given. As a failed attempt shows, when the formulation is changed, the decrease in budesonide during the same storage time increases by a factor of 7. Since this decrease in budesonide doses less than 1 mg is even more pronounced, the physicochemical stability of the effervescent tablet is preferably given

58112 ΒΙ with the quantitative composition listed in Table 1. In the case of orodispersible effervescent tablets containing less than 1 mg, budesonidanestability is even more pronounced.

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

<td></td><td colspan="7">Storage duration at 25 ° C / 60% relative humidity by months</td>

<td></td><td>Initial</td><td> 3</td><td> 6</td><td> 9</td><td> 12</td><td> 18</td><td> 27</td>

<td>Budesonide content [%]</td><td> 98,6</td><td> 99,7</td><td> 101,1</td><td> 99,8</td><td> 98,9</td><td> 96,8</td><td> 95,7</td>

<td>Sum of total impurities [%]</td><td> &lt; 0,1</td><td> 0,31</td><td> 0,66</td><td> 0,86</td><td> 0,81</td><td> 1,05</td><td> 1,63</td>

<td></td><td colspan="7">Storage duration at 30 ° C / 65% relative humidity by months</td>

<td></td><td>Initial</td><td> 3</td><td> 6</td><td> 9</td><td colspan="3"> 12</td>

<td>Budesonide content [%]</td><td> 98,6</td><td> 100,1</td><td> 100,4</td><td> 99,4</td><td colspan="3"> 98,2</td>

<td>Sum of total impurities [%]</td><td> &lt;0,1</td><td> &lt; 0,1</td><td> 0,91</td><td> 1,01</td><td colspan="3"> 1,31</td>

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

Primer 4:

Clinical data:

In a four-arm, double-blind, randomized placebo-controlled multicenter study, 2x1 mg / day or 2x2 mg / day of effervescent budesonide tablets were compared with 2x2 / day of an oral viscous suspension of budesonide or placebo in active eosinophilic esophagitis. Blank testing was provided using the "Double-Dummy" technique. The aim of the study was to show the advantage of budesonide formulations over placebo. The first primary endpoint was the rate of histological remission, with eosinophils (eos) of patients in remission reaching a mean number &lt;16 eos / mm2 hpf (high power field, ie field of view under a microscope with 400x magnification) after 2 weeks of therapy. The second endpoint was the measured difference in mean eos / mm² hpf between the start of the study and the end of therapy. Both of the described action parameters were affirmatively described in a closed-label assay procedure to allow comparison between all three verum groups with placebo grappa. The design of this study including the described endpoints is almost identical to the study described in Straumann et al., 2010 aaO.

Surprisingly, the results of all three test formulations were not only significantly better than placebo but were also significantly better than the budesonide formulation, described in Straumann et al., 2010 aaO, at a dose of 2x1 mg / day. the result is significant.

Table 4 shows the results of histological remission, defined as in medium &lt;16 eos / mm2 hpf. Patients who completed the study prematurely without subsequent histological examination were analyzed as patients who were not in remission. In the sensitivity analysis, only those patients who completed the study were analyzed.

58112 ΒΙ

Table 4: Histological remission

Number (%) of patients with histological remission

<td colspan="4">BUU-2 / EEA</td><td colspan="2">Straumann (2010 op. Cit.)</td>

<td colspan="2">budesonid 2x1 mg</td><td rowspan="2">budesonid 2x2 mg tableta</td><td rowspan="2">placebo</td><td rowspan="2">budesonide 2x1 mg suspension</td><td rowspan="2">placebo</td>

<td></td><td>tablet</td>

<td>FAS At wk 12**</td><td></td><td></td><td></td><td></td><td></td>

<td>(LOCF) HERE</td><td> 19/19 (100%)</td><td> 18/19(95%)</td><td> 0/19 (0%)</td><td> 13/18 (72%)</td><td> 2/18 (11%)</td>

<td>[95% RCI]</td><td> [64.7%; 100%]</td><td> [57.6%; 99.5%]</td><td> -</td><td>NA</td><td> -</td>

<td>p-valuc *</td><td> &lt; 0.0001</td><td> &lt; 0.0001</td><td> -</td><td> &lt; 0.0001</td><td> -</td>

<td colspan="3">PP</td>

<td>At wk 12“</td><td></td><td></td>

<td>(LOCF) HERE</td><td> 19/19(100%)</td><td> 17/17(100%)</td>

<td>[95% RCI]</td><td> [63.1%; 100%]</td><td> [61.3%; 100%]</td>

<td>p-value *</td><td> &lt; 0.0001</td><td> &lt; 0.0001</td>

Histological emission defined &lt;5 eos / hpf (according to &lt;16 eos / mm² hpf) FAS, Full Analyze Set; PP, according to Protocol Analysis Set; RCI, Repeated confidence interval (as opposed to verum and placebo) * for the advantage of verum over placebo ”At wk 12, for 12 weeks For co-primary endpoint analysis, an advantage over placebo was shown. (Table 5). (Comparison with Strauman is not possible, because this endpoint has not been examined with Strauman)

<td></td><td>Budesonid 1 mg tableta (n=19)</td><td>Budesonid 2 mg tableta (n=19)</td><td>Budesonide 2 mg suspension (n = 19)</td><td>Placebo (n=19)</td>

<td>Prosek</td><td></td><td></td><td></td><td> -7.882</td>

<td></td><td> -119.919 (79.275)</td><td></td><td></td><td> (157.939</td>

<td>(SD)</td><td></td><td> -128.120 (78.457)</td><td> -96.665 (124.253)</td><td> )</td>

<td>n</td><td>n= 19</td><td>n= 18</td><td>n — 18</td><td>n — 19</td>

<td>p-value *</td><td> 0.0006</td><td> 0.0005</td><td> 0.0041</td><td> -</td>

for the advantage of verum over placebo ------------------------------------------ --------------------------------------------------- ------ 5 --------------- Table 5: Difference in mean eos / mm hpf (FAS) [0043] In addition, for all verum groups it was shown that in all segments of the esophagus, the load of eosinophils could be almost completely eliminated (in the range of 0.2-2.7 eos / mm² hpf). This result confirms that the pharmaceutical formulation according to the invention distributes the active substance throughout the esophagus. This is shown in Figure 1.

Figure 1 shows the mean eosinophil load in a particular segment of the esophagus. The esophagus is divided into the proximal part, the middle part (Mid) and the distal part. The mean number of eosin / mm is given²HPF. The abbreviation EOT means "End of Treatment".

58112 ΒΙ

Primer 5:

In addition to the described effect on histology, it could be shown that the formulation therapy according to the invention for two weeks leads to a statistically significant and clinically relevant improvement in eosinophilic esophagitis relative to the endoscopic picture. This is shown in Figure 2.

Figure 2 shows the mean endoscopic activity score. The abbreviation BUET means orodispersible effervescent tablet containing budesonide. The abbreviation 2x1 means double administration of one tablet with 1 mg of active substance. The abbreviation 2x2 means twice daily administration of an orodispersible effervescent tablet with 2 mg of active substance. Baseline means baseline, EOT means "kgaj therapy". Here, Baseline means the first visit of the patient at which he begins therapy, and EOT is the last visit during therapy. Since LOCF (Last observation carried forward) is always applied, EOT can occur at different times, but always with all test parameters of the last patient visit according to the protocol.

Primer 6:

Orodispersible effervescent tablets according to the invention with 2 mg budesonide per tablet were given during the study to a group of patients aged between 20 and 50 years. Patients were treated in the test group with a budesonide tablet of 2 mg per day. Control Grapa was given an orodispersible effervescent tablet without the active substance (placebo). During the 15-day treatment, the effervescent orodispersible budesonide tablet was found to be well tolerated and the histological and clinical parameters significantly improved compared to the placebo group. The orodispersible effervescent tablet was marked as positive in terms of use by all subjects.

Primer 7:

In further studies, serum / biomarkers were identified to control and verify the response to drug therapy for eosinophilic esophagitis (EoE). EoEpatients were admitted to the clinical study, who received topical steroid therapy (orodispersible effervescent tablet in accordance with the patent). Different serum markers were tested for their suitability in terms of how much the response to therapy and the success of therapy affect the changes of these serum markers. The test material for serum samples comes from the clinical study (Example 4) described in the patent application.

The "eosinophil cationic protein, ECP" has been shown to be a particularly suitable marker. This is a cytotoxic protein, which is released from granules of activated eosinophilic granulocytes (Ro ± enberg, Gastroenterology 2009, 1238-1249). This protein is known to be suitable for controlling the response to topical fluticasone therapy (Schlag et al., J Clin Gastroenterol. 2014, 600-606).

It has surprisingly been found that ECP does not only show clinical results. In addition to the apparent correlation between histological remission and declining serum ECP levels during treatment for two weeks with 1 resp. 2 mg with orodispersible effervescent tablets of budesonide has been shown to be a lasting success after two weeks of treatment. This is shown in Figure 3 (right view with Follow-up Phase, FU; FU duration: 2 weeks).

An additional effect can be derived from the performed experiments. The formulation according to the invention is, in addition to effective treatment, also suitable for achieving a lasting clinical effect after the end of therapy. There is no frequent Rebound-Effect when drug therapy is completed.

Primer 8:

Specifying the long-term clinical effect

58112 Β1 In additional experiments performed, a long-lasting clinical effect can be shown by showing the dysphagia score during the subsequent observation period without treatment. This instrument, the so-called patient reported outcome, documents the frequency of dysphagia events from 0 (no events) to 4 (several events per day) as well as the intensity of these events from 0 (no swallowing problems) to 5 (long-term, complete obstruction requiring endoscopic intervention). . The results of the BUU-2 study for this score show that the effect of therapy lasts, measured as the mean change (in%) between the last therapy and the end of the observation time in the verum groups (1 mg and 2 mg budesonide). In both groups, this change is negative, so the score improved from high to low. In the placebo group, this value worsened significantly with + 25.5%. The results of these tests are summarized in Figure 4.