A drug delivery system comprising an anti-inflammatory agent or a salt thereof applied to the esophageal mucosa

Abstract

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

Description

Technical Field

[0001] The present invention specifically relates to a drug delivery system containing an anti-inflammatory agent or a salt thereof, which is applied to the esophageal mucosa and is used for treating esophageal diseases, particularly eosinophilic esophagitis and / or esophageal stricture.

Background Art

[0002] Examples of esophageal diseases include eosinophilic esophagitis. Eosinophilic esophagitis is a chronic immune-mediated inflammatory disease of the esophagus. Current treatment options for eosinophilic esophagitis include corticosteroids. Steroids are typically administered orally as a viscous suspension, as an effervescent tablet, or as an aerosol spray. However, many patients respond poorly or not at all to currently marketed steroid preparations. Furthermore, the recurrence rate is high after discontinuation of steroid treatment, and long-term treatment is required to maintain remission.

[0003] Janus kinase (JAK) inhibitors are compounds that inhibit the activity of one or more of the enzymes of the JAK family (JAK1, JAK2, JAK3, TYK2), thereby interfering with the JAK-STAT signaling pathway. They are used in the treatment of neovascularization and immune-mediated inflammation, such as inflammatory bowel disease or rheumatoid arthritis. Tofacitinib (Xeljanz®), an inhibitor of JAK1 and JAK3, is approved for the systemic treatment of rheumatoid arthritis and severe atopic dermatitis. JAK inhibitors for topical administration are currently under development for atopic dermatitis. Tofacitinib was also found to minimize the number of eosinophils seen in esophageal biopsies and significantly improve the appearance of the esophagus after 3 months of treatment in a 34-year-old man who had been diagnosed with eosinophilic esophagitis for a long time (Non-Patent Document 1). Furthermore, AS1517499, leflunomide, and ruxolitinib, which are JAK-STAT6 pathway inhibitors, have been described as blocking the secretion of eotaxin-3 by epithelial cells and fibroblasts derived from patients with eosinophilic esophagitis (Non-Patent Document 2). However, there have been no reports on the topical and local administration of JAK inhibitors to the esophagus.

[0004] Calcineurin inhibitors are compounds that inhibit calcineurin, an enzyme that activates T cells. Since T cells play a major role in cell-mediated immunity, calcineurin inhibitors suppress the cell-mediated immune response. Calcineurin inhibitors are administered systemically for the treatment of immune-mediated diseases and for the prevention of rejection after organ transplantation. Furthermore, some basic scientific research has described rapamycin-induced autophagy of esophageal epithelial cells via mTORC signaling in eosinophilic esophagitis (Non-Patent Document 3). However, there have been no reports on the topical and local administration of calcineurin inhibitors to the esophagus.

[0005] Systemically administered purine analogs have been established for decades in the treatment of chronic inflammatory bowel diseases, particularly ulcerative colitis and Crohn's disease. In small case series, two systemically administered purine analogs, azathioprine (AZA) and 6-mercaptopurine (6-MP), have been shown to be effective in the treatment of refractory eosinophilic esophagitis (Non-Patent Document 4). However, there has been no report on the topical and local administration of purine analogs to the esophagus.

[0006] Drug delivery to the membranes of the gastrointestinal tract, particularly the esophagus, is usually carried out by submucosal application guided by endoscopy. The topical application of the active ingredient involves drug-coated esophageal stents or oral viscous drugs. Currently under investigation are orally dispersible or orally disintegrating tablets, aerosols, or gel-like drugs with high viscosity to increase the contact time.

[0007] However, the topical application of the active ingredient to the membranes of the gastrointestinal tract, particularly the esophagus, has several problems. For example, it is very difficult to topically apply a high dose of the drug over a sufficient period to achieve a therapeutically effective local concentration. Possible causes for the concentration at the treatment site being too low include degradation or deactivation of the drug by digestive secretions and enzymes, dilution effect by intestinal fluid, poor absorption, prodrugs that require activation that is not possible at the treatment site, and the residence time at the site of action being too short to effectively express the drug action. When using a liquid or gel-like drug delivery system, the short residence time and / or too low local concentration at the site of action are particularly problematic. Therefore, a high dose must be administered to achieve a sufficient concentration at the treatment site. Usually, administering the active ingredient at a higher dose is associated with an increase in side effects due to intestinal absorption and higher bioavailability. Therefore, the dose of the active ingredient should be kept as low as possible.

[0008] There is still a need for a suitable drug delivery system that can deliver an anti-inflammatory agent or a salt thereof for effective treatment while enabling administration at the lowest possible dose to reduce side effects, particularly for delivery to the esophagus.

Prior Art Documents

Non-Patent Documents

[0009]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

[0010] One object of the present invention is to provide a drug delivery system that enables oral / local administration of an anti-inflammatory agent or a salt thereof used for the treatment of esophageal diseases, which has enhanced local efficacy.

[0011] A further object of the present invention is to provide a delivery system that enables the application of an anti-inflammatory agent or a salt thereof at a relatively low dose, thereby minimizing potential side effects.

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

Means for Solving the Problems

[0013] In a first aspect, the present invention is a drug delivery system for application to the esophageal mucosa, comprising at least one sheet-like, particularly film-shaped, foil-shaped, or oblat-shaped formulation containing a pharmaceutically active ingredient, a release mechanism, and a trigger mechanism wherein the trigger mechanism is adapted to cause release by the release mechanism of the formulation at a predetermined site of action, and the release mechanism is adapted to release the formulation while moving along the esophageal mucosa, the drug delivery system further comprises a shell that houses the formulation, the shell includes an opening configured as part of the release mechanism for the formulation to exit the shell, and the trigger mechanism is a holding device that is part of the formulation or attached to the formulation, such that the formulation opens or spreads as the dosage form descends along the esophageal mucosa and exits through the opening from the shell, characterized in that the pharmaceutically active ingredient comprises an anti-inflammatory agent or a salt thereof, and preferably one or more additional pharmaceutically active ingredients. A drug delivery system is provided.

[0014] In one embodiment, the anti-inflammatory agent reduces or prevents inflammation, preferably inflammation of the esophageal epithelium, and / or fibrosis, preferably subepithelial fibrosis of the esophagus.

[0015] 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.​

[0016] 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.

[0017] In one embodiment, the calcineurin inhibitor is selected from the group consisting of sirolimus (rapamycin), tacrolimus (FK-506), pimecrolimus, and cyclosporine A.

[0018] In one embodiment, the purine analog is azathioprine (AZA) or 6-mercaptopurine (6-MP).

[0019] In one embodiment, the salt of the anti-inflammatory agent is selected from citrate, phosphate, and borate, preferably citrate.

[0020] 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.

[0021] In one embodiment, the sheet-like, particularly film-shaped, foil-shaped, or oblate-shaped formulation containing the pharmaceutically active ingredient contains polyvinyl alcohol (PVA).

[0022] In one embodiment, the sheet-like, particularly film-shaped, foil-shaped, or oblate-shaped formulation containing the pharmaceutically active ingredient contains a plasticizer, preferably glycerol.

[0023] In one embodiment, the one or more additional pharmaceutically active ingredients are steroids, preferably steroids selected from the group consisting of budesonide, fluticasone, and mometasone.

[0024] In a second aspect, the present invention provides a drug delivery system for use in therapy or for the treatment or prevention of esophageal diseases, preferably refractory esophageal diseases, or esophageal diseases such as inflammatory diseases caused by or related to immune system deficiencies, fibrosis, or allergies, preferably allergies caused by or related to environmental allergens and / or food allergens, or for the treatment or prevention of eosinophilic esophagitis, preferably refractory eosinophilic esophagitis, and / or esophageal stricture.

DETAILED DESCRIPTION OF THE INVENTION

[0025] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0026] Note that the use of the indefinite article "a" or "an" means "one or more". Thus, for example, the term "an esophageal disease" includes the incorporation of "one" or "two or more" esophageal diseases.

[0027] As used herein, the term "comprising" or "comprises" means "including, but not limited to". This term is open-ended and is intended to specify the presence of any of the recited features, elements, integers, steps, or components, but not to exclude the presence of one or more additional features, elements, integers, steps, components, or groups thereof. Thus, the term "comprising" or "comprises" includes the more restrictive terms "consisting of" and "consisting essentially of". In one embodiment, the term "comprising" or "comprises" as used throughout this application and particularly within the claims may be replaced with the term "consisting of".

[0028] Drug delivery systems that include, but are different in terms of the pharmaceutically active ingredient and its application, are described in PCT / EP2015 / 002601, the entire content of which is incorporated herein by reference, particularly with respect to the embodiments of Figures 8a, 8b, and 8c of PCT / EP2015 / 002601. In other words, the size, shape, and composition of the shell, the opening, the release and trigger mechanisms, as well as the retention device are already described in the aforementioned reference at least to a significant extent.

[0029] The drug delivery system described in PCT / EP2015 / 002601 is designed to include at least one sheet-like, in particular film-shaped, foil-shaped, or oblong-shaped formulation containing a pharmaceutically active ingredient, a release mechanism, and a trigger mechanism, and the trigger mechanism is adapted to cause the release by the release mechanism of the sheet-like formulation, in particular at a predetermined site of action in the gastrointestinal tract. From the embodiments of FIGS. 8a, 8b, and 8c of PCT / EP2015 / 002601, it can be seen that the dosage form has an elongated strip-shaped formulation, which contains a pharmaceutically active ingredient. The formulation can be arranged in a compact state and a deployed state. The dosage form includes a capsule device having a hollow space for accommodating the miniaturized formulation, for example having a shell, the capsule device having an opening, and the first end of the formulation in the compact state extending from this opening, so that the formulation can be withdrawn from the hollow space to the peripheral region of the capsule, thereby causing the formulation to transition from the compact state to the deployed state.

[0030] The drug delivery system according to the present invention is orally administered and improves the local utility of the anti-inflammatory agent or its salt contained in the formulation. This is in contrast to oral administration systems such as conventional tablets or capsules that are delivered to the treatment target site / location only by entering the blood circulation through gastrointestinal absorption.

[0031] The local utility is improved because the anti-inflammatory agent or a salt thereof is provided in a formulation in the form of a sheet, particularly in the form of a film, foil, oblate, or elongated strip. Advantageously, this enables the sheet-like formulation (and the anti-inflammatory agent or a salt thereof present therein) to be directly released to the treatment target site / location (treatment site), for example, the esophageal mucosa. Thereby, preferably, a large area of the sheet-like formulation is exposed to the mucosa, i.e., the esophageal mucosa. When exposed to the mucosa, the sheet-like formulation releases the anti-inflammatory agent or a salt thereof. Further, as a result of preferably direct contact between the mucosa and the formulation, the anti-inflammatory agent or a salt thereof exerts an effective action at the treatment site. Since the anti-inflammatory agent or a salt thereof is directly delivered to the treatment site, a small amount of the agent suffices, and as a result, the systemic bioavailability is reduced compared to the use of conventional formulations such as suspensions or solutions, and the concentration in adjacent, for example, healthy regions decreases. Further, direct delivery to the treatment site further enables the dose of the anti-inflammatory agent or a salt thereof contained in the formulation to be reduced, thereby advantageously further reducing side effects.

[0032] The drug delivery system according to the present invention further advantageously enables simple, particularly space-saving storage, as well as relatively simple and clear handling. The anti-inflammatory agent or a salt thereof contained in the drug delivery system according to the present invention has improved stability compared to solutions and gels, for example, in high temperature and high humidity conditions. Usually, there is no free water remaining in the drug delivery system according to the present invention, which further improves the stability of the composition and reduces the risk of, for example, mold growth in the composition or otherwise rendering it unusable. Additional additives such as preservatives or other stabilizers can be avoided, which is advantageous since it is known that such additives can cause allergies or further side effects.

[0033] Also, the degradation of the drug active ingredient by, for example, gastric acid and / or digestive enzymes before reaching the predetermined action site is advantageously minimized by the drug delivery system according to the present invention.

[0034] Release mechanism The release mechanism relates to a mechanism for deploying and releasing a sheet-like formulation from a capsule device, such as a shell. The shell houses the sheet-like formulation in a compact form. The release mechanism releases the formulation from the shell after a trigger mechanism has initiated the release. The release of the sheet-like formulation by the release mechanism preferably occurs by at least partially pulling the formulation out of the shell. Thus, the sheet-like formulation is configured such that the sheet-like formulation can be deployed by the release mechanism to a predetermined extent. For example, the shell houses the formulation in a folded form, and the release mechanism deploys the formulation from a small, e.g., folded form, to an unfolded, e.g., spread-out form. Thus, the release mechanism causes the spreading of the formulation. In the compact form, the formulation has a smaller spatial extent, e.g., the formulation is in a lump, coiled, or rolled, or otherwise in a smaller spatial pattern. This also enables the provision of a small dosage form, i.e., a small shell, which in particular makes the oral intake of the drug delivery system more convenient for the patient. In the unfolded form, the surface area of the sheet-like formulation increases upon deployment of the sheet-like formulation, e.g., by spreading, and in particular, the surface area of a formulation containing an anti-inflammatory agent or a salt thereof increases. Preferably, the surface area of the formulation, in particular the surface area in contact with the esophageal mucosa and containing an anti-inflammatory agent or a salt thereof, is approximately the same as the surface area of the esophageal mucosa. The release of the formulation occurs while the shell descends along the esophageal mucosa. For example, while the patient swallows the dosage form, the formulation is released from the shell through an opening. Thus, the shell includes an opening configured as part of the release mechanism for the formulation to exit the shell.

[0035] Opening In this regard, the opening forms an aperture in the shell, i.e., the capsule device. In a preferred embodiment of the drug delivery system, the opening is formed as a slit. The slit is arranged such that the sheet-like formulation is released from the shell through this opening. Such slits can be embodied in various arrangements and configurations. Such openings are described, for example, in EP21175427.0, EP21175436.1, PCT / EP2015 / 002601, and PCT / EP2020 / 056934, regarding the capsule device and the opening, the entire texts of which are incorporated herein by reference in their entirety.

[0036] Trigger mechanism / Holding device The drug delivery system includes a trigger mechanism, which is adapted to cause the release by the release mechanism of the sheet-like formulation at a predetermined site of action. The trigger mechanism is a holding device that is part of the formulation or attached to the formulation.

[0037] Preferably, the formulation includes a holding device, and more preferably, the formulation includes a holding device at one end of the formulation, and one end in particular protrudes from the shell through the opening. When the holding device is fixed, the formulation can be pulled from the capsule device by a pulling movement and / or force. The fixing of the holding device is preferably obtained by connecting the holding device to a holder. Such a holder can be a cord member such as a cord, string, or ligature. In a preferred embodiment, the holding device is connected to one end of the formulation and one end of the cord, while the other end of the cord is fixed to an applicator, for example, to a holder of the applicator.

[0038] Preferably, the holding device is attached to the sheet-like formulation. Thereby, the holder, i.e., the cord member, or a part of the cord member forms the holding device. For example, one end of the cord connected to the formulation forms the holding device.

[0039] Instead, the holding device is adapted to be fixed in the mouth or held by hand during administration of the drug delivery system, so that the dosage form opens and / or spreads as the formulation descends the esophageal mucosa, opening from the shell and exiting through the opening.

[0040] In a preferred embodiment, a part of the string member is connected to the end portion of the formulation protruding from the opening of the capsule device. Thereby, the holding device is formed by the protruding end portion of the formulation and the string member connected thereto, and a further part of the string member acts as a holder to hold the holding device so as not to move during swallowing of the formulation, thereby generating an attractive force acting on the formulation, and this attractive force pulls the formulation out of the capsule device while the capsule device descends the esophagus.

[0041] 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 the "site of action" and "site of application" refer to a predetermined location where the formulation is released. Furthermore, the anti-inflammatory agent or a salt thereof released at each "site of action" or "site of application" may exert its actual biochemical effect at another location in the body or at another site in the biochemical cycle, for example during or after metabolism by the liver, or when or after the agent reaches the target molecule. The "site of action" and "site of application" as used herein do not necessarily refer to the location of the biochemical and medical effects of the pharmaceutically active ingredient.

[0042] Capsule device / shell The drug delivery system according to the present invention further includes a shell, the shell containing at least one sheet-like, particularly film-shaped, foil-shaped, or oblate-shaped formulation containing an anti-inflammatory agent or a salt thereof, the shell including an opening configured such that the formulation exits the shell as part of the release mechanism, so that the formulation opens or spreads as the dosage form descends the esophageal mucosa, opening from the shell and exiting through the opening. The shell can be further prepared to protect the formulation from accidental release. The shell is a capsule device, particularly having the shape of a capsule.

[0043] In a preferred embodiment, the shell comprises a first half of the capsule shell and a second half of the capsule shell, and the capsule device is formed by sliding the first half of the capsule shell into the second half of the capsule shell to a joining position, so that an opening is formed at the joining position by the second half of the capsule shell overlapping the cross-section of the opening in the first half of the capsule shell.

[0044] In a further embodiment, the two capsule halves fit into each other, but the opening of the first half of the capsule shell is further covered by an overlapping wall portion, such as a piece of cloth or tape, provided, and the wall portion is attached to the first half of the capsule shell and / or the second half of the capsule shell.

[0045] In an alternative embodiment, the capsule halves are shaped like two nut shells and are positioned one above the other to form a capsule. The opening is formed, in particular, by a cutout at the edge of one of the two shells. Alternatively, the cutout can be formed at the edges of both halves, in which case the two halves form an opening when positioned one above the other and aligned.

[0046] In a preferred embodiment of the drug delivery system according to the present invention, the shell is made of a material selected from the group comprising hard gelatin, polymers, such as thermoplastic substances such as Eudragit. In this regard, in particular, materials that have already been successfully tested, used and / or approved, for example, for oral dosage forms, can be beneficial.

[0047] Such capsule devices or shells are further described, for example, in EP21175427.0, EP21175436.1, and PCT / EP2020 / 056934, and with respect to the capsule devices, the entire texts thereof are incorporated herein by reference.

[0048] The condition to be treated The drug delivery system described in this specification is for therapeutic use. In one embodiment, the drug delivery system is for the treatment and prevention of esophageal diseases, preferably refractory esophageal diseases. In one embodiment, the drug delivery system is for the treatment and prevention of allergies, preferably allergies caused by or related to environmental allergens and / or food allergens. In one embodiment, the drug delivery system is for the treatment and prevention of inflammatory diseases. In one embodiment, the drug delivery system is for the treatment and prevention of fibrosis. In one embodiment, the drug delivery system is for the treatment and prevention of eosinophilic esophagitis, preferably refractory eosinophilic esophagitis. In one embodiment, the drug delivery system is for the treatment and prevention of esophageal strictures.

[0049] As used herein, the term "treatment and / or prevention" includes any method of ameliorating a particular condition to be treated or preventing the occurrence of a condition to be treated. This term also includes preventing the worsening of a condition and minimizing the severity of a condition.

[0050] An esophageal disease can be any disease or disorder that interferes with the function or structure of the esophagus. Esophageal diseases include, but are not limited to, for example, refractory esophageal diseases after primary treatment. For example, refractory esophageal diseases relate to esophageal diseases in which treatment has been unsuccessful or insufficient, i.e., esophageal diseases in which symptoms specific to the esophageal disease persist despite treatment. Refractory esophageal diseases can also refer to recurrence after treatment. Thus, in one embodiment, the present invention relates to the treatment of refractory esophageal diseases in the sense of secondary treatment.

[0051] Preferred esophageal diseases include esophageal diseases caused by or related to immune system deficiencies. For example, the esophageal disease can be a Th 2 lymphocyte-mediated disease or disorder involving the proliferation and / or activation of lymphocytes. For example, inappropriate proliferation and / or activation can be increased proliferation and / or increased activation of Th 2 lymphocytes. Inappropriate Th 2 lymphocyte proliferation and / or activation can be increased proliferation and / or increased activation of Th 2Lymphocyte activity can also be accompanied by increased cytokine release or cytokine release in response to inappropriate stimuli. The inappropriate stimulating factors can be allergens, for example, environmental allergens in air or food.

[0052] 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 according to the present invention is esophageal stricture.

[0053] 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 eosinophil-predominant mucositis. The main complication associated with eosinophilic esophagitis is the infiltration of eosinophils into the submucosa of the esophagus, leading to fibrosis. Untreated eosinophilic esophagitis results in esophageal remodeling, wall thickening, abnormal fragility, and strictures due to fibrosis, ultimately causing structural and functional damage to the esophagus due to complications such as acute food impaction. Treatment options include diet, esophageal dilation, and medications such as corticosteroids or compounds to relieve reflux. Diet involves the sequential elimination of specific foods for the purpose of identifying food allergens that cause inappropriate responses and inflammation in the immune system. Diet is cumbersome and requires high patient motivation. Esophageal dilation provides symptom improvement in 75% of patients with fibro-stenotic eosinophilic esophagitis, but dilation does not affect the underlying inflammation and is therefore not suitable as a standalone treatment. The classical medical treatment for eosinophilic esophagitis involves proton pump inhibitors or locally administered steroids such as budenoside, fluticasone, or mometasone. Steroids are administered locally as an oral viscous suspension, as a foaming tablet as an aerosol spray. These dosage forms typically have a short contact time, which may be a contributing factor to inappropriate responses and lack of long-term remission. Furthermore, the recurrence rate is high after discontinuation of steroid treatment, and long-term treatment is required to maintain remission. Therefore, there remains a need in the art for novel treatment options.

[0054] The dosing frequency, treatment period, or timing of administration of the drug delivery device is not limited and is determined by the specific disease to be treated and / or the amount of the pharmaceutically active ingredient per drug delivery device. For example, the drug delivery device can be administered once or twice a day. When the drug delivery device is administered once a day, it is preferably administered in the evening to enhance patient compliance. The drug delivery system of the present invention is preferably administered before bedtime, i.e., after dinner and after oral hygiene. The treatment period can be from 7 days to 40 days, preferably from 14 days to 30 days, more preferably from 20 days to 28 days. The treatment can include the treatment period of a single treatment cycle or multiple cycles, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more cycles.

[0055] Pharmaceutically active ingredient As used herein, the term "pharmaceutically active ingredient" is used interchangeably with the terms "active ingredient" or "API" and refers to an anti-inflammatory agent or a salt thereof.

[0056] The term "therapeutically effective dose" or "effective amount" means the dose or amount that produces the desired effect for which it is administered. The exact dose or amount depends 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 has an effect of improving the disease (symptoms). Since prevention can be considered as treatment, the therapeutically effective amount can be a "preventively effective amount".

[0057] "Anti-inflammatory agent or a salt thereof" refers to a compound such as a small molecule that reduces, prevents, inhibits, or interferes with an inflammatory response of the immune system, preferably a chronic inflammatory response. For example, an anti-inflammatory agent or a salt thereof can reduce, prevent, inhibit, or interfere with inflammation of the esophageal mucosa, more preferably the esophageal epithelium. Alternatively, or in addition, an anti-inflammatory agent or a salt thereof can reduce, prevent, inhibit, or interfere with fibrosis of the esophageal mucosa, more preferably beneath the esophageal epithelium. At the molecular function level, an anti-inflammatory agent or a salt thereof can reduce, prevent, inhibit, or interfere with lymphocyte activity such as lymphocyte proliferation and / or cytokine release. Alternatively, an anti-inflammatory agent or a salt thereof can reduce, prevent, inhibit, or interfere with the movement of leukocytes, such as granulocytes, preferably eosinophils, from the bloodstream into tissues, preferably into the esophagus, more preferably into the esophageal mucosa, for example chemotaxis. An anti-inflammatory agent or a salt thereof 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 agents or salts thereof described herein are particularly stable when formulated as salts. Salts include, but are not limited to, citrate, phosphate, and borate salts, preferably citrate salts.

[0058] In one aspect of the invention, the anti-inflammatory agent or a salt thereof is an immunosuppressive agent. The immunosuppressive agent can 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.

[0059] In a preferred embodiment, the anti-inflammatory agent or a salt thereof is a tyrosine kinase inhibitor, more preferably a JAK inhibitor.

[0060] Tyrosine kinase is an enzyme that phosphorylates substrates, i.e., transfers the terminal gamma-phosphate group of a nucleotide, such as ATP, to the hydroxy group of a substrate, such as a protein. The name tyrosine kinase refers to the substrate specificity of the kinase, i.e., tyrosine kinase phosphorylates the hydroxy group of the amino acid tyrosine. Tyrosine kinase inhibitors can be directed against cytoplasmic tyrosine kinases such as JAK kinases.

[0061] As used herein, "JAK inhibitor" 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: JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). JAK kinases associate with the intracellular domain of cytokine receptors, cross-phosphorylate, and transmit extracellular signals through phosphorylation of signal transducers and activators of transcription (STAT). Phosphorylated STAT forms dimers, translocates to the nucleus, and acts as a transcription factor there to regulate gene expression. Thus, a JAK inhibitor can reduce or block the expression and / or activity of one or more members of the JAK family (JAK1, JAK2, JAK3, TYK2), thereby interfering with the JAK-STAT signaling pathway.

[0062] JAK inhibitors are used in the treatment of new tissue formation and immune-mediated inflammation, such as inflammatory bowel disease or rheumatoid arthritis. Tofacitinib (Xeljanz®), a JAK1 and JAK3 inhibitor, is approved for the systemic treatment of rheumatoid arthritis. A placebo-controlled phase IIa trial using tofacitinib topically for the treatment of atopic dermatitis has shown promising results. Tofacitinib has also been shown to minimize the number of eosinophils seen on esophageal biopsy and significantly improve the appearance of the esophagus after 3 months of treatment in a 34-year-old male who had been diagnosed with eosinophilic esophagitis for a long time. JAK inhibitors have also been shown to be effective in hypereosinophilic syndrome, bronchial asthma, and eosinophilic fasciitis. Furthermore, JAK-STAT6 pathway inhibitors have been described as blocking the secretion of eotaxin-3 stimulated by Th 2 cytokines, suggesting a potential role for JAK-STAT inhibitors in the treatment of both epithelial inflammation and subepithelial fibrosis. Therefore, JAK inhibitors are promising candidates for disease-modifying remission of eosinophilic esophagitis and as secondary treatment for patients with eosinophilic esophagitis who show only a limited response to steroids, especially.

[0063] JAK inhibitors can be small molecules. Furthermore, JAK inhibitors can reduce or prevent the release of eosinophil chemoattractants, preferably eotaxin-3, from epithelial cells and / or fibroblasts, preferably esophageal epithelial cells and / or epithelial fibroblasts.

[0064] Furthermore, the JAK inhibitor may have selectivity for one or more JAK kinases. For example, JAK inhibitors such as upadacitinib or abrocitinib may have selectivity for JAK1. Alternatively, JAK inhibitors such as baricitinib or ruxolitinib may have selectivity for JAK1 and JAK2. In another embodiment, JAK inhibitors such as tofacitinib or filgotinib may have selectivity for JAK1 and JAK3. In yet another embodiment, JAK inhibitors such as brepocitinib may have selectivity for JAK1 and TYK2. The JAK inhibitor may be a pan-JAK inhibitor such as delgocitinib that has selectivity for all isozymes. Furthermore, the JAK inhibitor may act dually on JAK kinases and also on other tyrosine kinases. For example, JAK inhibitors such as gusacitinib may act dually on JAK kinases and tyrosine protein kinase SYK (also known as spleen tyrosine kinase).

[0065] In a preferred embodiment, the JAK inhibitor is selected from the group consisting of upadacitinib (ABT-494), baricitinib, brepocitinib, abrocitinib (PF-04965842), filgotinib (ATI-502), tofacitinib, ruxolitinib, delgocitinib (JTE-052), cerdulatinib, gusacitinib (ASN002), and itacitinib (TD-1473), more preferably tofacitinib.

[0066] 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.

[0067] In a further embodiment, the anti-inflammatory agent or a salt thereof is a calcineurin inhibitor. A calcineurin inhibitor is a compound that inhibits, reduces, blocks, or interferes with calcineurin, an enzyme that activates T cells through the nuclear factor of activated T cells (NF-AT), a transcription factor. Since T cells play a major role in cell-mediated immunity, calcineurin inhibitors suppress the cell-mediated immune response. Calcineurin inhibitors are administered systemically for the treatment of immune-mediated diseases and for the prevention of rejection after organ transplantation. Topical calcineurin inhibitors have been widely used since 2000 for the treatment of immune-mediated diseases in the skin, eyes, and the eye, nose, and throat (ENT) region, such as atopic dermatitis. The effectiveness of these agents in these indications has been confirmed in multiple controlled trials. The risk of systemic side effects is low. Because the effectiveness of topical treatment with calcineurin inhibitors for immune-mediated diseases has been confirmed in multiple cases, their excellent safety profile when used topically, and their mode of action, these compounds are promising for the topical treatment of eosinophilic esophagitis.

[0068] In one embodiment, the calcineurin inhibitor reduces or blocks the activation of a lymphocyte transcription factor, preferably a T-lymphocyte transcription factor, more preferably the 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.

[0069] In a further embodiment, the anti-inflammatory agent or a salt thereof is a purine analogue. As used herein, a purine analogue refers to a compound having a structural and / or functional similarity to purine. A purine analogue having a structural similarity to purine can be a purine derivative, such as thiopurine.

[0070] Systemically administered purine analogs have been established for decades in the treatment of chronic inflammatory bowel diseases, particularly ulcerative colitis and Crohn's disease. In small case clinical trials, two systemically administered purine analogs, azathioprine (AZA) and 6-mercaptopurine (6-MP), have been shown to be effective in the treatment of refractory eosinophilic esophagitis. Topical azathioprine has been used in the treatment of atopic dermatitis and chronic oral graft-versus-host disease. In a prospective single-blind trial, 70 young patients with moderate or severe atopic dermatitis were treated twice daily for 8 weeks either with steroid cream alone or in combination with a steroid and azathioprine emollient cream. The combination of steroid and azathioprine was slightly superior to steroid monotherapy and was well tolerated. One case of refractory oral graft-versus-host disease was treated with azathioprine in the form of a suspension administered both topically and systemically. The additional topical administration was considered to add some clinical usefulness and was well tolerated. Taken together, first, the effects observed with systemically administered purine analogs in eosinophilic esophagitis and, second, the effects of topically administered azathioprine in skin and oral immune-mediated diseases, these compounds, particularly azathioprine, are promising for further evaluation in the topical treatment of eosinophilic esophagitis.

[0071] In a preferred embodiment, the purine analog is a thiopurine analog selected from the group consisting of azathioprine or 6-mercaptopurine.

[0072] The present invention provides a drug delivery system comprising an anti-inflammatory agent described herein or a salt thereof. The drug delivery system described herein may also include one or a combination (e.g., two or more different ones) of the anti-inflammatory agents described herein or salts thereof.

[0073] Additional pharmaceutically active ingredient The API within this dosage form can be administered together with additional APIs.

[0074] Additional APIs that may be present in addition to the anti-inflammatory agent or a salt thereof are referred to herein as "additional drug active ingredients" or "additional active ingredients" or "additional APIs". In principle, any additional drug active agent that enhances or increases the effectiveness of the anti-inflammatory agent or a salt thereof may be used. Such additional APIs can be selected by those skilled in the art according to the condition to be treated and / or prevented based on their general knowledge. For the purposes of the present invention, the additional drug active agent can be a steroid selected from the group consisting of steroids such as budesonide, fluticasone, and mometasone, or an antibody, preferably an anti-IL-5 antibody, preferably beralizumab, an anti-IL-13 antibody, preferably RCP4046, and an anti-IL4 / 13 antibody, preferably dupilumab.

[0075] Formulation In a preferred embodiment of the drug delivery system according to the present invention, the sheet-like formulation is an oblate or formed as an oblate. The term "oblate" as used herein refers to a sheet, which includes several layers and is used to encapsulate the anti-inflammatory agent or a salt thereof.

[0076] Such an oblate can follow the irregular surface contour of a predetermined site of action, particularly the esophageal mucosa, especially after the oblate absorbs the moisture contained in the esophageal mucosa. In addition, the sheet-like formulation of the dosage form according to the present invention can be gellable or swellable.

[0077] In a preferred embodiment of the drug delivery system according to the present invention, the thickness of the sheet-like formulation is 0.01 mm to 2 mm, preferably 0.03 mm to 1 mm, preferably 0.05 mm to 0.1 mm. This is beneficial for providing a relatively thin sheet-like formulation.

[0078] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-like formulation has an area of 0.5 to 25 cm 2 , preferably 1 to 10 cm 2 .

[0079] The sheet-like preparation can have different shapes. In particular, the sheet-like preparation can have a round, triangular, square, or polygonal shape. In one embodiment, the opening is adapted to the respective shape of the preparation.

[0080] In a preferred embodiment of the drug delivery system according to the present invention, a sheet-like preparation, particularly a film-shaped, foil-shaped, or oblate-shaped preparation, containing an anti-inflammatory agent or a salt thereof, 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, and most preferably 0.01 to 10% by weight.

[0081] The sheet-like preparation containing an anti-inflammatory agent can have a single-layer or multi-layer structure, and at least one (preferably the first) layer contains an anti-inflammatory agent or a salt thereof.

[0082] In a preferred embodiment, the sheet-like preparation has a multi-layer structure of a plurality of layers, at least one first layer contains an anti-inflammatory agent or a salt thereof, and at least one further layer contains at least one further pharmaceutically active ingredient, which can be either the same or a different anti-inflammatory agent or a salt thereof, or not an anti-inflammatory agent or a salt thereof such as a steroid.

[0083] In a preferred embodiment, the layer containing an anti-inflammatory agent or a salt thereof and / or the further layer containing an additional pharmaceutically active ingredient includes a polymer, preferably a film-forming polymer.

[0084] The polymer in the layer can function simply as a carrier for the anti-inflammatory agent or a salt thereof and / or the additional API, or as a reservoir thereof. Such a layer can release the anti-inflammatory agent or a salt thereof and / or the additional pharmaceutically active ingredient under the influence of a fluid. The anti-inflammatory agent or a salt thereof and / or the additional API can be released immediately or in a sustained-release manner.

[0085] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-like formulation comprises at least one first layer containing an anti-inflammatory agent or a salt thereof, and / or a further layer containing an anti-inflammatory agent or a salt thereof and / or an additional API, and at least one first layer and / or the further layer is an adhesion layer.

[0086] In a preferred embodiment of the drug delivery system according to the present invention, at least one first layer containing an active ingredient and / or a further layer containing an active ingredient comprises a polymer, preferably a film-forming polymer, and the polymer is a water-dispersible and / or hydrolyzable and / or water-disintegrating film-forming polymer.

[0087] The polymer of the first layer containing the active substance and / or the polymer of the further layer containing the active substance may be selected, in particular, from the group consisting of polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetate, polyethylene glycol, polyethylene oxide polymer, polyurethane, polyacrylic acid, polyacrylate, polymethacrylate, poly(methyl vinyl ether-maleic anhydride), starch, starch derivatives, natural gums, alginate, pectin and gelatin, pullulan, proteins forming gels, chitosan, agar, agarose, carrageenan, xanthan, tragacanth, dextran, and cellulose ethers such as ethyl cellulose, hydroxyethyl cellulose, propyl cellulose, carboxymethyl cellulose, sodium-carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate, povidone, and copovidone. In a preferred embodiment, the polymer is polyvinyl alcohol, preferably polyvinyl alcohol 18-88.

[0088] The polymers can be used individually or in combination to produce a sheet-like formulation for a dosage form according to the present invention having desired properties such as adhesion, release, or disintegration characteristics. The sheet-like formulation according to the present invention can consist of one polymer layer.

[0089] The sheet-like preparation for the dosage form according to the present invention may also have a structure of two or more layers, in which case at least one of these layers contains an anti-inflammatory agent or a salt thereof. It is also possible for the plurality of layers to contain either an anti-inflammatory agent or a salt thereof, or an additional API.

[0090] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-like preparation containing an anti-inflammatory agent or a salt thereof comprises or consists of a single-layer structure, and the (preferably first) layer contains an anti-inflammatory agent or a salt thereof, preferably tofacitinib citrate. The layer contains a polymer, preferably a film-forming polymer, and the polymer is a water-dispersible and / or hydrolyzable and / or water-disintegrable film-forming polymer. The polymer is a polymer described herein, preferably polyvinyl alcohol, preferably polyvinyl alcohol 18-88. The layer further contains an additive such as a plasticizer described herein, preferably glycerol.

[0091] In another preferred embodiment of the drug delivery system according to the present invention, the sheet-like preparation containing an anti-inflammatory agent or a salt thereof comprises at least one first active ingredient-free layer that does not contain a pharmaceutically active ingredient.

[0092] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-like preparation, particularly in the form of a film, foil, or oblate, containing a pharmaceutically active ingredient comprises at least one further active ingredient-free layer that does not contain a pharmaceutically active ingredient.

[0093] In a preferred embodiment of the drug delivery system according to the present invention, the first active ingredient-free layer and / or at least one further active ingredient-free layer is a water-insoluble layer, preferably selected from the group consisting of ethyl cellulose and / or a combination of ethyl cellulose and other water-insoluble substances, a hydrophobic plasticizer, particularly triethyl citrate, and / or a dye, and / or a fragrance, and / or a flavoring agent.

[0094] In particular, the use of ethyl cellulose can be beneficial due to its properties including good processability, biocompatibility, and water-insolubility.

[0095] In a preferred embodiment of the drug delivery system according to the present invention, the first active ingredient-free layer and / or at least one additional active ingredient-free layer is an adhesion layer of a desired thickness.

[0096] The adhesion layer can be a mucoadhesive polymer selected from the group comprising cellulose derivatives such as hydroxypropyl cellulose, 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.

[0097] Additionally or alternatively, the adhesion layer can contain a solvent selected from the group comprising water, ethanol, methanol, acetone, organic solvents, and mixtures thereof.

[0098] Furthermore, the formulation may additionally contain additives such as coloring agents, fragrances, flavoring agents, preservatives, antioxidants, penetration enhancers, solubilizing agents, disintegration accelerators, pore-forming agents, lubricants, and mixtures thereof. In particular, the following substances: lubricants, flow promoters, binders, additional active ingredients, disintegrants, antioxidants, chelating agents, coating agents, flow agents, preservatives, fillers, surfactants, plasticizers, and pigments are suitable as additives. Furthermore, the additives are from the following groups: pore-forming agents, penetration enhancers, solubilizing agents, emulsifiers including polyethoxylated sorbitan fatty acid esters, ethoxylated fatty alcohols, and lecithin; plasticizers including polyethylene glycol, glycerol and other polyhydric alcohols, higher alcohols such as dodecanol, undecanol, or octanol, sorbitol, mannitol and other sugar alcohols, dexpanthenol and triglycerides; fillers including highly dispersed silicon dioxide, titanium oxide, zinc oxide, chalk, and starch; coloring agents; sweeteners and flavoring agents; wetting agents; preservatives; pH adjusters and antioxidants; disintegration accelerators; penetration enhancers that improve the absorption of the pharmaceutical active ingredient into the mucosa such as cell uptake, for example, fatty acids, their salts, and fatty acid esters, preferably saturated fatty acids such as octanoic acid (C8), decanoic acid (C10), octadecanoic acid (C18), or unsaturated fatty acids such as oleic acid (C18), S-acetylcysteine (NAC) or its salt, terpenes, glycolipids, medium-chain triglycerides, synthetic waxes such as isopropyl myristate, branched fatty alcohols such as oitanoal G (registered trademark), urea, polypropylene glycol, dimethyl sulfoxide, azone, azone analogs, polyhydric alcohols such as propanediol, tocopherol, or essential oils such as menthol, may be more preferably selected. A preferred plasticizer is glycerol.

[0099] The sheet-like preparation may further contain at least one flavoring additive. Advantageously, this makes it possible to mask bitter or otherwise unpleasant-tasting pharmaceutically active ingredients, but it can also be beneficial to accelerate the onset of the effect of the pharmaceutically active ingredient. Flavoring additives are known to those skilled in the art. Such flavoring additives may include, in particular, sugar alcohols selected from mannitol, sorbitol, xylitol, maltitol, lactitol, erythritol, trehalose, and isomalt, and sodium bicarbonate.

[0100] In particular, additives such as penetration enhancers can improve the local utility of the active ingredient.

[0101] According to a preferred embodiment, the drug delivery system according to the invention, in particular the sheet-like preparation, is intended to enable a time-delayed release of the active ingredient. The anti-inflammatory agent or a salt thereof is preferably released over 4 hours, preferably over 6 hours, most preferably over 8 hours. In order to achieve a delayed release of the active ingredient in the case of a two-layer or multi-layer preparation, at least one layer containing the anti-inflammatory agent or a salt thereof, in particular a polymer layer, has a delayed release of the active ingredient.

[0102] For the delayed release of the active ingredient, the film-shaped preparation is preferably formulated as a slowly soluble or slowly disintegrating film that completely disintegrates or dissolves only after several hours. Preferably, they completely disintegrate or completely dissolve only after 4 hours, preferably only after 6 hours, even more preferably only after 8 hours, or even only after 24 hours.

[0103] In particular, the anti-inflammatory agent or a salt thereof and any additional API present optionally are released within 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 to 6 hours.

[0104] The sheet-like preparation can be prepared by a method basically known to those skilled in the art, for example, by a liquid composition containing a polymer, an anti-inflammatory agent or its salt / additional pharmaceutically active ingredient, and optionally additives, and a solvent, and coating an inert support by a method involving a doctor blade (for example, solvent casting method), a spray processor, or an extrusion processor. The thin film layer obtained by such a method is dried. In the case of a multilayer sheet-like preparation, one or more coatings can be applied to the existing film layer as well, or they can be manufactured separately and then laminated.

[0105] During the manufacture of the preparation, it is necessary to take into account the temperature sensitivity, pH sensitivity, and / or solubility of the anti-inflammatory agent or its salt used. Therefore, from the viewpoint that the dose required for local / topical administration is less compared to systemic administration, an impregnation method can be used. In such a method, a solution containing the anti-inflammatory agent or its salt is simply applied to the polymer film, for example, by spraying or dropping, and finally dried.

[0106] In a preferred embodiment, the anti-inflammatory agent or its salt can be incorporated so as to be embedded in the polymer film, for example, by a solvent casting method. Such methods are known to those skilled in the art and are further described in the examples provided herein.

[0107] In all of these methods, consideration is required for the solvents used and the drying conditions. As a very simple drying method, lyophilization can be used.

[0108] Furthermore, depending on the stability of the anti-inflammatory agent or its salt to be incorporated, for example, as described in Example 2 of this specification, melt extrusion of the polymer and the anti-inflammatory agent or its salt is also conceivable.

[0109] Alternatively, a solution containing the anti-inflammatory agent or its salt can be applied to the polymer film by an inkjet method.

[0110] In one embodiment, the formulation is manufactured such that the anti-inflammatory agent or its salt is present only in a specific portion within the film, thereby enabling mucosal treatment of only the individualized designated area.

[0111] Alternatively, and preferably, the first region of the sheet-like formulation can contact the esophageal mucosa, and the second region of the sheet-like formulation can contact the buccal mucosa. Thus, while the esophageal mucosa can be treated with the anti-inflammatory agent or its salt, the second anti-inflammatory agent or its salt, an additional API can treat, not treat, or release an additive to the buccal mucosa. In particular, a flavoring agent and / or a local anesthetic can be released, thereby in particular increasing or decreasing the saliva production volume and / or making the application of the drug delivery system more comfortable and / or suppressing nausea. Alternatively, the first region of the sheet-like formulation can contact the esophageal mucosa, and the second region of the sheet-like formulation can contact the mucosa of the upper part of the stomach such as the cardia, or the mucosa of the cardia and the fundus of the stomach. Therefore, it becomes possible to locally treat each part of the esophagus and the stomach.

[0112] In another preferred embodiment, the drug delivery system, particularly the capsule device, includes a weight device. The weight device is configured to provide negative buoyancy to the capsule device. In the experiments of the inventors underlying the findings of this preferred embodiment, it has been found that, for example, reducing buoyancy by increasing the mass of the capsule device increases the reliability of the mechanical process by which the formulation unfolds from the miniaturized state to the deployed state. In the case of an elongated sheet-like formulation, it has become significantly easier and more efficient for the elongated sheet-like formulation to unwind from the state where it is wound around a spool and enter the deployed state. The problem underlying this preferred embodiment is that occasional deficiencies are observed in the transition of the formulation from the miniaturized state to the deployed state. The present invention already improves the efficiency of deployment or, individually, unwinding by providing a gap between the opening and the formulation, but the weight device further increases the efficiency of deployment. Also, it is presumed that even when the patient swallows appropriately in the presence of water or an aqueous solution, the capsule device will not be completely filled with water, and air bubbles may remain within the capsule device. That air contributes to buoyancy, and the weight device assists in counteracting the buoyancy effect by assisting in expelling the air or by utilizing gravity through the use of a material denser than water. Further details regarding the weight can be inferred from WO2020 / 183005, which is incorporated herein by reference.

[0113] The drug delivery system according to the present invention can also be adapted to be applied to the nasopharyngeal mucosa.

[0114] When a sheet-like formulation locally and / or over a long period of time releases an anti-inflammatory agent or a salt thereof, optionally together with additional APIs, the response to treatment can be improved, and in particular, the local effect of the anti-inflammatory agent or a salt thereof can be enhanced, for example, by a penetration enhancer. Such penetration enhancers are known in the art. Furthermore, since the area of action spreads spatially, the need for systemic administration can be reduced.

[0115] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-like formulation is 0.5 - 25 cm2 preferably 2 to 25 cm in length 2 preferably 5 to 25 cm in length 2 preferably 5 to 15 cm in length 2 preferably 0.5 cm in length 2 larger than and preferably 40 cm 2 having an area and / or surface area smaller than. Preferably, the ratio of the length of the sheet-like formulation to the width of the sheet-like formulation is 40:1 to 400:1, or preferably 60:1 to 300:1, or preferably 80:1 to 200:1. The width can be, for example, the average of the widths of the sheet-like formulation measured perpendicular to the length of the sheet-like formulation. The ratio can be the ratio of the length of the sheet-like formulation to the perimeter of the sheet-like formulation, particularly its average, and the perimeter can be, for example, twice the width of the sheet-like formulation in the case of an elongated sheet-like formulation.

[0116] In certain embodiments of the drug delivery system according to the present invention, the sheet-like formulation is in a solid state, particularly while in a small form and / or immediately after release. This can beneficially enhance, enable, or facilitate some of the advantages described above. In particular, this can enhance the storage stability when the sheet-like formulation is in a solid state before release. In particular, this can enhance and / or enable the targeted and / or sustained release of the anti-inflammatory agent or its salt when the sheet-like formulation is in a solid state after release. Additionally, or alternatively, in certain embodiments of the drug delivery system according to the present invention, the sheet-like formulation is configured to dissolve, for example, undergo in vivo degradation, immediately after release, after a delay, in a time-controlled manner, or upon stimulation. This can beneficially enhance, enable, or facilitate some of the advantages described above. In particular, this can improve user convenience as there is no need to recover the sheet-like formulation.

[0117] Additionally, or alternatively, in certain embodiments of the dosage forms according to the present invention, the sheet-like formulation is preferably made to dissolve, e.g., undergo in vivo degradation, in a time-controlled manner, e.g., within 1 hour, or within 1 - 2 hours, or within 1 - 5 hours, or within 1 - 12 hours, or within 1 - 24 hours. This improves user convenience as there is no need to retrieve the sheet-like formulation.

[0118] Applicator / Holder In one embodiment, an applicator having a holder functions to assist in swallowing a capsule device when used in combination with a drinking cup. The applicator used in combination with the drinking cup allows a patient to ingest the drug delivery system as if drinking from a bottle. Thus, the applicator is placed in the drinking cup as a mouthpiece. The drug delivery system is located within the holder of the applicator. When drinking, the liquid in the drinking cup flows through the applicator and the holder therein, whereby the formulation is released from the holder and carried into the patient's mouth, which the patient then swallows. The string member is the holder and is wound around the holder. The string member is further connected to the holder and the formulation end, and the formulation end extends through the opening. Thus, when the formulation exits the holder during drinking, the holder unwinds until it is taut. Thereby, a force is exerted on the formulation and the formulation is pulled out of the capsule.

[0119] Such applicators and drinking cups are described, for example, in PCT / EP2020 / 056927, and with respect to the applicator, drinking cup, and string, the entire text thereof is incorporated herein by reference. Such holders are further described, for example, in EP21175427.0 and EP21175436.1, and with respect to the holder, the entire text thereof is incorporated herein by reference.

[0120] In a preferred embodiment, the retainer is wound around the support structure of the holder, with one end of the retainer attached to the support structure and the other end connected to the formulation of the capsule device. Thus, the capsule device is positioned and held within the applicator holder. When the patient swallows the dosage form, the retainer begins to loosen from the support structure. Since the applicator and the support structure have a cylindrical shape such that the support structure fits within the applicator and is rotatably installed therein in particular, the retainer can be loosened from the structure by rotating the structure.

[0121] This is particularly beneficial as it enables the administration of the capsule device without the assistance of an expert, especially when the dosage form is administered regularly, particularly up to daily maximum.

[0122] In a preferred embodiment of the drug delivery system according to the present invention, the release mechanism includes a retainer, which is preferably a string that can be deployed from a compact form to a deployed form and is connected to one end of the formulation protruding from the capsule device. Examples of strings include, but are not limited to, multifilament strings or threads.

[0123] Exemplary embodiments of the present invention are described in more detail below with reference to the accompanying drawings and samples, from which further features, advantages, and embodiments may be known.

Brief Description of the Drawings

[0124]

Fig. 1a-b

Fig. 2

Fig. 3

Fig. 4

Fig. 5a-b

Fig. 6

Fig. 7

Fig. 8a-b

Fig. 9a-b

Fig. 10

[0125] Fig. 1a shows a schematic view of a drug delivery system 1 having a capsule device 2 in which an opening 3 is formed by fitting a first half capsule shell 2a and a second half capsule shell 2b into each other. A formulation 4 in a small form within the capsule 2 is shown, with one end 4a thereof extending from the opening 3. The direction of movement of the formulation 4 when it is pulled out from the capsule 2, i.e., from the first half capsule shell 2a, through the opening 3, is indicated by an arrow. In Fig. 1a, an opening 3 formed laterally with respect to the central axis A of the capsule 2 and arranged in the first half capsule shell 2a is shown. In Fig. 2b, an opening 3 formed along the central axis A of the capsule 2 and arranged in the first half capsule shell 2a is shown.

[0126] Figure 2 shows a schematic view of the formulation 4 in a partially expanded form. The formulation 4 having a sheet-like shape is depicted. The central region of the formulation 4 is indicated by a dashed line in order to show, in Figure 2, essentially the end 4a of the formulation 4 protruding from the opening 3 of the capsule device 2 and the end 4b of the formulation 4 which is still slightly coiled. The coiled end 4b shows the small form of the formulation 4. At the end 4a extending from the opening 3, a holding device 5 having a cloth-like shape is shown. The holding device 5 includes an elongate piece 5a. The elongate piece 5a functions as a connector connecting the holding device 5 and the end 4a of the formulation 4 in the embodiment shown in Figure 2. Instead, the end 4a of the formulation 4 is directly connected to a holding body, such as a string. In such an embodiment, the holding devices 5, 5a are formed by the holding body itself.

[0127] Figure 3 shows this preferred embodiment. The end 4a of the formulation 4 having a sheet-like shape is shown, where the holding body 6 overlaps with the end portion having the length d of the formulation 4 and forms the holding devices 5, 5a. The connection between the holding body 6 and the end 4a of the formulation 4 is made such that when the holding body 6 is stretched, for example, by swallowing the dosage form 1, the pulling force can move through this connection and the formulation 4 is pulled out from the capsule device 2.

[0128] Figure 4 shows the formulation 4 divided into several layers. In the embodiment shown in Figure 4, the formulation is an oblate containing three separate layers 7. One upper layer 7a is formed as an adhesive layer, the central layer 7b contains an anti-inflammatory agent or a salt thereof, and the layer depicted at the bottom in Figure 4 shows a protective layer, for example, a protective layer against water.

[0129] Figures 5a and 5b respectively show schematic views of the capsule device 2 of the drug delivery system 1 having an opening 3 formed by overlapping wall portions 9 or by fitting two capsule shell halves 2a, 2b into each other. As shown in Figure 5a, the first capsule shell half 2a is slid over the second capsule shell half as indicated by the dashed line. The second capsule shell half includes a recess 8. By partially covering and sliding the two halves 2a, 2b over each other, the first capsule shell half 2a partially covers the recess 8 of the second capsule shell half 2b. Thereafter, the further provided wall portion 9 covers the remaining opening space formed by the recess 8, thus forming the opening 3 as an opening through which the formulation 4 can exit the shell 2.

[0130] Alternatively, Figure 5b shows an embodiment in which the two capsule shell halves 2a, 2b overlap at the joining position to such an extent that one wall of the first capsule shell half, particularly the cylindrical wall, overlaps the opening 10 of the second capsule shell half 2b to form the opening 3.

[0131] Figure 6 shows a translucent schematic view of the drug delivery system 1. The first and second capsule shell halves 2a, 2b are joined at the joining position, thereby covering the opening 10 of the second capsule shell half 2b at this position to form the opening 3. The end portion 4a of the formulation 4 extending through the opening 3 is shown. The pharmaceutical dosage form 1 further includes a weight element 11, and the weight element 11 is within the first capsule shell half 2a. The weight extends from the first capsule shell half 2a into the second half 2b, but the step 11a protrudes from the outside to the inner space of the capsule device 2 to position the weight 11 and prevent the weight from moving within the capsule. In Figure 6, the formulation 4 located below the weight 11 is shown. The step prevents the weight 11 from sliding into the formulation 4.

[0132] Figure 7 shows a schematic view of an applicator 12 having a holder 13 and a retainer 6 wound around the holder 13, with the drug delivery system 1 positioned within the holder 13. The applicator and the holder preferably have a cylindrical shape. The capsule device 2 is positioned within the holder 13, with the first half 2a facing towards the applicator cap 12a. The cap 12a is removed during use. In the embodiment shown in Figure 7, the capsule device 2 further includes a weight 11 within the first capsule shell half 2a and a formulation 4 within the second capsule shell half 2b. In the embodiment shown in Figure 7, the first capsule shell half 2a is further pressed towards the bottom of the applicator 12. Thus, a curved holder 13a is positioned above the capsule device 2. The holder 13a is curved such that its shape follows the shape of the first capsule shell half 2a. Pushing the capsule 2 into the holder 13 is achieved by a compression spring 14, one end of which is attached to the cap 12a of the applicator 12 and the other end of which is attached to the curved holder 13a. A drying element 15 is positioned within the applicator 12, at the cap 12a of the applicator 12. This prevents the formulation 4 from being damaged by moisture. The applicator 12 does not necessarily include the curved holder 13, the drying element 15, or the compression spring 14.

[0133] Figures 8a and 8b respectively show schematic diagrams of the drug delivery system 1 before swallowing (Figure 8a) and during swallowing (Figure 8b) when the patient ingests the drug delivery system using the applicator and the drinking cup. Figure 8a shows the administration of the drug delivery system including the capsule device 2 described herein by the patient. The drinking cup 16 is filled with liquid and the applicator 12 is attached to the cup 16. The applicator 12 includes the holder 6 and the drug delivery system 1, the drug delivery system 1 further includes the capsule device 2, the holder 6 is connected to the formulation 4, and the formulation 4 is at least partially coiled within the capsule device 2. Figure 8b illustrates the procedure when the dosage form 1 is sent towards the stomach through the esophagus when the patient swallows the dosage form 1. The holder 6 pulls the formulation 4 out of the capsule device 2. Then the formulation 4 spreads along the esophagus and the active ingredient of the dosage form 1 is delivered to the esophageal mucosa.

Explanation of Reference Numerals

[0134] 1 Drug delivery system 2 Capsule device 2a First half of the capsule shell 2b Second half of the capsule shell 3 Opening 4 Formulation 4a Formulation end extending from the opening 4b Coiled formulation end 5 Retaining device 5a Elongated piece 6 Holder 7 Layer 7a Adhesive layer 7b Layer containing the active ingredient of the drug 7c Protective layer 8 Dimple 9 Wall portion 10 Opening 11 Weight element 11a Step 12 Applicator 12a Applicator cap 13 Holder 13a Curved holder 14 Spring 15 Drying element 16 Cups

Example 1

[0135] Example 1: Preparation of Polymer Film Using Tofacitinib A "base polymer mixture" was prepared without adding tofacitinib with the components and amounts listed in Table 1.

[0136] JPEG2025518373000002.jpg40170*Generally, the amount of HCl required can vary depending on the polymer batch and is preferably adjusted to an acidic pH (pH 6.0 or lower). The acidic pH is advantageous for the stability of tofacitinib.

[0137] After adjusting the pH to pH 4.0, tofacitinib was added at room temperature, and a film laminate was prepared by the solvent casting method, i.e., the polymer mixture containing tofacitinib was spread and the solvent was evaporated. The film was dried at room temperature.

[0138] The obtained film was flexible, and no particles were detected on the film surface.

[0139] Furthermore, the tofacitinib content of the film was analyzed. For this purpose, six circular samples with a diameter of 1.9 cm (2.84 cm 2 ) were cut out at random positions on the film and analyzed by UV / Vis spectroscopy in a pH 4.0 citrate buffer containing 20% methanol. The absorption spectra compared with a reference sample (tofacitinib dissolved in a pH 4.0 citrate buffer containing 20% methanol) are shown in Figure 10. From the comparison of the spectra of the film samples and the reference sample, it was confirmed that tofacitinib can be stably prepared in the film used for the drug delivery device of the present invention.

[0140] Furthermore, the tofacitinib content on the film was as shown in Table 2.

[0141] JPEG2025518373000003.jpg37170

[0142] Note that the standard deviation and the maximum drug loading are determined by the process technology and are not intended to indicate any limitation in principle.

[0143] From the results in Table 2, it can be seen that a 10 mg loading of tofacitinib is possible on a 10 cm 2 film, allowing the preparation of films with a wide range of therapeutic drug dosages. Therefore, the drug delivery system of the present invention enables the administration of a high local concentration of the agent while providing a favorable systemic safety profile. Example 2

[0144] Example 2: Preparation of a polymer film by melt extrusion - Selection of a suitable polymer base: Select a polymer base that is compatible with the active ingredient intended for use. Typical polymers are polyvinyl alcohol (PVA), cellulose ether, and polyethylene glycol (PEG), which are combined with a suitable plasticizer. - Preparation of the active ingredient: The active ingredient is usually prepared in a suitable formulation (e.g., as a powder or granule). - Mixing of the components: Mix the polymer base and the active ingredient with a mixer to form a homogeneous mixture. - Extrusion: Feed the mixture into an extruder, melt it at a high temperature, and extrude it through a die. The die forms a film, and the film is placed on a cooling plate. - After the polymer compound is extruded from the die by melt extrusion, the extruded film can be subjected to a rolling process to further optimize its thickness and properties. The rolling process can include either cold rolling or hot rolling, depending on the requirements specific to the film. - Post-treatment: After the extrusion process, cut the extruded film into the desired size and shape. Next, the film is usually subjected to further processes such as drying, coating, or lamination to improve its physical and pharmaceutical properties.

Claims

1. A drug delivery system applied to the esophageal mucosa, A sheet-like formulation containing a pharmacoactive ingredient, Release mechanism, and Trigger mechanism Includes, The trigger mechanism is configured to cause the release of the formulation by the release mechanism at a predetermined site of action, and the release mechanism is configured to release the formulation while moving along the esophageal mucosa. The drug delivery system further includes a shell, the shell containing the formulation, the shell including an opening configured as part of the release mechanism to allow the formulation to exit the shell, and the trigger mechanism being a retaining device, which is part of the formulation or attached to the formulation, so that the formulation opens or spreads as the dosage form descends the esophageal mucosa and exits the shell through the opening. The drug active ingredient is characterized by comprising an anti-inflammatory agent or a salt thereof. Drug delivery system.

2. The drug delivery system according to claim 1, wherein the anti-inflammatory agent reduces or inhibits inflammation and / or fibrosis.

3. The drug delivery system according to claim 2, wherein the anti-inflammatory agent includes an immunosuppressant.

4. The drug delivery system according to claim 3, wherein the immunosuppressant comprises a tyrosine kinase inhibitor, and 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).

5. The drug delivery system according to claim 3, wherein the immunosuppressant comprises a calcineurin inhibitor, and the calcineurin inhibitor is selected from the group consisting of sirolimus (rapamycin), tacrolimus (FK-506), pimecrolimus, and cyclosporine A.

6. The drug delivery system according to claim 3, wherein the immunosuppressant comprises a purine analog, and the purine analog is azathioprine (AZA) or 6-mercaptopurine (6-MP).

7. The drug delivery system according to claim 1, wherein the salt of the anti-inflammatory agent is selected from citrate, phosphate, and borate.

8. The drug delivery system according to claim 1, wherein the salt of the anti-inflammatory agent is a salt of a JAK inhibitor.

9. The drug delivery system according to claim 1, wherein the sheet-like formulation containing the pharmacoactive ingredient contains polyvinyl alcohol (PVA).

10. The drug delivery system according to claim 1, wherein the sheet-like formulation containing the pharmacoactive ingredient contains a plasticizer.

11. The drug delivery system according to claim 1, wherein the pharmacoactive component further comprises one or more additional pharmacoactive components, and the one or more additional pharmacoactive components is a steroid.

12. A drug delivery system according to any one of claims 1 to 11, used for therapeutic purposes.

13. A drug delivery system according to claim 12, used for the treatment or prevention of esophageal disease.

14. A drug delivery system according to claim 13, used for the treatment or prevention of esophageal diseases caused by or related to a defect in the immune system.

15. A drug delivery system according to claim 13, used for the treatment or prevention of eosinophilic esophagitis and / or esophageal stricture.

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