Orally applicable suspension for the treatment of eosinophilic esophagitis in children

Abstract

Disclosed is an orally applicable suspension comprising a) topically acting micronized budesonide, b) an aqueous base, c) at least one viscosity-increasing agent selected from a methylcellulose or a derivative thereof, d) a buffering agent which allows the adjustment of the final suspension to a pH value of 3.5 to 4.5, e) an antimicrobial preservative, f) a suspension stabilizing agent, in particular ethylenediaminetetramethyl acetic acid, whereby the suspension has a dynamic viscosity in the range of 800 mPa*s to 2000 mPa*s and the final suspension contains a concentration of 0.1 mg / ml to 0.5 mg / ml budesonide for use in the treatment of eosinophilic esophagitis of a patient having an age of about 1 year to about 17 years whereby 0.5 to 1.0 mg budesonide are administered in 2.5 to 5.0 ml suspension once or twice a day.

Description

[0001] Orally applicable suspension for the treatment of eosinophilic esophagitis in children

[0002] Eosinophilic esophagitis (EoE) is a chronic immune / antigen-mediated disorder of the esophagus characterized histologically by eosinophil-predominant mucosal inflammation and clinically by symptoms of esophageal dysfunction. Its incidence in children has been increasing and is currently similar to that of pediatric inflammatory bowel disease (IBD). EoE involves progressive esophageal remodeling that can lead to esophageal dysmotility and strictures, if untreated. Therapeutic targets currently include improvement of symptoms, remission of histopathological features and prevention of long-term complications (Oliva et al., Digestive Diseases and Sciences (2019), 64; 1571-1578).

[0003] Topical corticosteroids (tCS), predominantly fluticasone and budesonide, are considered on the one hand the most effective first-line treatment and on the other hand an option for maintenance therapy in any line of EoE treatment. These drugs induce histological remission, lead to the resolution of clinical symptoms and prevent fibrosis. The way that topical corticosteroids are administered significantly affects their effectiveness. There is no commercially available steroid drug formulation to be applied topically to the esophagus in children. For adults with EoE, budesonide orodispersible tablets (i.e. Jorveza®) were recently designed. In children, however, swallowed metered-dose inhalers (MDI) steroids were used.

[0004] EP 3 834 819 describes the treatment of a six-year old male patient with oral prednisone and the treatment of a five-year old girl with Pulmicort® mixed with sucralose.

[0005] Clinical studies were limited to swallowing aerosolized or nebulized corticosteroid formulations that were developed for asthma. Dellon ES, Sheik O, et al. disclose that viscous topical therapy is more effective than nebulized steroid therapy for patients with eosinophilic esophagitis (Gastroenterology 2012; 143:321-324). For topical corticosteroid therapy of EoE in children and adolescents, fluticasone or budesonide was used. Budesonide was prepared as aqueous solution mixed with sucralose resulting in a viscous solution. Sometimes, instead of sucralose, Duocal® was used which is a viscous mixture of oil and glucose (ClaBen, Gastro-News 2017, 04(1), page 26).

[0006] For the treatment of children, in particular young children, it is difficult to find a pharmaceutical solution which is accepted by children and their caregivers and which provides the desired healing effects.

[0007] EP 2 886 121 discloses an aqueous suspension of budesonide having a pH of 4.0 to 5.0 which can be used for the treatment of eosinophilic esophagitis whereby a treatment for up to 2 weeks has been suggested. However, disadvantages caused by longer treatment with corticosteroids could be a bar speaking against long term treatment.

[0008] EoE is a chronic, immune / antigen-mediated disease characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation exclusively in the esophageal mucosa. The disease affects not only adults but also young children with 1 year and adolescents up to 18 years. The major challenge of the treatment of EoE is the identification and selection of a suitable dosage form that considers the physico-chemical characteristics of the active pharmaceutical ingredient and that facilitates its delivery to the affected areas of the esophagus after oral administration to ensure topical treatment, i.e. the drug product should be orally applied but locally acting in the esophagus. While these attributes of the dosage form are age-independent and apply to the entire patient population, there are special and critical features that are unique to the pediatric patient population. The general and critical features or quality attributes require the selection of a suitable age-appropriate pediatric dosage form providing the following characteristics:

[0009] • The age-appropriate pediatric dosage form must be accepted by the target population and their caregivers, in order to ensure compliance with the treatment regimen (“acceptability”).

[0010] • The age-appropriate pediatric dosage form must allow a flexible and safe dosing regimen that takes into account the developmental status of the various pediatric populations (“dosing flexibility”).

[0011] • The age-appropriate pediatric dosage form must deliver the active pharmaceutical ingredient to the target site of action, i.e. esophagus (..esophagus targeting") where it should be available to exert its efficacy („biopharmaceutical fitness”). • The age-appropriate pediatric dosage form must ensure a sustainable / lasting availability of the active pharmaceutical ingredient at the target site of action after swallowing the formulation considering that fractions of the dosage form which have moved into the stomach are lost to contribute to the efficacy of the active pharmaceutical ingredient (“sustainability”).

[0012] • The age-appropriate pediatric dosage form must be physically, chemically and microbiologically stable and manufacturable in order to be commercially viable (“commercial viability”).

[0013] Budesonide is a potent glucocorticosteroid with a high topical anti-inflammatory activity and with low systemic effects. It has been widely used as active pharmaceutical ingredient for the treatment of asthma or inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis. In addition, it is also used to treat EoE in adults.

[0014] On the other hand, it is well known that a treatment with a corticosteroid over longer periods may result in undesired side effects, including an increased dose to manage physical stress, steroid withdrawal syndrome, insomnia, mood changes, elevated blood pressure or blood sugar levels, gastrointestinal symptoms, to name only a few.

[0015] Different budesonide formulations and dosage forms that target the lung or different regions of the gastrointestinal tract have been developed over the last decades. They are already commercially available and marketed worldwide. However, none of these drug products can be considered as a suitable age-appropriate pediatric dosage form that meets the above- mentioned critical quality attributes in its entirety, and none of these drug products is suitable to treat eosinophilic esophagitis in children.

[0016] In addition, liquid and solid formulations are generally considered as the first choice when selecting an age-appropriate pediatric dosage form for oral administration. However, budesonide tends to be susceptible to chemical degradation in liquid and semi-solid formulations especially when not sufficiently stabilized. This strongly limits the number of potential age-appropriate pediatric dosage forms of budesonide. Therefore, and opposed to adults, children are currently excluded from a suitable treatment of eosinophilic esophagitis with a budesonide-containing drug product meeting all the required features. The major challenge of the development was the identification and selection of a suitable age-appropriate pediatric dosage form considering the physico-chemical properties of budesonide and meeting the core enabling criteria for appropriateness such as acceptability, dosing flexibility, esophagus targeting, biopharmaceutical fitness, sustainability and commercial viability.

[0017] From a stability point of view solid dosage forms are generally preferred over liquid dosage forms. Potential formulations are powders and granules, tablets or minitablets, orodispersible tablets, chewable or effervescent tablets and capsules. When administered to children, however, all these formulations will quickly pass the esophagus after swallowing and deliver budesonide predominantly into the stomach. Esophagus targeting, the essential criterion for the selection of a suitable dosage form to treat eosinophilic esophagitis will not be achieved in the target pediatric population.

[0018] It is an object of the present invention to provide a stable viscous suspension of budesonide which allows good treatment results, in particular high rates of remission which should be achieved with the use of a low concentration of budesonide. An important aspect thereby is that the viscous budesonide suspension provides improved adherence of the suspension containing the budesonide at the inflamed parts of the esophagus which are frequently located in the area where the esophagus enters the stomach.

[0019] A further object of the invention is to provide a suitable dosage regimen which helps to bring the young and vulnerable patients in remission and in a maintenance status without undesired side effects.

[0020] Surprisingly, a stable liquid dosage form of budesonide could be developed that overcame the described obstacles of the solid dosage forms. The especially preferred age-appropriate pediatric dosage form to target the esophagus is a highly viscous aqueous suspension of budesonide in a concentration of about 0.2 mg / mL that is presented in a 200 mL amber glass bottle (type III glass) as multi-dose container with a child-resistant closure (white LDPE screw cap with an internal colorless LDPE flow limiter). The required doses are withdrawn from the bottle using a suitable measuring device (i.e. oral syringe) that also allows flexible dosing. After first opening, the flow limiter remains in the bottle neck and enables the insertion of the oral syringe for withdrawal of the suspension. The drug product is stable under long-term storage conditions and provides a sufficiently long in-use stability after first opening.

[0021] Usually, an oral suspension comprises the suspended active pharmaceutical ingredient with defined characteristics in terms of crystallinity and particle size distribution, the viscosityincreasing agent that affects the physical stability of the formulation and the components of the outer phase of the suspension affecting the chemical stability, preservation, organoleptic properties and safety of the formulation. The invention comprises an aqueous oral suspension of the active pharmaceutical ingredient budesonide which is per se practically insoluble in water. As the vehicle is already saturated with dissolved budesonide, the undissolved drug particles are immediately available for dissolution after delivery to the esophagus.

[0022] The present invention in its broadest sense relates to the use of an orally applicable suspension for use for the induction and maintenance of remission in pediatric EoE patients comprising the following components:

[0023] A topically acting micronized crystalline glucocorticosteroide for the present invention is budesonide.

[0024] The orally applicable suspension is aqueous. The main component is therefore purified water which can be used for pharmaceutical purposes. Another very important component is a viscosity-increasing agent which is in the present case selected from methylcellulose or a derivative thereof. The methylcellulose preferably used in the present invention is a methyl ester of cellulose that contains about 20-50% of methoxy groups. Methylcellulose is soluble in water and a wide range of viscosity grades can be obtained depending on the average molecular weight range which is between 10000 and 220000 Da. Depending on the particular type of methylcellulose the amount required for obtaining a dynamic viscosity in the range of 800 mPa*s to 2000 mPa*s is added. The amount of the methylcellulose which is added to the solution is preferably less than 2% weight / weight. The viscosity is influenced by the length of the cellulose chain and the degree of methylation.

[0025] Methylcellulose is a nonionic water-soluble cellulose ether where some of the hydroxy groups of cellulose are substituted with methyl groups leading to methoxy groups. It is a pharmacopoeial excipient and described in the European Pharmacopoeia (Ph. Eur.), the Pharmacopoeia of the United States (USP) and other Pharmacopoeias. As partly O- methylated cellulose the content of methyl groups ranges from 26.0 per cent to 33.0 per cent. The average degree of substitution is 1.5 ranging from 1.4 to 2.0 so that on average one glucopyranose unit contains 1.5 methoxy groups. Methylcellulose is a polymer comprising numerous linked glucopyranose units with a mean chain length of 200 to 1000 and relative molecular weights of 20,000 to 150,000. The viscosity of methylcellulose solutions is related to the concentration and molecular weight of the polymer.

[0026] Different grades and viscosity specifications of methylcellulose are available. The manufacturers of the polymer usually classify the grades by the viscosity of 2% aqueous solutions measured at 20°C. Available grades and viscosity specifications are presented below:

[0027] • Methylcellulose, 4 mPa*s 3.2 - 4.8 mPa*s (range: 80 - 120%)

[0028] • Methylcellulose, 15 mPa*s 12.0 - 18.0 mPa*s (range: 80 - 120%)

[0029] • Methylcellulose, 25 mPa*s 22.0 - 30.0 mPa*s (range: 80 - 120%)

[0030] • Methylcellulose, 100 mPa*s 80 - 120 mPa*s (range: 80 - 120%)

[0031] • Methylcellulose, 400 mPa*s 320 - 480 mPa*s (range: 80 - 120%)

[0032] • Methylcellulose, 1500 mPa*s 1125 - 2100 mPa*; (range: 75 - 140%)

[0033] • Methylcellulose, 4000 mPa*s 3000 - 5600 mPa*; (range: 75 - 140%)

[0034] Methylcellulose dissolves in cold water giving a colloidal solution. Despite its insolubility in hot water, the hot water method is preferably used to prepare the colloidal solutions. After dispersing and wetting the polymer in hot water, the mixture is cooled down so that complete dissolution can be achieved that results in a clear solution. The invented budesonide 0.2 mg / mL oral suspension is preferably manufactured using methylcellulose grade 1500 mPa*s at a concentration of 20 mg / mL. However, adjustment of the visocsity can also be accomplished with other methylcellulose grades or with combinations or blends of different methylcellulose grades. Thus the preferred target viscosity of 1000 mPa*s (within the range of 800 to 1200 mP*s) of the drug product can be reliably adjusted.

[0035] Those methylcelluloses are usually used in the oral application suspension in a range from 10 mg / ml to 50 mg / ml, preferably 15 mg / ml to 25 mg / ml and most preferred 20 mg / ml.

[0036] The orally applicable suspension must have a well-defined pH value whereby two aspects have to be observed. On the one hand the pH must be in a range where the suspended budesonide is highly stable and on the other hand the pH must be in a range which is well accepted when the suspension is applied to the patient. Many buffers used for pharmaceutical formulations are systems comprising carbonates, citrates, tartrates and various phosphate salts. In the present case a citrate buffering system is especially preferred.

[0037] The orally applicable suspension also contains preservatives which prevent the growth of undesired microorganisms like bacteria or fungi in the suspension once it is opened for the first time. There is always a risk of microbial contamination by applying the syrup with a syringe. Therefore, a preservative is used in the present case which is well tolerable for the target patient group. Suitable antimicrobial preservatives for oral liquid formulations are sorbic acid or its potassium salt, benzoic acid or its sodium salt, parahydroxybenzoate esters (especially methyl and ethyl) or their sodium salts and ethanol. They are used alone or in combinations. However, the selection of a suitable antimicrobial preservative or combination of preservatives should be carefully conducted when used in pediatric formulations. In particular preferred is sodium benzoate.

[0038] The dissolved and undissolved budesonide are stabilized by adjusting the pH value of the aqueous continuous external phase to 3.5 to 4.5 and by adding the disodium salt of ethylenediaminetetraacetic acid (EDTA) as stabilizer to the outer phase. Under these conditions the chemical and microbiological long-term stability of the suspension can be ensured.

[0039] It is of utmost importance that the orally applicable suspension has an appropriate viscosity. The viscosity is measured according to the methods as described in the European Pharmacopeia [2.2.10], The viscosity ranges from 500 mPa*s to 2000 mPa*s, preferably from 800 mPa*s to 1200 mPa*s and particularly preferred to about 1000 mPa*s.

[0040] The concentration of the glucocorticosteroid is in the range of about 0.1 -1.0 mg / ml budesonide. Preferred ranges are from 0.1 -0.5 mg / ml whereby 0.2 mg / ml is particularly preferred.

[0041] In order to allow a good suspension of the glucocorticosteroid, the pharmaceutically active agents are applied in a micronized form. This is a particular treatment of the budesonide whereby at least 95% of the budesonide microparticles have a diameter of less than 10 pm. Particularly preferred is that at least 95% of the budesonide microparticles have a diameter of less than 5 pm.

[0042] The selection of the appropriate dynamic viscosity is of high importance. Preferably the viscosity is in a range of 1000-1500 mPa*s and especially preferred is a viscosity of about 1200 mPa*s whereby the viscosity is dependent on the type of methylcellulose and not on the amount of viscosity enhancer.

[0043] The acceptance of the orally applicable suspension by the patient depends strongly on the taste. Whereas it is possible to use artificial sweeteners like sucralose in the present case a naturally occurring sweetener as sucrose is preferred.

[0044] Furthermore, the orally applicable suspension contains a flavoring agent whereby cassis aroma is particularly preferred.

[0045] Since the orally applicable suspension is to be applied to children it contains no surfactant and it contains no antioxidant. This can advantageously increase the willingness of patients or their caregivers to take medication with the orally applicable suspension according to the invention.

[0046] In order to avoid any undesired side effects, the orally applicable suspensions according to the invention contain no other viscosity-increasing agent except methylcellulose or derivatives thereof as described above. Different types of methylcellulose as described above can be mixed.

[0047] The orally applicable suspension according to the present invention is intended for use in the treatment of eosinophilic esophagitis in children who are patients having an age from about 1 to 2 years to about 17 years. The amount of the glucocorticosteroid, in particular the budesonide, is 0.5 to 1 mg per dose, which is administered in an amount of 2.5-5.0 ml suspension depending on the concentration of the orally applicable suspension. Such dose is applied once or twice a day, preferably twice a day, namely one dose in the morning and one dose in the evening. By using this method of treatment acute phases of the disease can be treated and it is also possible to bring the patient into remission whereby the suspension is applied for at least 48 weeks. The dosage regime according to the present invention comprises several aspects:

[0048] The orally applicable suspension can be used for young patients having an age of about one year to about 17 years whereby 0.1 to 0.5 mg budesonide administered in 2.5 to 5.0 ml suspension once or twice a day. The treatment starts regularly with an induction period of 12 weeks whereby either 0.5 mg or 1.0 mg budesonide are administered once daily or twice daily followed by an optional induction period of up to 12 weeks (twice daily administration with either 0.5 mg or 1 .0 mg budesonide). Thereafter the treatment is continued for 24 weeks in a maintenance period whereby either 0.5 mg or 1 .0 mg budesonide are administered once daily or twice daily.

[0049] Surprisingly, histologically remission (defined by significant drop of eosinophils) and an improvement of the clinical response (>30% drop in the total score of a questionnaire of patient-related outcomes) can be obtained by treatment with the budesonide suspension after 12 weeks of induction therapy during the induction period.

[0050] Although good results can be obtained after an induction period of 12 weeks during the induction period, the rate of patients with in particular histological remission and clinical response is increasing after a further induction period of 12 weeks. In a maintenance period of up to 24 weeks (up to 48 weeks total treatment) with budesonide suspension according to the invention, maintenance of stable remission rates in pediatric EoE patients can be achieved.

[0051] An outstanding advantage of the dosage regime of the present invention is that despite the long treatment with a corticosteroid no negative effects concerning the cortisol level could be observed even after a daily treatment of up to 2 mg corticosteroid for 48 weeks. This could not be expected.

[0052] The orally applicable suspension according to the invention is prepared in a special process whereby in a first process step an aqueous base is mixed with the viscosity-increasing agent producing a first suspension without the pharmaceutically active agent. The solution is usually produced by temperature treatment which means that the solution is slightly heated.

[0053] In a second step an aqueous solution containing a buffering agent, an antimicrobial preservative and a suspension stabilizing agent is prepared. In a third step the solution containing the viscosity-increasing agent obtained from step 1 is mixed with the solution containing the buffering agent, an antimicrobial preservative and a suspension stabilizing agent and in a fourth step the micronized corticosteroid is suspended under stirring in the solution as described above. Finally, the flavoring agent is added before the budesonide solution is filled into light protected bottles. The preparation of the solution must be prepared by observing the strictest standards of good manufacturing practice for preparing syrups.

[0054] Technologically the invention comprises the following features:

[0055] • Micronized crystalline budesonide is suspended in an appropriate aqueous continuous external phase or vehicle having a pH value of 3.5 to 4.5. Within this pH range, budesonide is most stable and simultaneously optimal conditions for sodium benzoate are guaranteed. Moreover, the low solubility of the active pharmaceutical ingredient in water is beneficial so that long-term chemical and physical stability of the drug molecule can be ensured without the use of undesired stabilizing agents such as antioxidants. The properties of budesonide do not change upon storage and in-use so that the safety, efficacy and drug delivery remain unaltered.

[0056] • An inert and mucoadhesive nonionic cellulose derivative is used as suspending and thickening agent in order to increase and adjust a pH-independent but timedependent shear-thinning / pseudoplastic viscosity of the vehicle. The suspending and viscosity-increasing agent is preferably methylcellulose, a partly O-methylated cellulose. The thixotropic properties of the vehicle facilitate (a) the applicability of the oral suspension in terms of withdrawal and pallatabiltiy, (b) the extension of the contact time of the oral suspension with the mucosa of the esophagus and (c) the homogeneous distribution of budesonide after moderate shaking (dose uniformity). The colloid also enables the dispersion of the solid particles in the liquid by forming physically stable suspensions upon shaking without the use of a wetting agent or surfactant. Omitting surfactant is beneficial for the patient since it reduces chances of irritation at the inflamed esophageal mucosa. Within the aqueous suspension, budesonide is only dissolved partially. The majority of active ingredient is undissolved and readily available at the target location. Together with the usage of micronized crystalline budesonide enabling drastically higher speed of dissolution, surfactants can be omitted.

[0057] The dynamic viscosity of the oral suspension is preferably adjusted in the range of 800 mPa*s to 1200 mPa*s, preferably to 1000 mPa*s. The highly viscous oral suspension can be easily resuspended by avoiding foaming, air entrapment and rapid re-sedimentation. This avoids dosing errors due to an inhomogeneous distribution of the active pharmaceutical ingredient. • The budesonide concentration of the oral suspension is preferably adjusted to 0.2 mg / mL resulting in an optimal dose volume ranging from 2.5 ml to 5 ml which equals the volume of a usual gulp. The dose volume, the bioadhesive nature of the colloid and the viscosity of the vehicle facilitate the lining of the pediatric esophagus with micronized crystalline budesonide after swallowing so that local activity of the active pharmaceutical ingredient can be increased thereby reducing loss of budesonide by passaging into the stomach. Uniform withdrawal of the dose is preferably achieved by using a 5 ml CE-certified oral syringe consisting of a barrel with an embossed graduation for 2.5 ml respectively 5 ml and a plunger.

[0058] • The components of the suspending vehicle comprise sucrose as sweetening agent, citric acid as buffering agent or acidity regulator, sodium benzoate as antimicrobial preservative, disodium edetate as stabilizing agent and Cassis aroma (Blackcurrant flavor) as flavoring agent. These components are compatible with the active pharmaceutical ingredient and the viscosity-increasing agent. The acceptance of the formulation by the pediatric population with regard to its organoleptic properties (taste and aroma) is greatly enhanced by the qualitative and quantitative composition of the oral suspension.

[0059] • The concentration of budesonide in the oral suspension is preferably 0.02%. The high viscosity of the vehicle, its pleasant taste and the use of micronized and lowconcentrated budesonide avoids the feeling of grittiness in the mouth and thus greatly enhances the acceptance of the suspension to children.

[0060] The examples described in the following illustrate the present invention and preferred embodiments without, however, limiting the scope of protection. In the examples and in the present invention the following abbreviations are used:

[0061] • ACTH - adrenocorticotropic hormone

[0062] • ADR - Adverse Drug Reaction

[0063] • AE - Adverse Events

[0064] • AESI - Adverse Event of Special Interest

[0065] • BID - Twice Daily

[0066] • BL - Baseline

[0067] • BOS - Budesonide Oral Suspension

[0068] • BOS-H - Budesonide Oral Suspension (High Dose)

[0069] • BOS-L - Budesonide Oral Suspension (Low Dose)

[0070] • BUU - Budesonide Suspension (= BOS)

[0071] • DB - Double-Blind (may correspond with the initial 12 week induction period)

[0072] • EoEHSS - EoE histological scoring system

[0073] • eos - eosinophils

[0074] • EOT - End of T reatment

[0075] • EREFS - Endoscopic Reference Score

[0076] • FAS - Full Analysis Set

[0077] . FU - Follow-Up • hpf - high power field

[0078] • IMP - Investigational Medicinal Product

[0079] • LOCF - Last Observation Carried Forward

[0080] • OD - Once Daily

[0081] • OLE - Open Label Extension (may correspond with 24 week maintenance period)

[0082] • OLI - Open Label Induction (may correspond with the further 12 week induction period)

[0083] • PEESS - Pediatric Eosinophilic Esophagitis (EoE) Symptom Severity Module Version 2.0: Parent Report for Children and Teens (Ages 2-18) and Children and Teens Report (Ages 8-18). Bibliographic reference(s) of the original questionnaire Franciosi JP, Hommel KA, DeBrosse CW, Greenberg AB, Greenler AJ, Abonia JP, Rothenberg ME, Varni JW. Development of a validated patient-reported symptom metric for pediatric eosinophilic esophagitis: qualitative methods. BMC Gastroenterol. 2011 Nov 18;11 :126. Copyright: © Children’s Hospital Medical Center, 2010.

[0084] • PLAC - Placebo

[0085] • PP - per protocol

[0086] • SAE - Serious Adverse Event

[0087] • SCR - Screening

[0088] • TAP - Tapering

[0089] • w - week

[0090] Preferred embodiments of the present invention to be used in the dosage regime can be summarized as follows:

[0091] An orally applicable suspension comprising a) topically acting micronized crystalline budesonide, b) an aqueous base, c) at least one viscosity-increasing agent selected from a methylcellulose or a derivative thereof, d) a buffering agent which allows the adjustment of the final suspension to a pH value of 3.5 to 4.5, e) an antimicrobial preservative, f) a suspension stabilizing agent, in particular ethylenediaminetetramethyl acetic acid, whereby the suspension has a dynamic viscosity in the range of 800 mPa*s to 2000 mPa*s. In another embodiment the orally applicable suspension contains a concentration of 0.1 mg / ml to 1.0 mg / ml budesonide.

[0092] In another preferred embodiment the orally applicable suspension the budesonide has a concentration of 0.2 mg / ml.

[0093] In a further embodiment in the orally applicable suspension at least 95% of the budesonide microparticles have a diameter of less than 10 pm.

[0094] In another embodiment the orally applicable suspension has a dynamic viscosity in the range of 1000 to 1500 mPa*s, preferably in the range of 1000-1200 mPa*s.

[0095] In another also preferred embodiment methylcellulose having a viscosity specification of 1125-2100 mPa*s resulting in 1500 mPa*s is used in the orally applicable suspension.

[0096] In a further embodiment the orally applicable suspension contains as sweetener sucrose.

[0097] In a further embodiment the orally applicable suspension contains as flavoring agent a cassis aroma.

[0098] In a preferred embodiment the orally applicable suspension contains no surfactant and no antioxidant.

[0099] In a preferred embodiment the orally applicable suspension contains no other viscosityincreasing agent except methylcellulose or a derivative thereof.

[0100] The orally applicable suspension is used for the treatment of eosinophilic esophagitis of patients having an age of about one year to about 17 years whereby 0.5 to 1.0 mb budesonide are administered in 2.5 to 5.0 ml suspension once or twice a day.

[0101] In preferred embodiments the treatment comprises an induction period of 12 weeks optionally followed by a further induction period of up to 12 weeks and a maintenance period of 24 weeks whereby 0.5 or 1 .0 mg budesonide is administered once daily or twice daily. In preferred embodiments the treatment using the orally applicable suspension according to the invention comprises that after 12 weeks of induction treatment during the induction period both, histological remission defined as peak of <16 eos / mm2hpf and clinical response is reached. Hence, patients having an age of about 1 year to about 17 years whereby 0.5 to 1 .0 mg budesonide are administered in 2.5 to 5.0 ml suspension once or twice a day, can be treated successfully.

[0102] Further preferred embodiments are lined out in the claims and / or below.

[0103] In a preferred embodiment the clinical response is based on a questionnaire of patient- related outcomes. This embodiment is preferred as it provides recordable and comparable outcomes to monitor the treatment of patients.

[0104] In a more preferred embodiment clinical response is defined as > 30% drop in total PEESS. PEESS, as defined herein is an accepted questionnaire of patient related outcomes, providing recordable and comparable outcomes to monitor the treatment of patients very precisely.

[0105] Preferably histological remission is defined as 0 eos / mm2hpf. This embodiment is particularly advantageous as already after 12 weeks of treatment during the induction period according to the invention the rate of patients with the more stringent eosinophil count of 0 eosinophils per hpf can be determined. Hence, patients having an age of about 1 year to about 17 years whereby 0.5 to 1 .0 mg budesonide are administered in 2.5 to 5.0 ml suspension once or twice a day, can be treated successfully.

[0106] In preferred embodiments the treatment using the orally applicable suspension according to the invention comprises that after 12 further weeks of induction treatment during the further induction period both, histological response defined as peak of <48 eos / mm2 hpf, and clinical response is reached. This embodiment is particularly advantageous for patients having an age of about 1 year to about 17 years that require further treatment, especially following and induction treatment in which 0.5 to 1.0 mg budesonide are administered in 2.5 to 5.0 ml suspension once or twice a day in an induction period. In a preferred embodiment the clinical response is based on a questionnaire of patient- related outcomes. This embodiment is preferred as it provides recordable and comparable outcomes to monitor the treatment of patients.

[0107] In a more preferred embodiment clinical response is defined as > 30% drop in total PEESS. PEESS, as defined herein is an accepted questionnaire of patient related outcomes, providing recordable and comparable outcomes to monitor the treatment of patients very precisely.

[0108] In a preferred embodiment the treatment using the orally applicable suspension according to the invention comprises that the dosage of 0.5 mg or 1 .0 mg budesonide are administered twice daily to increase the rate of patients with histological remission and clinical response by at least 25% in comparison to once daily administration of 0.5 mg or 1.0 mg budesonide. This embodiment is particularly advantageous during the induction period, particularly as patient can transition earlier into the maintenance period as described herein.

[0109] In a preferred embodiment the treatment using the orally applicable suspension according to the invention comprises that the dosage of 0.5 mg or 1 .0 mg budesonide are administered once and / or twice daily for 24 weeks in comparison to 12 weeks administration of 0.5 mg or 1 .0 mg budesonide once and / or twice daily to increase the rate of patients with histological remission and clinical response by at least 25%. Surprisingly, a longer treatment duration using the described dosing regimen has a positive effect on histological remission and clinical response, especially as described herein. This is particularly advantageous as a treatment according to the invention using the orally applicable suspension is safe for 24 weeks, particularly as described and / or claimed herein. Therefore, the induction and the further induction period is 24 weeks in total, as it is preferred embodied.

[0110] In a preferred embodiment the treatment using the orally applicable suspension according to the invention comprises that the reduction in total PEESS after 48 weeks of treatment is at least 85% compared to prior treatment. Surprisingly, a longer treatment has a positive effect on clinical response, especially as described herein. This is particularly advantageous as a treatment according to the invention using the orally applicable suspension is safe for up to and including 48 weeks, particularly as described and / or claimed herein. In preferred embodiments the treatment using the orally applicable suspension according to the invention comprises that histological remission and clinical response can be obtained in patients of ages between 2 and 17 years, preferably in patients of age 2 to 11 and / or patients of age 12 to 17 years, in particular by administering 0.5 mg to 1 mg budesonide daily for the patients between 2 to 11 years and / or by administering 1 mg to 2 mg budesonide daily for the patients between 12 to 17 years. These embodiments allow a suitable age- appropriate pediatric dosage regimen and form. This is particularly advantageous when the treatment comprises an induction period of 12 weeks optionally followed by a further induction period of up to 12 weeks and a maintenance period of 24 weeks whereby 0.5 or 1.0 mg budesonide is administered once daily or twice daily. The appropriate pediatric dosage regimen and form provided by the described embodiment is very advantageous, since the treatment of EoE patients with the orally applicable suspension is safe for 12, 24 and up to and including 48 weeks.

[0111] In preferred embodiments the treatment using the orally applicable suspension according to the invention comprises that the morning cortisol level of the treated patient does not fall under a level bearing the risk of clinical complications. Preferably, the morning cortisol level does not fall under around 5.0 pmol / l. These embodiments are particularly advantageous, since the treatment of EoE patients with the orally applicable suspension is safe for 12, 24 and up to and including 48 weeks. The safe treatment of EoE patients, especially for longer periods, according to these embodiments, particularly in combination with other embodiments described and / or claimed herein, is of particular advantage as EoE is a chronic immune / antigen-mediated disorder of the esophagus that might require permanent or frequent (over a longer period of several weeks) treatment of the patient.

[0112] In preferred embodiments the treatment using the orally applicable suspension according to the invention comprises that following oral administration the orally applicable suspension has an esophageal transit time of 0.1 to 40 minutes, particularly 0.2. to 36 minutes, most particular about 4 minutes. The esophageal transit time is preferably defined as the required for the orally applicable suspension to transit the esophagus after swallowing, preferably after a single swallow. The advantage of the above-described embodiments is a prolonged contact time of the budesonide with the oral esophageal mucosa, especially when the orally applicable suspension has a final budesonide concentration of 0.2 mg / ml as described and / or claimed herein. A further advantage of the described and / or claimed esophageal transit time of the orally applicable suspension can be or is that histological remission and clinical response, preferably as described and / or claimed herein, can be reached, particularly following a treatment duration of 12, 24 and / or up to and including 48 weeks, preferably as described and / or claimed herein.

[0113] In a preferred method for the preparation of a preferred orally applicable suspension the following steps are performed whereby in a first process step the aqueous base is mixed with the viscosity-increasing agent whereby a suspension without pharmaceutically active agent is produced by temperature treatment, in a second step an aqueous solution containing a buffering agent, an antimicrobial preservative and a suspension stabilizing agent is prepared, in a third step the suspension obtained from step one is mixed with the solution obtained in step two and in a fourth step the micronized glucocorticosteroid is suspended under stirring into the mixture of step three and finally the flavoring agent is added before the orally applicable suspension is filled in a light protected bottle.

[0114] The present invention is further described and illustrated by the examples and the figures.

[0115] The figures show the preferred embodiments:

[0116] Figure 1 shows a scheme for the preparation of a preferred suspension.

[0117] Figure 2 illustrates the dosing scheme.

[0118] Figure 3 shows the histological results of the clinical study.

[0119] Figure 4 shows the advantage of the dosage regime according to the invention compared with the study of the prior art (Gupta 2015).

[0120] Figure 5 shows the different stages of the treatment regime whereby the open label induction (OLI) phase is optional.

[0121] Figure 6 provides a definition of the relevant clinical and / or histological parameters.

[0122] Figure 7 provides a definition of the primary endpoints of the double-blind (DB) induction phase.

[0123] Figure 8 shows the rate of patients achieving the primary endpoint after the DB induction phase.

[0124] Figure 9 shows the rate of patients achieving the primary endpoint after the DB induction phase grouped by age.

[0125] Figure 10 illustrates the effect of the optional further induction period. Figure 11 shows the rate of patients in clinical remission after the 24 weeks OLE maintenance therapy.

[0126] Figure 12 is an analysis of the rate of patients in clinical response measured in patients receiving active treatment for at least 48 weeks.

[0127] Figure 13 shows patients with clinical relapse defined as an >30% increase in the total score of PEESS.

[0128] Figure 14 demonstrates that practically no clinically relevant adverse events could be observed in the DB induction phase.

[0129] Figure 15 demonstrates that practically no clinically relevant adverse events could be observed in the second further induction phase (OLI).

[0130] Figure 16 shows that practically no clinically relevant adverse events could be observed in the 24 weeks maintenance phase (OLE).

[0131] Figure 17 shows clearly that the morning cortisol does not drop under a critical value in all clinical phases.

[0132] Figure 18 shows the esophageal transition time of the orally applicable budesonide suspension according to the invention.

[0133] Example 1

[0134] A scheme for the preparation of an orally applicable suspension according to the invention is shown in Fig. 1.

[0135] The preferred suspending and thickening agent of the invention is methylcellulose. Other pharmaceutically acceptable, inert and mucoadhesive nonionic cellulose derivatives could be used as suspending and thickening agent as minor component. Minor component means that such a component is present in an amount not exceeding 1 mg / ml, preferably not exceeding 0.5 mg / ml of the final orally applicable suspension. The advantage of methylcellulose is that the viscosity can be adjusted independently of the pH value. Thus, the viscosity can or is preferably adjusted at an acidic pH value, in particular in a range of pH 3.5 to 4.5. Moreover, it is of utmost importance that the solution when used by the patient adheres to the esophagus of the patient for sufficient time to develop its therapeutic effect.

[0136] The orally applicable solution according to the invention adheres very well to patient’s esophagus and it does not cause an uncomfortable feeling. Budesonide 0.2 mg / ml oral suspension is a whitish, highly viscous suspension with a characteristic cassis flavor. One bottle of the 200 ml amber glass bottle contains > 160 ml of the liquid preparation. The drug product is usually manufactured in batches of approximately 434 kg resulting in 2500 bottles with a filling volume of 165 ml. The qualitative and quantitative composition of the invention per mL of the suspension, per dose of 5 ml and per batch of 434 kg are presented below.

[0137] Table 1 shows a preferred composition of the orally applicable solution according to the invention.

[0138] Table 1

[0139] The manufacturing process of budesonide 0.2 mg / ml oral suspension comprises the process steps to prepare the bulk suspension and the filling process. The flow chart as shown in Fig. 1 describes the manufacturing process of the bulk suspension (batch size 434.115 kg).

[0140] Example 2 (selection of the appropriate methylcellulose)

[0141] The described invention has been successfully tested in children in clinical studies. Several drug product batches were manufactured to supply the clinical trials. All the tested batches had the invented qualitative and quantitative composition as described above using methylcellulose, 1500 mPa*s with a concentration of 20 mg / ml (equivalent to 1.90%). The measured dynamic viscosity of the clinical batches is presented below (method: rotating viscosity according to Ph. Eur. 2.2.10, rotational speed = 35 sec1, 20°C, duration of measurement = 60 sec):

[0142] • Batch V2188 1153 mPa*s

[0143] • Batch V2253 1015 mPa*s

[0144] • Batch V2270 1187 mPa*s

[0145] • Batch V3031 1186 mPa*s

[0146] • Batch V3086 1149 mPa*s

[0147] • Batch V3111 986 mPa*s

[0148] The specific viscosity values were obtained by using appropriate amounts of methylcellulose having 1500 mPa*s.

[0149] Example 3 (phase 2 / 3 clinical study)

[0150] In the phase 2 / 3 clinical study BUU-5 / EEA (more details in Example 6) using the suspension described herein, two different dosing schemes were used. The dosing scheme is shown in Figure 2.

[0151] After 12 weeks of treatment the rate of patients with histological remission (i.e. eosinophil count of < 5 eosinophils per hpf corresponding to < 16 eosinophils per mm2hpf) was determined. The results are shown in Figure 3A. It turned out that the high dose budesonide solution (1.0 - 2.0 mg daily, BID) resulted in very high percentage of histological remission after a treatment of 12 weeks only. The low dose (0.5- 1.0 mg daily, OD) resulted also in a remission substantially higher than treatment with placebo but it seems that a high dosage budesonide treatment is better for obtaining a quick histological remission.

[0152] In addition, after 12 weeks of treatment the rate of patients with the more stringent eosinophil count of 0 eosinophils per hpf was determined (..histological deep remission", Figure 3B).

[0153] A comparison between the two dosing schemes is shown in Table 2.

[0154] Table 2

[0155] It turned out that the high dose budesonide solution resulted in very high percentage of histological remission as well as histological deep remission after a treatment of 12 weeks only. The low dose resulted also in remission rates substantially higher than treatment with placebo, but it seems that a high dosage budesonide treatment is preferred for obtaining a quick histological remission.

[0156] The study using the suspension described herein (BUU-5 / EEA) is a similar study to a study assessing efficacy and safety of an oral budesonide suspension in a comparable paediatric patient population suffering from EoE. (GUPTA et al., Clinical Gastroenterol, and Hepatol. 2015, vol. 13, No. 1 , pp 66-67). Here, a dose of 1.4 and 2.0 mg was given in a 7 ml and 10 ml volume either in a once daily or in a twice daily dosing regimen. Similarly to the study BUU-5 / EEA, efficacy was analysed by measuring the number of eosinophils per hpf after 12 weeks of treatment. However, efficacy outcomes were defined and named slightly differently: Histological response was defined as eos < 6 per hpf, histological remission as eos < 1 per hpf (see Table 3).

[0157] Table 3

[0158] Surprisingly, with only around half the dose of budesonide similar and even better results could be obtained in both dosing regimens (OD and BID) with the budesonide oral suspension according to the invention in comparison to the Gupta study, even though the criteria were more stringent in the BUU-5 / EEA study. Adjusted to the daily dose exposure of either 1.0 -2.0 mg according to the invention and 1.4 mg - 2.0 mg (as prior art) this reflects a doubling of efficacy in both histological response and remission. The results of the Gupta study are compared with the present invention (Falk) which are shown in Figures 4A and B. In Fig. 4A the proportion of patients with eos <5 per hpf vs eos <6 per hpf is shown and in Fig. 4B the proportion of patients with eos = 0 per hpf vs eos <1 per hpf is shown. The explanation for the superior results may be that on the one hand the pharmaceutical formulation according to the invention is superior over the formulation used by Gupta and / or on the other hand that the used dosage regimes provide a surprising advantage when applied for a longer period of time (at least 12 weeks, preferably at least 24 weeks and for up to at least 48 weeks) to vulnerable patients having an age up to 17 years.

[0159] Example 4 (stability of the orally applicable suspension)

[0160] One of the difficulties of a suspension is that such a suspension must be stable in various respects. On the one hand, budesonide is stable against degradation when it is not in an aqueous environment. In solution or suspension, however, budesonide may be degraded which leads to undesired degradation products of budesonide not highly pharmacologically active anymore.

[0161] Another problem is that suspensions are under the risk of microbial degradation. The addition of preservants may, however, not be desired in particular when the suspension is designed for children or adolescents. The orally applicable suspension according to the invention has therefore been tested with regard to its stability over several months. The results are shown in Table 4. It is evident that the orally applicable suspension according to the present invention is surprisingly stable which allows a convenient handling in practice.

[0162]

[0163] Table 4: Stability data

[0164] Example 5 (adherence of active agent to the oesophagus)

[0165] In order to show superior adherence of the pharmacologically active agent to the esophagus an experiment with radioactively labeled microspheres was performed. The suspension according to the invention having 0.2 mg budesonide per milliliter was radioactively labeled with the gamma emitting nuclide111ln. The orally applicable budesonide suspension (Budesonide OS-BOS) according to the invention was compared with a Budesonide orodispersible tablet (ODT) designated Jorveza which was also labeled with Indium (111ln).

[0166] The passage of the labeled product (BOS vs. ODT) was observed in a scintigraphy and the following conclusions can be drawn from the experiment (see Figure 18):

[0167] • The transit time of the orally applicable budesonide suspension according to the invention is substantially longer than the time range expected for non - viscous liquids which shows the surprising favourable properties of BOS for oesophageal targeting.

[0168] • When an orodispersible tablet cannot be given to the patient due to his / her age the orally applicable suspension according to the invention provides a good alternative to ODT as shown by the scintigraphy results.

[0169] • The esophageal transit time of BOS is 0.1 to 40 minutes, particularly 0.2. to 36 minutes, most particular about 4 minutes (Fig. 18 B).

[0170] Example 6 a) BUU-5 study phases are shown in Fig. 5

[0171] Study BUU-5 was a double-blind, randomized, multicenter, placebo-controlled, comparative, Phase ll / lll clinical trial in children and adolescents with EoE, >2 to <18 years of age. The trial was conducted with three treatment groups with parallel group comparison to compare a 12-week oral treatment with different daily doses of budesonide oral suspension (BOS) as described in this invention vs. placebo for the treatment of active EoE. The up to 4-week screening period was followed by a 12-week double-blind (DB) treatment period, an optional 12-week open-label induction (OLI) treatment for eligible patients, an optional 24-week open-label extension (OLE) treatment with budesonide oral suspension for eligible patients, a 3-week tapering phase, and a 4-week follow-up period after the patient’s last end of treatment visit. Thus, patients could be treated with budesonide oral suspension up to 48 weeks.

[0172] In more detail: aa) Screening phase: 1-4 weeks prior to baseline visit. Baseline characteristics of the double-blind treatment phase refer to data collected at baseline visit. ab) Double-blind (DB), randomized (1:1:1) treatment phase (corresponding to the first 12 weeks induction period):

[0173] Patients were stratified by their age at baseline visit: Stratum I (Age 2 to 11 years) and Stratum II (Age 12 < 18 years). Patients were randomized to receive a 12-week, doubleblind treatment (with the possibility of early termination after 8 weeks of treatment in case of lack of efficacy). The budesonide doses tested were in stratum I: age 2 to 11 years at DB V1: 1x0.5 mg / day (low-dose), and 2x0.5 mg / day (high-dose), and in stratum II: age 12 to <18 years at DB V1: 1x1 mg / day (low-dose), and 2x1 mg / day (high-dose). ac) Open-label induction (OU) treatment phase (optional, corresponds to a second 12 week induction period, when applied):

[0174] Patients eligible for the OLI treatment were those that completed the DB phase, but did not achieve histological remission or clinical remission, patients who were prematurely withdrawn due to lack of efficacy after at least 8 weeks of DB treatment and patients experiencing either a food impaction requiring an endoscopic intervention or dilation at any time during the DB phase. These patients were offered an optional 12-week open-label induction treatment with 2x0.5 mg / day (stratum I) or 2x1 mg / day (stratum II) budesonide oral suspension (high dose). ad) Open-label extension (OLE) phase (corresponding to the up to 24 weeks maintenance period):

[0175] Patients completing the DB treatment phase being in pathological remission and in clinical response or clinical remission; and patients completing the OLI treatment phase being in pathological response or pathological remission and in clinical response or clinical remission were offered an optional 24-week open-label extension treatment with 1x0.5 mg / day (stratum I) or 1x1 mg / day (stratum II) budesonide oral suspension or, according to the investigator’s discretion, with an escalated dose of 2x0.5 mg / day (stratum I) or 2x1 mg / day (stratum II) budesonide oral suspension, resembling maintenance therapy in clinical praxis. ae) Tapering phase:

[0176] All patients entered a 3-week tapering phase after their last treatment in the DB, OLI, or OLE phase, as applicable, except if medically contraindicated. af) Follow-up phase:

[0177] All patients were followed up 4 weeks after their last end of treatment visit.

[0178] Example 7: Clinical cut-offs as definitions used according to the present invention; efficacy outcomes

[0179] A definition of the clinical cut-offs “active disease”, “clinical response” and “clinical remission”, as well as the histological cut-offs “active disease”, “histological response”, “histological remission” and “deep remission” is given in Fig. 6. a) Primary efficacy endpoint as measurement of success of treatment (Fig. 7)

[0180] The primary endpoint of the DB induction period was rate of patients with both histological remission and clinical response at DB week 12 (LOCF) defined as:

[0181] - Histological remission, i.e. , peak of <16 eos / mm2 hpf at DB week 12 (LOCF), AND

[0182] - Clinical response defined as:

[0183] Stratum I: Age 2 to 11 years at DB \ / 1:

[0184] > 30% drop in the total score of PEESS Version 2.0 - parent report for children and teens (ages 2-18) from baseline to DB week 12 (LOCF),

[0185] Stratum II: Age 12 to < 18 years at DB V1: > 30% drop in the total score of PEESS Version 2.0 - children and teens report (ages 8-18) from baseline to DB week 12 (LOCF). b) Rate of patients with HISTOLOGICAL REMISSION AND CLINICAL RESPONSE (PEESS) (Primary efficacy endpoint, shown in Fig. 8)

[0186] The primary confirmatory analysis of the composite primary endpoint rate of patients with histological remission and clinical response at DB Week 12 (LOCF) was performed based on 76 patients included in the full analysis set (FAS-DB).

[0187] The rates of patients achieving the composite endpoint of histological remission and clinical response at DB week 12 (LOCF) were clinically relevant and significantly higher in the BUU- L (46.2%) and BUU-H (69.2%) groups) versus the Placebo group (0.0%), with clinically relevant better results in the BUU-H treatment group compared to the BUU-L treatment group (FAS-DB). c) Rate of patients with HISTOLOGICAL REMISSION AND CLINICAL RESPONSE (PEESS) stratified by age group (as shown in Fig. 9)

[0188] Patients were stratified according to their age at baseline into one of two age groups: Stratum I: age 2 to 11 years at DB V1 or stratum II: age 12 to <18 years at DB V1.

[0189] A subgroup analyses of the primary endpoint stratified by age group (stratum I: age 2 to 11 years; stratum II: age 12 to <18 years) was in line with the primary outcome and supported the superiority of both active groups versus placebo and at the same time the clinically relevant better performance of the higher dose compared to the lower dose independent of age. d) Rate of patients with HISTOLOGICAL REMISSION AND CLINICAL RESPONSE (PEESS) in OLI phase (Fig. 10)

[0190] A prolonged treatment with BUU-H for up to 12 weeks in patients not appropriately responding to BUU-H or BUU-L (i.e. 8 patients of the BUU-H and 14 patients of the BUU-L group treated in the OLI phase) during the first 12 weeks was safe and offered an additional value by bringing cumulative 45 of 52 patients (86.5%) into histological remission and clinical response after 12 (placebo during DB induction phase) up to 24 weeks (active treatment during DB induction phase) of treatment. Fig. 10b shows the improvement obtainable with the optional further induction period of 12 weeks (OLI) grouped by treatment in the DB induction phase. e) Rate of patients in Clinical Remission at OLE week 24 (Fig 11)

[0191] Because EoE is a chronic condition and the vast majority of patients experience a relapse rapidly after discontinuation of treatment, long-term management of EoE is required. The OLE phase gives first hints regarding efficacy of the budesonide suspension in a maintenance phase in clinical praxis. Surprisingly, this 24-week period of maintenance treatment did not only demonstrate steady levels of rate of patients with clinical remission at end of treatment (EoT), but increasing rates of patients in clinical remission compared to OLE baseline independent of their history in induction therapy (high-dose during DB, low- dose during DB or OLI patients). f) PEESS Score and rate of patients with Clinical Response in patients receiving treatment for > 48 weeks (Fig 12)

[0192] 13 patients received active treatment during DB induction phase, entered the further optional OLI induction period and participated also in the 24 weeks OLE maintenance treatment phase and therefore received active treatment for > 48 weeks. The PEESS Score of these patients was evaluated over the various treatment phases (DB, OLI and OLE) and is depicted in Fig. 12. Surprisingly, a clear reduction in treatment symptoms as evaluated by PEESS was visible. The reduction in total PEESS after 48 weeks of treatment (at OLE week 24) is at least 85% compared to prior treatment as shown in the table on the right hand of Fig. 12. More specifically, the mean reduction increases from 37.1 % at DB EoT (after 12 weeks of treatment) to 86.5% at OLE EoT (after > 48 weeks of treatment).

[0193] Clinical response, defined as a reduction in total PEESS of >30%, is reached by 38.46% of patients after DB EoT and by 100% after OLI EoT and surprisingly still by 100% of patients after OLE EoT, indicating stable clinical response rates, i.e. symptom-free time period also during maintenance therapy, which can be seen as key goal in any chronic disease. g) Rate of patients with a clinical relapse (Fig. 13)

[0194] Clinical Relapse was defined as a > 30% increase in the total score of PEESS from OLE baseline. The rate of patients with clinical relapse is demonstrated in Fig. 13.

[0195] Importantly, there was no patient with food impaction needing endoscopic intervention and no patient needing endoscopic dilation.

[0196] The percentage of patients with clinical relapse decreases with pre-longed induction treatment (inclusion into the further optional induction period (OLI phase)). Similarly, time to clinical relapse increases with pro-longed induction treatment.

[0197] Example 8

[0198] Safety a) Adverse events / Withdrawals during DB phase (Fig. 14)

[0199] In total, 252 DB treatment-emergent adverse events (TEAEs) were reported for 61 patients (80.3%). In the BUll-L group, 87 DB TEAEs occurred in 19 patients (73.1%), in the BUll-H group, 98 DB TEAEs occurred in 22 patients (84.6%), and in the Placebo group, 67 DB TEAEs occurred in 20 patients (83.3%). Ten pre-treatment adverse events (AEs) were reported for 7 patients (26.9%) in the BUll-L group, 7 pre-treatment AEs for 6 patients (23.1%) in the BUll-H group, and 9 pre-treatment AEs for 8 patients (33.3%) in the Placebo group.

[0200] The majority of the TEAEs were of mild severity with 82 AEs in 18 patients (69.2%) in the BUll-L group, 86 AEs in 21 patients (80.8%) in the BUll-H group and 61 AEs in 18 patients (75.0%) in the Placebo group assessed as mild. Moderate TEAEs comprised 4 AEs reported for 4 patients (15.4%) in the BUll-L group, 10 AEs reported for 7 patients (26.9%) in the BUll-H group and 5 AEs reported for 3 patients (12.5%) in the Placebo group. Only 2 TEAEs were considered severe, i.e., 1 AE (dermatitis atopic) reported for 1 patient (3.8%) in the BUll-L group and 1 AE (cough) reported for 1 patient (4.2%) in the Placebo group. A total of 3 AEs in 3 patients (11.5%) in the BUll-L group, 3 AEs in 3 patients (11.5%) in the BUll-H group, and 8 AEs in 3 patients (12.5%) taking Placebo were rated as adverse drug reaction (ADR), as a causal relationship with the active ingredient was considered at least possible. Of these, 3 ADRs were also categorized as AEs of special interest (AESI); “cortisol decreased” was reported for each 1 patient in the BUll-H group and Placebo group, respectively, and “esophageal candidiasis” was reported for 1 patient in the BUll-H group.

[0201] The observed adverse events (AEs) are summarized in Fig. 14. The rate of adverse events were comparable between all groups. b) Adverse events / Withdrawals during OLI phase (Fig. 15)

[0202] In total, 115 AEs occurred in 36 patients (80.0%); Two AEs in 2 patients (4.4%) were classified as post-OLI treatment AEs (TAP after OLI treatment), and 113 AEs in 35 patients (77.8%) were classified as OLI TEAEs.

[0203] A total of 8 AEs in 7 patients (15.6%) were rated as ADRs, as a causal relationship with budesonide was considered at least possible. c) Adverse events / Withdrawals during OLE phase (Fig. 16)

[0204] In total, including OLE TEAEs and TAP after OLE TEAEs, 207 AEs occurred in 46 patients (74.2%). A total of 5 patients (8.1 %) experienced 6 ADRs that were OLE treatment- emergent. Three of the six ADRs were deemed as unexpected ADRs: 1 vomiting, 1 increased white blood cell count and 1 joint swelling. The other 3 ADRs were classified as AESIs: 2 oropharyngeal candidiasis and 1 blood cortisol decreased. All the three events were of mild intensity and the outcome was resolved. The results are shown in Fig. 15.

[0205] During up to 52-week open-label treatment with budesonide oral suspension no safety concerns have been identified and no increase in adverse reactions typically associated with long-term glucocorticosteroid use have been observed. BUU 0.5 mg OD or BID in children and BUU 1 mg OD or BID in adolescents are suitable doses for maintaining remission and continue to show an overall positive benefit / risk profile in long-term treatment of EoE. Example 9

[0206] Comparison of morning cortisol levels between baseline and end of treatment (EoT) of DB, OLI and OLE phase (Fig. 17)

[0207] During DB, OLI, and OLE phase, laboratory parameters as well as heart rate, body temperature, body weight, and blood pressure in general did not provide evidence for any safety concerns. A small decrease in morning serum cortisol measured between 7 a.m. and 9 a.m., which is a known pharmacodynamic effect of the glucocorticosteroid budesonide, was seen from Screening / DB Baseline to DB Week 12 in the BUU-H and BUU-L group (Fig. 17). Similarly, a small decrease in morning serum cortisol from OLI Baseline to OLI Week 12 and from OLE baseline to OLE week 24 was measured. However, Figure 17 shows clearly that the morning cortisol levels do not drop under a critical value, which is considered to be around 5.0 pmol / l, and the decrease is therefore considered not clinically relevant.

[0208] In general, safety data of the clinical study BUU-5 provide clear evidence that the dosage regimes according to the present invention can be applied to vulnerable young patients over a time period of up to 48 weeks in order to bring them into and / or to maintain stable remission.

Claims

Claims1. Orally applicable suspension comprising a) topically acting micronized crystalline budesonide, b) an aqueous base, c) at least one viscosity-increasing agent selected from a methylcellulose or a derivative thereof, d) a buffering agent which allows the adjustment of the final suspension to a pH value of 3.5 to 4.5, e) an antimicrobial preservative, f) a suspension stabilizing agent, in particular ethylenediaminetetramethyl acetic acid, whereby the suspension has a dynamic viscosity in the range of 800 mPa*s to 2000 mPa*s and the final suspension contains a concentration of 0.1 mg / ml to 0.5 mg / ml budesonide for use in the treatment of eosinophilic esophagitis of a patient having an age of about 1 year to about 17 years whereby 0.5 to 1.0 mg budesonide are administered in 2.5 to 5.0 ml suspension once or twice a day.

2. Orally applicable suspension for use according to claim 1, whereby in an induction period of 12 weeks either 0.5 mg or 1.0 mg budesonide are administered once daily or twice daily and whereby in an optional further induction period of up to 12 weeks either 0.5 mg or 1.0 mg budesonide are administered twice daily and whereby subsequent to the induction period and the optional further induction period in an optional maintenance period of 24 weeks either 0.5 mg or 1.0 mg budesonide are administered once daily or twice daily.

3. Orally applicable suspension for use according to any of claims 1 or 2 whereby after 12 weeks of induction treatment during the induction period both, histological remission defined as peak of <16 eos / mm2hpf, preferably 0 eos / mm2hpf and clinical response, preferably where the clinical response is based on a questionnaire of patient-related outcomes, more preferred where clinical response is defined as > 30% drop in total PEESS, is reached.

4. Orally applicable suspension for use according to any of claims 1 or 2 whereby after12 further weeks of induction treatment during the further induction period both, histological response defined as peak of<48 eos / mm2hpf, and clinical response, preferably where the clinical response is based on a questionnaire of patient-related outcomes, more preferred where clinical response is defined as > 30% drop in total PEESS, is reached.

5. Orally applicable suspension for use according to any of claims 1 to 4 whereby the dosage of 0.5 mg or 1 .0 mg budesonide are administered twice daily to increase the rate of patients with histological remission and clinical response by at least 25% in comparison to once daily administration of 0.5 mg or 1.0 mg budesonide.

6. Orally applicable suspension for use according to any of claims 1 to 5 whereby the dosage of 0.5 mg or 1.0 mg budesonide are administered once and / or twice daily for 24 weeks in comparison to 12 weeks administration of 0.5 mg or 1.0 mg budesonide once and / or twice daily to increase the rate of patients with histological remission and clinical response by at least 25%.

7. Orally applicable suspension for use according to any of claims 1 to 6, wherein the reduction in total PEESS after 48 weeks of treatment is at least 85% compared to prior treatment.

8. Orally applicable suspension for use according to claims 1 to 7 wherein the induction and the further induction period is 24 weeks in total.

9. Orally applicable suspension for use according to any of claims 1 to 8 wherein the dynamic viscosity is in the range of 800 mPa*s to 1200 mPa*s, preferably wherein the dynamic viscosity is about 1000 mPa*s.

10. Orally applicable suspension for use according to any of claims 1-9 wherein the budesonide concentration is 0.2 mg / ml in the suspension.11 . Orally applicable suspension for use according to any of claims 1 to 10 which contains no surfactant and no antioxidant.

12. Orally applicable suspension for use according to any of claim 1 to 11 for maintaining clinical remission whereby the orally applicable suspension is applied for at least 24 weeks in the maintenance period.

13. Orally applicable suspension for use according to any of claims 1 to 12 wherein histological remission and clinical response can be obtained in patients of ages between 2 and 17 years, preferably in patients of age 2 to 11 and / or patients of age 12 to 17 years, in particular by administering 0.5 mg to 1 mg budesonide daily for the patients between 2 to 11 years and / or by administering 1 mg to 2 mg budesonide daily for the patients between 12 to 17 years.

14. Orally applicable suspension for use according to any of claims 1 to 13 wherein the morning cortisol level of the treated patient does not fall under a level bearing the risk of clinical complications.

15. Orally applicable suspension for use according to any of claims 1 to 14 which, following oral administration has an esophageal transit time of 0.1 to 40 minutes, particularly 0.

2. to 36 minutes, most particular about 4 minutes.

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