Drug delivery system comprising anti-inflammatory agent or salt thereof for application to esophageal mucosa

Abstract

The present invention relates to a drug delivery system for application to the esophageal mucosa, comprising at least one sheet-like formulation, in particular a film-shaped, foil-shaped or sheet-like formulation, comprising an anti-inflammatory agent or a salt thereof, a release mechanism, and a triggering mechanism, the triggering mechanism being adapted to trigger the release of the sheet-like formulation by the release mechanism at a predetermined site of action.

Description

Technical Field

[0001] The present invention relates to a drug delivery system comprising an anti-inflammatory agent or a salt thereof, in particular for application to esophageal mucosa and for treating esophageal diseases, in particular eosinophilic esophagitis and / or esophageal stricture. Background Art

[0002] Esophageal diseases include, for example, eosinophilic esophagitis. Eosinophilic esophagitis is a chronic, immune-mediated inflammatory disease of the esophagus. Current treatment options for eosinophilic esophagitis involve corticosteroids. Steroids are usually administered orally in the form of viscous suspensions, effervescent tablets, or aerosol sprays. However, many patients have limited or no response to currently available steroid preparations. In addition, after cessation of steroid therapy, relapse rates are high, requiring long-term treatment to maintain remission.

[0003] Janus kinase (JAK) inhibitors are compounds that inhibit the activity of one or more JAK family enzymes (JAK1, JAK2, JAK3, TYK2), thereby interfering with the JAK-STAT signaling pathway. They are used to treat neoplasia and immune-mediated inflammation, such as inflammatory bowel disease or rheumatoid arthritis. ) is a JAK1 and JAK3 inhibitor that has been approved for systemic treatment of rheumatoid arthritis and severe atopic dermatitis. Topically administered JAK inhibitors are currently in development for the treatment of atopic dermatitis. Tofacitinib has also been shown to significantly improve the appearance of the esophagus, with minimal numbers of eosinophils found in esophageal biopsies after 3 months of treatment in a 34-year-old man with a long-standing diagnosis of eosinophilic esophagitis (Alvarez et al., 2019, “Treatment-resistant eosinophilicoesophagitis successfully managed with tofacitinib”, BMJ Case Rep. 12:e232558.doi:10.1136 / bcr-2019-232558). In addition, JAK-STAT6 pathway inhibitors AS1517499, leflunomide, and ruxolitinib have been described to block the secretion of eotaxin-3 by epithelial cells and fibroblasts in patients with eosinophilic esophagitis (Cheng et al., 2016, "JAK-STAT6 Pathway Inhibitors Block Eotoaxin-3 Secretion by Epithelial Cells and Fibroblasts from Esophageal Eosinophilia Patients: Promising Agents to Improve Inflammation and Prevent Fibrosis in EoE", PLOS ONE 11(6): e0157376.doi:101371 / journal.pone.0157376). However, regional and local administration of JAK inhibitors to the esophagus has not been reported.

[0004] Calcineurin inhibitors are compounds that inhibit calcineurin, which is an enzyme that activates T cells. Due to the key role of T cells in cell-mediated immunity, calcineurin inhibitors inhibit cell-mediated immune responses. Calcineurin inhibitors are systemically administered for the treatment of immune-mediated diseases and prevention of organ rejection after transplantation. In addition, a basic science study describes that in eosinophilic esophagitis, rapamycin induces autophagy of esophageal epithelial cells through mTORC signaling (Whelan et al., 2018, "Rapamycin-mediated autophagy activation ameliorates eosinophilic esophagitis-associated alterations in epithelial tissue architecture", Gastroenterology. 154 (6): S-108). However, there has been no report on the regional and local administration of calcineurin inhibitors to the esophagus.

[0005] For decades, systemically administered purine analogs have been established in the treatment of chronic inflammatory bowel disease, particularly ulcerative colitis and Crohn's disease. In a small case series, two systemically administered purine analogs azathioprine (AZA) and 6-mercaptopurine (6-MP) have been shown to be effective for the treatment of refractory eosinophilic esophagitis (Netzer et al., 2007, "Corticosteroid-dependent Eosinophilic Oesophagitis: Azathioprine and 6-Mercaptopurine can induce and maintain long-term remission.", Europ. J. Gastroent. Hepatol. 19: 865-869). However, there is no report that purine analogs are regionally and locally applied to the esophagus.

[0006] Drugs are delivered to the gastrointestinal membranes, especially the esophageal membrane, usually via endoscopically guided submembranous application. Topical applications of active ingredients include drug-coated esophageal stents or oral viscous medications. Current investigations involve orodispersible or orally disintegrating tablets, aerosols, or gel-like medications with higher viscosity to increase contact time.

[0007] However, there are some challenges in applying active ingredients topically to the gastrointestinal membrane, especially the esophageal membrane. For example, it is difficult to topically apply a high dose of drug sufficient to achieve a therapeutically effective local concentration over a period of time. Possible reasons for too low concentrations at the site to be treated include degradation or inactivation of the drug by digestive secretions and enzymes, dilution by intestinal fluid, malabsorption, unavailability of prodrugs that require activation at the site to be treated, and too short a residence time at the site of action to effectively exert the drug's effect. When using liquid or gel-like drug delivery systems, short residence time at the site of action and / or too low local concentrations are particularly a problem. Therefore, high doses must be applied to achieve sufficient concentrations at the site to be treated. Higher applied doses of active ingredients are usually accompanied by an increase in intestinal absorption side effects and higher bioavailability; therefore, the dose of the active ingredient should be kept as low as possible.

[0008] There remains a need for suitable drug delivery systems, particularly for delivery to the esophagus, which can deliver anti-inflammatory agents or salts thereof for effective treatment while allowing the administration of the lowest possible dose to reduce side effects. Summary of the invention

[0009] Purpose of the Invention

[0010] An object of the present invention is to provide a drug delivery system capable of oral / topical administration of an anti-inflammatory agent or a salt thereof for treating esophageal diseases with enhanced local efficacy.

[0011] Another object of the present invention is to provide a delivery system that allows the use of an anti-inflammatory agent or a salt thereof at comparably low doses, thereby minimizing potential side effects.

[0012] The objects of the invention are achieved by the subject matter of the independent claims. Preferred embodiments are the subject matter of the dependent claims.

[0013] Claimed Subject Matter

[0014] In a first aspect, the present invention provides a drug delivery system for esophageal mucosa, comprising at least one sheet-like preparation containing an active pharmaceutical ingredient, in particular a film-shaped, foil-shaped or wafer-shaped preparation.

[0015] Formulations;

[0016] Release agencies; and

[0017] Trigger mechanism, where

[0018] The trigger mechanism is suitable for triggering the release mechanism to release the preparation at a predetermined site of action, and wherein the release mechanism is suitable for releasing the preparation while moving along the esophageal mucosa,

[0019] wherein the drug delivery system further comprises a housing, wherein the housing contains a formulation, and wherein the housing comprises an aperture as part of a release mechanism, the aperture being configured to allow the formulation to exit the housing, and wherein the trigger mechanism is a retaining device that is part of or attached to the formulation such that the formulation spreads or unfolds as the dosage form moves down the esophageal mucosa and exits the housing through the aperture,

[0020] It is characterized in that the active pharmaceutical ingredient comprises an anti-inflammatory agent or a salt thereof, and preferably one or more additional active pharmaceutical ingredients.

[0021] In one embodiment, the anti-inflammatory agent reduces or blocks inflammation, preferably in the esophageal epithelium, and / or fibrosis, preferably in the esophageal subepithelium.

[0022] In one embodiment, the anti-inflammatory agent comprises an immunosuppressant, preferably selected from the group consisting of tyrosine kinase inhibitors, calcineurin inhibitors, and purine analogs, preferably thiopurine analogs.

[0023] In one embodiment, the tyrosine kinase inhibitor is a Janus kinase (JAK) inhibitor selected from the group consisting of upadacitinib (ABT-494), baricitinib, brepocitinib, abrocitinib (PF-04965842), ifidancitinib (ATI-502), tofacitinib, ruxolitinib, delgocitinib (JTE-052), cerdulatinib, gusacitinib (ASN002) and izencitinib (TD-1473), preferably tofacitinib.

[0024] In one embodiment, the calcineurin inhibitor is selected from the group consisting of sirolimus (rapamycin), tacrolimus (FK-506), pimecrolimus, and cyclosporine A.

[0025] In one embodiment, the purine analog is azathioprine (AZA) or 6-mercaptopurine (6-MP).

[0026] In one embodiment, the salt of the anti-inflammatory agent is selected from citrate, phosphate and borate, preferably citrate.

[0027] In one embodiment, the salt of the anti-inflammatory agent is a salt of a JAK inhibitor, preferably a salt of tofacitinib, more preferably tofacitinib citrate.

[0028] In one embodiment, the sheet-shaped formulation, in particular the film-shaped, foil-shaped or sheet-shaped formulation comprising the active pharmaceutical ingredient comprises polyvinyl alcohol (PVA).

[0029] In one embodiment, the sheet-shaped formulation, in particular a film-shaped, foil-shaped or sheet-shaped formulation comprising the active pharmaceutical ingredient comprises a plasticizer, preferably glycerol.

[0030] In one embodiment, the one or more additional active pharmaceutical ingredients is a steroid, preferably a steroid selected from the group consisting of budesonide, fluticasone and mometasone.

[0031] In a second aspect, the present invention provides a drug delivery system according to any one of the preceding claims for use in treatment; or for the treatment or prevention of esophageal diseases, preferably refractory esophageal diseases; or for the treatment or prevention of esophageal diseases caused by or associated with immune system defects, such as inflammatory diseases, fibrosis or allergies, preferably allergies caused by or associated with environmental allergens and / or food allergens; or for the treatment or prevention of eosinophilic esophagitis, preferably refractory eosinophilic esophagitis and / or esophageal stenosis. DETAILED DESCRIPTION

[0032] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0033] It is noted that use of the indefinite article "a" or "an" means "one or more." Thus, for example, the term "esophageal disease" includes the incorporation of "an" and "more than one" esophageal disease.

[0034] As used herein, the terms "include" or "comprising" mean "including, but not limited to". The terms are intended to be open-ended to specify the presence of any stated features, elements, integers, steps, or components, but do not preclude the presence of adding one or more other features, elements, integers, steps, components, or combinations thereof. The terms "include" or "comprising" therefore encompass the more restrictive terms "consisting of" and "consisting essentially of". In one embodiment, the terms "include" or "comprising" used throughout the application, especially in the claims, may be replaced by the term "consisting of".

[0035] Drug delivery systems comprising pharmaceutical formulations, but with different active pharmaceutical ingredients, and their uses are described in PCT / EP2015 / 002601, which is incorporated herein by reference in its entirety, in particular with respect to the invention according to PCT / EP2015 / 002601. Figure 8a , 8bIn other words, the size, shape and composition of the housing, aperture, release and trigger mechanism and retaining device have been described in the references at least to a large extent.

[0036] The drug delivery system as described in PCT / EP2015 / 002601 is designed such that it comprises at least one sheet-like preparation, in particular a film-shaped, foil-shaped or sheet-shaped preparation, comprising an active pharmaceutical ingredient; a release mechanism; and a trigger mechanism, wherein the trigger mechanism is suitable for triggering the release mechanism to release the sheet-like preparation at a predetermined site of action, in particular the gastrointestinal tract. Figure 8a , 8b , 8c, the dosage form has an elongated strip-shaped preparation containing an active pharmaceutical ingredient. The preparation can be arranged in a compact state and an expanded state. The dosage form has a capsule device, such as a shell, which includes a hollow space for accommodating a compact preparation, the capsule device has a hole, and the first end of the preparation extends through the hole in the compact state, so that the preparation can be pulled out of the hollow space into the surrounding area of ​​the capsule, thereby converting the preparation from the compact state to the expanded state.

[0037] The drug delivery system according to the present invention is orally administered, and improves the local utilization of the anti-inflammatory agent or its salt contained in the preparation. This is in contrast to traditional oral administration systems (such as tablets or capsules), which enter the blood circulation through gastrointestinal absorption and only reach the part / position to be treated.

[0038] Because anti-inflammatory agent or its salt is provided in the form of sheet preparation, particularly film-shaped, foil-shaped, thin sheet or strip preparation, local utilization is improved. This advantageously allows sheet preparation (and anti-inflammatory agent or its salt present therein) to be directly released to the position / position (treatment site) to be treated, such as esophageal mucosa. Therefore, preferably, a large area of ​​sheet preparation is exposed to mucosa, i.e., exposed to esophageal mucosa. When exposed to mucosa, the sheet preparation releases anti-inflammatory agent or its salt. In addition, preferred direct contact between mucosa and preparation causes the effective effect of anti-inflammatory agent or its salt at treatment site. Due to the direct delivery of anti-inflammatory agent or its salt to treatment site, compared with the use of conventional preparations such as suspension or solution, less medicament is needed to cause systemic bioavailability reduction and concentration reduction in adjacent areas such as healthy areas. In addition, direct delivery to treatment site also allows the dosage of anti-inflammatory agent or its salt contained in the preparation to be reduced, thereby advantageously further reducing side effects.

[0039] Drug delivery system according to the present invention also advantageously allows relatively simple and discrete processing and simple, particularly space-saving storage.When compared with solution and gel, the anti-inflammatory agent or its salt included in the drug delivery system according to the present invention has improved stability, for example, under high heat and high humidity.No free water is usually left in the drug delivery system according to the present invention, which further improves stability and reduces the risk of compositions such as moldiness or unavailable.Extra additives can be avoided, such as preservatives or other stabilizers, which is advantageous because known these additives can cause allergies or other side effects.

[0040] Furthermore, the destruction of the active pharmaceutical ingredient before reaching the intended site of action, for example by gastric acid and / or digestive enzymes, is advantageously minimized by the drug delivery system according to the present invention.

[0041] Release mechanism

[0042] Release mechanism relates to the mechanism that sheet preparation is expanded and released from capsule device (such as shell).Described shell contains sheet preparation of compact form.After trigger mechanism has started to release, described release mechanism releases preparation from shell.Described release mechanism preferably releases sheet preparation by can at least partially pull out shell of preparation.Therefore, sheet preparation is adjusted so that described sheet preparation can be expanded to predetermined degree by release mechanism.For example, described shell contains preparation of folded form, and described release mechanism expands preparation from its compact form (such as, from folded form) into its expanded form (such as, unfolded form).Therefore, described release mechanism causes the unfolding of preparation.In compact form, described preparation has less spatial range, such as, preparation is gathered together, coiled or wound or forms less spatial form in another way.This also allows to provide small dosage form, i.e. small shell, which makes oral intake of particularly drug delivery system more convenient for patient.In its expanded form, the surface area of ​​described sheet preparation increases by expansion, such as by unfolding sheet preparation, particularly the surface area of ​​preparation containing anti-inflammatory agent or its salt increases. Preferably, the surface area of ​​the preparation, particularly the surface area containing the anti-inflammatory agent or its salt and contacting the esophageal mucosa, is in the order of magnitude of the surface area of ​​the esophageal mucosa. When the shell moves downward along the esophageal mucosa, the preparation is released. For example, during the process of the patient swallowing the dosage form, the preparation is released from the shell through the hole. Therefore, the shell includes a hole as a part of the release mechanism, and the hole is configured to allow the preparation to leave the shell.

[0043] hole

[0044] In this respect, the hole is in the shell, i.e., forms an opening in the capsule device. In a preferred embodiment of the drug delivery system, the hole is formed as a slit. The slit is arranged so that the sheet preparation is released from the shell through the hole. This slit can be embodied in different arrangements and structures. For example, this hole is described in EP21175427.0, EP21175436.1, PCT / EP2015 / 002601 and PCT / EP2020 / 056934, and these patents are incorporated herein by reference in their entirety about the contents of the capsule device and hole.

[0045] Trigger mechanism / holding device

[0046] The drug delivery system comprises a trigger mechanism, wherein the trigger mechanism is suitable for triggering a release mechanism to release the sheet-like preparation at a predetermined action site, wherein the trigger mechanism is a holding device that is a part of the preparation or attached to the preparation.

[0047] Preferably, the preparation comprises a retaining device, and further preferably, the preparation comprises a retaining device positioned at one end of the preparation, and the retaining device particularly extends out of the shell through a hole. When the retaining device is fixed, the preparation can be taken out from the capsule device by pulling motion and / or force. The fixing of the retaining device is preferably realized by the retaining device being connected to a retainer. This retainer can be a rope member, such as a thick rope, a fine line or a tether. In a preferred embodiment, the retaining device is connected to an end of the preparation and an end of the thick rope, and the other end of the thick rope is fixed to an applicator, such as a retainer fixed to an applicator.

[0048] Preferably, the holding means is attached to the sheet-like preparation. Thus, the retainer, ie the string member or a part of the string member, forms the holding means. For example, one end of a thick string connected to the preparation forms the holding means.

[0049] Alternatively, the retaining device is adapted to be secured in the oral cavity, or the retaining device is adapted to be held in the hand during administration of the drug delivery system, such that the dosage form is spread and / or unfolded while the dosage form moves down the esophageal mucosa and exits the housing through the aperture.

[0050] In a preferred embodiment, a portion of the string member is connected to an end of the preparation, which extends out of the hole of the capsule device. Therefore, the holding device is formed by the extended end of the preparation and the string member connected thereto, and another portion of the string member serves as a retainer to retain the holding device so that it does not move when the preparation is swallowed, thereby generating a pulling force on the preparation, and when the capsule device moves down the esophagus, the pulling force pulls the preparation out of the capsule device.

[0051] It should be understood that the terms "site of action" and "site of application" as used herein are used interchangeably. In this regard, it should also be understood that "site of action" and "site of application" refer to the intended location of release of the formulation. In addition, the anti-inflammatory agent or salt thereof released at the "site of action" or "site of application" may also exert its actual biochemical effect at another location in the body or at another location in the biochemical cycle, for example, during or after liver metabolism or when the agent reaches its target molecule. As used herein, "site of action" and "site of application" do not necessarily refer to the location of the biochemical, medical action of the active pharmaceutical ingredient.

[0052] Capsule device / housing

[0053] The drug delivery system according to the present invention also includes a shell, wherein the shell contains at least one sheet preparation, particularly film-shaped, foil-shaped or thin sheet-shaped preparation, the preparation comprises an anti-inflammatory agent or its salt, and wherein the shell includes a hole as a part of a release mechanism, the release mechanism is configured to allow the preparation to leave the shell, so that when the dosage form moves downward along the esophageal mucosa and leaves the shell through the hole, the preparation is spread out or launched. The shell can be further prepared so that it protects the preparation from undesirable release. The shell is a capsule device, particularly with the shape of a capsule.

[0054] In a preferred embodiment, the shell includes a first half capsule shell and a second half capsule shell, and the capsule device is formed by sliding the first half capsule shell into the second half capsule shell to a mating position, so that the hole is formed in the mating position by overlapping the cross-section of the second half capsule shell with the opening located in the first half capsule shell.

[0055] In another embodiment, the two capsule halves are nested within each other, and the opening of the first capsule housing half is covered by a further provided overlapping wall portion, such as a patch or tape, attached to the first and / or second capsule housing half.

[0056] In another embodiment, the capsule halves are shaped like two nut shells and are positioned on top of each other to form a capsule. The hole is formed by a cutout, particularly in the edge of one of the two shells. Alternatively, the cutout may be formed on the edge of the two halves, which, when positioned and aligned on top of each other, form the hole.

[0057] In a preferred embodiment of the drug delivery system according to the invention, the shell is made of a material selected from the group consisting of hard gelatin, polymers, thermoplastics (e.g. Eudragit, etc.). In this respect, in particular, materials that have been successfully tested, used and / or authorized may be beneficial, for example for oral dosage forms.

[0058] For example, such a capsule device or housing is further described in EP21175427.0, EP21175436.1 and PCT / EP2020 / 056934, and the contents of these patents regarding the capsule device are incorporated herein by reference in their entirety.

[0059] Condition to be treated

[0060] The drug delivery system described herein is used in therapy. In one embodiment, it is suitable for treating and preventing esophageal diseases, preferably refractory esophageal diseases. In one embodiment, it is suitable for treating and preventing allergies, preferably allergies caused by or associated with environmental allergens and / or food allergens. In one embodiment, it is suitable for treating and preventing inflammatory diseases. In one embodiment, it is suitable for treating and preventing fibrosis. In one embodiment, it is suitable for treating and preventing eosinophilic esophagitis, preferably refractory eosinophilic esophagitis. In one embodiment, it is suitable for treating and preventing esophageal stenosis.

[0061] In this application, the term "treatment and / or prevention" includes any means of improving a condition to be treated or preventing the condition to be treated from occurring. It also includes preventing the condition from getting worse and minimizing the severity of the condition.

[0062] Esophageal disease can be any disease or condition that interferes with the function or structure of the esophagus. Esophageal disease includes, but is not limited to, refractory esophageal disease, such as after first-line treatment. For example, refractory esophageal disease relates to esophageal disease for which treatment is unsuccessful or inadequate, i.e., despite treatment, the specific symptoms of the esophageal disease persist. Refractory esophageal disease may also refer to recurrence after treatment. Therefore, in one embodiment, the present invention relates to the treatment of refractory esophageal disease, i.e., second-line treatment.

[0063] Preferred esophageal diseases include esophageal diseases caused by or associated with immune system defects. For example, the esophageal disease may be a Th2-lymphocyte mediated disease or condition involving inappropriate Th2-lymphocyte proliferation and / or activity. For example, inappropriate proliferation and / or activity may be increased proliferation and / or increased activity of Th2-lymphocytes. Inappropriate Th2-lymphocyte activity may also involve an increase in cytokine release or cytokine release in response to inappropriate stimulation. Inappropriate stimulation may be an allergen, such as an environmental allergen in the air or food.

[0064] In a preferred embodiment of the present invention, the esophageal disease is eosinophilic esophagitis, including but not limited to refractory eosinophilic esophagitis. In another embodiment, the esophageal disease to be treated in the context of the present invention is esophageal stricture.

[0065] Eosinophilic esophagitis is a chronic, immune-mediated inflammatory disease of the esophagus. Clinically, eosinophilic esophagitis is associated with symptoms such as dysphagia, food impaction, chest pain, heartburn, and spontaneous perforation. Histologically, eosinophilic esophagitis is characterized by mucosal inflammation dominated by eosinophils. A major complication associated with eosinophilic esophagitis is the infiltration of eosinophils into the subepithelial layer of the esophagus, resulting in fibrosis. Untreated eosinophilic esophagitis leads to esophageal remodeling with fibrosis, wall thickening, abnormal fragility, and stricture, ultimately causing structural and functional damage to the esophagus with complications such as acute food impaction. Treatment options include diet, esophageal dilation, and medications such as corticosteroids or compounds to reduce reflux. The diet involves the serial elimination of specific foods with the goal of identifying food allergens that cause inappropriate responses of the immune system and inflammation. The diet is tedious and requires a high level of patient motivation. Although esophageal dilation leads to symptomatic improvement in 75% of patients with fibrostenotic eosinophilic esophagitis, dilation does not affect the underlying inflammation and is therefore not suitable as a stand-alone therapy. Traditional medical treatments for eosinophilic esophagitis include proton pump inhibitors or topically applied steroids such as budesonide, fluticasone, or mometasone. Steroids are topically applied in the form of oral viscous suspensions, effervescent tablets, or aerosol sprays. These dosage forms typically have a low contact time, which may be a relevant factor for inappropriate responses and missed long-term remissions. In addition, after cessation of steroid therapy, relapse rates are high and long-term treatment is required to maintain remission. Therefore, there is still a need for new treatment options in the art.

[0066] The frequency of administration of the drug delivery device and the treatment period or application time point are not limited and may depend on the specific disease to be treated and / or the amount of active pharmaceutical ingredient of each drug delivery device. For example, the drug delivery device may be applied once a day or twice a day. If the drug delivery device is applied once a day, it is preferably applied at night to increase the patient's compliance. The drug delivery system of the present invention is preferably applied before going to sleep, i.e. after dinner and after oral hygiene. The treatment period may be between 7 days and 40 days, preferably 14 days to 30 days, more preferably 20 days to 28 days. Treatment may include a single treatment cycle or multiple cycles of the treatment period, such as 2, 3, 4, 5, 6, 7, 8, 9, 10 or more treatment periods.

[0067] Active pharmaceutical ingredients

[0068] As used herein, the term "active pharmaceutical ingredient" is used interchangeably with the term "active ingredient" or "API" and refers to an anti-inflammatory agent or a salt thereof.

[0069] The term "therapeutically effective dose" or "effective amount" refers to a dose or amount that produces the desired effect of administration. The exact dose or amount will depend on the purpose of the treatment and can be determined by those skilled in the art using known techniques. The term "therapeutically effective amount" is an amount that is effective to improve (the symptoms of) the disease. A therapeutically effective amount can be a "prophylactically effective amount" because prevention can be considered a therapy.

[0070] "Anti-inflammatory agent or its salt" refers to a compound, such as a small molecule, that reduces, prevents, blocks or interferes with an inflammatory response (preferably a chronic inflammatory response) of the immune system. For example, the anti-inflammatory agent or its salt can reduce, prevent, block or interfere with inflammation in the esophageal mucosa, more preferably inflammation in the esophageal epithelium. Alternatively, or in addition, the anti-inflammatory agent or its salt can reduce, prevent, block or interfere with fibrosis in the esophageal mucosa, more preferably fibrosis in the subepithelial membrane of the esophagus. At the molecular functional level, the anti-inflammatory agent or its salt can reduce, prevent, block or interfere with the proliferation and / or activity of lymphocytes, such as the release of cytokines. Alternatively, the anti-inflammatory agent or its salt can reduce, prevent, block or interfere with the movement of leukocytes (such as granulocytes, preferably eosinophils) from the blood circulation to tissues (preferably to the esophagus, more preferably to the esophageal mucosa), such as chemical attraction. The anti-inflammatory agent or its salt can exist as any type of compound, including but not limited to ionic compounds such as salts. The inventors have found that the anti-inflammatory agent or its salt described herein is particularly stable when formulated as a salt. Salts include, but are not limited to, citrate, phosphate, and borate, with citrate being preferred.

[0071] In one aspect of the present invention, the anti-inflammatory agent or salt thereof is an immunosuppressant. The immunosuppressant may be a tyrosine kinase inhibitor, preferably a cytoplasmic tyrosine kinase inhibitor, such as a JAK inhibitor; a calcineurin inhibitor and a purine analog, preferably a thiopurine analog.

[0072] In a preferred embodiment, the anti-inflammatory agent or salt thereof is a tyrosine kinase inhibitor, more preferably a JAK inhibitor.

[0073] A tyrosine kinase is an enzyme that phosphorylates a substrate, i.e., it transfers the terminal γ-phosphate group of a nucleotide (e.g., ATP) to the hydroxyl group of a substrate (e.g., a protein). The name tyrosine kinase refers to the substrate specificity of the kinase, i.e., the tyrosine kinase phosphorylates the hydroxyl group of the amino acid tyrosine. The tyrosine kinase inhibitor may be directed against cytoplasmic tyrosine kinases, such as JAK kinases.

[0074] "JAK inhibitor" as used herein refers to a compound that reduces, blocks, inhibits or interferes with the expression or activity of JAK kinases. The JAK kinase family includes four isozymes, JAK 1, JAK 2, JAK 3 and tyrosine kinase 2 (TYK 2). JAK kinases are associated with the intracellular domain of cytokine receptors, cross-phosphorylating and transmitting extracellular signals by phosphorylating signal transduction and transcription activator proteins (STATs). Phosphorylated STATs form dimers and are transported to the nucleus, where they act as transcription factors and regulate gene expression. Therefore, JAK inhibitors can reduce or block the expression and / or activity of one or more JAK family members (JAK1, JAK2, JAK3, TYK2), thereby interfering with the JAK-STAT signal transduction pathway.

[0075] JAK inhibitors are used to treat neoplasia and immune-mediated inflammation, such as inflammatory bowel disease or rheumatoid arthritis. ) is a JAK1 and JAK3 inhibitor that has been approved for the systemic treatment of rheumatoid arthritis. A placebo-controlled phase IIa study using tofacitinib for the topical treatment of atopic dermatitis showed convincing results. Tofacitinib has also been shown to significantly improve the appearance of the esophagus and to minimize the number of eosinophils found in esophageal biopsies after 3 months of treatment in a 34-year-old man with a long-standing diagnosis of eosinophilic esophagitis. JAK inhibitors have also been shown to be effective in hypereosinophilic syndrome, bronchial asthma, and eosinophilic fasciitis. In addition, JAK-STAT6 pathway inhibitors have been described to block Th2 cytokine-stimulated eotaxin-3 secretion from epithelial cells and fibroblasts from patients with eosinophilic esophagitis, suggesting a potential role for JAK-STAT inhibitors in the treatment of epithelial inflammation and subepithelial fibrosis. Therefore, JAK inhibitors are promising drug candidates for disease remission and treatment of eosinophilic esophagitis, especially as second-line therapy for patients who show limited response to steroids.

[0076] The JAK inhibitor may be a small molecule. Furthermore, the JAK inhibitor may reduce or block the release of eosinophil chemoattractants, preferably eotaxin-3, from epithelial cells and / or fibroblasts, preferably esophageal epithelial cells and / or epithelial fibroblasts.

[0077] In addition, JAK inhibitors can be selective for one or more JAK kinases. For example, JAK inhibitors can be selective for JAK 1, such as upadacitinib or abrocitinib. Alternatively, JAK inhibitors can be selective for JAK 1 and JAK 2, such as baricitinib or ruxolitinib. In another embodiment, JAK inhibitors can be selective for JAK 1 and JAK 3, such as tofacitinib or ifidancitinib. In another embodiment, JAK inhibitors can be selective for JAK 1 and TYK 2, such as brepocitinib. JAK inhibitors can also be pan-JAK inhibitors that are selective for all isozymes, such as digaotinib. In addition, JAK inhibitors can play a dual role for JAK kinases and other tyrosine kinases. For example, JAK inhibitors can play a dual role for JAK kinases and tyrosine protein kinase SYK (also known as spleen tyrosine kinase), such as gusacitinib.

[0078] In a preferred embodiment, the JAK inhibitor is selected from the group consisting of upadacitinib (ABT-494), baricitinib, brepocitinib, abrocitinib (PF-04965842), ifidacitinib (ATI-502), tofacitinib, ruxolitinib, digaotinib (JTE-052), seletinib, gusacitinib (ASN002) and izencitinib (TD-1473), more preferably tofacitinib.

[0079] In a further preferred embodiment, the anti-inflammatory agent or a salt thereof is a salt of a JAK inhibitor, preferably a salt of tofacitinib, more preferably tofacitinib citrate.

[0080] In a further embodiment, the anti-inflammatory agent or salt thereof is a calcineurin inhibitor. Calcineurin inhibitors are compounds that inhibit, reduce, block or interfere with calcineurin, an enzyme that activates T cells through the transcription factor nuclear factor (NF-AT) that activates T cells. Due to the key role of T cells in cell-mediated immunity, calcineurin inhibitors inhibit this cell-mediated immune response. Calcineurin inhibitors are administered systemically for the treatment of immune-mediated diseases and the prevention of organ rejection after transplantation. Since 2000, topical calcineurin inhibitors have been widely used to treat immune-mediated diseases of the skin (such as atopic dermatitis), immune-mediated diseases of the eyes and eye-nose-throat (ENT) area. Their efficacy for these indications has been demonstrated in multiple controlled trials. The risk of systemic side effects is minimal. The multiple proven efficacy of topical treatment of immune-mediated diseases with calcineurin inhibitors, their excellent safety profile when used topically, and their mode of action make these compounds promising for topical treatment of eosinophilic esophagitis.

[0081] In one embodiment, the calcineurin inhibitor reduces or blocks the activation of lymphocyte transcription factors, preferably the activation of T lymphocyte transcription factors, more preferably the activation of nuclear factor of activated T cells (NF-AT). In a preferred embodiment, the calcineurin inhibitor is selected from the group consisting of tacrolimus (FK-506), pimecrolimus, sirolimus (rapamycin) and cyclosporin A.

[0082] In another further embodiment, the anti-inflammatory agent or salt thereof is a purine analog. As used herein, a purine analog refers to a compound having structural and / or functional similarity to purine. A purine analog having structural similarity to purine can be a purine derivative, such as a thiopurine.

[0083] Systemically administered purine analogs have been established for decades in the treatment of chronic inflammatory bowel disease, particularly ulcerative colitis and Crohn’s disease. In a small clinical trial, two purine analogs, azathioprine (AZA) and 6-mercaptopurine (6-MP), administered systemically have been shown to be effective in the treatment of refractory eosinophilic esophagitis. Topical azathioprine has been used to treat atopic dermatitis and chronic oral graft-versus-host disease. In a prospective, single-blind study, 70 young patients with moderate or severe atopic dermatitis were treated twice daily for 8 weeks with either a steroid cream alone or a combination of a steroid and an azathioprine moisturizer. The combination of steroids and azathioprine was slightly superior to steroid monotherapy and was well tolerated. A case of refractory oral graft-versus-host disease was treated with azathioprine in the form of a suspension, administered topically and systemically. Additional topical application appeared to add some clinical benefit and was well tolerated. In conclusion, the observations of effects of systemically administered purine analogs, first in eosinophilic esophagitis, and of topically administered azathioprine, second in immune-mediated skin and oral diseases, make these compounds, especially azathioprine, promising for further evaluation in the topical treatment of eosinophilic esophagitis.

[0084] In a preferred embodiment, the purine analog is an azathioprine analog selected from the group consisting of azathioprine or 6-mercaptopurine.

[0085] The present invention provides a drug delivery system comprising an anti-inflammatory agent or a salt thereof as described herein. The drug delivery system described herein may also include one or a combination of (eg, two or more different) anti-inflammatory agents or salts thereof described herein.

[0086] Additional Active Pharmaceutical Ingredients

[0087] The API in this dosage form may be administered together with an additional API.

[0088] Additional APIs that may be present in addition to the anti-inflammatory agent or its salt are referred to herein as "additional active pharmaceutical ingredients" or "additional active ingredients" or "additional APIs". In principle, any additional pharmaceutically active agent that enhances or increases the efficacy of the anti-inflammatory agent or its salt may be used. Such additional APIs may be selected by the skilled person according to his or her general knowledge according to the condition to be treated and / or prevented. For the purposes of the present invention, the additional pharmaceutically active agent may be a steroid, for example a steroid selected from the group consisting of budesonide, fluticasone and mometasone; or an antibody, preferably selected from the group consisting of an anti-IL-5 antibody (preferably beralizumab), an anti-IL-13 antibody (preferably RCP4046) and an anti-IL4 / 13 antibody (preferably dupilumab).

[0089] preparation

[0090] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-like preparation is a sheet or is formed into a sheet. The term "sheet" used herein refers to a sheet-like object including a plurality of layers for encapsulating an anti-inflammatory agent or a salt thereof.

[0091] Such a sheet can conform to the irregular surface contours of the intended site of action, in particular the irregular surface contours of the esophageal mucosa, in particular after the sheet absorbs the moisture contained in the esophageal mucosa. In addition, the sheet-like preparation of the dosage form according to the present invention can be gellable or swellable.

[0092] In a preferred embodiment of the drug delivery system according to the present invention, the thickness of the sheet-like preparation is 0.01 mm to 2 mm, preferably 0.03 mm to 1 mm, preferably 0.05 mm to 0.1 mm. This is conducive to providing a sheet-like preparation with a relatively small thickness.

[0093] In a preferred embodiment of the drug delivery system according to the present invention, the area of ​​the sheet preparation is 0.5 to 25 cm 2 , preferably 1 to 10 cm 2 .

[0094] The sheet preparation can have different shapes. In particular, the sheet preparation can have a circular, triangular, quadrilateral or polygonal shape. In one embodiment, the hole is adapted to the corresponding shape of the preparation.

[0095] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-shaped preparation comprising an anti-inflammatory agent or a salt thereof, particularly a film-shaped, foil-shaped or thin sheet-shaped preparation, contains an anti-inflammatory agent or a salt thereof in an amount of 0.0001 to 50% by weight, preferably 0.001 to 25% by weight, most preferably 0.01 to 10% by weight.

[0096] The sheet preparation containing an anti-inflammatory agent may have a single-layer or multi-layer structure, in which at least one layer (preferably the first layer) contains the anti-inflammatory agent or a salt thereof.

[0097] In a preferred embodiment, the sheet preparation has a multilayer structure of multiple layers, wherein at least the first layer contains an anti-inflammatory agent or a salt thereof, and wherein at least another layer contains at least one additional active pharmaceutical ingredient, which is the same or different anti-inflammatory agent or a salt thereof, or is not an anti-inflammatory agent or a salt thereof, such as a steroid.

[0098] In a preferred embodiment, the layer containing the anti-inflammatory agent or a salt thereof and / or the further layer containing the additional active pharmaceutical ingredient comprises a polymer, preferably a film-forming polymer.

[0099] The polymer in the layer may be used only as a carrier for the anti-inflammatory agent or its salt and / or additional API, or it may be used as a reservoir thereof. Such a layer may release the anti-inflammatory agent or its salt and / or additional active pharmaceutical ingredient under the action of a fluid. The anti-inflammatory agent or its salt and / or additional API may be released immediately or in a controlled release manner.

[0100] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-like preparation comprises at least one first layer containing an anti-inflammatory agent or a salt thereof and / or another layer containing an anti-inflammatory agent or a salt thereof and / or an additional API, wherein the at least one first layer and / or another layer is an adhesive layer.

[0101] In a preferred embodiment of the drug delivery system according to the present invention, at least one first layer containing the active ingredient and / or the further layer containing the active ingredient comprises a polymer, preferably a film-forming polymer, wherein the polymer is a water-dispersible and / or decomposable and / or water-disintegrable film-forming polymer.

[0102] The polymer for the first layer containing the active substance and / or for the further layer containing the active substance can be selected from the group comprising polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetate, polyethylene glycol, polyethylene oxide polymers, polyurethanes, polyacrylic acid, polyacrylates, polymethacrylates, poly(methyl vinyl ether-maleic anhydride), starch, starch derivatives, natural gums, alginates, pectins and gelatins, pullulan, gel-forming proteins, chitosan, agar, agarose, carrageenan, xanthan gum, tragacanth gum, dextran and cellulose ethers such as ethylcellulose, hydroxyethylcellulose, propylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylethylcellulose, cellulose acetate, povidone and copovidone. In a preferred embodiment, the polymer is polyvinyl alcohol, preferably polyvinyl alcohol 18-88.

[0103] The polymers can be used alone or in combination with one another to produce a sheet preparation for a dosage form according to the invention which has the desired properties, such as adhesion, release or disintegration properties.The sheet preparation according to the invention can consist of a single polymer layer.

[0104] Furthermore, the sheet-like preparation according to the dosage form of the present invention may have a two-layer or multi-layer structure, at least one layer containing an anti-inflammatory agent or a salt thereof. It is also possible that multiple layers contain an anti-inflammatory agent or a salt thereof or an additional API.

[0105] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-like preparation comprising an anti-inflammatory agent or a salt thereof comprises a monolayer structure or is composed of a monolayer structure, wherein the (preferably first) layer contains an anti-inflammatory agent or a salt thereof, preferably tofacitinib citrate. The layer comprises a polymer, preferably a film-forming polymer, wherein the polymer is a water-dispersible and / or decomposable and / or water-disintegratable film-forming polymer. The polymer is a polymer as described herein, preferably polyvinyl alcohol, preferably polyvinyl alcohol 18-88. The layer also comprises an additive as described herein, such as a plasticizer, preferably glycerol.

[0106] In another preferred embodiment of the drug delivery system according to the present invention, the sheet-form preparation comprising an anti-inflammatory agent or a salt thereof comprises at least one first active ingredient-free layer containing no active pharmaceutical ingredient.

[0107] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-shaped preparation, particularly the film-shaped, foil-shaped or sheet-shaped preparation, comprising the active pharmaceutical ingredient comprises at least one other active ingredient-free layer containing no active pharmaceutical ingredient.

[0108] In a preferred embodiment of the drug delivery system according to the present invention, the first inactive ingredient layer and / or at least one other inactive ingredient layer is a water-insoluble layer, which preferably comprises a water-insoluble substance selected from ethylcellulose and / or a combination of ethylcellulose and other water-insoluble substances, a hydrophobic plasticizer, especially triethyl citrate, and / or a dye and / or an aromatic and / or a flavoring agent.

[0109] In particular, the use of ethylcellulose may be beneficial due to its properties, including good processability, biocompatibility, and water insolubility.

[0110] In a preferred embodiment of the drug delivery system according to the present invention, the first inactive ingredient layer and / or at least one other inactive ingredient layer is an adhesive layer of a desired thickness.

[0111] The adhesive layer may be a mucoadhesive polymer selected from the group consisting of cellulose derivatives such as hydroxypropylcellulose, starch and starch derivatives, polyvinyl alcohol, polyethylene oxide, polyethylene, polypropylene, polyacrylic acid and polyacrylate derivatives, polyvinyl pyrrolidone, povidone, copovidone, sodium alginate, gelatin, xanthan gum, carrageenan, pectin, dextran, lectin, chitosan, pullulan and mixtures thereof.

[0112] Additionally, or alternatively, the adhesive layer may comprise a solvent selected from the group consisting of water, ethanol, methanol, acetone, organic solvents and mixtures thereof.

[0113] In addition, the formulation may also contain additives such as colorants, fragrances, flavoring agents, preservatives, antioxidants, penetration enhancers, solubilizers, disintegration accelerators, pore formers, lubricants and mixtures thereof. In particular, the following substances qualify as additives: lubricants, lubricants, glidants, binders, additional active ingredients, disintegrants, antioxidants, chelating agents, coating agents, flow agents, preservatives, fillers, surfactants, plasticizers and pigments. In addition, the additives may be selected from the following groups: pore formers, penetration enhancers, solubilizers, emulsifiers, including polyethoxylated sorbitan fatty acid esters, ethoxylated fatty alcohols and lecithin; plasticizers, including polyethylene glycol, glycerol and other polyols, higher alcohols such as dodecanol, undecanol or octanol, sorbitol, mannitol and other sugar alcohols, dexpanthenol and triglycerides; fillers, including highly dispersed silicon dioxide, titanium dioxide, zinc oxide, chalk and starch; colorants; sweeteners and flavoring agents; wetting agents; preservatives agents; pH regulators and antioxidants; disintegration accelerators; penetration enhancers that promote reabsorption of the active pharmaceutical ingredient into the mucosa, such as cellular uptake, for example fatty acids, their salts and fatty acid esters, preferably saturated fatty acids such as caprylic acid (C8), capric acid (C10), octadecanoic acid (C18), or unsaturated fatty acids such as oleic acid (C18), salcaprozate (SNAC) or its salts, terpenes, glycolipids, medium chain triglycerides, synthetic waxes such as isopropyl myristate, branched fatty alcohols such as Eutanol Urea, polypropylene glycol, dimethyl sulfoxide, azone, azone analogs, polyols such as propylene glycol, tocopherol or essential oils such as menthol. A preferred plasticizer is glycerol.

[0114] The sheet preparation may further comprise at least one taste-masking additive. This advantageously masks the active pharmaceutical ingredient of bitterness or other unpleasant tastes, but is also conducive to accelerating the onset of the active pharmaceutical ingredient. The taste-masking additive is well known to those skilled in the art. This taste-masking additive can especially include sugar alcohols and sodium bicarbonate selected from mannitol, sorbitol, xylitol, maltitol, lactitol, erythritol, threitol and isomalt.

[0115] In particular, the additives may increase the local availability of the active ingredient, such as penetration enhancers.

[0116] According to a preferred embodiment, the drug delivery system according to the present invention, particularly the sheet preparation, is intended to achieve the delayed release of active ingredients. The anti-inflammatory agent or its salt is preferably released in a period of 4 hours, preferably in a period of 6 hours, and most preferably in a period of 8 hours. In order to achieve the delayed release of active ingredients in the case of a double or multi-layer preparation, at least one layer in the layer containing the anti-inflammatory agent or its salt, particularly the polymer layer, has the delayed release of active ingredients.

[0117] For delayed release of the active ingredient, the film-shaped preparations are preferably formulated as slowly dissolving or slowly disintegrating films, which completely disintegrate or dissolve only after a few hours. Preferably, they completely disintegrate or dissolve only after 4 hours, preferably only after 6 hours, even most preferably only after 8 hours or even only after 24 hours.

[0118] In particular, the anti-inflammatory agent or salt thereof and optionally the additional API are released over a period of 15 minutes to 24 hours, 2 hours to 24 hours, 3 hours to 12 hours, 4 hours to 8 hours or 5 hours to 6 hours.

[0119] The sheet-like preparation can be prepared by a person skilled in the art by methods known in principle, for example by coating an inert support with a liquid composition comprising a polymer, an anti-inflammatory agent or a salt thereof / additional active pharmaceutical ingredient and optional additives and a solvent, by a method involving, for example, a doctor blade (e.g., solvent casting), a spray processor or an extrusion processor. The film layer obtained in this way is dried. For multilayer sheet-like preparations, one or more coatings can be applied to an existing film layer in the same manner, or can be manufactured separately and subsequently laminated.

[0120] In the process of preparing the formulation, the temperature sensitivity, pH sensitivity and / or solubility of the anti-inflammatory agent or its salt used need to be considered. Therefore, in view of the lower dose required for regional / local administration compared with systemic administration, an impregnation method can be used. In this method, only a solution containing the anti-inflammatory agent or its salt is applied, such as sprayed or dripped on the polymer film and finally dried.

[0121] In a preferred embodiment, the anti-inflammatory agent or salt thereof may be incorporated so that it is embedded in a polymer film, for example by solvent casting. These methods are known to the skilled artisan and are further described in the examples provided herein.

[0122] In all these methods, attention should be paid to the solvent used and the drying conditions. As a very good drying method, freeze drying can be used.

[0123] Furthermore, depending on the stability of the incorporated anti-inflammatory agent or salt thereof, melt extrusion of the polymer and the anti-inflammatory agent or salt thereof is also conceivable, for example, as described in Example 2 herein.

[0124] Alternatively, a solution containing the anti-inflammatory agent or a salt thereof may be applied to the polymer film by inkjetting.

[0125] In one embodiment, the formulation is prepared so that the anti-inflammatory agent or salt thereof is present only in certain portions of the membrane, which would allow for tailored treatment of the mucosa only in designated areas.

[0126] Alternatively, and preferably, the first area of ​​the sheet preparation can contact with esophageal mucosa, and the second area of ​​the sheet preparation can contact with oral mucosa. In this way, esophageal mucosa can be treated with anti-inflammatory agents or their salts, and oral mucosa is treated or untreated with the second anti-inflammatory agent or its salt, additional API, or additives are released to oral mucosa. Especially, flavoring agents and / or local anesthetics can be released, particularly in order to increase or reduce the generation of saliva and / or make the application of the drug delivery system more pleasant and / or suppress the impulse of vomiting. Alternatively, the first area of ​​the sheet preparation can contact with esophageal mucosa, and the second area of ​​the sheet preparation can contact with the mucosa of the upper stomach (such as cardia or cardia and fundus). Therefore, it is possible to locally treat esophagus and part of the stomach.

[0127] In another preferred embodiment, the drug delivery system, particularly the capsule device, includes a sinker device. The sinker device is configured to provide negative buoyancy to the capsule device. In the experiment of the inventor who supported the discovery of this preferred embodiment, it was found that reducing buoyancy, such as by increasing the mass of the capsule device, led to the reliability of the mechanical process of expanding the preparation from a compact state to an extended state. In the case of a strip preparation, the unwinding of the preparation from a compact state (wherein the strip preparation is wound around the winding shaft) to an extended state is significantly promoted and more effective. The potential problem of this preferred embodiment is that it is observed that the transition of the preparation from a compact state to an extended state is sometimes incomplete. Although the present invention has improved the efficiency of expansion or unwinding by providing a spacing between the opening and the preparation, the sinker device also improves the efficiency of expansion. It is believed that the capsule device, even if swallowed correctly by the patient in the presence of water or an aqueous solution, will not be completely filled with water, but bubbles will sometimes remain in the capsule device. Air contributes to buoyancy, and the sinker device assists in resisting the buoyancy effect by assisting in replacing air or by using a material denser than water using gravity. Further details about the sedimentation section can be inferred from WO2020 / 183005, which is incorporated herein by reference.

[0128] The drug delivery system according to the present invention may also be suitable for application to the nasopharyngeal mucosa.

[0129] When the sheet-like preparation releases the anti-inflammatory agent or its salt locally and / or over a prolonged period of time, optionally together with an additional API, the therapeutic response can be improved, in particular the local effect of the anti-inflammatory agent or its salt can be increased, for example, by a penetration enhancer. Such penetration enhancers are known in the art. In addition, the necessity for systemic administration can be reduced, in particular due to the spatial extension of the area of ​​action.

[0130] In a preferred embodiment of the drug delivery system according to the present invention, the area and / or surface area of ​​the sheet-like preparation is 0.5 to 25 cm 2, preferably 2 to 25 cm 2 , preferably 5 to 25 cm 2 , preferably 5 to 15 cm 2 , preferably greater than 0.5 cm 2 , and preferably less than 40cm 2 Preferably, the ratio of the length of the sheet to the width of the sheet is 40:1 to 400:1, or preferably 60:1 to 300:1, or preferably 80:1 to 200:1. The width may be the average width of the sheet, for example measured perpendicularly to the length of the sheet. The ratio may be the ratio of the length and the circumference of the sheet, in particular the average value of the sheet, wherein in the case of a strip-shaped sheet, the circumference may be, for example, twice the width of the sheet.

[0131] In some embodiments of the drug delivery system according to the present invention, the sheet preparation is in the solid state, particularly when it is in compact form and / or after it has just released. This can beneficially enhance, realize or promote some of the above-mentioned advantages. Especially, when it is in the solid state before release, this can improve storability. Especially, when it is in the solid state after release, this can enhance and / or realize the targeting and / or sustained release of anti-inflammatory agent or its salt. In addition, or alternatively, in some embodiments of the drug delivery system according to the present invention, the sheet preparation is suitable for dissolving immediately, after delay, in a time-controlled mode or under a certain stimulation after its release, such as biodegradation. This can beneficially enhance, realize or promote some of the above-mentioned advantages. Especially, this can improve the convenience of the user, because the sheet preparation does not need to be removed.

[0132] Additionally, or alternatively, in certain embodiments of the dosage form according to the invention, the sheet is adapted to dissolve, e.g. biodegrade, preferably in a time-controlled manner, e.g. within one hour, or within one to two hours, or within one to five hours, or within one to twelve hours, or within one to twenty-four hours. This improves user convenience, as the sheet does not need to be removed.

[0133] Applicator / Retainer

[0134] In one embodiment, an applicator with a retainer is used to assist in swallowing the capsule device in combination with a drinking cup. The applicator combined with the drinking cup allows the patient to take the drug delivery system, just like drinking water from a bottle. Therefore, the applicator is mounted on the drinking cup as an access port (mouthpiece). The drug delivery system is located in the retainer of the applicator. When drinking, the liquid of the drinking cup rinses the internal applicator and retainer, which can release the preparation from the retainer and deliver it to the patient's mouth, and then the patient swallows it. The rope member is a retainer and is wrapped around the retainer. The rope member is also connected to the retainer and the end of the preparation extending through the hole. Therefore, during drinking, when the preparation leaves the retainer, the retainer is unwound until it is tightened. Then a force is applied to the preparation to pull the preparation out of the capsule.

[0135] Such an applicator and drinking cup are described, for example, in PCT / EP2020 / 056927, the contents of which are incorporated herein by reference in their entirety with respect to the applicator, drinking cup and thread. Such a retainer is further described, for example, in EP21175427.0 and EP21175436.1, the contents of which are incorporated herein by reference in their entirety with respect to the retainer.

[0136] In a preferred embodiment, the retainer is wound around the support structure of the holder, and one end of the retainer is attached to the support structure and the other end is connected to the dosage of the capsule device. Therefore, the capsule device is positioned and retained inside the holder of the applicator. When the patient swallows the dosage form, the retainer begins to unwind from the support structure. The applicator and the support structure have a cylindrical shape so that the support structure fits into the applicator and is particularly mounted therein in a rotatable form so that the retainer can be unwound from the structure by rotating the structure.

[0137] This is particularly advantageous if the dosage form is to be administered regularly, in particular up to daily, since administration of the capsule device can be accomplished without professional assistance.

[0138] In a preferred embodiment of the drug delivery system according to the present invention, the release mechanism comprises a retainer, which is preferably a thin line, wherein the thin line can be expanded from a compact form to an extended form and is connected to one end of the preparation extending from the capsule device. The thin line includes but is not limited to a multifilament line or a yarn.

[0139] Exemplary embodiments of the invention will be described in more detail below with reference to the accompanying drawings and samples, from which further features, advantages and embodiments will become apparent. BRIEF DESCRIPTION OF THE DRAWINGS

[0140] Figure 1a ,1b Each shows a schematic diagram of a capsule device of a drug delivery system.

[0141] Figure 2 A schematic diagram of the formulation in partially expanded form is shown.

[0142] Figure 3 A schematic diagram of one end of a dosage form connected to a retainer for pulling the dosage form out of a capsule device is shown.

[0143] Figure 4 A schematic diagram of the formulation as a three-layer sheet is shown.

[0144] Figure 5a , 5b Each shows a schematic diagram of a capsule device having an aperture formed by overlapping wall portions or by telescoping two capsule half shells into one another.

[0145] Figure 6 A schematic semi-transparent view of a drug delivery system is shown.

[0146] Figure 7 A schematic diagram of an applicator is shown having a holder and a retainer wrapped around the holder with a drug delivery system located inside the holder.

[0147] Figure 8a , 8b Each shows before swallowing the drug delivery system ( Figure 8a ) and period ( Figure 8b ), Schematic diagram of a patient taking a drug delivery system using an applicator and a drinking cup.

[0148] FIG. 9 shows the drug delivery system before swallowing ( Figure 9a ) and after ( Figure 9b ), schematic diagram of a drug delivery system including a sinker for administration by a patient using an applicator and a drinking cup.

[0149] Fig.10 Shown are the absorption spectra of tofacitinib in the formulations (samples) of the drug delivery system of the present invention compared to the reference formulation.

[0150] Figure 1a A schematic diagram of a drug delivery system 1 having a capsule device 2 having a first capsule shell half 2a and a second capsule shell half 2b, which are nested with each other to form a hole 3. A dosage form 4 is shown in its compact form within the capsule 2, with one end 4a extending out of the hole 3. The arrow indicates the direction of movement of the dosage form 4 as it is pulled out of the capsule 2, i.e., the first capsule shell half 2a, through the hole 3. Figure 1aIn FIG. 1 , it is shown that the hole 3 is formed laterally to the central axis A of the capsule 2 and is arranged in the first half capsule shell 2a. Figure 2 In b, it is shown that the hole 3 is formed along the central axis A of the capsule 2 and is arranged in the first half capsule shell 2a.

[0151] Figure 2 A schematic diagram of a partially expanded form of the formulation 4 is shown. The formulation 4 is drawn to have a sheet-like shape. The central area of ​​the formulation 4 is indicated by a dotted line, so Figure 2 Basically, the end 4a of the preparation 4 protruding from the hole 3 of the capsule device 2 and the still slightly coiled end 4b of the preparation 4 are shown. The coiled end 4b represents a compact form of the preparation 4. At the end 4a extending through the hole 3, the retaining device 5 is shown to have a patch-like shape. The retaining device 5 includes a strip 5a. The strip 5a is Figure 2 In the embodiment shown, it is used as a connector to connect the holding means 5 to the end 4a of the preparation 4. Alternatively, the end 4a of the preparation 4 is directly connected to the retainer, such as a thin wire. In such an embodiment, the holding means 5, 5a is formed by the retainer itself.

[0152] Figure 3 This preferred embodiment is shown. The end 4a of the preparation 4 is shown to have a sheet-like shape, and the retainer 6 overlaps the end of the preparation 4 with a length d to form a retaining device 5, 5a. The connection between the retainer 6 and the end 4a of the preparation 4 is such that when the retainer 6 is tightened to pull the preparation 4 out of the capsule device 2, for example by swallowing the dosage form 1, the pulling force can be transmitted through the connection.

[0153] Figure 4 Formulation 4 is shown divided into several layers. Figure 4 In the embodiment shown, the preparation is a sheet comprising three different layers 7. A top layer 7a is formed as an adhesive layer, a middle layer 7b contains an anti-inflammatory agent or a salt thereof, and Figure 4 The lowest drawn layer in the graph shows a protective layer, for example a water protective layer.

[0154] Figure 5a , 5b Each shows a schematic diagram of a capsule device 2 of a drug delivery system 1 having a hole 3 formed by overlapping wall portions 9 or by telescoping two capsule half shells 2a, 2b. Figure 5aAs shown, the first half capsule shell 2a is slit on the second half capsule shell, as shown by the dotted line. The second half capsule shell includes a recess 8. By partially sliding the two half bodies 2a, 2b against each other, the first half capsule shell 2a partially covers the recess 8 of the second half capsule shell 2b. Then, a wall portion 9 is further provided to cover the remaining open space formed by the recess 8, so that the hole 3 is formed as an opening, through which the preparation 4 can leave the shell 2.

[0155] Alternatively, Figure 5b An embodiment is shown in which the two capsule shell half 2a, 2b overlap in the joined position to such an extent that the opening 3 is formed by a particularly cylindrical wall of the first capsule shell half, which overlaps the opening 10 of the second capsule shell half 2b.

[0156] Figure 6 A schematic semi-transparent view of a drug delivery system 1 is shown. The first and second capsule shell halves 2a, 2b are joined in a joined position, thereby forming a hole 3 by covering the opening 10 of the second capsule shell half 2b in this position. The end 4a of the formulation 4 is shown extending through the hole 3. The drug dosage form 1 further includes a sinker element 11, which is located in the first capsule shell half 2a. The sinker extends from the first capsule shell half 2a into the second capsule shell half 2b, while the groove 11a extends from the outside of the capsule device 2 into the inner space to position the sinker 11 and prevent the sinker from moving within the capsule. Figure 6 In FIG. 4 , the preparation 4 is shown to be located below the sedimentation 11. The groove prevents the sedimentation 11 from sliding into the preparation 4.

[0157] Figure 7 A schematic diagram of an applicator 12 is shown, the applicator having a holder 13 and a retainer 6 wrapped around the holder 13, while the drug delivery system 1 is located inside the holder 13. The applicator and the holder preferably have a cylindrical shape. The capsule device 2 is located inside the holder 13, with the first half 2a pointing towards the applicator cover 12a. The cover 12a is removed for use. Figure 7 In the illustrated embodiment, the capsule device 2 further comprises a sedimentation portion 11 located in the first half capsule shell 2a and a formulation 4 located in the second half capsule shell 2b. Figure 7In the embodiment shown, the first half capsule shell 2a is additionally pressed toward the bottom of the applicator 12. Thus, the curved retainer 13a is located above the capsule device 2. The retainer 13a is curved so that its shape matches the shape of the first half capsule shell 2a. Pressing the capsule 2 into the retainer 13 is achieved by a compression spring 14, one end of which is attached to the cover 12a of the applicator 12 and the other end is attached to the curved retainer 13a. A drying element 15 is located inside the applicator 12, at the cover 12a of the applicator 12. This prevents the preparation 4 from being damaged by moisture. The applicator 12 does not necessarily include a curved retainer 13, a drying element 15 or a compression spring 14.

[0158] Figure 8a , 8b Each shows before swallowing the drug delivery system ( Figure 8a ) and period ( Figure 8b ), a schematic diagram of a patient taking the drug delivery system 1 using the applicator and drinking cup. Figure 8a A patient is shown receiving an application of a drug delivery system as described herein comprising a capsule device 2. A drinking cup 16 is filled with a liquid and an applicator 12 is attached to the cup 16. The applicator 12 comprises a retainer 6 and a drug delivery system 1, which further comprises a capsule device 2 connected to a formulation 4, and the formulation 4 is at least partially coiled inside the capsule device 2. Figure 8b It is illustrated that when a patient swallows the dosage form 1, the dosage form 1 is then delivered to the stomach through the esophagus. The retainer 12 pulls the preparation 4 out of the capsule device 2. The preparation 4 then spreads along the esophagus, thereby delivering the active ingredient of the dosage form 1 to the esophageal mucosa.

[0159] Reference Symbols List

[0160] 1 Drug delivery system

[0161] 2 Capsule device

[0162] 2a The first half of the capsule shell

[0163] 2b Second half capsule shell

[0164] 3 holes

[0165] 4 Preparation

[0166] 4a The end of the preparation extending through the hole

[0167] 4b Coiled end of preparation

[0168] 5. Holding device

[0169] 5a band

[0170] 6 Retainer

[0171] 7th floor

[0172] 7a Adhesion layer

[0173] 7b Layer containing active pharmaceutical ingredient

[0174] 7c protective layer

[0175] 8 concavity

[0176] 9 Wall section

[0177] 10 Opening

[0178] 11 Sedimentation Components

[0179] 11a groove

[0180] 12 Applicators

[0181] 12a Applicator Cap

[0182] 13 Retainer

[0183] 13a Bent retainer

[0184] 14 Spring

[0185] 15 Drying element

[0186] 16 drinking cups

[0187] Example

[0188] Example 1: Preparation of polymer films containing tofacitinib

[0189] A "base polymer mixture" was prepared using the ingredients and amounts shown in Table 1 without the addition of tofacitinib.

[0190] Table 1

[0191]

[0192]

[0193] * Generally, the amount of HCl required may vary depending on the batch of polymer and is preferably adjusted to an acidic pH (pH 6.0 or lower). Acidic pH is beneficial to the stability of Tofacitinib.

[0194] After adjusting the pH to pH 4.0, tofacitinib was added at room temperature and membrane laminates were prepared by solvent casting, i.e. spreading the polymer mixture containing tofacitinib and evaporating the solvent. The membranes were dried at room temperature.

[0195] The resulting film was flexible, and no particles were detected on the film surface.

[0196] In addition, the content of tofacitinib in the membrane was analyzed. To this end, six sections with a diameter of 1.9 cm (2.84 cm) were cut at random locations on the membrane. 2 ) and analyzed by UV / Vis spectroscopy in citrate buffer (pH 4.0, containing 20% ​​methanol). The absorption spectra were compared with those of a reference sample (tofacitinib dissolved in citrate buffer, pH 4.0, containing 20% ​​methanol). Fig.10 Comparison of the spectra of the film samples with those of the reference samples confirmed that tofacitinib can be stably prepared in the film for use in the drug delivery device of the present invention.

[0197] In addition, the content of tofacitinib on the membrane is shown in Table 2.

[0198] Table 2

[0199]

[0200] *Standard deviation, **Relative standard deviation

[0201] It must be noted that the standard deviation and the maximum value of the drug loading are determined by the process technology and do not represent any limitation in principle.

[0202] The results in Table 2 show that 10 cm 2 A membrane loading of 10 mg tofacitinib is possible and allows the preparation of membranes with a wide therapeutic dose range. Thus, the drug delivery system of the present invention allows the administration of local high concentrations of the agent while providing a favorable systemic safety profile.

[0203] Example 2: Preparation of polymer films by melt extrusion

[0204] -Choose a suitable polymer matrix: Choose a polymer matrix that is compatible with the active ingredient you intend to use. Typical polymers are polyvinyl alcohol (PVA), cellulose ethers and polyethylene glycol (PEG), combined with a suitable plasticizer.

[0205] -Preparation of the active ingredient: The active ingredient is generally prepared into a suitable formulation (eg, as a powder or granules).

[0206] - Mixing components: Mix the polymer matrix and active ingredient in a mixer to form a homogeneous mixture.

[0207] - Extrusion: The mixture is fed into an extruder where it melts at high temperature and is forced through a die. The die forms a film which is deposited on a cooling plate.

[0208] - During the melt extrusion process, after the polymer compound is forced through the die, the extruded film may undergo a rolling process to further optimize its thickness and properties. Depending on the specific requirements of the film, the rolling process may include cold rolling or hot rolling.

[0209] -Post-processing: After the extrusion process, the extruded film is cut into the desired size and shape. The film is then usually further processed, such as drying, coating or lamination, to improve its physical and pharmaceutical properties.

Claims

1. A drug delivery system for esophageal mucosa, comprising at least one sheet-shaped preparation, in particular a film-shaped, foil-shaped or sheet-shaped preparation, comprising an active pharmaceutical ingredient; Release agencies; and Trigger mechanism, where The trigger mechanism is suitable for triggering the release mechanism to release the preparation at a predetermined action site, and wherein the release mechanism is suitable for releasing the preparation while moving along the esophageal mucosa, wherein the drug delivery system further comprises a housing, wherein the housing contains the formulation, and wherein the housing comprises an aperture as part of the release mechanism, the aperture being configured to allow the formulation to exit the housing, and wherein the trigger mechanism is a retaining device that is part of or attached to the formulation such that the formulation spreads or unfolds when the dosage form moves down the esophageal mucosa and exits the housing through the aperture, Features The active pharmaceutical ingredient comprises an anti-inflammatory agent or a salt thereof, and preferably one or more additional active pharmaceutical ingredients.

2. A drug delivery system according to claim 1, wherein the anti-inflammatory agent reduces or blocks inflammation, preferably in the esophageal epithelium, and / or fibrosis, preferably in the subepithelial membrane of the esophagus.

3. The drug delivery system according to claim 1 or 2, wherein the anti-inflammatory agent comprises an immunosuppressant, preferably selected from the group consisting of: a tyrosine kinase inhibitor, a calcineurin inhibitor and a purine analog, preferably a thiopurine analog.

4. The drug delivery system according to claim 3, wherein the tyrosine kinase inhibitor is a Janus kinase (JAK) inhibitor selected from the group consisting of upadacitinib (ABT-494), baricitinib, brepocitinib, abrocitinib (PF-04965842), ifidacitinib (ATI-502), tofacitinib, ruxolitinib, digaotinib (JTE-052), seletinib, gusacitinib (ASN002) and izencitinib (TD-1473), preferably tofacitinib.

5. The drug delivery system according to claim 3, wherein the calcineurin inhibitor is selected from the group consisting of sirolimus (rapamycin), tacrolimus (FK-506), pimecrolimus and cyclosporin A. The drug delivery system according to claim 3 , wherein the purine analog is azathioprine (AZA) or 6-mercaptopurine (6-MP).

7. A drug delivery system according to any one of the preceding claims, wherein the salt of the anti-inflammatory agent is selected from citrate, phosphate and borate, preferably citrate.

8. The drug delivery system according to any one of the preceding claims, wherein the salt of the anti-inflammatory agent is a salt of a JAK inhibitor, preferably a salt of tofacitinib, more preferably tofacitinib citrate.

9. The drug delivery system according to any one of the preceding claims, wherein the sheet-shaped formulation, in particular the film-shaped, foil-shaped or sheet-shaped formulation comprising the active pharmaceutical ingredient comprises polyvinyl alcohol (PVA).

10. The drug delivery system according to any one of the preceding claims, wherein the sheet-shaped formulation, in particular the film-shaped, foil-shaped or sheet-shaped formulation comprising the active pharmaceutical ingredient comprises a plasticizer, preferably glycerol.

11. The drug delivery system according to any one of the preceding claims, wherein the one or more additional active pharmaceutical ingredients is a steroid, preferably a steroid selected from the group consisting of budesonide, fluticasone and mometasone.

12. A drug delivery system according to any preceding claim for use in therapy.

13. The drug delivery system according to claim 12, for use in treating or preventing esophageal diseases, preferably refractory esophageal diseases.

14. The drug delivery system according to claim 12 or 13, for treating or preventing esophageal diseases caused by or associated with immune system defects, such as inflammatory diseases, fibrosis or allergies, preferably allergies caused by or associated with environmental allergens and / or food allergens.

15. The drug delivery system according to any one of claims 12 to 14, for use in treating or preventing eosinophilic esophagitis, preferably refractory eosinophilic esophagitis and / or esophageal stenosis.

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