Drug delivery system for esophageal mucosa comprising reflux inhibitor

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-shaped formulation, comprising a reflux inhibitor, a release mechanism, and a trigger mechanism, the trigger 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 including a reflux inhibitor, particularly for application to the esophageal mucosa and for the treatment of esophageal diseases, particularly gastroesophageal reflux disease. Background Art

[0002] Gastroesophageal reflux disease (GERD) is a chronic disease with relapses and remission phases over time (Antunes et al., "Gastroesophageal Reflux Disease", StatPearls Publishing, 2021). The overall prevalence of gastroesophageal reflux disease is 18-28% in the U.S. population and 9.8%-18% in Europe. Gastroesophageal reflux disease is characterized by the reflux of gastric contents (which may include bile and other duodenal-gastric reflux components) into the esophagus. Although the stomach itself is not affected by gastric acid, gastric acid is very harmful to tissues outside the stomach such as the esophagus. Typically, patients with gastroesophageal reflux disease have symptoms such as heartburn, reflux, and very little dysphagia. Common atypical manifestations are chronic cough or asthma, as well as non-cardiac chest pain. Patients may suffer from esophageal damage or erosion, which may lead to further diseases from erosive esophagitis (EE) to Barrett's disease (BE).

[0003] Currently, gastroesophageal reflux disease is treated by controlling gastric acid with proton pump inhibitors (PPIs). PPIs are able to achieve up to 80-90% healing rates of the esophageal mucosa within a treatment period of 8-12 weeks and lead to resolution of typical symptoms of the disease, particularly heartburn, reflux-induced chest pain, and dysphagia. However, PPIs are 20-30% less effective for non-erosive reflux disease (NERD). In addition, up to 40% of patients with persistent reflux symptoms do not respond to proton pump inhibitors.

[0004] The primary mechanism of gastroesophageal reflux is transient lower esophageal sphincter relaxation (TLESR), which occurs in patients with gastroesophageal reflux disease. TLESR is the relaxation of the lower esophageal sphincter (LES) in the absence of swallowing, allowing gastric contents to pass through the esophagus. The lower esophageal sphincter is a smooth muscle within the wall of the esophagus that forms a valve at the end of the esophagus that connects to the stomach and represents a therapeutic target for local treatment of gastroesophageal reflux disease. For example, US 9,925,375 and US10,661,081 describe a non-invasive device for treating gastroesophageal reflux disease and the digestive system. The device is placed on the skin of the patient's abdomen and electrically stimulates the abdominal muscles. This treatment results in dynamic movements of the digestive system, resulting in the treatment of various digestive symptoms or diseases.

[0005] 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.

[0006] 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.

[0007] There remains a need for suitable drug delivery systems, particularly for delivery to the esophagus, that can deliver active pharmaceutical ingredients for effective treatment while allowing for administration of the lowest possible dose to reduce side effects. Summary of the invention

[0008] Purpose of the Invention

[0009] An object of the present invention is to provide a drug delivery system that enables oral / topical administration of reflux inhibitors, such as GABA type B receptor agonists, for the treatment of gastroesophageal reflux disease with enhanced local efficacy.

[0010] Another object of the present invention is to provide a delivery system that allows the use of low doses of reflux inhibitors, such as GABAB type receptor agonists, thereby minimizing potential side effects.

[0011] 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.

[0012] Claimed Subject Matter

[0013] In a first aspect, the present invention relates to a drug delivery system for application to the 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; a release mechanism; and a trigger mechanism, wherein the trigger mechanism is suitable for triggering the release of the preparation by the release mechanism at a predetermined site of action, 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 shell, wherein the shell contains the preparation, and wherein the shell comprises a hole as part of the release mechanism, the hole being configured to allow the preparation to leave the shell, and wherein the trigger mechanism is a retaining device, the retaining device is part of the preparation or attached to the preparation, so that when the dosage form moves down the esophageal mucosa and leaves the shell through the hole, the preparation spreads or unfolds, characterized in that the active pharmaceutical ingredient comprises a reflux inhibitor, preferably a reflux inhibitor that reduces or blocks temporary lower esophageal reflux relaxation, such as a gamma-aminobutyric acid (GABA) type B receptor agonist.

[0014] In one embodiment, the active pharmaceutical ingredient (API) in the drug delivery system includes a gamma-aminobutyric acid (GABA) type B receptor agonist.

[0015] In one embodiment, the active pharmaceutical ingredient is a GABA B receptor agonist selected from the group consisting of: γ-aminobutyric acid (GABA) or a salt thereof, β-phenyl-γ-aminobutyric acid (Phenibut) or a salt thereof, 4-Fluorophenibut or a salt thereof, isovaline or a salt thereof, 3-aminopropylphosphonic acid or a salt thereof, 3-aminopropylmethylphosphonic acid (SKF-97,541) or a salt thereof, [3-amino-2-hydroxypropyl]-methylphosphonic acid (CGP 44532) or a salt thereof, 4-amino-3-(4-chlorophenyl)butyric acid (Baclofen) or a salt thereof, [(2R)-3-amino-2-fluoropropyl]phosphonic acid (Lesogaberan) or a salt thereof, [2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol] (CGP7930) or a salt thereof, (S)-3-amino-2-hydroxypropylphosphonic acid (C3H 10 O3NP; AZD9343) or a salt thereof and Arbaclofen placarbil or a salt thereof.

[0016] In one embodiment, the GABA type B receptor agonist comprises 4-amino-3-(4-chlorophenyl)butyric acid (baclofen) or a salt thereof.

[0017] In one embodiment, the GABA type B receptor agonist comprises the R-enantiomer of 4-amino-3-(4-chlorophenyl)butyric acid (baclofen) or a salt thereof.

[0018] In one embodiment, the active pharmaceutical ingredient (API) in the drug delivery system comprises a hormone, such as a peptide hormone. Examples of peptide hormones are gastrin, motilin or pancreatic polypeptide.

[0019] In one embodiment, the active pharmaceutical ingredient (API) in the drug delivery system includes a neurotransmitter, such as histamine, acetylcholine, muscarinic acid, substance P, or bombesin.

[0020] In one embodiment, the active pharmaceutical ingredient (API) in the drug delivery system includes another drug, such as bethanechol, carbachol, pilocarpine, metoclopramide, domperidone, cisapride, 5-HT3-antagonists, cyproheptadine, pizotifen, or alpha-adrenergic substances. Examples of 5-HT3-antagonists are dolasetron, granisetron, ondansetron, palonosetron, tropisetron, alosetron, or ramosetron.

[0021] In one embodiment, the active pharmaceutical ingredient (API) in the drug delivery system includes a food component, such as a food protein.

[0022] 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).

[0023] In a second aspect, the drug delivery system of the present invention is used in therapy.

[0024] In a third aspect, the drug delivery system is used to treat or prevent esophageal diseases; or to treat or prevent esophageal diseases caused by or associated with gastroesophageal reflux, such as gastroesophageal reflux disease, non-erosive reflux disease, esophagitis, in particular erosive esophagitis and / or cancer, for example esophageal cancer, such as adenocarcinoma, squamous cell carcinoma or Barrett's esophagus; or to treat or prevent gastroesophageal reflux disease. DETAILED DESCRIPTION

[0025] 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.

[0026] Unless expressly stated otherwise, terms expressed herein in the singular also include the plural terms and vice versa.

[0027] As used herein, the indefinite article "a" or "an" also includes the definite article "the", unless stated otherwise.

[0028] 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".

[0029] 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 , 8b In 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.

[0030] 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.

[0031] The drug delivery system according to the present invention is orally administered and improves the local availability of the reflux inhibitor. 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 site / position to be treated.

[0032] Because the reflux inhibitor is provided in the form of a sheet preparation, particularly a film-shaped, foil-shaped, thin sheet-shaped or strip-shaped preparation, local availability is improved. This advantageously allows the sheet preparation (and the reflux inhibitor present therein) to be released directly to the site / position to be treated (treatment site), such as the esophageal mucosa. Therefore, preferably, a large area of ​​the sheet preparation is exposed to the mucosa, i.e., to the esophageal mucosa. When exposed to the mucosa, the sheet preparation releases the reflux inhibitor. In addition, the preferred direct contact between the mucosa and the preparation leads to the effective effect of the reflux inhibitor at the treatment site. Since the reflux inhibitor is delivered directly to the treatment site, less reflux inhibitor is required to cause a decrease in systemic bioavailability and a decrease in concentration in adjacent areas such as healthy areas compared to the use of conventional preparations such as suspensions or solutions. In addition, direct delivery to the treatment site also allows the dosage of the reflux inhibitor contained in the preparation to be reduced, thereby advantageously further reducing side effects.

[0033] 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 reflux inhibitor 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 these additives are known to cause allergies or other side effects.

[0034] 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.

[0035] Release mechanism

[0036] Release mechanism relates to the mechanism that sheet preparation is expanded and released from capsule device (for example 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 partly 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 (for example, from folded form) into its expanded form (for example, unfolded form).Therefore, described release mechanism causes the unfolding of preparation.In compact form, described preparation has less spatial range, for example, preparation is gathered together, coiled or wound around or forms less spatial form in another way.This also allows to provide little dosage form, i.e. little 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, for example, by unfolding sheet preparation, particularly the surface area of ​​preparation containing active pharmaceutical ingredient increases. Preferably, the surface area of ​​the preparation, particularly the surface area containing active ingredients 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.

[0037] hole

[0038] 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.

[0039] Trigger mechanism / holding device

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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 active pharmaceutical ingredient 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 active pharmaceutical ingredient reaches its target molecule. "Site of action" and "site of application" as used herein do not necessarily refer to the location of the biochemical, medical action of the active pharmaceutical ingredient.

[0046] Capsule device / housing

[0047] Drug delivery system according to the present invention also includes shell, wherein the shell contains at least one sheet preparation, particularly film-shaped, foil-shaped or thin sheet preparation, the preparation comprises active pharmaceutical ingredient, and wherein the shell comprises 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] Condition to be treated

[0054] Drug delivery system as described herein is used in therapy. In one embodiment, it is applicable to the treatment and prevention of esophageal diseases, exemplary esophageal diseases caused by or associated with gastroesophageal reflux, such as gastroesophageal reflux disease, non-erosive reflux disease, esophagitis, particularly erosive esophagitis and / or cancer, such as esophageal cancer, such as adenocarcinoma, squamous cell carcinoma, particularly Barrett's esophagus. In one embodiment, the drug delivery system according to the present invention is applicable to the treatment and / or prevention of gastroesophageal reflux disease. In addition, the drug delivery system is applicable to the treatment and / or prevention of non-erosive reflux disease. In addition, the drug delivery system is applicable to the treatment and / or prevention of erosive esophagitis. In addition, the drug delivery system is applicable to the treatment and / or prevention of cancer, such as adenocarcinoma, particularly Barrett's esophagus.

[0055] Barrett's esophagus is a serious complication of gastroesophageal reflux disease. In Barrett's esophagus, the normal tissue lining the esophagus is replaced by tissue that resembles the lining of the intestines. Barrett's esophagus does not have any specific symptoms, although people with Barrett's esophagus may have symptoms related to gastroesophageal reflux disease. However, it does increase the risk of developing esophageal adenocarcinoma, a serious, potentially fatal form of esophageal cancer. Diagnosis of Barrett's esophagus can be done using endoscopy, histology, and / or the use of biomarkers, such as described in US 20120009597A1.

[0056] In this application, the term "treatment and / or prevention" includes any means of improving a certain condition or disease to be treated or preventing the condition or disease to be treated from occurring. It also includes preventing the condition or disease from getting worse and minimizing the severity of the condition or disease.

[0057] As used herein, esophageal cancer refers to cancers that begin in the esophagus, including but not limited to squamous cell carcinoma and adenocarcinoma.

[0058] The primary mechanism of gastroesophageal reflux is transient lower esophageal sphincter relaxation that occurs in patients with gastroesophageal reflux disease. "Transient lower esophageal sphincter relaxation" or "TLESR" as used herein refers to the relaxation of the lower esophageal sphincter in the absence of swallowing. Thus, transient lower esophageal sphincter relaxation may result in inappropriate opening of the lower esophageal sphincter, thereby allowing gastric acid to enter the esophagus. Without being bound by any theory, transient lower esophageal sphincter relaxation may be triggered by specific receptors located on nerves within the gastric muscularis or receptors located within the gastric mucosa.

[0059] Rohof et al. (Neurogastroenterol. Motil. (2012) 24:383-391) identified gamma-aminobutyric acid (GABA) type B receptors (also known as GABAB Hyland et al. (Frontiers in Pharmacology 1 (2014), Article 124: 1-9) reported that GABA B Expression of GABA receptor subunit 1 on myenteric and submucosal neurons in the mouse colon and ileum. In addition, a meta-analysis of nine clinical studies found that baclofen (GABA B GABA receptor agonists) reduce the number and duration of reflux episodes, as well as the incidence of transient lower esophageal sphincter relaxation (Vela MF, Tutuian R, Katz PO, Castell DO. Aliment Pharmacol. Ther. 2003 Jan; 17(2): 243-51, Li S, Shi S, Chen F, Lin J. Gastroenterol Res Pract. 2014; 2014 (): 307805, Wise J, Conklin JL. Curr. Gastroenterol. Rep. 2004 Jun; 6(3): 213-9). In addition, baclofen was found to control transient lower esophageal sphincter relaxation after systemic administration (Lidums, Gastroenterology, 118: 2000; 7-13). Therefore, GABA B Receptor agonists, especially baclofen, are promising candidates for the drug delivery devices of the present invention.

[0060] Active pharmaceutical ingredients

[0061] In the claimed drug delivery system, a reflux inhibitor, such as a GABA B-type receptor agonist; a hormone, such as gastrin, motilin, histamine or pancreatic polypeptide; a neurotransmitter, such as histamine, acetylcholine, muscarinic acid, substance P or bombesin; another drug, such as bethanechol, carbachol, pilocarpine, metoclopramide, domperidone, cisapride, a 5-HT3-antagonist, cyproheptadine, pizotifen or an alpha-adrenergic substance; or a food component, is used as the main active pharmaceutical ingredient.

[0062] The term "active pharmaceutical ingredient" as used herein is used interchangeably with the term "active ingredient" or API and refers to a reflux inhibitor. Other APIs that may be present in addition to the reflux inhibitor are referred to herein as "additional active pharmaceutical ingredients" or "additional active ingredients" or "additional APIs".

[0063] 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.

[0064] In one embodiment, the active pharmaceutical ingredient is a reflux inhibitor.

[0065] As used herein, "reflux inhibitors" include, but are not limited to, compounds that interfere with, reduce, inhibit and / or block reflux, particularly gastroesophageal reflux. In specific embodiments, the reflux inhibitor interferes with, reduces, inhibits and / or blocks temporary lower esophageal reflux relaxation. In one embodiment, the reflux inhibitor increases or improves lower esophageal pressure, thereby preferably reducing, inhibiting and / or blocking temporary lower esophageal sphincter relaxation. In one embodiment, the reflux inhibitor improves the function of the smooth muscle of the lower esophageal sphincter, such as improving or increasing contractility, thereby preferably reducing, inhibiting and / or blocking temporary lower esophageal sphincter relaxation. In one embodiment, the reflux inhibitor increases distal esophageal sphincter function. In a preferred embodiment, the reflux inhibitor is a GABA B-type receptor agonist. In one embodiment, the reflux inhibitor is a protein, such as an antibody, such as an antibody capable of activating a GABAB-type receptor, or a hormone or neurotransmitter or a food protein. The protein can be a mammalian protein, preferably a human or mouse protein. The protein can be administered as an active protein or an inactive protein precursor, pre-protein or pro-protein. The protein can be administered as a nucleic acid encoding the protein. In one embodiment, the reflux inhibitor is a small molecule, such as a small molecule with a molecular weight of about 900 g / mol or less. In one embodiment, the reflux inhibitor is a hormone, such as gastrin, motilin, histamine, or pancreatic polypeptide; a neurotransmitter, such as histamine, acetylcholine, muscarinic, substance P, or bombesin; another drug, such as bethanechol, carbachol, pilocarpine, metoclopramide, domperidone, cisapride, 5-HT3-antagonists, cyproheptadine, pizotifen, or an alpha-adrenergic substance; or a food component.

[0066] In one embodiment, the active pharmaceutical ingredient is a GABA type B receptor agonist or a salt thereof.

[0067] As used herein, "GABA B receptor agonist" refers to a compound that activates the GABA B receptor to produce a biological response, including but not limited to endogenous agonists, i.e., agonists that are naturally produced by the body and activate the receptor, such as GABA, or exogenous agonists, such as drugs, for example, β-phenyl-γ-aminobutyric acid (Phenibut) or its salts, 4-Fluorophenibut or its salts, isovaline or its salts, 3-aminopropylphosphonic acid or its salts, 3-aminopropylmethylphosphonic acid (SKF-97,541) or its salts, [3-amino-2-hydroxypropyl]-methylphosphonic acid (CGP) or its salts. 44532) or its salts, 4-amino-3-(4-chlorophenyl)butyric acid (baclofen) or its salts, [(2R)-3-amino-2-fluoropropyl]phosphonic acid (Lesogaberan) or its salts, [2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol] (CGP7930) or its salts, (S)-3-amino-2-hydroxypropylphosphonic acid (C3H 10 O3NP; AZD9343) or a salt thereof and Arbaclofen placarbil or a salt thereof.

[0068] In one embodiment, the GABA B receptor agonist, preferably an exogenous agonist, is an agonist that at least partially mimics the response of an endogenous agonist. In one embodiment, the GABA B receptor agonist, preferably an exogenous agonist, activates the receptor with a response comparable to that of an endogenous agonist such as GABA. In a specific embodiment, the agonist is a selective agonist, i.e., it is specific for the GABA B receptor. In another embodiment, the GABA B receptor agonist is a co-agonist, e.g., an agonist that produces a response together with another (co) agonist.

[0069] As used herein, a "biological response" refers to any biological response of a GABA B receptor. In one embodiment, the biological response is a response induced by GABA. In another embodiment, the biological response is a modulation of neurotransmitter release, such as inhibition or activation. In another embodiment, the biological response is a modulation of neurotransmitter release, such as inhibition or activation. 2+ In another embodiment, the biological response is regulated by inwardly coupled rectifier K + Channels regulate neurotransmitter release and mediate slow inhibitory postsynaptic potentials, preferably at the postsynaptic site.

[0070] In one embodiment, the GABA B receptor agonist is selected from the group consisting of: γ-aminobutyric acid (GABA) or a salt thereof, β-phenyl-γ-aminobutyric acid (Phenibut) or a salt thereof, 4-Fluorophenibut or a salt thereof, isovaline or a salt thereof, 3-aminopropylphosphonic acid or a salt thereof, 3-aminopropylmethylphosphonic acid (SKF-97,541) or a salt thereof, [3-amino-2-hydroxypropyl]-methylphosphonic acid (CGP 44532) or a salt thereof, 4-amino-3-(4-chlorophenyl)butyric acid (Baclofen) or a salt thereof, [(2R)-3-amino-2-fluoropropyl]phosphonic acid (Lesogaberan) or a salt thereof, [2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol] (CGP7930) or a salt thereof, (S)-3-amino-2-hydroxypropylphosphonic acid (C3H 10 O3NP; AZD9343) or a salt thereof and Arbaclofen placarbil or a salt thereof.

[0071] In a preferred embodiment, the GABA type B receptor agonist comprises 4-amino-3-(4-chlorophenyl)butyric acid (baclofen), preferably (RS)-4-amino-3-(4-chlorophenyl)butyric acid.

[0072] In a further preferred embodiment, the GABA type B receptor agonist comprises 4-amino-3-(4-chlorophenyl)butyric acid (baclofen) and has the following formula:

[0073]

[0074]

[0075] or a salt thereof.

[0076] In one embodiment, the GABA type B receptor agonist comprises the R-enantiomer of 4-amino-3-(4-chlorophenyl)butyric acid (baclofen) or a salt thereof.

[0077] In one embodiment, the active pharmaceutical ingredient (API) comprises or is a hormone, such as histamine and / or a peptide hormone. Examples of peptide hormones include, but are not limited to, gastrin (e.g., UniProt P01350), motilin (e.g., UniProt P12872), and / or pancreatic polypeptide (e.g., UniProt P01298).

[0078] In one embodiment, the active pharmaceutical ingredient (API) comprises or is a neurotransmitter. Examples of neurotransmitters include, but are not limited to, histamine, acetylcholine, muscarine, substance P (e.g., UniProt P20366) and / or bombesin (e.g., UniProt P84214). In one embodiment, the neurotransmitter is preferably bombesin.

[0079] In one embodiment, the active pharmaceutical ingredient (API) comprises or is another drug such as bethanechol, carbachol, pilocarpine, metoclopramide, domperidone, cisapride, a 5-HT3-antagonist, cyproheptadine, pizotifen, or an alpha-adrenergic substance. Examples of 5-HT3-antagonists are dolasetron, granisetron, ondansetron, palonosetron, tropisetron, alosetron, or ramosetron.

[0080] In one embodiment, the active pharmaceutical ingredient (API) includes or is a food component, such as a food protein.

[0081] In one embodiment, the active pharmaceutical ingredient is a protein, and may be administered as an active protein.

[0082] In one embodiment, the active pharmaceutical ingredient is a protein and can be administered as an inactive protein, for example as a precursor protein, pre-protein or pro-protein. In this case, the inactive protein will be converted into its active form, for example after administration.

[0083] In one embodiment, the active pharmaceutical ingredient is a protein and may be administered as a nucleic acid encoding the protein.

[0084] 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 amount and / or properties of the active pharmaceutical ingredient of the specific disease to be treated and / or 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.

[0085] The present invention provides a drug delivery system comprising, that is, an active pharmaceutical ingredient, or a combination of active pharmaceutical ingredients, or an active pharmaceutical ingredient as described herein and an additional active pharmaceutical ingredient.

[0086] Additional Active Pharmaceutical Ingredients

[0087] The API in the present dosage form may be administered together with an additional API. Such additional API may be selected by the skilled person according to his or her general knowledge depending on the condition to be treated and / or prevented.

[0088] preparation

[0089] 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" as used herein refers to a sheet-like object comprising a plurality of layers for encapsulating an active pharmaceutical ingredient.

[0090] 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.

[0091] 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.

[0092] 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 .

[0093] 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.

[0094] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-shaped preparation comprising the active pharmaceutical ingredient, in particular a film-shaped, foil-shaped or sheet-shaped preparation, contains an active pharmaceutical ingredient having a drug content of 0.0001 to 50% by weight, preferably 0.001 to 25% by weight, and most preferably 0.01 to 10% by weight.

[0095] The sheet-form preparation containing the active pharmaceutical ingredient may have a single-layer or multi-layer structure, in which at least one layer (preferably the first layer) contains the active pharmaceutical ingredient.

[0096] In a preferred embodiment, the sheet-like preparation has a multilayer structure of multiple layers, wherein at least a first layer contains an active pharmaceutical ingredient, and wherein at least another layer contains at least one further active pharmaceutical ingredient, which is the same active pharmaceutical ingredient or an additional active pharmaceutical ingredient.

[0097] In a preferred embodiment, the layer containing the active pharmaceutical ingredient and / or the further layer containing the additional active pharmaceutical ingredient comprises a polymer, preferably a film-forming polymer.

[0098] The polymer in the layer may be used only as a carrier for the active pharmaceutical ingredient and / or additional API, or it may be used as a reservoir thereof. Such a layer may release the active pharmaceutical ingredient and / or additional active pharmaceutical ingredient under the action of a fluid. The active pharmaceutical ingredient and / or additional API may be released immediately or in a controlled release manner.

[0099] 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 active pharmaceutical ingredient and / or another layer containing an active pharmaceutical ingredient and / or an additional API, wherein the at least one first layer and / or another layer is an adhesive layer.

[0100] 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.

[0101] 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, more preferably polyvinyl alcohol 18-88.

[0102] 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.

[0103] In addition, 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 active pharmaceutical ingredient. It is also possible that multiple layers contain active pharmaceutical ingredients or additional APIs.

[0104] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-like preparation containing the reflux inhibitor comprises a monolayer structure or consists of a monolayer structure, wherein the (preferably first) layer contains a reflux inhibitor, preferably a GABAB type receptor agonist or a salt thereof, more preferably baclofen. 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.

[0105] In another preferred embodiment of the drug delivery system according to the present invention, the sheet-form preparation comprising an active pharmaceutical ingredient comprises at least one first active ingredient-free layer containing no active pharmaceutical ingredient.

[0106] 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.

[0107] 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.

[0108] In particular, the use of ethylcellulose may be beneficial due to its properties, including good processability, biocompatibility, and water insolubility.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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.

[0114] In particular, the additives may increase the local availability of the active ingredient, such as penetration enhancers.

[0115] 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 active pharmaceutical ingredient 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 multilayer preparation, at least one layer in the layer containing the active pharmaceutical ingredient, particularly the polymer layer, has the delayed release of the active ingredient.

[0116] 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.

[0117] In particular, the active pharmaceutical ingredient and optionally 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.

[0118] 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 active pharmaceutical ingredient / 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.

[0119] During the preparation of the formulation, the temperature sensitivity of the active pharmaceutical ingredient used needs to be taken into account. Therefore, in addition to taking into account the low doses required, an impregnation method can be used. In this method, the active pharmaceutical ingredient is only applied, for example sprayed or dripped onto the polymer film and finally dried.

[0120] Alternatively, the active pharmaceutical ingredient solution can be applied to the polymer film by an inkjet process.

[0121] In a preferred embodiment, the active pharmaceutical ingredient may be incorporated so that it is embedded in a polymer film, for example by solvent casting. These methods are known to the skilled person and are 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, evaporation or freeze drying can be used.

[0123] Furthermore, depending on the stability of the incorporated active pharmaceutical ingredient, melt extrusion of the polymer and active pharmaceutical ingredient is also conceivable, for example, as described in Example 2 herein.

[0124] In one embodiment, the formulation is prepared so that the active pharmaceutical ingredient is present only in certain portions within the membrane, which would allow for tailored treatment of the mucosa only in designated areas. In a specific embodiment, the formulation is prepared so that the active pharmaceutical ingredient is present only in one or more portions suitable for administration of the active pharmaceutical ingredient to the lower esophageal sphincter.

[0125] 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 active pharmaceutical ingredients, and oral mucosa is treated or untreated with the second active pharmaceutical ingredient, 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.

[0126] 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.

[0127] Preferred embodiments of the drug delivery system according to the present invention are suitable for application to the nasopharyngeal mucosa.

[0128] When the sheet-like preparation releases the active pharmaceutical ingredient 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 active pharmaceutical ingredient 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.

[0129] 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.

[0130] 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 active pharmaceutical ingredient. 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, for example biodegradable. 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.

[0131] 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.

[0132] Applicator / Retainer

[0133] 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.

[0134] 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.

[0135] 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.

[0136] This is particularly advantageous if the dosage form is to be administered regularly, particularly daily, since administration of the capsule device can be accomplished without professional assistance.

[0137] 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 wire, wherein the thin wire is expandable from a compact form to an expanded form and is connected to one end of the dosage form extending from the capsule device. BRIEF DESCRIPTION OF THE DRAWINGS

[0138] 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.

[0139] Figure 1a , 1bEach shows a schematic diagram of a capsule device of a drug delivery system.

[0140] Figure 2 A schematic diagram of the formulation in partially expanded form is shown.

[0141] 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.

[0142] Figure 4 A schematic diagram of the formulation as a three-layer sheet is shown.

[0143] 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.

[0144] Figure 6 A schematic semi-transparent view of a drug delivery system is shown.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] Fig.10 Shown are the absorption spectra of baclofen in the formulations (samples) of the drug delivery system of the present invention compared to the reference formulation.

[0149] 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 1a In 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.

[0150] 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.

[0151] 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.

[0152] 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 the active pharmaceutical ingredient, and Figure 4 The lowest drawn layer in the graph shows a protective layer, for example a water protective layer.

[0153] 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 5a As 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.

[0154] 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.

[0155] 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.

[0156] 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 7 In 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.

[0157] 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 8aA 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.

[0158] Reference Symbols List

[0159] 1 Drug delivery system

[0160] 2 Capsule device

[0161] 2a The first half of the capsule shell

[0162] 2b Second half capsule shell

[0163] 3 holes

[0164] 4 Preparation

[0165] 4a The end of the preparation extending through the hole

[0166] 4b Coiled end of preparation

[0167] 5. Holding device

[0168] 5a band

[0169] 6 Retainer

[0170] 7th floor

[0171] 7a Adhesion layer

[0172] 7b Layer containing active pharmaceutical ingredient

[0173] 7c protective layer

[0174] 8 concavity

[0175] 9 Wall section

[0176] 10 Opening

[0177] 11 Sedimentation Components

[0178] 11a groove

[0179] 12 Applicators

[0180] 12a Applicator Cap

[0181] 13 Retainer

[0182] 13a Bent retainer

[0183] 14 Spring

[0184] 15 Drying element

[0185] 16 drinking cups

[0186] Example

[0187] Example 1: Preparation of polymer film containing 4-amino-3-(4-chlorophenyl)butyric acid (baclofen)

[0188] A "base polymer mixture" was prepared using the ingredients and amounts shown in Table 1, without the addition of baclofen.

[0189] Table 1

[0190] Element Amount (g) Total proportion Solid ratio PVA 18-88 18.0 17％ 80％ glycerin 2.0 2％ 9％ Dem.water 80.0 76％ - 0.1M HCl 2.5 2％ - Baclofen 2.5 2％ 11％

[0191] After pH adjustment, baclofen was added at room temperature and film laminates were prepared by solvent casting, i.e. spreading the polymer mixture containing baclofen and evaporating the solvent. The films were dried at room temperature.

[0192] The resulting film is flexible and exhibits an optically uniform, bubble-free surface. In addition, the surface of the film is uniformly rough with particles of varying sizes.

[0193] Furthermore, the content of baclofen in the films was analyzed. For this purpose, six sections with a diameter of 1.9 cm (2.84 cm) were cut at random locations on the films. 2 ) and analyzed by UV / Vis spectroscopy in FSG medium at pH 1.2. Fig.10 Shown is the absorbance spectrum compared to a reference sample comprising baclofen dissolved in FSG medium at pH 1.2. Comparison of the spectra of the film samples with the spectra of the reference samples demonstrates that baclofen can be stably prepared in the film for use in the drug delivery device of the present invention.

[0194] In addition, the content of baclofen on the film is shown in Table 2.

[0195] Table 2

[0196]

[0197] *Standard deviation, **Relative standard deviation

[0198] The results in Table 2 show that 10 cm 2 Membranes loaded with 15 mg baclofen are possible and allow the preparation of membranes with a wide therapeutic dose range. It must be noted that the standard deviation and the maximum value of the drug loading are determined by the process technology and in principle do not represent any limitations.

[0199] Furthermore, in the art, oral administration of baclofen, i.e., absorption into the bloodstream through the digestive system, requires high doses of 15-75 mg per day. Furthermore, oral administration of baclofen is very limited in clinical applications because it is poorly tolerated due to severe side effects, such as neurological adverse events. Common side effects include drowsiness, weakness, headache, confusion, nausea, and dizziness. Regional and / or local administration of baclofen by the drug delivery system of the present invention can improve local administration to the target site, thereby increasing the value of the drug, particularly in the treatment of esophageal diseases.

[0200] Example 2: Preparation of polymer films by melt extrusion

[0201] -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.

[0202] - Active ingredient preparation: The active ingredient is usually prepared into a suitable formulation (eg, as a powder or granules).

[0203] - Mixing components: Mix the polymer matrix and active ingredient in a mixer to form a homogeneous mixture.

[0204] - 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.

[0205] - 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.

[0206] -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 a reflux inhibitor, preferably a reflux inhibitor that reduces or blocks transient lower esophageal reflux relaxations (TLESRs).

2. The drug delivery system of claim 1, wherein the reflux inhibitor comprises a GABA (gamma-aminobutyric acid) type B receptor agonist.

3. The drug delivery system according to claim 2, wherein the GABA B receptor agonist is selected from the group consisting of: γ-aminobutyric acid (GABA) or a salt thereof, β-phenyl-γ-aminobutyric acid (Phenibut) or a salt thereof, 4-Fluorophenibut or a salt thereof, isovaline or a salt thereof, 3-aminopropylphosphonic acid or a salt thereof, 3-aminopropylmethylphosphonic acid (SKF-97,541) or a salt thereof, [3-amino-2-hydroxypropyl]-methylphosphonic acid (CGP 44532) or a salt thereof, 4-amino-3-(4-chlorophenyl)butyric acid (baclofen) or a salt thereof, [(2R)-3-amino-2-fluoropropyl]phosphonic acid (Lesogaberan) or a salt thereof, [2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol] (CGP7930) or a salt thereof, (S)-3-amino-2-hydroxypropylphosphonic acid (AZD9343) or a salt thereof, and Arbaclofen placarbil or a salt thereof.

4. The drug delivery system according to claim 2 or 3, wherein the GABA type B receptor agonist comprises 4-amino-3-(4-chlorophenyl)butyric acid (baclofen) or a salt thereof.

5. The drug delivery system according to claims 2 to 4, wherein the GABA type B receptor agonist comprises the R-enantiomer of 4-amino-3-(4-chlorophenyl)butyric acid (baclofen) or a salt thereof.

6. 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).

7. A drug delivery system according to any one of the preceding claims for use in therapy.

8. A drug delivery system according to any one of the preceding claims for use in the treatment or prevention of oesophageal diseases.

9. A drug delivery system according to any one of the preceding claims for use in the treatment or prevention of esophageal diseases caused by or associated with gastroesophageal reflux, such as gastroesophageal reflux disease (GERD), non-erosive reflux disease (NERD), esophagitis, in particular erosive esophagitis (EE) and / or cancer, such as adenocarcinoma, in particular Barrett's esophagus (BE).

10. A drug delivery system according to any one of the preceding claims for use in the treatment or prevention of gastroesophageal reflux disease.

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