Drug delivery system comprising an anti-reflux agent 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, in particular film-shaped, foil-shaped or oblate-shaped formulation containing a reflux inhibitor, a release mechanism, and a trigger mechanism, the trigger mechanism being 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 a reflux inhibitor for application to the esophageal mucosa and for treating esophageal diseases, particularly gastroesophageal reflux disease.

Background Art

[0002] Gastroesophageal reflux disease (GERD) is a chronic disease that has recurrent and remission periods over time (Non-Patent Document 1). The overall prevalence of gastroesophageal reflux disease is 18 - 28% of the US population and 9.8% - 18% of the European population. Gastroesophageal reflux disease is characterized by the reflux of gastric contents (which may also include bile and other duodenogastric reflux components) into the esophagus. The stomach itself is protected from gastric acid, but gastric acid is extremely harmful to tissues outside the stomach such as the esophagus. Typically, patients suffering from gastroesophageal reflux disease have symptoms such as heartburn, regurgitation, and rarely dysphagia. Common atypical findings are chronic cough or asthma, and non-cardiac chest pain. There are also patients who suffer from esophageal lesions or erosions, and in some cases, may progress to further diseases ranging 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 can achieve a healing rate of up to 80 - 90% of the esophageal mucosa within 8 - 12 weeks of treatment, resulting in the resolution of typical symptoms of the disease, particularly heartburn, chest pain due to reflux, and dysphagia. However, the effectiveness of PPIs is 20 - 30% lower in non-erosive gastroesophageal reflux disease (NERD). Furthermore, up to 40% of patients with persistent reflux symptoms do not respond to proton pump inhibitors.

[0004] One dominant mechanism underlying gastroesophageal reflux is transient lower esophageal sphincter relaxation (TLESR), which occurs in patients with gastroesophageal reflux disease. Transient lower esophageal sphincter relaxation is the relaxation of the lower esophageal sphincter (LES), which allows gastric contents to pass into the esophagus in the absence of swallowing. The lower esophageal sphincter is smooth muscle within the esophageal wall that forms a valve at the junction of the esophagus and the stomach at the end of the esophagus and is a therapeutic target for local treatment of gastroesophageal reflux disease. For example, Patent Document 1 and Patent Document 2 describe non-invasive devices for the treatment of gastroesophageal reflux disease and digestive system. The device is placed on the skin of the patient's abdomen and electrically stimulates the abdominal muscles. As a result of this treatment, the digestive system moves greatly, which brings about the treatment of various digestion-related symptoms or diseases.

[0005] Drug delivery to the membranes of the gastrointestinal tract, particularly the esophagus, is usually carried out by submucosal application guided by an endoscopic method. Local application of the active ingredient involves drug-coated esophageal stents or oral viscous drugs. Currently under research drugs include orally dispersible or orally disintegrating tablets, aerosols, or gel-like drugs with high viscosity to increase the contact time.

[0006] However, local application of active ingredients to the membranes of the gastrointestinal tract, particularly the esophagus, has several challenges. For example, it is very difficult to locally 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 inactivation of the drug by digestive secretions and enzymes, dilution effect by intestinal fluid, poor absorption, prodrugs that require activation 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.

[0007] There remains a need for an appropriate drug delivery system that can deliver an active pharmaceutical ingredient for effective treatment while allowing for administration at the lowest possible dose to reduce side effects, particularly for delivery to the esophagus.

PRIOR ART DOCUMENTS

PATENT DOCUMENTS

[0008]

PATENT DOCUMENT 1

PATENT DOCUMENT 2

NON-PATENT DOCUMENTS

[0009]

NON-PATENT DOCUMENT 1

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0010] One object of the present invention is to provide a drug delivery system that enables oral / local administration of an anti-reflux agent, such as a GABA type B receptor agonist, for treating gastroesophageal reflux disease, 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-reflux agent, such as a GABA type B receptor agonist, at a low dose, thereby minimizing potential side effects.

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

MEANS FOR SOLVING THE PROBLEM

[0013] In a first aspect, the present invention is a drug delivery system for application to the esophageal mucosa, the drug delivery system comprising at least one sheet-like, particularly film-shaped, foil-shaped, or oblate-shaped formulation containing a pharmaceutically active ingredient, a release mechanism, and a trigger mechanism, the trigger mechanism being adapted to cause release by the release mechanism of the formulation at a predetermined site of action, the release mechanism being adapted to release the formulation while moving along the esophageal mucosa, the drug delivery system further comprising a shell that houses the formulation, the shell including an opening configured as part of the release mechanism for the formulation to exit the shell, the trigger mechanism being a retention 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, and the pharmaceutically active ingredient including an anti-reflux agent, preferably an anti-reflux agent that reduces or prevents transient lower esophageal reflux relaxation, such as a gamma-aminobutyric acid (GABA) type B receptor agonist.

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

[0015] In one embodiment, the drug active ingredient is gamma-aminobutyric acid (GABA) or a salt thereof, beta-phenyl-gamma-aminobutyric acid (phenibut) or a salt thereof, 4-fluorophenibut or a salt thereof, isovaline or a salt thereof, 3-aminopropylphosphinic acid or a salt thereof, 3-aminopropylmethylphosphinic acid (SKF-97,541) or a salt thereof, [3-amino-2-hydroxypropyl]-methylphosphinic acid (CGP 44532) or a salt thereof, 4-amino-3-(4-chlorophenyl)butyric acid (baclofen) or a salt thereof, [(2R)-3-amino-2-fluoropropyl]phosphinic 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-hydroxypropylphosphinic acid (C 3 H 10 O 3 NP, AZD9343) or a salt thereof, and is a GABA type B receptor agonist selected from the group consisting of albaclofen 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 drug active ingredient (API) in the drug delivery system comprises hormones such as peptide hormones. Examples of peptide hormones are gastrin, motilin, or pancreatic polypeptide.

[0019] In one embodiment, the drug active ingredient (API) in the drug delivery system comprises neurotransmitters such as histamine, acetylcholine, muscarine, substance P, or bombesin.

[0020] In one embodiment, the active pharmaceutical ingredient (API) within the drug delivery system includes other drugs 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) within the drug delivery system includes food components such as food proteins.

[0022] In one embodiment, the sheet-like, particularly film-shaped, foil-shaped, or oblate-shaped formulation containing the active pharmaceutical ingredient includes polyvinyl alcohol (PVA).

[0023] In a second aspect, the drug delivery system of the present invention is for use in treatment.

[0024] In a third aspect, the drug delivery system is for use in the treatment or prevention of esophageal diseases or for the treatment or prevention of gastroesophageal reflux disease, non-erosive gastroesophageal reflux disease, esophagitis, particularly erosive esophagitis, and / or cancer, such as esophageal cancer including adenocarcinoma, squamous cell carcinoma, etc., or Barrett's esophagus, which is caused by or associated with gastroesophageal reflux, or for use in the treatment or prevention of gastroesophageal reflux disease.

DETAILED DESCRIPTION OF THE INVENTION

[0025] Unless otherwise defined specifically, all scientific and technical terms used herein have the same meaning as commonly understood by those skilled in the technical field to which this disclosure belongs.

[0026] Terms used herein in the singular form refer to the plural form of the same terms and vice versa, unless otherwise specified herein.

[0027] As used herein, the indefinite articles "a" or "an" refer to the definite article "the" unless otherwise specified.

[0028] As used herein, the terms "comprising" or "comprises" mean "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 does not exclude the presence of one or more additional features, elements, integers, steps, components, or groups thereof. Thus, the terms "comprising" or "comprises" include the more restrictive terms "consisting of" and "consisting essentially of". In one embodiment, the terms "comprising" or "comprises" used throughout this application and particularly within the claims may be replaced with the term "consisting of".

[0029] Drug delivery systems other than those containing pharmaceuticals, but with different drug active ingredients and their applications, are described in the specification of 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 the specification of PCT / EP2015 / 002601. In other words, the size, shape, and composition of the shell, the opening, the release and trigger mechanisms, and the holding device are already described in the said reference document at least to a considerable extent.

[0030] The drug delivery system described in the specification of PCT / EP2015 / 002601 is designed to include at least one sheet-like, in particular film-shaped, foil-shaped, or oblate-shaped formulation containing a pharmaceutically active ingredient, a release mechanism, and a trigger mechanism, and the trigger mechanism is adapted to cause 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 the specification 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 a 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.

[0031] The drug delivery system according to the present invention is administered orally and improves the local utility of the reflux inhibitor. This is in contrast to oral administration systems such as conventional tablets or capsules that are delivered to the treatment target site / place only by entering the blood circulation through gastrointestinal absorption.

[0032] The local utility is improved because the anti-reflux agent is provided in a formulation in the form of a sheet, in particular a film form, foil form, oblate form, or elongated strip form. Advantageously, this enables the sheet-like formulation (and the anti-reflux agent present therein) to be directly delivered to the treatment target site / location (treatment site), for example, the esophageal mucosa. Thereby, preferably the 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-reflux agent. Further, as a result of the preferred direct contact between the mucosa and the formulation, the anti-reflux agent acts effectively at the treatment site. Since the anti-reflux agent is directly delivered to the treatment site, a small amount of the anti-reflux 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 is decreased. Further, direct delivery to the treatment site further enables the dose of the anti-reflux agent contained in the formulation to be reduced, thereby advantageously further reducing side effects.

[0033] The drug delivery system according to the present invention further advantageously enables simple, in particular space-saving storage, as well as relatively simple and clear handling. The anti-reflux agent contained in the drug delivery system according to the present invention has improved stability compared to solutions and gels, for example, under 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 such additives are known to be able to cause allergies or further side effects.

[0034] Also, the degradation of the pharmaceutically active ingredient by, for example, gastric acid and / or digestive enzymes before reaching the predetermined site of action is advantageously minimized by the drug delivery system according to the present invention.

[0035] Release mechanism The release mechanism relates to a mechanism for deploying and releasing a sheet-like formulation from a capsule device, e.g., 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 adapted 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 up, 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 the formulation containing the pharmaceutically active ingredient increases. Preferably, the surface area of the formulation, in particular the surface area containing the active ingredient and in contact with the esophageal mucosa, 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.

[0036] 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 European Patent No. 21175427.0, European Patent No. 21175436.1, PCT / EP2015 / 002601, and PCT / EP2020 / 056934, which are incorporated herein by reference in their entirety with respect to the capsule device and the opening.

[0037] Trigger mechanism / Holding device The drug delivery system includes a trigger mechanism that 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.

[0038] 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 suture. 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.

[0039] 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.

[0040] Instead, the holding device is adapted to be fixed in the oral cavity or held by hand during administration of the drug delivery system, so that the dosage form opens and / or spreads while descending the esophageal mucosa, opens from the shell and exits through the opening.

[0041] 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, a holding device is formed by the protruding end portion of the formulation and the string member connected thereto, and a further portion 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.

[0042] 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 a predetermined location where the formulation is released. Further, the pharmaceutically active ingredient released at each "site of action" and "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 pharmaceutically active ingredient 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.

[0043] Capsule device / shell The drug delivery system according to the present invention further includes a shell, the shell contains at least one sheet-like, particularly film-shaped, foil-shaped, or oblate-shaped formulation containing a pharmaceutically active ingredient, and the shell includes an opening configured such that the formulation can exit the shell as part of the release mechanism, so that the formulation opens or spreads while descending the esophageal mucosa and exits through the opening from the shell. The shell can be further prepared to protect the formulation from accidental release. The shell is a capsule device and particularly has the shape of a capsule.

[0044] In a preferred embodiment, the shell comprises a first capsule shell half and a second capsule shell half, and the capsule device is formed by sliding the first capsule shell half into the second capsule shell half to a joining position, so that an opening is formed at the joining position by the second capsule shell half overlapping the cross-section of the opening in the first capsule shell half.

[0045] In a further embodiment, the two capsule halves fit into each other, but the opening of the first capsule shell half 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 capsule shell half and / or the second capsule shell half.

[0046] 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 may be formed at the edges of both halves, in which case the two halves are positioned one above the other and aligned to form an opening when they are aligned.

[0047] 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, may be beneficial.

[0048] Such capsule devices or shells are further described, for example, in European Patent No. 21175427.0, European Patent No. 21175436.1, and PCT / EP2020 / 056934, and with respect to the capsule devices, the entire contents of which are incorporated herein by reference.

[0049] The condition to be treated The drug delivery system described herein is for use in treatment. In one embodiment, the drug delivery system is for the treatment and prevention of esophageal diseases, and illustratively includes esophageal diseases caused by or related to gastroesophageal reflux, such as gastroesophageal reflux disease, non-erosive gastroesophageal reflux disease, esophagitis, particularly erosive esophagitis, and / or cancer such as esophageal cancer, for example adenocarcinoma, squamous cell carcinoma, and particularly Barrett's esophagus. In one embodiment, the drug delivery system according to the present invention is for the treatment and / or prevention of gastroesophageal reflux disease. Further, the drug delivery system is for the treatment and / or prevention of non-erosive gastroesophageal reflux disease. Further, the drug delivery system is for the treatment and / or prevention of erosive esophagitis. Further, the drug delivery system is for the treatment and / or prevention of cancer such as adenocarcinoma, particularly Barrett's esophagus.

[0050] Barrett's esophagus is a serious complication of gastroesophageal reflux disease. In Barrett's esophagus, the normal tissue that covers the esophagus is replaced by tissue similar to that which covers the intestine. Patients with Barrett's esophagus may have symptoms related to gastroesophageal reflux disease, but Barrett's esophagus is asymptomatic. However, Barrett's esophagus increases the risk of developing esophageal adenocarcinoma, a potentially life-threatening and serious esophageal cancer. The diagnosis of Barrett's esophagus can be made by endoscopy, histological examination, and / or using biomarkers as described, for example, in U.S. Patent Application Publication No. 20120009597 A1.

[0051] As used herein, the term "treatment and / or prevention" includes any method that improves a particular condition or disease to be treated or prevents the occurrence of the condition or disease to be treated. This term also includes the prevention of the worsening of a condition or disease and the minimization of the severity of a condition or disease.

[0052] As used herein, esophageal cancer refers to cancer originating in the esophagus and includes, but is not limited to, squamous cell carcinoma and adenocarcinoma.

[0053] One dominant mechanism underlying gastroesophageal reflux is transient lower esophageal sphincter relaxation that occurs in patients with gastroesophageal reflux disease. As used herein, "transient lower esophageal sphincter relaxation" or "TLESR" refers to relaxation of the lower esophageal sphincter in the absence of swallowing. Thus, transient lower esophageal sphincter relaxation can result in inappropriate opening of the lower esophageal sphincter and permit gastric acid to enter the esophagus. Without being bound by any theory, transient lower esophageal sphincter relaxation can be caused by certain receptors in the intramuscular nerves of the gastric muscular layer or by receptors in the gastric mucosa.

[0054] Rohof et al. (Neurogastroenterol. Motil. (2012) 24: 383-391) identified gamma-aminobutyric acid (GABA) type B receptors (also referred to as GABA B receptors) in the neurons of the myenteric plexus of the human lower esophageal sphincter. Hyland et al. (Frontiers in Pharmacology 1 (2014), Article 124: 1-9) reported the expression of GABA B receptor subunit 1 on the myenteric and submucosal neurons of the mouse colon and ileum. Furthermore, in a meta-analysis of nine clinical trials, baclofen, a GABA B receptor agonist, was found to reduce not only the incidence of transient lower esophageal sphincter relaxation but also the number and duration of reflux episodes (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). Additionally, baclofen has been found to control transient lower esophageal sphincter relaxation after systemic administration (Lidums, Gastroenterology, 118:2000; 7-13). Thus, GABA BReceptor agonists, and in particular baclofen, are promising candidates for the drug delivery devices of the present invention.

[0055] Drug active ingredient In the claimed drug delivery system, a reverse flow inhibitor, such as a GABA type B receptor agonist; a hormone such as gastrin, motilin, histamine, or pancreatic polypeptide; a neurotransmitter such as histamine, acetylcholine, muscarine, 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 drug active ingredient.

[0056] The term "drug active ingredient" as used herein is used interchangeably with the terms "active ingredient" or API and refers to a reverse flow inhibitor. Additional APIs that may be present in addition to the reverse flow inhibitor are referred to herein as "additional drug active ingredients" or "additional active ingredients" or "additional APIs".

[0057] The term "therapeutically effective dose" or "effective amount" means a 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 using the skills known to those of ordinary skill in the art. The term "therapeutically effective amount" is an amount that has an effect of improving the disease (symptoms). Since prevention can be considered treatment, the therapeutically effective amount can be a "preventively effective amount".

[0058] In one embodiment, the drug active ingredient is a reverse flow inhibitor.

[0059] As used herein, the “anti-reflux agent” includes, but is not limited to, compounds that interfere with, reduce, inhibit, and / or prevent retrograde flow, particularly gastroesophageal reflux. In certain embodiments, the anti-reflux agent interferes with, reduces, inhibits, and / or prevents transient lower esophageal sphincter relaxation. In one embodiment, the anti-reflux agent increases or improves the pressure in the lower esophagus, thereby preferably reducing, inhibiting, and / or preventing transient lower esophageal sphincter relaxation. In one embodiment, the anti-reflux agent improves the function of the smooth muscle of the lower esophageal sphincter, for example, by improving or increasing its contractile force, thereby preferably reducing, inhibiting, and / or preventing transient lower esophageal sphincter relaxation. In one embodiment, the anti-reflux agent increases the function of the distal esophageal sphincter. In a preferred embodiment, the anti-reflux agent is a GABA type B receptor agonist. In one embodiment, the anti-reflux agent is a protein, such as an antibody, such as an antibody capable of activating the GABA type B receptor, or a hormone, or a 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 a precursor, preprotein, or proprotein of an inactive protein. The protein can be administered as a nucleic acid encoding the protein. In one embodiment, the anti-reflux agent is a small molecule, for example, a small molecule having a molecular mass of about 900 g / mol or less. In one embodiment, the anti-reflux agent is a hormone such as gastrin, motilin, histamine, or pancreatic polypeptide; a neurotransmitter such as histamine, acetylcholine, muscarine, substance P, or bombesin; another drug such as bethanechol, carbachol, pilocarpine, metoclopramide, domperidone, cisapride, 5-HT3-antagonist, cyproheptadine, pizotifen, or an alpha-adrenergic substance; or a food component.

[0060] In one embodiment, the pharmaceutically active ingredient is a GABA type B receptor agonist or a salt thereof.

[0061] As used herein, "GABA type B receptor agonist" refers to a compound that activates the GABA type B receptor to produce a biological response, including but not limited to endogenous agonists such as GABA, i.e., agonists that are naturally produced by the body and activate the receptor, 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-aminopropylphosphinic acid or its salts, 3-aminopropylmethylphosphinic acid (SKF-97,541) or its salts, [3-amino-2-hydroxypropyl]-methylphosphinic acid (CGP 44532) or its salts, 4-amino-3-(4-chlorophenyl)butyric acid (baclofen) or its salts, [(2R)-3-amino-2-fluoropropyl]phosphinic acid (lesogaberon) or its salts, [2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol] (CGP7930) or its salts, (S)-3-amino-2-hydroxypropylphosphinic acid (C 3 H 10 O 3 NP; AZD9343) or its salts, and albaclofen placarbil or its salts.

[0062] In one embodiment, the GABA type B receptor agonist, preferably an exogenous agonist, is an agonist that at least partially mimics the response of the endogenous agonist. In one embodiment, the GABA type B receptor agonist, preferably an exogenous agonist, activates the receptor with a response equivalent to that of an endogenous agonist such as GABA. In certain embodiments, the agonist is a selective agonist, i.e., specific for the GABA type B receptor. In another embodiment, the GABA type B receptor agonist is a co-agonist, for example, an agonist that produces a response in cooperation with a further (co-)agonist.

[0063] As used herein, the term "biological response" relates to any biological response of the GABA type B receptor. In one embodiment, the biological response is induced by GABA. In another embodiment, the biological response is the regulation of neurotransmitter release, such as inhibition or activation. In another embodiment, the biological response is preferably presynaptic and is the regulation of neurotransmitter release by inhibition of Ca 2+ influx. In another embodiment, the biological response is preferably postsynaptic and is the regulation of neurotransmitter release by coupling to inward rectifier K + channels and mediating delayed inhibitory postsynaptic potentials.

[0064] In one embodiment, the GABA type B receptor agonist is selected from the group consisting of gamma-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-aminopropylphosphinic acid or a salt thereof, 3-aminopropylmethylphosphinic acid (SKF-97,541) or a salt thereof, [3-amino-2-hydroxypropyl]-methylphosphinic acid (CGP 44532) or a salt thereof, 4-amino-3-(4-chlorophenyl)butyric acid (baclofen) or a salt thereof, [(2R)-3-amino-2-fluoropropyl]phosphinic acid (lesogaberon) 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-hydroxypropylphosphinic acid (C 3 H 10 O 3 NP; AZD9343) or a salt thereof, and arbaclofen placarbil or a salt thereof.

[0065] 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.

[0066] In a further preferred embodiment, the GABA type B receptor agonist includes 4-amino-3-(4-chlorophenyl)butyric acid (baclofen) and has the following formula:

Chemical formula

[0067] In one embodiment, the GABA type B receptor agonist includes the R-enantiomer of 4-amino-3-(4-chlorophenyl)butyric acid (baclofen) or a salt thereof.

[0068] In one embodiment, the active pharmaceutical ingredient (API) includes 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).

[0069] In one embodiment, the active pharmaceutical ingredient (API) includes 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.

[0070] In one embodiment, the active pharmaceutical ingredient (API) includes or is another drug such as bethanechol, carbachol, pilocarpine, metoclopramide, domperidone, cisapride, a 5-HT3 antagonist, cyproheptadine, pizotifen, and / or an alpha-adrenergic substance. Examples of 5-HT3 antagonists are dolasetron, granisetron, ondansetron, palonosetron, tropisetron, alosetron, or ramosetron.

[0071] In one embodiment, the drug active ingredient (API) comprises or is a food component, such as a food protein.

[0072] In one embodiment, the drug active ingredient is a protein and can be administered as an active protein.

[0073] In one embodiment, the drug active ingredient is a protein and can be administered as an inactive protein, such as a precursor protein, preprotein, or proprotein. In such cases, the inactive protein will be converted to the active form, for example, after administration.

[0074] In one embodiment, the drug active ingredient is a protein and can be administered as a nucleic acid encoding the protein.

[0075] The dosing frequency, treatment period, or time of administration of the drug delivery device is not limited and can be determined by the specific disease to be treated and / or the amount and / or nature of the drug active ingredient per drug delivery device. For example, the drug delivery device can be administered once a day 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 a treatment period of a single treatment cycle or multiple cycles, e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more cycles.

[0076] The present invention provides a drug delivery system comprising one, i.e., one, drug active ingredient, or a plurality of drug active ingredients, or a combination of one drug active ingredient described herein and one additional drug active ingredient.

[0077] Additional drug active ingredient The API within this dosage form can be administered together with additional APIs. 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.

[0078] Dosage form In a preferred embodiment of the drug delivery system according to the present invention, the sheet-like dosage form is or is formed as an oblate. As used herein, the term "oblate" refers to a sheet, which includes several layers and is used to enclose the pharmaceutically active ingredient.

[0079] 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 dosage form of the dosage form according to the present invention can be gellable or swellable.

[0080] In a preferred embodiment of the drug delivery system according to the present invention, the thickness of the sheet-like dosage form 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 sheet-like dosage form with a relatively small thickness.

[0081] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-like dosage form is 0.5 to 25 cm 2 preferably 1 to 10 cm 2 in area.

[0082] The sheet-like dosage form can have different shapes. In particular, the sheet-like dosage form can have a round, triangular, square, or polygonal shape. In one embodiment, the opening is adapted to the respective shape of the dosage form.

[0083] In a preferred embodiment of the drug delivery system according to the present invention, a sheet-like preparation containing a pharmaceutically active ingredient, particularly in the form of a film, foil, or oblate, contains a pharmaceutically active ingredient 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.

[0084] The sheet-like preparation containing a pharmaceutically active ingredient may have a single-layer or multi-layer structure, and at least one (preferably the first) layer contains a pharmaceutically active ingredient.

[0085] In a preferred embodiment, the sheet-like preparation has a multi-layer structure of a plurality of layers, at least one first layer contains a pharmaceutically active ingredient, and at least one additional layer contains at least one additional pharmaceutically active ingredient, which can be either the same pharmaceutically active ingredient or an additional pharmaceutically active ingredient.

[0086] In a preferred embodiment, the layer containing a pharmaceutically active ingredient and / or the additional layer containing an additional pharmaceutically active ingredient contains a polymer, preferably a film-forming polymer.

[0087] The polymer in the layer can function simply as a carrier for the pharmaceutically active ingredient and / or the additional API, or as its reservoir. Such a layer can release the pharmaceutically active ingredient and / or the additional pharmaceutically active ingredient under the influence of a fluid. The pharmaceutically active ingredient and / or the additional API may be released immediately or in a sustained-release manner.

[0088] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-like preparation includes at least one first layer containing a pharmaceutically active ingredient, and / or an additional layer containing a pharmaceutically active ingredient and / or an additional API, and at least one first layer and / or the additional layer is an adhesive layer.

[0089] 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, which is a water-dispersible and / or hydrolyzable and / or water-disintegrable film-forming polymer.

[0090] 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 comprising 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, more preferably polyvinyl alcohol 18-88.

[0091] The polymers can be used individually or in combination to produce a sheet-like formulation for a dosage form according to the invention having the desired properties as adhesion, release, or disintegration properties. The sheet-like formulation according to the invention can consist of one polymer layer.

[0092] The sheet-like formulation for a dosage form according to the invention can also have a structure of two or more layers, in which case at least one of these layers contains a pharmaceutically active ingredient. It is also possible for the plurality of layers to contain either a pharmaceutically active ingredient or an additional API.

[0093] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-like preparation containing the backflow inhibitor comprises or consists of a single-layer structure, and the (preferably first) layer contains a backflow inhibitor, preferably a GABA type B receptor agonist or a salt thereof, more preferably baclofen. 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.

[0094] In another preferred embodiment of the drug delivery system according to the present invention, the sheet-like preparation containing the pharmaceutically active ingredient comprises at least one first active ingredient-free layer that does not contain the pharmaceutically active ingredient.

[0095] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-like preparation containing the pharmaceutically active ingredient, particularly in the form of a film, foil, or oblate, comprises at least one additional active ingredient-free layer that does not contain the pharmaceutically active ingredient.

[0096] 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 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.

[0097] In particular, the use of ethyl cellulose can be beneficial due to its properties including good processability, biocompatibility, and water-insolubility.

[0098] 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.

[0099] The adhesion layer can be a mucoadhesive polymer selected from the group comprising cellulose derivatives such as hydroxypropylcellulose, starch and starch derivatives, polyvinyl alcohol, polyethylene oxide, polyethylene, polypropylene, polyacrylic acid and polyacrylate derivatives, polyvinylpyrrolidone, povidone, copovidone, sodium alginate, gelatin, xanthan gum, carrageenan, pectin, dextran, lectin, chitosan, pullulan, and mixtures thereof.

[0100] In addition or alternatively, the adhesion layer can contain a solvent selected from the group comprising water, ethanol, methanol, acetone, organic solvents, and mixtures thereof.

[0101] Furthermore, the formulation may additionally contain additives such as coloring agents, perfumes, flavoring agents, preservatives, antioxidants, penetration enhancers, solubilizers, disintegration accelerators, pore-forming agents, lubricants, and mixtures thereof. In particular, the following substances: lubricants, lubricants, flow accelerators, binders, additional active ingredients, disintegrants, antioxidants, chelating agents, coating agents, flow agents, preservatives, fillers, surfactants, plasticizers, and dyes are suitable as additives. Furthermore, the additives are from the following groups: pore-forming agents, penetration enhancers, solubilizers, 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, dexpanthol 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 drug 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-acetyl-L-cysteine (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.

[0102] The sheet-like preparation may further contain at least one flavoring additive. Advantageously, this makes it possible to hide bitter or otherwise unpleasant-tasting pharmaceutically active ingredients, but it may 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.

[0103] In particular, additives such as penetration enhancers can improve the local utility of the active ingredient.

[0104] 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 pharmaceutically active ingredient is preferably released over a period of 4 hours, preferably over a period of 6 hours, most preferably over a period of 8 hours. In the case of a two-layer or multi-layer preparation, at least one layer containing the pharmaceutically active ingredient, in particular a polymer layer, has a delayed release of the active ingredient in order to achieve a delayed release of the active ingredient.

[0105] 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.

[0106] In particular, the pharmaceutically active ingredient and any additional APIs 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.

[0107] Sheet-like formulations can be prepared by methods basically known to those skilled in the art, for example, by a liquid composition containing a polymer, a pharmaceutically active ingredient / additional pharmaceutically active ingredient, and optionally an additive, 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 formulation, one or more coatings can similarly be applied to the existing film layer, or they can be manufactured separately and then laminated.

[0108] During the manufacture of the formulation, it is necessary to take into account the temperature sensitivity of the pharmaceutically active ingredient used. Therefore, and in addition, from the perspective of the required low dose, an impregnation method can be used. In such a method, the pharmaceutically active ingredient is simply applied to the polymer film, for example, by spraying or dropping, and finally dried.

[0109] Alternatively, a solution of the pharmaceutically active ingredient can also be applied to the polymer film by an inkjet method.

[0110] In a preferred embodiment, the pharmaceutically active ingredient can be incorporated into the polymer film so as to be embedded, for example, by a solvent casting method. Such methods are known to those skilled in the art and are described in the examples provided herein.

[0111] In all of these methods, consideration is required for the solvents used and the drying conditions. As a very simple drying method, evaporation or lyophilization can be used.

[0112] Furthermore, depending on the stability of the pharmaceutically active ingredient to be incorporated, melt extrusion of the polymer and the pharmaceutically active ingredient can also be considered, as described, for example, in Example 2 of this specification.

[0113] In one embodiment, the formulation is manufactured such that the pharmaceutically active ingredient is present only in a specific portion within the film, thereby enabling mucosal treatment of only the individualized designated area. In a particular embodiment, the formulation is manufactured such that the pharmaceutically active ingredient is present only in one or more portions suitable for administering the pharmaceutically active ingredient to the lower esophageal sphincter.

[0114] Alternatively, and preferably, a first region of the sheet-like formulation can contact the esophageal mucosa and a second region of the sheet-like formulation can contact the buccal mucosa. Thus, while the esophageal mucosa can be treated with the pharmaceutically active ingredient, the second pharmaceutically active ingredient, an additional API, can treat, not treat, or release an additive to the buccal mucosa. In particular, a flavorant 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, a first region of the sheet-like formulation can contact the esophageal mucosa and a 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. Thus, it becomes possible to locally treat each part of the esophagus and the stomach.

[0115] 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 the 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 strip-like formulation, it becomes significantly easier and more efficient for the elongated strip-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 malfunctions are sometimes observed during the transition of the formulation from the miniaturized state to the deployed state. The present invention has already improved the efficiency of unfolding or unwinding individually by providing a gap between the opening and the formulation, but the weight device further increases the efficiency of unfolding. Also, even if the patient swallows appropriately in the presence of water or an aqueous solution, it is presumed that air bubbles may remain in the capsule device although the capsule device will not be completely filled with water. That air contributes to the 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 WO 2020 / 183005, which is incorporated herein by reference.

[0116] A preferred embodiment of the drug delivery system according to the present invention is adapted to be applied to the nasopharyngeal mucosa.

[0117] When the sheet-like formulation locally and / or over a long period of time releases the pharmaceutically active ingredient, optionally together with additional APIs, the response to treatment can be improved, and in particular, the local effect of the pharmaceutically active ingredient can be enhanced, for example, by a penetration enhancer. Such penetration enhancers are known in the art. Furthermore, since the area of action is spatially extensive in particular, the need for systemic administration can be reduced.

[0118] In a preferred embodiment of the drug delivery system according to the present invention, the sheet-like preparation has an area and / or surface area greater than 0.5 cm 2 and preferably greater than 2 cm 2 and preferably greater than 5 cm 2 and preferably between 5 cm and 15 cm 2 and preferably greater than 0.5 cm 2 and less than 40 cm 2 Preferably, the ratio of the length of the sheet-like preparation to the width of the sheet-like preparation is from 40:1 to 400:1, or preferably from 60:1 to 300:1, or preferably from 80:1 to 200:1. The width can be, for example, the average of the widths of the sheet-like preparation measured perpendicular to the length of the sheet-like preparation. The ratio can be the ratio of the length of the sheet-like preparation to the perimeter of the sheet-like preparation, in particular its average, and the perimeter can be, for example, twice the width of the sheet-like preparation in the case of an elongated sheet-like preparation.

[0119] In a particular embodiment of the drug delivery system according to the present invention, the sheet-like preparation is in a solid state, especially while in a particularly small form and / or immediately after release. This can usefully enhance, enable or facilitate some of the above advantages. In particular, this can enhance the storage stability when the sheet-like preparation is in a solid state before release. In particular, this can enhance and / or enable the targeted and / or sustained release of the pharmaceutically active ingredient when the sheet-like preparation is in a solid state after release. Additionally, or alternatively, in a particular embodiment of the drug delivery system according to the present invention, the sheet-like preparation is made to dissolve, for example, undergo in vivo degradation, immediately after release, after a delay, in a time-controlled manner or upon stimulation. This can usefully enhance, enable or facilitate some of the above advantages. In particular, this can improve the user convenience since there is no need to recover the sheet-like preparation.

[0120] 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.

[0121] Applicator / Holder In one embodiment, an applicator having a holder functions to assist in the swallowing of the capsule device in combination with a drinking cup. The applicator used in combination with the drinking cup enables the patient to ingest the drug delivery system as if drinking from a bottle. Thus, the applicator is installed 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, thereby releasing the formulation from the holder and transporting it 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.

[0122] Such an applicator and drinking cup are described, for example, in PCT / EP2020 / 056927, and the full text thereof regarding the applicator, drinking cup, and string is incorporated herein by reference in its entirety. Such a holder is further described, for example, in European Patent No. 21175427.0 and European Patent No. 21175436.1, and the full text thereof regarding the holder is incorporated herein by reference in its entirety.

[0123] 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 particularly within the applicator, the retainer can be loosened from the structure by rotating the structure.

[0124] This is particularly beneficial as it enables the administration of the capsule device without the assistance of a professional, especially when the dosage form is to be administered regularly, particularly daily.

[0125] 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.

[0126] 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

[0127]

Fig. 1a-b

Fig. 2

Fig. 3

Fig. 4

Fig. 5a-b

Fig. 6

Fig. 7

Fig. 8a-b

Fig. 9a-b

Fig. 10

[0128] 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 drawn 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.

[0129] 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 Figure 2 to show essentially, in Figure 2, 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 elongated piece 5a. The elongated 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. Alternatively, 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.

[0130] 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 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.

[0131] 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 the pharmaceutically active ingredient, and the layer depicted at the bottom in Figure 4 shows a protective layer, for example, a protective layer against water.

[0132] 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 and 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 overlapping and sliding the two halves 2a and 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, and thus the opening 3 is formed as an opening through which the formulation 4 can exit the shell 2.

[0133] Alternatively, Figure 5b shows an embodiment in which the two capsule shell halves 2a and 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 and the opening 3 is formed.

[0134] Figure 6 shows a semi-transparent schematic view of the drug delivery system 1. The first and second capsule shell halves 2a and 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 dosage form 1 further includes a weight element 11 which is within the first capsule shell half 2a. The weight extends from the first capsule shell half 2a into the second half 2b, but a step 11a projects 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.

[0135] 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 located within the applicator 12, positioned 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.

[0136] 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. Thereafter, 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

[0137] 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 Holding device 5a Elongated piece 6 Holder 7 Layer 7a Adhesive layer 7b Drug active ingredient-containing layer 7c Protective layer 8 Dimple 9 Wall portion 10 Opening 11 Hammer element 11a Step 12 Applicator 12a Applicator cap 13 Holder 13a Curved holder 14 Spring 15 Drying element 16 Drinking cup

Example 1

[0138] Example 1: Preparation of a polymer film using 4-amino-3-(4-chlorophenyl)butyric acid (baclofen) A "base polymer mixture" was prepared without adding baclofen with the components and amounts listed in Table 1.

[0139] JPEG2025518374000003.jpg51162

[0140] After adjusting the pH, baclofen was added at room temperature, and a film laminate was prepared by the solvent casting method, that is, the polymer mixture containing baclofen was spread and the solvent was evaporated. The film was dried at room temperature.

[0141] The obtained film was flexible and showed a visually homogeneous surface without bubbles. Furthermore, the film surface was uniformly rough due to particles of different sizes.

[0142] Furthermore, the baclofen 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 an FSG medium at pH 1.2. Figure 10 shows the absorption spectra compared with a reference sample containing baclofen dissolved in an FSG medium at pH 1.2. From the comparison of the spectra of the film sample and the reference sample, it is confirmed that baclofen can be stably prepared in the film used for the drug delivery device of the present invention.

[0143] Furthermore, the baclofen content on the film was as shown in Table 2.

[0144] JPEG2025518374000004.jpg43170

[0145] From the results in Table 2, 10 cm 2It can be seen that the film can be loaded with 15 mg of baclofen, and the preparation of films with a wide range of therapeutic drug dosages is allowed. Note that the standard deviation and the maximum drug load are determined by the process technology and are not intended to indicate any limitation in principle.

[0146] Furthermore, the oral administration of baclofen in the art, i.e., administration into the bloodstream through gastrointestinal absorption, requires a high dose of 15 - 75 mg per day. Additionally, the oral administration of baclofen used clinically is extremely limited because of its low tolerance due to severe side effects such as neurological adverse events. Common side effects include drowsiness, weakness, headache, delirium, nausea, and dizziness. The local and / or topical administration of baclofen by the drug delivery system of the present invention enables improved local administration to the target site, thereby increasing the value of the drug particularly in the treatment of esophageal diseases.

Example 2

[0147] Example 2: Preparation of Polymer Films by Melt Extrusion - Selection of appropriate 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 active ingredient: The active ingredient is usually prepared in a suitable formulation (e.g., as a powder or granule). - Mixing of 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, the extruded film is cut into the desired size and shape. Next, the film is typically 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 aforementioned drug active ingredient is characterized by containing a reflux inhibitor. Drug delivery system.

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

3. The GABA type B receptor agonist is gamma-aminobutyric acid (GABA) or its salts, β-phenyl-γ-aminobutyric acid (phenibut) or its salts, 4-fluorofenibut or its salts, isovaline or its salts, 3-aminopropylphosphinic acid or its salts, 3-aminopropylmethylphosphinic acid (SKF-97,541) or its salts, [3-amino-2-hydroxypropyl]methylphosphinic acid (CGP) A drug delivery system according to claim 2, selected from the group consisting of 44532) or a salt thereof, 4-amino-3-(4-chlorophenyl)butyrate (baclofen) or a salt thereof, [(2R)-3-amino-2-fluoropropyl]phosphinic 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-hydroxypropylphosphinic acid (AZD9343) or a salt thereof, and albaclofenplacarbil or a salt thereof.

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

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

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

7. A drug delivery system according to any one of claims 1 to 6, used for therapeutic purposes.

8. A drug delivery system according to claim 7, used for the treatment or prevention of esophageal disease.

9. A drug delivery system according to claim 8, used for the treatment or prevention of esophageal diseases caused by or related to gastroesophageal reflux.

10. A drug delivery system according to claim 9, used for the treatment or prevention of gastroesophageal reflux disease.

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