Oral mucosal delivery system containing remazolam

Abstract

The present invention relates to an oral mucosal delivery system for transmucosal administration of an active agent, said oral mucosal delivery system comprising an active agent-containing layer comprising remazolam, such remazolam oral mucosal delivery system for generating sedation; a method of producing sedation comprising applying such a remazolam oral mucosal delivery system; and methods of making such remazolam oral mucosal delivery systems.

Description

Technical Field

[0001] The present invention relates to an oral mucosal delivery system for transmucosal administration of remimazolam to the systemic circulation, and a method for manufacturing the same, a treatment method, and uses thereof. Background Art

[0002] Remimazolam (methyl 3-{(4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl}propionate) is a novel benzodiazepine sedative, which was identified as one of the lead compounds in a project focusing on ester-based benzodiazepine derivatives starting in the late 1990s, and has a short and predictable duration of action.

[0003] Remimazolam contains an ester group, which is rapidly hydrolyzed by tissue esterase (carboxylesterase 1) and converted into an inactive metabolite CNS7054, thus making it a very short-acting drug.

[0004]

[0005] It exhibits anxiolytic, amnestic, sedative, muscle relaxant, and anticonvulsant properties. Due to these properties, it is suitable for use in anesthesia practice and intensive care, such as for preoperative sedation, anti-anxiety, amnestic use in perioperative situations, rapid diagnosis, conscious sedation during surgery or endoscopic examination, for example, as a component for induction and maintenance of general anesthesia before and / or simultaneously with the administration of other anesthetics, and for intensive care sedation.

[0006] Two salt forms have been specifically developed: besylate and tosylate. Remimazolam besylate has been approved for general anesthesia in Japan and South Korea, and for procedural sedation in the United States, China, and Europe. The mesylate has been approved for procedural sedation in China.

[0007] Remimazolam besylate is produced in a lyophilized form for reconstitution. There is currently no ready-to-use formulation available.

[0008] In terms of the route of administration, due to a large amount of first-pass metabolism and elimination mediated by carboxylesterase in the liver, the oral bioavailability of remimazolam is poor (reported to be 1% to 2%). Intranasal administration achieves significantly higher bioavailability (about 50%), however, it may be associated with nasal discomfort / pain in some cases. Inhalation has been proposed as an alternative method.

[0009] Thus, so far, the main route considered for remimazolam has remained intravenous (IV) administration. In Europe, remimazolam besilate has been approved as Byfavo, 20 mg powder for injection solution. However, in certain cases, an alternative to the IV route will be required. The lyophilized form of the drug product requires reconstitution of the active ingredient prior to IV administration. Preparation of the injection requires strict hygienic conditions and needles should be handled with particular care. In particular, young patients are afraid of the pain associated with injection.

[0010] Accordingly, it would be desirable to provide alternative ready-to-use non-invasive remimazolam dosage forms (wherein it is to be understood that this includes remimazolam, its pharmaceutically acceptable salts or any other form). However, remimazolam is prone to degradation by hydrolysis and developing a formulation with sufficient stability to result in an appropriate shelf life is challenging. In addition, due to the low bioavailability as described above, the classical oral route (for which there is extensive knowledge of formulation technology) does not appear to be applicable and developing a suitable non-oral drug delivery route that is patient-friendly, fast-acting and provides appropriate pharmacokinetic characteristics can be considered an extremely demanding task.

[0011] Thus, unsurprisingly, so far there do not appear to be any viable remimazolam dosage forms available other than IV formulations and the applicant is not aware of any ongoing / recent research or investigations into alternative remimazolam dosage forms other than those described above.

[0012] Accordingly, there is a need for alternative dosage forms of remimazolam that overcome the disadvantages associated with low bioavailability upon oral administration as well as the disadvantages associated with intravenous administration. Summary of the Invention

[0013] It is an object of the present invention to provide a remimazolam dosage form that overcomes one or more of the above disadvantages of current remimazolam administration.

[0014] An alternative object of the present invention is to provide a non-invasive, patient-friendly and / or ready-to-use formulation-based remimazolam dosage form.

[0015] Another alternative object of the present invention is to provide a remimazolam dosage form that provides high bioavailability, particularly when compared to oral administration.

[0016] Yet another alternative object of the present invention is to provide a remimazolam dosage form that provides fast onset and / or reliable onset, particularly when compared to oral administration.

[0017] Yet another alternative object of the present invention is to provide a remimazolam dosage form that provides a high permeation rate of remimazolam sufficient to reach a therapeutically effective dose.

[0018] Another alternative object of the present invention is to provide a remimazolam dosage form that provides an extended duration of action compared to single-dose IV remimazolam.

[0019] Another alternative object of the present invention is to provide a remimazolam dosage form in which remimazolam is stable and can be stored, for example, at room temperature.

[0020] Another alternative object of the present invention is to provide a remimazolam dosage form that does not cause irritating sensations at the administration site.

[0021] Yet another alternative object of the present invention is to provide a remimazolam dosage form that meets the needs of convenient administration and handling, provides good patient compliance, and / or is easy to manufacture and cost-effective.

[0022] The present invention achieves one or more of the above and other objects. According to one aspect, the present invention relates to an oral mucosal delivery system for transmucosal delivery of an active agent, the oral mucosal delivery system comprising an active agent-containing layer, the active agent-containing layer comprising

[0023] i) remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof as the active agent, and

[0024] ii) a film-forming agent.

[0025] According to another aspect of the present invention, the oral mucosal delivery system according to the present invention is used to produce sedation, produce hypnosis, produce anti-anxiety, produce muscle relaxation, treat convulsions, or induce amnesia for perioperative events.

[0026] According to another aspect, the present invention also relates to a method for producing sedation, producing hypnosis, producing anti-anxiety, producing muscle relaxation, treating convulsions, or inducing amnesia for perioperative events, wherein the oral mucosal delivery system is administered to a subject.

[0027] According to another aspect, the present invention also relates to the use of the oral mucosal delivery system in the preparation of a medicament for producing sedation, producing hypnosis, producing anti-anxiety, producing muscle relaxation, treating convulsions, or inducing amnesia for perioperative events.

[0028] According to yet another aspect, the present invention relates to a pharmaceutical product comprising a package and one or more unit doses of the oral mucosal delivery system.

[0029] According to another aspect, the present invention relates to a method for manufacturing an active agent-containing layer, the manufacturing method comprising the following steps:

[0030] i. Combining at least (i) remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof as the active agent with (ii) a film-forming agent to obtain a mixture; and

[0031] ii. Form the active agent-containing layer.

[0032] According to another aspect, the present invention relates to a method for manufacturing an oral mucosal delivery system, the oral mucosal delivery system comprising an active agent-containing layer, the active agent-containing layer comprising (i) remimazolam, a pharmaceutically acceptable salt thereof or any other form as the active agent, and (ii) a film-forming agent, the manufacturing method comprising the following steps:

[0033] i. Combine at least the active agent and the film-forming agent to obtain a mixture; and

[0034] ii. Form the active agent-containing layer.

[0035] According to another aspect, the present invention relates to an oral mucosal delivery system obtainable by such a method.

[0036] According to certain embodiments, the present invention further relates to an oral mucosal delivery system for transmucosal administration of remimazolam, the oral mucosal delivery system comprising an active agent-containing layer, the active agent-containing layer comprising

[0037] i) 55 wt-% to 60 wt-% of remimazolam besylate;

[0038] ii) 10 wt-% to 15 wt-% of polyvinyl alcohol as the film-forming agent,

[0039] iii) 30 wt-% to 35 wt-% of a polyvinyl alcohol-polyethylene glycol graft copolymer,

[0040] iv) 0.05 wt-% to 1 wt-% of one or more sweeteners, and

[0041] v) 0.5 wt-% to 2 wt-% of a flavoring agent

[0042] wherein

[0043] the areal weight of the active agent-containing layer is less than or equal to 200 g / m².

[0044] According to certain embodiments, the present invention further relates to an oral mucosal delivery system for transmucosal administration of remimazolam, the oral mucosal delivery system comprising an active agent-containing layer, the active agent-containing layer comprising

[0045] i) 55 wt-% to 60 wt-% of remimazolam besylate;

[0046] ii) 15 wt-% to 20 wt-% of polyvinyl alcohol as the film-forming agent

[0047] iii) 20 wt-% to 26 wt-% of a polyvinyl alcohol-polyethylene glycol graft copolymer,

[0048] iv) 0.05 wt-% to 1 wt-% of one or more sweeteners, and

[0049] v) 0.5 wt-% to 2 wt-% of a flavoring agent

[0050] wherein

[0051] the areal weight of the active agent-containing layer is less than or equal to 200 g / m².

[0052] Within the meaning of the present invention, the term "oral mucosal delivery system" refers to a system for administering an active agent (remimazolam, its pharmaceutically acceptable salts or any other form) to the systemic circulation via transmucosal delivery by application to the oral mucosa, and refers to the entire single dosage unit applied to the mucosa of a patient and particularly containing a therapeutically effective amount of remimazolam, its pharmaceutically acceptable salts or any other form in the active agent-containing layer. The oral mucosal delivery system consists of one or more thin layers which are applied to the oral mucosa and adhere to the oral mucosa to deliver the active agent. A dosage form in the form of a film for application in the oral cavity is sometimes also referred to as an "oral thin film" or OTF. However, an OTF is not necessarily intended to adhere to the mucosa. In an oral mucosal delivery system, the active agent is contained in a soluble layer, and due to the film adhering to the mucosa, the active agent delivery is mainly achieved by a combination of local active agent release from the oral mucosal delivery system to the mucosa (i.e., the active agent dissolves and is directly released into the underlying mucosa) and "indirect" active agent delivery due to the migration of the active agent from the application site to other parts of the oral cavity once it has dissolved in saliva.

[0053] Within the meaning of the present invention, the term "oral mucosal delivery system" particularly refers to a system that is mucoadhesive and provides passive transmucosal delivery, which does not include active transport as in methods involving microporation. Furthermore, compared to certain oral thin films (sometimes referred to as "flash films") that are not necessarily mucoadhesive and are intended to disintegrate very rapidly in saliva, enteral delivery is not expected in an oral mucosal delivery system, although it is not excluded (e.g., by accidental swallowing of saliva).

[0054] Within the meaning of the present invention, the term "active agent-containing layer" refers to a layer containing an active agent and a film-forming agent, which will form a matrix with the active agent, and the matrix disintegrates and releases the active agent upon contact with saliva. The active agent-containing layer can be mucoadhesive (in the form of a mucoadhesive layer), or the oral mucosal delivery system can include a mucosal contact layer of an additional mucoadhesive to provide sufficient adhesion. In particular, the active agent-containing layer is a mucoadhesive layer.

[0055] Within the meaning of the present invention, the term "therapeutically effective amount" refers to the amount of the active agent in the oral mucosa delivery system which, when the oral mucosa delivery system is administered to a patient, is sufficient to provide a similar range of sedation and / or remimazolam blood levels compared to those obtained after a single IV administration of 0.01 to 0.5 mg / kg of remimazolam, its pharmaceutically acceptable salts or any other form (e.g., overall maximum plasma concentration c max of 189 to 6,960 ng / mL).

[0056] Within the meaning of the present invention, the terms "active substance", "active agent", etc. refer to remimazolam and its pharmaceutically acceptable salts or any other form, and in particular to any pharmaceutically acceptable chemical and morphological form and its physical state. These forms include, but are not limited to: remimazolam (free base form); protonated or partially protonated remimazolam; remimazolam salts, and in particular acid addition salts formed by the addition of inorganic or organic acids, such as remimazolam benzenesulfonate or remimazolam toluenesulfonate, hydrates, solvates, complexes, etc.; and remimazolam in particulate form, which may be micronized or may preferably not be micronized, crystalline and / or amorphous; and any mixture of the foregoing forms. When included in a medium such as a solvent, the active agent may be dissolved or dispersed, or partially dissolved and partially dispersed.

[0057] When referring to the active agent in a particular form for the manufacture of an oral mucosa delivery system, this does not exclude interactions between the active agent in this form and other components of the self-adhesive layer structure containing the active agent in the final oral mucosa delivery system, such as salt formation or complexation. This means that even if the active agent is included in its free base form, it may be present in the final oral mucosa delivery system in protonated or partially protonated form or in acid addition salt form, or, if the active agent is included in salt form, part of the active agent may be present in the final oral mucosa delivery system in free base form. Unless otherwise stated, the given amount of the active agent is calculated based on remimazolam in free base form. In particular, the amount of the active agent in the active agent-containing layer is related to the amount of the active agent contained in the oral mucosa delivery system during the manufacture of the oral mucosa delivery system and is calculated based on remimazolam in free base form. For example, when the oral mucosa delivery system contains a) 0.1 mmol (equal to 43.9 mg) of remimazolam base or b) 0.1 mmol (equal to 59.8 mg) of remimazolam benzenesulfonate during the manufacturing process, within the meaning of the present invention, the amount of the active agent in the self-adhesive layer structure is 0.1 mmol or 43.9 mg in both cases.

[0058] In the manufacturing process of an oral mucosa delivery system, the starting material of the active agent contained in the oral mucosa delivery system may be in particulate form. The active agent may be present, for example, in the mucoadhesive layer structure in the form of dispersed and / or dissolved particles.

[0059] Within the meaning of the present invention, the term "particle" refers to a solid particulate material comprising individual particles, the size of which is negligible compared to the material. In particular, the particles are solids, including plastic / deformable solids, including amorphous and crystalline materials.

[0060] Within the meaning of the present invention, the term "dispersion" refers to a step or combination of steps in which the starting material (e.g., remimazolam) is not completely dissolved. In the context of the present invention, dispersion includes dissolving a portion of the starting material (e.g., remimazolam particles) according to the solubility of the starting material (e.g., the solubility of remimazolam in the coating composition).

[0061] Terms such as "dissolution", "dissolvable", "dissolve" with respect to the active agent-containing layer of the oral mucosa delivery system and with respect to the film-forming agent when casting into a film should be understood very broadly and not in the strict scientific sense of dissolving a molecule in a solvent. Any transition from the solid state to the liquid state of the layer involved, such as dispersion, formation of a suspension, gelation of the film and disintegration into smaller gel parts, etc., should be regarded as "dissolution" in the context of the present invention, as long as the "dissolved" material can move freely in a liquid (e.g., saliva). In a preferred embodiment, this meaning is limited to the usual chemical meaning of dissolving a molecule in a solvent. It should be noted that the term "dissolve" with respect to the substance itself (such as the active agent remimazolam or any excipient) will continue to be used in the usual chemical sense of dissolving a molecule in a solvent. For example, remimazolam in dissolved form clearly does not include remimazolam in dispersed form. The film-forming agent itself may be present in the coating composition in a dissolved form in the usual chemical sense (e.g., not dispersed, in the form of small gel parts, etc.) during the manufacturing process of the oral mucosa delivery system, but when the film-forming agent is cast into a film, "dissolving" such a film also includes gelation of the film and disintegration into smaller gel parts.

[0062] Within the meaning of the present invention, the term "mucoadhesivity" refers to a material that adheres specifically to the mucosa and is in contact with the mucosa, but it is preferably non-sticky and can be touched (e.g., with a finger) and manipulated, for example, for application in the oral cavity, without inadvertently adhering to the skin of the finger in the dry state. When in contact with the mucosa, the mucoadhesive layer is "self-adhesive", i.e., it provides an adhesive force to the mucosa such that usually no other aids are required for fixation. The adhesion strength is preferably strong enough such that typical movements within the oral cavity are not sufficient to move the mucoadhesive layer adhered to the mucosa.

[0063] Within the meaning of the present invention, the term "areal weight" refers to the dry weight of a specific layer (e.g., the active agent-containing layer) in g / m 2 . Due to manufacturing variability, the tolerance of the areal weight value is ±10%, preferably ±7.5%.

[0064] Unless otherwise specified, "%" refers to weight %.

[0065] Within the meaning of the present invention, the term "polymer" refers to any substance composed of so-called repeating units obtained by polymerizing one or more monomers, and includes homopolymers composed of one type of monomer and copolymers composed of two or more types of monomers. The polymer can have any structure, such as linear polymers, star polymers, comb polymers, brush polymers, and in the case of copolymers, can have any monomer arrangement, such as alternating, statistical, block copolymers or graft polymers. The minimum molecular weight varies according to the polymer type and is known to the person skilled in the art. The polymer can, for example, have a molecular weight above 2,000, preferably above 5,000 and more preferably above 10,000 daltons. Correspondingly, compounds with a molecular weight below 2,000, preferably below 5,000 or more preferably below 10,000 daltons are generally referred to as oligomers.

[0066] The oral mucosa delivery system according to the present invention can be characterized by certain parameters as measured in in vitro permeation tests.

[0067] The in vitro permeation test is carried out using human or animal mucosa and preferably using porcine mucosa with a skinning knife thickness of 400 μm and an intact barrier function, and using phosphate buffer pH 5.5 or 7.4 as the receptor medium (37 °C), with the receptor medium added with or without up to 40% by volume of an organic solvent, such as ethanol, acetonitrile, isopropanol, dipropylene glycol, PEG400, so that the receptor medium can, for example, contain 60% by volume of phosphate buffer pH 5.5, 30% by volume of dipropylene glycol and 10% by volume of acetonitrile.

[0068] Unless otherwise stated, the in vitro permeation test was carried out using porcine mucosal (esophageal mucosa) with a thickness of 400 μm and intact barrier function, and phosphate buffer pH 7.4 as the receptor medium (37 °C). The amount of active substance permeating into the receptor medium was determined periodically by collecting sample volumes using an HPLC method with a UV photometric detector. The measured amount of permeated active substance relates to the amount permeated between the last two sampling points and not to the total amount permeated so far. In the context of the present invention, artificial saliva refers to an aqueous solution of 0.520 g / L potassium thiocyanate, 1.470 g / L potassium chloride, 0.190 g / L sodium dihydrogen phosphate monohydrate, and 2.650 g / L disodium hydrogen phosphate dihydrate, adjusted to pH 7.0 + / - 0.05 using 1 N NaOH.

[0069] Thus, in the context of the present invention, the unit of the parameter "amount of permeation" is μg / cm 2 , and relates to the amount of active substance permeating per unit release area within a sampling interval over a certain elapsed time. For example, in the in vitro permeation test described above, where the amount of active substance permeating into the receptor medium is measured, for example, at 0, 2, 4, 8, 12, and 24 minutes, the "amount of permeation" of the active substance within the sample interval from 8 minutes to 12 minutes can be given, for example, and corresponds to the measured value at 12 minutes.

[0070] The amount of permeation can also be given as the "cumulative amount of permeation", which corresponds to the cumulative amount of active substance permeated at a specific time point. For example, in the in vitro permeation test described above, where the amount of active substance permeating into the receptor medium is measured, for example, at 0, 2, 4, 8, 12, and 24 minutes, the "cumulative amount of permeation" of the active substance at 12 minutes corresponds to the sum of the amounts of permeation from 0 minutes to 2 minutes, from 2 minutes to 4 minutes, from 4 minutes to 8 minutes, and from 8 minutes to 12 minutes.

[0071] In the context of the present invention, the unit of the parameter "mucosal permeation rate" within a sample interval over a certain elapsed time is μg / (cm 2 min), and is calculated by dividing the amount of permeation (in μg / cm 2 ) within the sample interval measured by the in vitro permeation test described above by the number of minutes of the sample interval. For example, the mucosal permeation rate in the in vitro permeation test described above, where the amount of active substance permeating into the receptor medium is measured, for example, at 0, 2, 4, 8, 12, and 24 minutes, the "mucosal permeation rate" at 12 minutes is calculated by dividing the amount of permeation within the sample interval from 8 minutes to 12 minutes by 4 minutes.

[0072] "Cumulative mucosal permeation rate" can be calculated from the corresponding cumulative permeation amount by dividing the cumulative permeation amount by the elapsed time. For example, in the in vitro permeation test described above, where, for example, the amount of active substance permeating into the receptor medium is measured at 0, 2, 4, 8, 12, and 24 minutes, the "cumulative mucosal permeation rate" at 12 minutes is obtained by dividing the cumulative permeation amount at 12 minutes (see above) by 12 minutes.

[0073] Within the meaning of the present invention, the above parameters permeation amount and mucosal permeation rate (and cumulative permeation amount and cumulative mucosal permeation rate) refer to the average values calculated from three in vitro permeation test experiments.

[0074] The oral mucosal delivery system according to the present invention can also be characterized by certain parameters measured, for example, in in vivo non-clinical or clinical studies.

[0075] Within the meaning of the present invention, the term "administration" means applying the dosage form (i.e., the oral mucosal delivery system) to the oral mucosa of a patient and then maintaining the dosage form on the mucosa until the layer structure containing the active agent dissolves.

[0076] Within the meaning of the present invention, the term "room temperature" means the unchanged temperature in the laboratory room where the experiment is conducted, and is generally within 15°C to 35°C, preferably about 18°C to 25°C.

[0077] Within the meaning of the present invention, the term "patient" means a subject who has exhibited a clinical manifestation of one or more specific symptoms indicating the need for treatment or surgery, particularly the need for sedation, a subject undergoing preventive or prophylactic treatment for a disease, or a subject diagnosed with a disease to be treated that requires sedation.

[0078] Within the meaning of the present invention, the term "pharmacokinetic parameter" refers to a parameter that describes the plasma curve, such as C obtained, for example, in a clinical study by administering a single dose or multiple doses of an oral mucosal delivery system to healthy human subjects. max 、C t and AUC t1-t2 . Using arithmetic and geometric means, such as mean C max 、mean AUC t and mean AUC INF , as well as other statistical values, such as the corresponding standard deviation and standard error, minimum value, maximum value, and median value (median) when ranking the list of values, to summarize the pharmacokinetic parameters of individual subjects. In the context of the present invention, pharmacokinetic parameters, such as C max 、C t and AUC t1-t2, refers to the arithmetic or geometric mean, and preferably refers to the geometric mean. It cannot be excluded that the absolute mean values obtained from a certain oral mucosa delivery system in clinical studies may vary to some extent between different studies. To compare the absolute mean values between studies, a reference formulation, such as any future product based on the present invention, can be used as an internal standard. The comparison of the AUC per unit release area of the corresponding reference product in earlier and later studies can be used to obtain a correction factor to take into account the differences between studies.

[0079] Within the meaning of the present invention, the parameter "AUC" corresponds to the area under the plasma concentration-time curve. The AUC value is proportional to the amount of active agent absorbed into the blood circulation and is thus a measure of bioavailability.

[0080] Within the meaning of the present invention, the parameter "AUC t1-t2 " has the unit (ng / ml) hour and relates to the area under the plasma concentration-time curve from t1 to t2 hours and is calculated by the linear trapezoidal method.

[0081] Within the meaning of the present invention, the parameter "C max " has the unit (ng / ml) and relates to the maximum observed plasma concentration of the active agent.

[0082] Within the meaning of the present invention, the parameter "C t " has the unit (ng / ml) and relates to the plasma concentration of the active agent observed at the t-th hour.

[0083] Within the meaning of the present invention, the parameter "t max " has the unit hour and relates to the time point at which the C max value is reached. In other words, t max is the time point at which the maximum plasma concentration is observed.

[0084] Within the meaning of the present invention, the term "average plasma concentration" has the unit (ng / ml) and is the average of the individual plasma concentrations of the active agent (such as remimazolam) at each time point. Within the meaning of the present invention, the unit of "bioavailability" is %, which refers to the dose-normalized ratio of C max after IV administration compared to that after oral mucosa administration Cmax dose-normalized, or the dose-normalized ratio of the dose-normalized AUC after IV administration compared to the dose-normalized AUC after oral mucosa administration.

[0085] Within the meaning of the present invention, the term "coating composition" refers to a composition that contains all components of the active agent-containing layer in a solvent.

[0086] Within the meaning of the present invention, the term "dissolving" in the context of preparing a coating composition, such as dissolving components of the coating composition like active agents, refers to the process of obtaining a solution that is clear and free of any particles visible to the naked eye.

[0087] Within the meaning of the present invention, the term "foam" refers to a state of a liquid or solid material that entraps a relatively large amount of air cavities separated by relatively thin layers of material. In contrast, a "monolithic film" refers to a uniform film consisting of a single continuous phase that is substantially free of a large number of pores or trapped air cavities.

[0088] Within the meaning of the present invention, the term "desiccant" refers to a hygroscopic material that absorbs or adsorbs water molecules from the surrounding air and thereby reduces the humidity level.

[0089] Within the meaning of the present invention, the term "solvent" refers to any liquid substance, preferably water or a volatile organic liquid such as methanol, ethanol, isopropanol, acetone, ethyl acetate, dichloromethane, hexane, n - heptane, heptane, toluene, and mixtures thereof.

[0090] Within the meaning of the present invention and unless otherwise specified, the term "about" refers to an amount that is ±10% of the disclosed amount. In some embodiments, the term "about" refers to an amount that is ±5% of the disclosed amount. In some embodiments, the term "about" refers to an amount that is ±2% of the disclosed amount. BRIEF DESCRIPTION OF THE DRAWINGS

[0091] Figure 1 Depicts a cross - section of a pharmaceutical product of the present invention, which pharmaceutical product comprises a unit dose of the oral mucosa delivery system of the present invention in a sachet and a folded polyethylene terephthalate foil within a primary package.

[0092] Figure 2a Depicts the sedation levels as measured during in - vivo studies of a placebo oral mucosa delivery system.

[0093] Figure 2b Depicts the sedation levels as measured during in - vivo studies of an oral mucosa delivery system prepared according to Example 1c.

[0094] Figure 2c Depicts the sedation levels as measured during in - vivo studies of an oral mucosa delivery system prepared according to Example 1d.

[0095] Figure 2d Depicts the sedation levels as measured during in - vivo studies after intravenous administration of remimazolam besylate.

[0096] Figure 3a Depicts the remimazolam plasma concentrations obtained in in - vivo studies of an oral mucosa delivery system prepared according to Example 1c.

[0097] Figure 3b Depicts the plasma concentration of CNS7054 obtained in the in vivo study of the oral mucosal delivery system prepared according to Example 1c.

[0098] Figure 4a Depicts the remimazolam plasma concentration obtained in the in vivo study of the oral mucosal delivery system prepared according to Example 1d.

[0099] Figure 4b Depicts the plasma concentration of CNS7054 obtained in the in vivo study of the oral mucosal delivery system prepared according to Example 1d.

[0100] Figure 5a Depicts the remimazolam plasma concentration obtained in the in vivo study after IV administration of remimazolam besylate.

[0101] Figure 5b Depicts the plasma concentration of CNS7054 obtained in the in vivo study after IV administration of remimazolam besylate.

[0102] Figure 6a Depicts the remimazolam mucosal permeation rate of the oral mucosal delivery system prepared according to Example 2a when dissolved in artificial saliva or 0.9% NaCl, or the remimazolam mucosal permeation rate of remimazolam besylate when dissolved in artificial saliva and adjusted to pH 2, 3, 4.5, or 6.0, respectively.

[0103] Figure 6b Depicts the remimazolam mucosal permeation rate of the oral mucosal delivery system prepared according to Example 2a when dissolved in artificial saliva or 0.9% NaCl, or the remimazolam mucosal permeation rate of the remimazolam besylate lyophilized product when dissolved in artificial saliva or 0.9% NaCl, or the remimazolam mucosal permeation rate of remimazolam besylate when dissolved in artificial saliva. Detailed Description

[0104] Oral Mucosal Delivery System

[0105] The present invention relates to an oral mucosal delivery system for transmucosal administration of an active agent, the oral mucosal delivery system comprising an active agent-containing layer containing remimazolam, a pharmaceutically acceptable salt thereof, or any other form as the active agent.

[0106] The active agent-containing layer comprises i) remimazolam, a pharmaceutically acceptable salt thereof, or any other form as the active agent, and ii) a film-forming agent.

[0107] Thus, an oral mucosal delivery system for transmucosal administration of an active agent comprises an active agent-containing layer, the active agent-containing layer comprising:

[0108] i) Remimazolam, its pharmaceutically acceptable salts or any other form as an active agent, and

[0109] ii) A film-forming agent.

[0110] The oral mucosa administration route is a relatively new form of drug delivery, which means that the understanding of formulation technology is limited. Therefore, formulating a suitable dosage form for transmucosal delivery via an oral mucosal dosage form is challenging. As further explained above, the oral mucosal delivery system of the present invention unexpectedly shows the ability to provide appropriate transmucosal drug delivery, thereby avoiding the first-pass effect associated with enteral delivery and achieving high bioavailability, as confirmed by the preclinical results further shown below.

[0111] The oral mucosal dosage form is non-invasive, simple and ready-to-use, and in this regard, addresses the needs and drawbacks of IV formulations.

[0112] Also as outlined above, the oral mucosal delivery system consists of one or more thin layers, and thus in certain embodiments, the oral mucosal delivery system is in the form of a thin film. This thin film can have a circular, rectangular or square shape, or any other shape.

[0113] The thin film has a certain degree of thickness, because otherwise it will be difficult to incorporate the required amount of active substance, and because very thin films are not easy to manufacture, especially in terms of providing a uniform thickness. Therefore, in certain embodiments, the oral mucosal delivery system is in the form of a thin film, wherein the thin film has an area weight of at least 100 g / m², at least 110 g / m² or at least 120 g / m², or has an area weight of less than or equal to 400 g / m², less than or equal to 300 g / m² or less than or equal to 250 g / m², and / or wherein the thin film has an area weight of 100 g / m² to less than or equal to 230 g / m² or 300 g / m² to less than or equal to 400 g / m².

[0114] In certain embodiments of the present invention, the oral mucosal delivery system for transmucosal administration of an active agent is in the form of a thin film, wherein the thin film has a length of at least 0.5 cm 2 、or less than or equal to 10 cm 2 、or about 1.5 cm 2 、about 3 cm 2 or about 6 cm 2 in size.

[0115] In some embodiments, the oral mucosal delivery system for transmucosal administration of an active agent according to the present invention does not contain preservatives.

[0116] Active agent-containing layer

[0117] As outlined in more detail above, the oral mucosa delivery system according to the present invention comprises an active agent-containing layer, said active agent-containing layer comprising remimazolam, a pharmaceutically acceptable salt thereof or any other form as the active agent and a film-forming agent.

[0118] Also as outlined above and without wishing to be bound by theory, it is believed that a sufficient amount of the active agent contained in the oral mucosa delivery system is necessary to achieve certain advantageous features of the oral mucosa delivery system according to the present invention, such as good in vitro permeation. On the other hand, a thick layer may not only cause an uncomfortable feeling in the mouth, but is also difficult to manufacture and may result in the layer taking too long to dissolve to obtain the desired release profile. In addition, if the amount of the active agent is too high, this may not only lead to undesirable storage stability problems, such as recrystallization of the active agent when the active agent is present in a dissolved form, but may also result in a potentially irritating feeling in the mouth due to the too high drug concentration.

[0119] The amount of the active agent contained in the oral mucosa delivery system can be controlled bidirectionally by adjusting the concentration and / or areal weight of the active agent-containing layer. Thus, in certain embodiments of the present invention, the active agent-containing layer comprises at least 20 wt-%, at least 25 wt-% or at least 30 wt-% of the active agent, and / or less than or equal to 60 wt-%, less than or equal to 55 wt-% or less than or equal to 50 wt-% of the active agent, and / or 20 wt-% to 60 wt-%, 25 wt-% to 55 wt-% or 30 wt-% to 50 wt-% of the active agent.

[0120] In certain embodiments of the present invention, the active agent-containing layer comprises at least 4 mg / cm², at least 6 mg / cm² or at least 8 mg / cm² of the active agent, and / or less than or equal to 15 mg / cm², less than or equal to 13 mg / cm² or less than or equal to 11 mg / cm² of the active agent, and / or 4 to 15 mg / cm², 6 to 13 mg / cm² or 8 to 11 mg / cm² of the active agent.

[0121] In terms of the amount of the active agent, the oral mucosa delivery system may comprise at least 5 mg, at least 10 mg or at least 15 mg of the active agent, and / or less than or equal to 80 mg, less than or equal to 70 mg or less than or equal to 60 mg of the active agent, and / or 5 to 80 mg, 10 to 70 mg or 15 to 60 mg of the active agent.

[0122] As outlined above, the amount of the active agent given herein is expressed as remimazolam in free base form. That is, when the oral mucosa delivery system comprises at least 10 mg of remimazolam, this corresponds to at least 13.6 mg of remimazolam besylate as described above.

[0123] The correct dissolution behavior of the active agent-containing layer is very important for controlling the delivery route. The faster the disintegration of the oral mucosal delivery system, the more beneficial it is for dissolution into saliva rather than direct delivery to the mucosa at the adhesion site. For achieving particularly high penetration rates, indirect delivery that can utilize the entire mucosa for drug delivery is very important. This means that the oral mucosal delivery system should disintegrate relatively quickly.

[0124] Since the active agent-containing layer preferably can directly adhere to the mucosa, in certain preferred embodiments of the present invention, the active agent-containing layer has mucoadhesiveness. As will be further outlined in detail below, haptics is an important aspect of the oral mucosal delivery system. Therefore, in certain embodiments, the active agent-containing layer is in the form of a foam or a flexible single-piece film. Such an active agent-containing layer in the form of a foam or being flexible will provide a more pleasant taste and is thus beneficial in this sense.

[0125] In certain embodiments of the present invention, the active agent-containing layer contains less than or equal to 3% by weight, less than or equal to 2 wt-%, less than or equal to 1 wt-%, or less than or equal to 0.5 wt-% of water.

[0126] It was further unexpectedly found that at a specific pH, the mucosal penetration rate of the oral mucosal delivery system of the present invention is favorable at a certain pH. Therefore, in some embodiments of the present invention, the oral mucosal delivery system is in the form of a thin film, and when a sample film of the oral mucosal delivery system with a size of 5.75 cm 2 is dissolved in 5 mL of artificial saliva or 0.9% NaCl solution, the pH of the resulting solution measured by a pH electrode is in the range of pH 3.0 to pH 3.7.

[0127] Active agent

[0128] According to the present invention, the active agent-containing layer contains remimazolam, a pharmaceutically acceptable salt thereof, or any other form, especially in a therapeutically effective amount, as the active agent.

[0129] Although according to the present invention, the active agent can be present in the oral mucosal delivery system in any form (for example, in the free base form, in the pharmaceutically acceptable salt form, or in any mixture thereof), and especially in the active agent-containing layer, it is preferred that remimazolam is present in the pharmaceutically acceptable salt form.

[0130] That is, in some specific embodiments of the present invention, the oral mucosal delivery system contains the active agent in the form of remimazolam besylate or in the form of remimazolam tosylate.

[0131] In addition, in certain embodiments of the present invention, the active agent in the active agent-containing layer is in dissolved or dispersed form, or in the form of non-micronized particles.

[0132] The active agent in the active agent-containing layer may be (completely) dissolved, or the active agent-containing layer may contain active agent particles, preferably composed of the active agent in its free, dissociated form, such that the active agent is present in a dispersed form. It goes without saying that if the active agent is present in a dispersed form, the active agent-containing layer may still contain the active agent in dissolved form as well, depending on the solubility of the active agent in the active agent-containing layer (which may be, for example, saturated or supersaturated).

[0133] In a preferred embodiment, the active agent is completely dissolved, for example, at least 90 mol%, preferably at least 95 mol%, more preferably at least 98 mol% or most preferably at least 99 mol% of the active agent in the active agent-containing layer is present in dissolved form. It is also preferred that the active agent-containing layer does not contain active agent crystals.

[0134] As outlined above, the amount of the active agent in the oral mucosa delivery system is considered important for the good release of the active substance and can be adjusted, for example, by the active agent concentration. Thus, in certain embodiments, the concentration of the active agent in the active agent-containing layer ranges from 20 wt-% to 60 wt-%, 25 wt-% to 55 wt-% or 30 wt-% to 50 wt-% of the active agent-containing layer.

[0135] The oral mucosa delivery system according to the present invention advantageously exhibits improved stability in terms of the active agent content and the degradation of the active agent.

[0136] Thus, in certain embodiments, the active agent-containing layer initially (i.e., shortly after manufacture, such as within one week) contains at least 95%, preferably at least 97%, more preferably at least 98% and even more preferably at least 99% of the theoretical amount of the active agent contained in the active agent-containing layer. The theoretical amount of the active agent is calculated based on the active agent dose used for the coating composition and the (actual) areal weight of the coated and dried active agent-containing layer of the tested oral mucosa delivery system.

[0137] The active agent-containing layer may initially also contain a total amount of remimazolam-related degradation substances that is less than or equal to 0.4 wt-%, less than or equal to 0.3 wt-% or less than or equal to 0.2 wt-%.

[0138] In certain other embodiments, the oral mucosa delivery systems according to the present invention are stable upon storage, i.e., they can maintain the initial remimazolam content value or exhibit a small amount of degradation products, as follows:

[0139] In one of such embodiments, after storage at 60 °C for up to 6 weeks or 9 weeks, the active agent-containing layer contains at least 95%, preferably at least 97%, more preferably at least 98% and even more preferably at least 99% of the theoretical amount of remimazolam contained in the active agent-containing layer.

[0140] When subjected to a storage stability test and stored at 60 °C for up to 6 weeks, the active agent-containing layer may also contain a total amount of remimazolam-related degradation substances that is less than or equal to 0.5 wt-% or less than or equal to 0.4 wt-%.

[0141] The method for determining the total amount of remimazolam content and remimazolam-related degradation substances is preferably carried out by validated HPLC-UV as described in the Examples section.

[0142] Film-forming agent

[0143] As outlined above, the oral mucosal delivery system according to the present invention comprises an active agent-containing layer, which contains remimazolam, a pharmaceutically acceptable salt thereof or any other form, and a film-forming agent as the active agent.

[0144] This film-forming agent forms a matrix and provides sufficient cohesion of the active agent-containing layer as long as it remains in a dry state. According to certain embodiments, once moistened, i.e., when in contact with the mucosa, the film-forming agent may also provide sufficient adhesion to the mucosa. In such embodiments, and generally speaking, the film-forming agent may be selected from mucoadhesive polymers.

[0145] The film-forming agent is the main control of the dissolution / disintegration behavior of the active agent-containing layer. By selecting an appropriate film-forming agent, the adhesion to the mucosa and the disintegration behavior can be appropriately adjusted, for example, in terms of the disintegration time and the integrity of the oral mucosal delivery system.

[0146] Film-forming agents suitable as film-forming agents according to the present invention are, for example, selected from the group consisting of: polymers such as polyvinylpyrrolidone (commercially available as Kollidon® 30F from BASF), methylcellulose (commercially available as Methocel® from Colorcon), ethylcellulose (commercially available as Ethocel® from Colorcon), hydroxyethylcellulose (commercially available as Natrosol® 250 L from Ashland Industries), hydroxypropylcellulose (commercially available as Klucel® from Ashland Industries), hydroxypropylmethylcellulose (also known as hypromellose, commercially available as Pharmacoat® from Shin-Etsu), sodium carboxymethylcellulose (uncrosslinked sodium carboxymethylcellulose, also known as CMC or carboxymethyl cellulose, commercially available as Blanose® from Ashland Industries), graft copolymers based on polyethylene glycol - polyvinyl acetate and polyvinylcaprolactam (commercially available as Soluplus® from BASF), polyvinyl alcohol (commercially available as Emprove® from Merck), polyvinyl alcohol - polyethylene glycol copolymer (commercially available as Kollicoat® IR from BASF), polyvinylpyrrolidone - polyvinyl acetate copolymer (also known as copovidone and, for example, commercially available as Kollidon® VA64 from BASF), polyethylene oxide, polyethylene glycol, methacrylic acid - methyl methacrylate copolymer (commercially available as Eudragit® L100, Eudragit® L12,5, Eudragit® S100 and Eudragit® S12,5 from Evonik) and methacrylic acid - ethyl methacrylate copolymer (commercially available as Eudragit® L100-55 and Eudragit® L30D55 from Evonik), and natural film-forming agents such as shellac, pectin, gelatin, alginate, pullulan and starch derivatives, and any mixtures thereof. Commercially available mixtures are, for example, Kollidon ® SR (a mixture in the form of a physical mixture of 80% polyvinyl acetate and 19% polyvinylpyrrolidone (Kollidon® 30), wherein approximately 0.8% sodium dodecyl sulfate and approximately 0.2% silica are used as stabilizers) and Kollicoat ® protect (a mixture containing 55% - 65% polyethylene glycol - polyvinyl alcohol graft copolymer, 35% - 45% polyvinyl alcohol and 0.1% - 0.3% silica as a processing aid).

[0147] The film-forming agent should not only provide sufficient cohesion for the active agent-containing layer, but preferably also provide a film that is non-tacky in the dry state, so that the patient can touch and manipulate the active agent-containing layer, for example, applying an oral mucosal delivery system containing the active agent-containing layer to the oral mucosa without adhering to the fingers. In addition, since the film-forming agent is the main control of the dissolution behavior of the active agent-containing layer, and the dissolution behavior cannot be too fast or too slow, the film-forming agent is preferably soluble, dispersible or otherwise disintegratable in an aqueous medium, especially in saliva, or simply in water. On the other hand, in terms of the simplicity of manufacturing and allowing anhydrous manufacturing methods (which are advantageous in terms of the stability of the active agent), film-forming agents soluble in other solvents such as C1-C3 alcohols, such as ethanol, are also preferred.

[0148] The inventors have surprisingly found that, in summary, polymers such as polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymers, polyethylene oxide, polyvinylpyrrolidone, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymers, polyethylene glycol, hydroxypropylmethylcellulose or any mixture thereof are preferably used for the film-forming agent.

[0149] Preferred film-forming agents are polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymers, especially polyvinyl alcohol. The polyvinyl alcohol-polyethylene glycol graft copolymer is commercially available as Kollicoat® IR from BASF. Kollicoat® IR is particularly preferred and is a polymer composed of 75% polyvinyl alcohol units and 25% polyethylene glycol units, and also contains approximately 0.3% colloidal silica to improve the flow properties, with an MW of 45,000 AMU. Polyvinyl alcohol is commercially available from Kuraray under the trade name Mowiol and from Merck under the trade names Parteck ® MX and Emprove® and are available in several grades, varying according to the degree of hydrolysis and molecular weight. In certain preferred embodiments, the film-forming agent is polyvinyl alcohol having a molecular weight in the range of 10,000 to 250,000, or a mixture of two or more polyvinyl alcohols, each having a molecular weight in the range of 10,000 to 250,000. The molecular weight is determined as the average weight of the molar mass Mw by gel permeation chromatography (GPC) combined with static light scattering (absolute method) on a re-acetylated sample.

[0150] The Mowiol partially hydrolyzed grades differ from each other due to the molecular weight MW and are as follows:

[0151] PVA 3-83 has an MW of approximately 14,000

[0152] PVA 4-88 has an MW of approximately 31,000

[0153] PVA 5-88 has an MW of approximately 37,000

[0154] PVA 8-88 has an MW of approximately 67,000

[0155] PVA 18-88 has an MW of approximately 130,000

[0156] PVA 23-88 has an MW of approximately 150,000

[0157] PVA 26-88 has an MW of approximately 160,000

[0158] PVA 40-88 has an MW of approximately 205,000.

[0159] The fully hydrolyzed grades of Mowiol differ from each other due to the molecular weight MW and are as follows:

[0160] PVA 3-98 has an MW of approximately 16,000

[0161] PVA 4-98 has an MW of approximately 27,000

[0162] PVA 6-98 has an MW of approximately 47,000

[0163] PVA 10-98 has an MW of approximately 67,000

[0164] PVA 20-98 has an MW of approximately 130,000

[0165] PVA 56-98 has an MW of approximately 150,000

[0166] PVA 28-99 has an MW of approximately 160,000

[0167] Parteck ® The PVA of grade MXP 4-88 has an MW of 32,000 and Parteck ® The PVA of grade MXP 3-82 has an MW of 47,000. In these grade names, the first number gives the apparent viscosity (mPa • s) of a 4% aqueous solution at 20 °C and the second number gives the degree of hydrolysis (%). Thus, Parteck ® MXP 3 - 82 shows a viscosity of 3 mPa • S and a degree of hydrolysis of 82%, while Parteck ® MXP 4 - 88 shows a viscosity of 4 mPa • s and a degree of hydrolysis of 88%.

[0168] To provide sufficient cohesion to the active agent-containing layer, a certain amount of film-forming agent should be included. Thus, in some preferred embodiments, the active agent-containing layer comprises at least 10 wt-%, at least 13 wt-% or at least 15 wt-% of the film-forming agent, less than or equal to 75 wt-%, less than or equal to 50 wt-% or less than or equal to 30 wt-% of the film-forming agent, and / or 10 wt-% to 75 wt-%, 13 wt-% to 50 wt-% or 15 wt-% to 30 wt-% of the film-forming agent.

[0169] However, the amount of the film-forming agent should be adjusted according to the presence of other excipients in the formulation. As will be outlined in the next section, the above figures take into account the possible presence of a certain amount of plasticizer.

[0170] In other embodiments, the active agent-containing layer does not contain a plasticizer and comprises at least 50 wt-%, at least 60 wt-% or at least 65 wt-% of the film-forming agent, less than or equal to 85 wt-%, less than or equal to 75 wt-% or less than or equal to 70 wt-% of the film-forming agent, and / or 50 wt-% to 85 wt-%, 60 wt-% to 75 wt-% or 65 wt-% to 70 wt-% of the film-forming agent. The active agent-containing layer may also consist essentially of the active agent and the film-forming agent.

[0171] The film-forming agent as disclosed above may be present as the film-forming agent in the active agent-containing layer, but may also be included in any other (optional) layer or optional overcoat layer.

[0172] Plasticizer

[0173] The active agent-containing layer of the oral mucosal delivery system according to the present invention comprises remimazolam, its pharmaceutically acceptable salts or any other form as the active agent and a film-forming agent. Depending on factors such as the type and amount of the film-forming agent, the form and amount of the active agent, and other components of the formulation or manufacturing method, incorporation of a plasticizer may be beneficial. The plasticizer will provide greater flexibility to the active agent-containing layer and will reduce the risk of the layer becoming brittle over time. The plasticizer can also improve the tactile sensation of the oral mucosal delivery system when applied to the oral mucosa, i.e., provide a good feeling in the mouth.

[0174] Thus, in some embodiments of the present invention, the active agent-containing layer may also comprise a plasticizer.

[0175] In other words, in some specific embodiments, the active agent-containing layer comprises:

[0176] i) Remimazolam, its pharmaceutically acceptable salts or any other form as the active agent,

[0177] ii) A film-forming agent, and

[0178] iii) Plasticizer.

[0179] The plasticizer is selected from the group consisting of linear or branched, saturated or unsaturated alcohols having 6 to 20 carbon atoms, triglycerides, polyethylene glycols, or polyvinyl alcohol-polyethylene glycol graft copolymers. Particularly preferred are polyethylene glycols and polyvinyl alcohol-polyethylene glycol graft copolymers. In a further preferred embodiment, the polyvinyl alcohol-polyethylene glycol graft copolymer is used as the plasticizer, and the film-forming agent is preferably polyvinyl alcohol (grades 4-88 and 40-88) having a molecular weight of 31,000 or 205,000 or any mixture thereof.

[0180] In certain embodiments of the present invention, the active agent-containing layer comprises at least 5 wt-%, at least 15 wt-%, or at least 20 wt-% of the plasticizer, less than or equal to 50 wt-%, less than or equal to 40 wt-%, or less than or equal to 35 wt-% of the plasticizer, and / or 5 wt-% to 50 wt-%, 15 wt-% to 40 wt-%, or 20 wt-% to 35 wt-% of the plasticizer.

[0181] To provide a good balance between the amounts of the film-forming agent and the plasticizer (which, on the one hand, provides the matrix of the active agent-containing layer) and the amount of the active agent, it is useful to keep the total amount of the film-forming agent and the plasticizer within a certain range or to provide the two components in a specific ratio.

[0182] Thus, in some specific embodiments of the present invention, the active agent-containing layer comprises the total amount of the film-forming agent and the plasticizer, wherein the total amount is at least 30 wt-%, at least 35 wt-%, or at least 40 wt-% of the active agent-containing layer, less than or equal to 80 wt-%, less than or equal to 60 wt-%, or less than or equal to 45 wt-% of the active agent-containing layer, and / or 30 wt-% to 80 wt-%, 35 wt-% to 60 wt-%, or 40 wt-% to 45 wt-% of the active agent-containing layer. In additional specific embodiments, the active agent-containing layer comprises a plasticizer, wherein the film-forming agent is polyvinyl alcohol, and wherein the ratio of polyvinyl alcohol to the plasticizer is at least 20:80, or less than or equal to 50:50, or 20:80 to 50:50, or about 25:75 or about 40:60.

[0183] In certain embodiments of the present invention, the active agent-containing layer does not contain a plasticizer and contains at least 50 wt-%, at least 60 wt-%, or at least 65 wt-% of a film-forming agent, less than or equal to 85 wt-%, less than or equal to 75 wt-%, or less than or equal to 70 wt-% of a film-forming agent, and / or 50 wt-% to 85 wt-%, 60 wt-% to 75 wt-%, or 65 wt-% to 70 wt-% of a film-forming agent, and / or the active agent-containing layer consists essentially of (i) an active agent and (ii) a film-forming agent.

[0184] Other excipients

[0185] The active agent-containing layer of the oral mucosa delivery system according to the present invention may contain other excipients common in the art, such as fatty acids, sweeteners, flavoring agents, coloring agents, penetration enhancers, solubilizers, plasticizers, wetting agents, disintegrants, emulsifiers, antioxidants, stabilizers, buffering agents, and other film-forming agents.

[0186] In certain embodiments, the active agent-containing layer further contains one or more excipients selected from the group consisting of sweeteners, flavoring agents, antioxidants, and pH regulators. As outlined above, the active agent is preferably present in the form of an acid addition salt of benzenesulfonate or toluenesulfonate, which may provide the desired pH value. Therefore, the presence of a pH regulator does not always seem necessary, i.e., in certain embodiments, the active agent-containing layer does not contain a pH regulator.

[0187] The excipients may be present in the active agent-containing layer in an amount of 0.001 wt-% to 15 wt-% of the active agent-containing layer per excipient. In one embodiment, the total amount of all excipients is 0.001 wt-% to 25 wt-% of the active agent-containing layer. Hereinafter, when a range of the amount of a specified additive is given, such a range refers to the amount of each individual additive.

[0188] It should be noted that in pharmaceutical preparations, the preparation components are classified according to their physicochemical and physiological properties and according to their functions. This particularly means that substances or compounds belonging to one class do not exclude being preparation components belonging to another class. In such cases, for calculations in patent claims (e.g., for determining weight percentages, ratios, etc.), such substances or compounds can preferably be assigned to the appropriate class first mentioned in the corresponding claim. For example, a polymer such as a polyvinyl alcohol-polyethylene glycol graft copolymer can be a plasticizer or a film-forming agent. Some substances can be, for example, typical softeners but at the same time act as permeation enhancers. A person skilled in the art can determine to which class or classes of preparation components a certain substance or compound belongs based on their common general knowledge. Details regarding excipients and additives are provided below, however, these details should not be understood as being exclusive. Other substances not explicitly listed in this specification can also be used according to the present invention, and substances and / or compounds specifically listed for one class of preparation components do not exclude being used as another class of preparation components in the context of the present invention.

[0189] Substances capable of masking or modifying the taste, or which can otherwise mitigate any potential unpleasant effects of remimazolam, are particularly preferably used as excipients.

[0190] Thus, in certain preferred embodiments, the active agent-containing layer further comprises one or more excipients selected from the group consisting of sweeteners and flavoring agents.

[0191] In certain preferred embodiments, the active agent-containing layer comprises one or more natural or artificial sweeteners, optionally selected from the group consisting of: sucrose, glucose, fructose, sorbitol, mannitol, isomalt, maltitol, lactitol, xylitol, erythritol, sucralose, acesulfame potassium, N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-α-L-aspartyl]-L-phenylalanine 1-methyl ester (advantame), N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester (neotame), aspartame, cyclamate, neohesperidin, neotame, steviol glycosides, thaumatine, and sodium saccharin. Preferably, the sweetener is selected from the group consisting of: sucralose, acesulfame potassium, advantame, N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester (neotame), aspartame, thaumatine, and particularly preferably, the sweetener is N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester (neotame) or N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-α-L-aspartyl]-L-phenylalanine 1-methyl ester (advantame) or a mixture thereof. In such embodiments, i.e., where the active agent-containing layer comprises one or more natural or artificial sweeteners, the active agent-containing layer may comprise at least 0.05 wt-% or at least 0.5 wt-% of the sweetener, less than or equal to 2 wt-% or less than or equal to 1 wt-% of the sweetener, and / or from 0.05 wt-% to 2 wt-% or from 0.5 wt-% to 1 wt-% of the sweetener.

[0192] In still further preferred embodiments, the active agent-containing layer comprises one or more natural or artificial flavoring agents selected from the group consisting of vanillin, methyl salicylate, menthol, manzanate, diacetyl acetate, acetyl propionyl acetate, acetoin acetate, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl sebacate, allyl hexanoate, ethyl maltol, 2,4-dithiolane, ethyl vanillin, and eucalyptol, and flavoring compositions such as mint essence and MANE essences such as MANE orange essence or MANE tutti frutti essence. Flavoring compositions such as MANE orange essence, which is a combination of linalool, α-pinene, citral, δ-3-carene, β-pinene, and myrcene, and MANE tutti frutti essence, which is a combination of geranyl acetate, vanillin, limonene, and allyl hexanoate, are preferred. In such embodiments, i.e., where the active agent-containing layer comprises one or more flavoring agents, the active agent-containing layer may comprise at least 0.05 wt-% or at least 0.5 wt-% of the flavoring agent, less than or equal to 5 wt-% or less than or equal to 2 wt-% of the flavoring agent, and / or from 0.05 wt-% to 5 wt-% or from 0.5 wt-% to 2 wt-% of the flavoring agent.

[0193] Suitable flavoring agents are also commercially available from Mane, and any of those flavoring agents identified by notes such as apple, caramel, chocolate, lemon, mint, etc. can be used as the flavoring agent in the present invention.

[0194] As described above, the active agent-containing layer according to the present invention may comprise a pH regulator. The pH regulator may be selected, for example, from monobasic and polybasic acids, monoamines, diamines and triamines, buffer solutions having mixtures of weak acids and their conjugate bases, amine derivatives, inorganic base derivatives, and polymers having basic and acidic functional groups, respectively. The active agent-containing layer according to the present invention may also comprise an antioxidant. Suitable antioxidants are, for example, ascorbic acid, α-tocopherol, ascorbyl palmitate, and sodium metabisulfite.

[0195] Pharmaceutical product

[0196] As described above, according to one aspect, the present invention relates to a pharmaceutical product comprising a package and one or more unit doses of an oral mucosal delivery system.

[0197] In certain embodiments, the packaging is in the form of a sachet. The sachet can be made of a multilayer film material that includes an outer-facing paper layer, an intermediate polyethylene layer, and an inner-facing aluminum layer. To protect the contained unit dose of the oral mucosal delivery system from, for example, moisture or oxygen, the sachet can be sealed with a sealant. In certain embodiments, the sealant is selected from the group consisting of: ethylene copolymers (modified ionomers, which can be commercially obtained, for example, as Surlyn®), or polyethylene terephthalate copolymers and cycloolefin copolymers.

[0198] In certain embodiments, as a further protective measure against the related degradation of moisture and the active agent, the sachet is filled with nitrogen. The sachet can also contain one or more desiccants, but does not necessarily contain desiccants. In certain embodiments, the desiccant includes silica gel, 4Å molecular sieve, and / or 4Å zeolite molecular sieve as desiccants, and / or is in the form of an adhesive film. The adhesive film can be attached to the inner-facing side of the sachet. Such a sticky desiccant can be commercially obtained as DesiMax.

[0199] In other embodiments, the pharmaceutical product includes a folded polyethylene terephthalate foil within the primary packaging, where one or more unit doses of the oral mucosal delivery system are surrounded by the folded polyethylene terephthalate foil, and the folded polyethylene terephthalate foil is folded up and protects the unit dose from further contact with the packaging. In this case, the sachet can contain one or more desiccants in the form of an adhesive film, and the adhesive film is attached to the outer-facing side of the folded polyethylene terephthalate foil to avoid contact with the oral mucosal delivery system. Such a configuration is shown in Figure 1 In other embodiments, the pharmaceutical product does not include such a folded polyethylene terephthalate foil.

[0200] Methods of producing sedation and other methods

[0201] According to a specific aspect of the present invention, the oral mucosal delivery system according to the present invention is used to produce sedation, hypnosis, anti-anxiety, muscle relaxation, treat convulsions, or induce amnesia for perioperative events. According to another aspect, the present invention relates to a method of producing sedation, hypnosis, anti-anxiety, muscle relaxation, treating convulsions, or inducing amnesia for perioperative events, wherein the oral mucosal delivery system is administered to a subject, and preferably a human patient. In yet another aspect, the present invention relates to the use of the oral mucosal delivery system in the preparation of a medicament for producing sedation, hypnosis, anti-anxiety, muscle relaxation, treating convulsions, or inducing amnesia for perioperative events.

[0202] As mentioned above, remimazolam is a very promising ultra-short-acting sedative that has been approved for both procedural sedation and general anesthesia.

[0203] Thus, in certain embodiments, the sedation as mentioned in the different aspects above is procedural sedation, such as sedation for dental procedures or for diagnostic procedures, preoperative sedation, and / or conscious sedation. Sedation can be induced before and / or during various procedures (such as endoscopy, colonoscopy, or other diagnostic or surgical procedures). As used herein, "procedural sedation" includes, but is not limited to, sedation during the performance of endoscopy (preferably upper gastrointestinal endoscopy or colonoscopy), dental procedures, diagnostic procedures, imaging, or brief unpleasant procedures (such as, for example, changing a wound dressing or manipulating a catheter, such as removing a central catheter).

[0204] In terms of the sedative effect, in certain embodiments, mild sedation, moderate sedation, deep sedation, or general anesthesia is achieved. In certain embodiments, the sedation or general anesthesia achieved has a duration of 5 to 30 minutes, 8 to 20 minutes, or 10 to 15 minutes.

[0205] To achieve sedation, in certain embodiments, the oral mucosal delivery system is administered by applying an active agent-containing layer to the mucosa of the oral cavity of a human patient, and particularly to the buccal mucosa, sublingual mucosa, gingival mucosa, or palatal mucosa, and maintaining it on the mucosa until it dissolves.

[0206] As outlined above, transmucosal delivery avoids the first-pass effect, and thus, the oral mucosal delivery system according to the present invention has a lower risk of any unintended effects (such as those due to hepatic metabolism) and is advantageous in terms of patient acceptability compared to IV administration. Therefore, there is no limitation on the patient population. The subject can be a human patient with or without liver injury, including the elderly and children.

[0207] Manufacturing method

[0208] The present invention further relates to a method for manufacturing an active agent-containing layer for an oral mucosal delivery system, and the corresponding active agent-containing layer and the corresponding oral mucosal delivery system.

[0209] According to the present invention, the method for manufacturing the active agent-containing layer comprises the following steps:

[0210] i. Combining at least (i) remimazolam, its pharmaceutically acceptable salts, or any other form as the active agent with (ii) a film-forming agent to obtain a mixture; and

[0211] ii. Forming the active agent-containing layer.

[0212] In such a method, suitable film-forming agents are the same as those mentioned previously.

[0213] Step ii) of forming the active agent-containing layer can be carried out by any known method. In certain embodiments, the method is a hot melt method, a coating method or a foam forming method.

[0214] The hot melt method can be a hot melt extrusion method or a vacuum compression molding method, wherein:

[0215] The hot melt extrusion method comprises the following steps ii):

[0216] a. Introducing a mixture containing an active agent and a film-forming agent (with or without other excipients) into an extruder;

[0217] b. Heating the mixture to at least the softening temperature of the mixture; and

[0218] c. Extruding the heated mixture containing the film-forming agent and the active agent in the form of a film to obtain the active agent-containing layer.

[0219] whereas

[0220] The vacuum compression molding method comprises the following steps ii):

[0221] a. Introducing a mixture containing an active agent and a film-forming agent (with or without excipients) into a sample chamber; and

[0222] b. Compacting the mixture while applying a vacuum and heating the mixture to at least the softening temperature of the mixture to obtain the active agent-containing layer.

[0223] On the other hand, the coating method may comprise the following steps:

[0224] i. Dispersing or dissolving the active agent in a solution of a film-forming agent with or without other excipients to obtain a coating composition, and

[0225] ii. a. Coating the coating composition on a coating substrate; and

[0226] b. Drying the laminated section in an oven to obtain the active agent-containing layer in the form of a flexible single-piece film.

[0227] Finally, the foam forming method may comprise the following steps:

[0228] i. Dispersing or dissolving the active agent in an aqueous solution of the film-forming agent with or without other excipients to obtain a coating composition, and

[0229] ii. a. Foaming the coating composition to obtain a foam coating composition;

[0230] b. Coating the foam coating composition on a coating substrate; and

[0231] c. Dry the laminated section in an oven to obtain the active agent-containing layer in the form of a foam.

[0232] In such an embodiment, foaming can be carried out by introducing nitrogen gas into the composition while stirring. In such an embodiment, stirring can be carried out particularly at a high speed, and / or a foaming device including a foaming head with a dispersion unit is used.

[0233] According to another aspect, the present invention relates to a method for manufacturing an oral mucosa delivery system, the oral mucosa delivery system including an active agent-containing layer, the active agent-containing layer comprising (i) remimazolam benzenesulfonate, a pharmaceutically acceptable salt thereof or any other form as the active agent, and (ii) a film-forming agent, the manufacturing method comprising the following steps:

[0234] i. Combine at least the active agent and the film-forming agent to obtain a mixture; and

[0235] ii. Form the active agent-containing layer.

[0236] According to another aspect, the present invention relates to an oral mucosa delivery system that can be obtained by such a method.

[0237] According to certain embodiments, one or more unit doses of the oral mucosa delivery system can be packaged in a primary package to provide a pharmaceutical product. In such an embodiment, the primary package can be in the form of a sachet as further described above. The packaging step can be carried out under a nitrogen atmosphere to obtain a nitrogen-filled sachet that prevents environmental moisture.

[0238] Examples

[0239] The present invention will now be described more fully with reference to the accompanying examples. However, it should be understood that the following description is only illustrative and should not be construed as a limitation of the present invention in any way. The numerical values regarding the amounts of ingredients or areal weights in the composition provided in the examples may vary slightly due to manufacturing variability.

[0240] Examples 1A - 1H

[0241] Preparation of the coating composition (active agent-containing layer) and coating of the coating composition

[0242] The formulations of Examples 1a - 1h are summarized in Tables 1 - 6. In these tables and hereinafter, "Amt [g]" refers to the amount (grams). The active agent remimazolam benzenesulfonate was ground in a mortar.

[0243] For Example 1a, load remimazolam besylate (also referred to as RMZ hereinafter) into a beaker. Then add purified water and stir the mixture at 1000 rpm for 1 minute. Then add PEG300 and stir it again at 1000 rpm for 1 minute. Add Kollicoat while stirring at 1000 - 2000 rpm ® Protect. After the last addition, continue to stir at 2000 rpm for 5 minutes.

[0244] Coat the resulting active agent-containing foam coating composition on polyethylene terephthalate (100 µm thickness) and dry it at 70 °C for 45 minutes. The coating thickness gives an area weight of 232 g / m².

[0245] Table 1 Example 1a - Foam (API dispersion)

[0246]

[0247] For Example 1b, load remimazolam besylate into a beaker, and add PEG 300 and 199.61 g of purified water. Vortex the beaker, then add a solution of 26.2 g of 14.48 g Methocel E3LV and 8.07 g Methocel E50LV in 127.55 g of purified water. Stir the mixture at 1000 rpm for 10 minutes, then at 2000 rpm for 5 minutes, and then at 100 rpm for 5 minutes.

[0248] Coat the resulting active agent-containing coating composition on polyethylene terephthalate (100 µm thickness) and dry it at 70 °C for 45 minutes. The coating thickness gives an area weight of 103 g / m².

[0249] Table 2 Example 1b - Film (API dispersion)

[0250]

[0251] For Example 1c, load remimazolam besylate into a beaker, and add PEG 300 and a solution of 87.7 g of 700g PVA 4 - 88 in 1300.1 g of purified water. Stir the mixture until remimazolam besylate is dispersed in the mixture and then foam is formed.

[0252] Coat the resulting active agent-containing foam coating composition on Polyslik 111 / 80 (one-side silicated) and dry it at 70 °C for 15 minutes. The coating thickness gives an area weight of 181 g / m².

[0253] Table 3 Example 1c - Foam (API dispersion)

[0254]

[0255] For Example 1d, preheat the heating mantle to 150 °C. Charge Polyox N10 into a beaker and place the beaker in the preheated heating mantle. Stir Polyox N10 at 57 rpm for 45 minutes, then at 150 rpm for 65 minutes, and then at 250 rpm for 130 minutes. The temperature of Polyox N10 is 136 °C. Add remimazolam besylate while stirring at 300 rpm. Continue stirring at 520 rpm for 15 minutes. The temperature is 135 °C at this time.

[0256] Coat the resulting active agent-containing coating composition onto polyethylene terephthalate (100 μm thickness) using a hot melt coater, where both the top roll and the bottom roll are heated to 150 °C and the gap width is 405 mm. The coating thickness gives an areal weight of 355 g / m².

[0257] Table 4 Example 1d - Melt (API dispersion)

[0258]

[0259] For Examples 1e and 1g, charge purified water into a beaker and add the film-forming agent (Kollidon VA64 or Soluplus) while stirring at 1500 rpm. Continue stirring at 250 rpm for 1.25 hours and then let it swell overnight. The next day, charge remimazolam besylate into the beaker. Add PEG 300 and then mix manually. Then, add the swollen mixture of the film-forming agent in purified water, and subsequently stir the newly formed mixture at 250 rpm for 45 minutes.

[0260] Coat the active agent-containing coating composition onto Polyslik (silylated on one side) and dry it at 70 °C for 25 minutes. The coating thickness gives an areal weight of 244 g / m² (1e) or 123 g / m² (1g).

[0261] For Examples 1f and 1h, charge remimazolam besylate into a beaker and add methanol until remimazolam besylate dissolves. Then add the film-forming agent (Kollidon VA64 or Soluplus) while stirring, and then add PEG 300 to the mixture.

[0262] Coat the active agent-containing coating composition onto Polyslik 111 / 80 (silylated on one side) and dry it at 70 °C for 30 minutes. The coating thickness gives an areal weight of 63 g / m².

[0263] Table 5 Examples 1e and 1f - Films (API dispersion)

[0264]

[0265] Table 6 Examples 1g and 1h - Films (API dispersion)

[0266]

[0267] Preparation of oral mucosa delivery systems (relating to all examples)

[0268] Individual oral mucosa delivery systems were then punched out from the active agent-containing layer. The oral mucosa delivery systems were then sealed into moisture-proof and vapor-proof Surlyn® pouches. For Example 1D, the oral mucosa delivery systems were sealed into Surlyn® pouches together with two absorbent patches (DesiMax).

[0269] Stability study for evaluating the stability of remimazolam besylate in different formulations

[0270] The oral mucosa delivery systems prepared according to Examples 1a - 1h were sealed in Surlyn® packaging materials and stored at 25°C / 60% RH and 40°C / 75% RH for 2, 4, and 8 weeks. The samples were analyzed to obtain a rapid stability assessment of potential API-excipient-solvent interactions that could lead to any instability and thus to the formation of new impurities and / or degradation products (e.g., by hydrolysis). Tests for remimazolam content and degradation products were carried out after 2 weeks, 4 weeks, and 8 weeks of storage.

[0271] At the specified time intervals shown in Table 7, samples were collected and assayed for content and tested for remimazolam degradation products. Thus, 20.0 mL of diluent (H2O / ACN 3:1 (v / v)) was added to the corresponding samples and stirred for approximately 45 minutes. Subsequently, aliquots of the resulting sample solutions were centrifuged at 10,000 rpm for 10 minutes (at approximately 5°C) and analyzed by a validated HPLC-UV method. Drug-free matrix samples served as references to determine potential interferences from the excipients used. The results are shown in Table 8.

[0272]

[0273] 1 Analysis was carried out only when degradation was shown in the 40°C samples.

[0274] Table 8

[0275]

[0276] n.t. Not further investigated due to high degradation

[0277] In all formulations, different amounts of degradation products CNS7054 (hydrolysis) and CNS7084 were measured. In addition, different amounts of unknown impurities were detected in all formulations.

[0278] For the PVA 4-88-based foam (Example 1c) and Polyox™ N10-based melt (Example 1d) formulations, the amounts of degradation products were within acceptable limits, but unknown impurities were detected in both formulations. For all other methods, high degradation (especially hydrolysis) and unknown impurities were detected.

[0279] In vivo studies of Examples 1c and 1d using Göttingen minipigs

[0280] To evaluate the pharmacokinetic characteristics and effects of an oral mucosal delivery system containing remimazolam besylate administered buccally, in vivo experiments were conducted using Göttingen minipigs (female, approximately 3 months old, weighing 7 kg at the start of the study). Three minipigs were used. Each animal received a single oral mucosal delivery system of Example 1c (foam) and 1d (melt) prepared as described above, with a nominal amount of 20 mg remimazolam (formulated as 27.2 mg nominal remimazolam besylate) (except for animal No. 3 in Phase 1, where only half of each type of oral mucosal delivery system was placed on each side). The oral mucosal delivery system foam was cut into two pieces to fit the buccal mucosa. The groups, dose levels, and animal numbers are summarized in Table 9.

[0281] Table 9

[0282]

[0283] The formulations of the placebo systems corresponding to Example 1c (foam) and 1d (melt) are summarized in Table 10 below. The coating compositions were prepared as described above for Examples 1c and 1d.

[0284] Table 10

[0285]

[0286] Doses were administered by buccal administration (oral mucosal delivery system; melt and foam) or IV administration (10 mg remimazolam, formulated as remimazolam besylate) according to the treatment regimen shown in Table 9. The intervals between dosing times were at least 48 hours to allow for proper washout. Treatment using the oral mucosal delivery system was conducted as follows:

[0287] 1. Anesthetize the animals with isoflurane via a face mask to obtain a sufficient depth of anesthesia, which helps to place the oral mucosal delivery system without applying pressure to the animals. The duration and concentration of isoflurane anesthesia are similar for all animals.

[0288] 2. Place the oral mucosal delivery system on the buccal mucosa. In the first stage, apply a small amount of saline to the mucosa to facilitate a single dissolution process.

[0289] 3. Close the mouth of the minipig for 1 - 2 minutes and then open it to check whether the oral mucosal delivery system is completely dissolved. If the oral mucosal delivery system is not dissolved, conduct further checks every 1 - 2 minutes as needed.

[0290] 4. Once the oral mucosal delivery system is dissolved, discontinue the isoflurane treatment.

[0291] To evaluate bioavailability, the animals also received a single intravenous (IV) dose. The IV dose volume was administered as a bolus over an approximately 1 - minute period.

[0292] The RMZ IV dose formulation was prepared in a glass container. To prepare the stated formulation (stock solution) at a nominal 5 mg / mL, the drug product vial (50 mg of RZM powder) was reconstituted with 10 mL of 0.9% w / v sodium chloride solution. The reconstituted solution of RMZ was clear and colorless to slightly yellow. The reconstituted RMZ drug product should be used within 24 hours.

[0293] No local reaction was observed at the administration site 90 minutes after dosing.

[0294] Monitor and record the reflexes and depth of sedation every 5 minutes from the end of isoflurane use until the animals are fully awake. In the first stage, record the time from induction to complete recovery from isoflurane sedation. The sedation depth scores are shown in Table 11 below.

[0295] Table 11

[0296]

[0297] Monitor the reflexes and depth of anesthesia every 5 minutes for at least 1 hour, and the depth of sedation is characterized as listed in Table 11. The monitoring data for different animals are shown in Table 12, and the sedation curves are illustrated in Figures 2a to 2c . In the first stage, when the animals received the placebo, only the effect of isoflurane gradually disappeared within 5 - 10 minutes. Therefore, all sedation observed at 10 minutes was considered to be related to the test article.

[0298] Table 12

[0299]

[0300] For IV administration, the effect of the test article directly replaced isoflurane, i.e., no decrease in sedation was observed, followed by an increase. For the hot melt buccal mucosal delivery system, a high variability among animals was observed. The effect was observed in two of the three animals, as animal No. 2 did not show sedation 10 minutes later (i.e., by the end of the isoflurane effect). In the two animals showing RMZ-related effects, the maximum sedation scores observed were 1 and 3, and complete recovery was not observed until 35 minutes and 60 minutes, respectively. For the foam buccal mucosal delivery system, less variability among animals was observed compared to the hot melt variant. The effect was observed in all three animals, with the highest score reaching 2 in two animals and 1 in one animal. Complete recovery from the RMZ-related effect was not observed in the three animals until 35, 40, and 60 minutes after placement of the buccal mucosal delivery system.

[0301] Blood samples were collected from all animals after each administration in Phases 2 - 4. Blood samples were collected at 8 time points after application of the buccal mucosal delivery system. Samples were collected at the following time points: before treatment, and 2, 5, 10, 20, 40, 60, and 90 minutes after treatment.

[0302] The concentrations of RMZ and CNS7054 in minipig plasma were determined using validated liquid - liquid extraction followed by LC - MS / MS. All samples collected before the start of treatment were measured to be below the limit of quantification (0.100 ng / mL).

[0303] Individual plasma concentrations are listed in Table 13 and are depicted graphically in Figures 3a to 5b . Additionally, for both RMZ and CNS7054 and after either IV administration or administration of either of the two buccal mucosal delivery system formulations, basic pharmacokinetic parameters for each individual animal such as the maximum plasma concentration (c max ), the time to reach the maximum plasma concentration (t max ), and the exposure defined as the area under the curve (AUC 0-t ) are summarized in Table 13.

[0304] Table 13

[0305]

[0306] NQ – Not quantifiable (set to 0 for PK analysis); AUC0 - t was calculated using the trapezoidal method

[0307] The two buccal mucosal delivery system formulations were similar in RMZ plasma pharmacokinetics (PK) and c maxThe aspects are roughly equivalent. The hot-melt formulation of Example 1d showed a higher variability in the PK profile of RMZ. However, this was to some extent driven by the results observed in Animal No. 1, where a higher c was reached at a later time point. max Compared with the hot-melt formulation of the oral mucosal delivery system, the foam formulation of the oral mucosal delivery system was associated with a faster release (t max : 10 - 20 minutes for the foam, compared with 20 - 40 minutes for the hot-melt) and a more uniform PK profile. However, this conclusion was based on only a small number of animals. The PK profile of the major metabolite CNS7054 of RMZ was consistent with the observations for RMZ, and the c was reached slightly faster with the foam formulation of the oral mucosal delivery system compared with the hot-melt formulation of the oral mucosal delivery system. max This, together with a slightly higher c max reached, led to a trend of higher metabolite exposure when the foam formulation of the oral mucosal delivery system was administered compared with when the hot-melt formulation of the oral mucosal delivery system was administered.

[0308] To evaluate the bioavailability (BA), the dose-normalized c max (c max / D) and dose-normalized AUC (AUC 0-t / D) of two formulations of the oral mucosal delivery system of RMZ were determined. The results are summarized in Table 14.

[0309] Table 14

[0310]

[0311] The range of BA based on c max for the hot-melt oral mucosal delivery system formulation of Example 1d was between 6% - 25%, and for the foam oral mucosal delivery system formulation of Example 1c was between 9% - 25%. The corresponding results for BA based on AUC were 16% - 51% and 24% - 41%. Although the average exposure parameters of the two RMZ oral mucosal delivery system formulations were similar, the higher variability observed after administering the hot-melt oral mucosal delivery system formulation of Example 1d may indicate a lower adhesion potential to the oral mucosa, which may cause the film to detach from the application site and occasionally and unpredictably swallow the drug. Therefore, a decrease in BA can be observed due to the strong first-pass elimination of the swallowed dose portion. After administering the foam formulation of the oral mucosal delivery system of Example 1c, the relative exposure to CNS7054 was generally higher, which was consistent with faster absorption compared with the hot-melt formulation of the oral mucosal delivery system of Example 1d. Taken together, the PK results showed that remimazolam had a very promising bioavailability (BA) when administered as an oral mucosal delivery system.

[0312] Example 2A - 2B

[0313] Preparation of the Coating Composition (Including the Active Agent Layer) and Coating of the Coating Composition

[0314] The formulations of Examples 2a - 2b are summarized in Table 15.

[0315] For Example 2a, remimazolam besylate and purified water were charged into a beaker. The mixture was stirred manually until homogeneous. Then Kollicoat IR was added, and the mixture was stirred manually again until homogeneous. PVA 40 - 88 and purified water were added to the mixture, and the mixture was stirred manually again until homogeneous, then stirred at 220 rpm for 50 minutes, and the mixture was foamed by stirring at 2000 rpm for 4 minutes.

[0316] The resulting active agent - containing composition was coated on Polyslik 111 / 80 and dried at 70 °C for 25 minutes.

[0317] For Example 2b, ascorbic acid, sucralose, sodium saccharin and purified water were charged into a beaker. The mixture was stirred until all sweeteners were dissolved, then remimazolam besylate was added. The mixture was stirred manually until homogeneous, then Kollicoat IR was added and stirred manually until homogeneous. Then, a mixture of PVA 40 - 88 and purified water was added, and the composition was stirred manually until homogeneous, then stirred at 220 rpm for 50 minutes, and the mixture was foamed by stirring at 2000 rpm for 4 minutes.

[0318] The resulting active agent - containing composition was coated on Polyslik 111 / 80 and dried at 70 °C for 25 minutes.

[0319] Table 15

[0320]

[0321] Preparation of the Oral Mucosal Delivery System (Relating to Examples 2a and 2b)

[0322] Then individual oral mucosal delivery systems were punched out from the active agent - containing layer. Then the oral mucosal delivery systems were sealed into waterproof and vapor - permeable Surlyn® pouches, either without a water absorbent patch, or together with two water absorbent patches (DesiMax).

[0323] Stability Study for Evaluating the Stability of Remimazolam Besylate in Different Formulations

[0324] This stress stability study for Examples 2a and 2b was conducted at 60 °C, and the measurement time points were at 2 weeks (2W), 6 weeks (6W), and 9 weeks (9W). According to the estimation of Arrhenius kinetics, 9W was set as the real-time time extrapolated to 2 years.

[0325] For each measurement time point, a total of 9 samples were provided, including 3 samples for determining the water content by the Karl Fischer method and 6 samples for analyzing the degradation products and content determination (n = 3 for testing), with 3 samples as spares.

[0326] The results of the stability studies for Examples 2a and 2b are shown in Tables 16 and 17.

[0327] Table 16

[0328]

[0329] *The initial value was determined without the water absorbent.

[0330] **Testing was only continued for the samples containing the water absorbent.

[0331] Table 17

[0332]

[0333] *The initial value was determined without the water absorbent.

[0334] **Stopped due to high degradation.

[0335] n.t. = not tested

[0336] The stress stability study shows that Example 2a (the base formulation without sweeteners and antioxidants) produced by the water-based production method is only stable in terms of degradation when bagged with a water absorbent. Assuming Arrhenius kinetics; all samples of the base formulation bagged with a water absorbent can potentially be stable at 25 °C for at least 2 years.

[0337] This assumption can be supported by the results obtained from samples stored at 25 °C for more than 5 months and 6 months, as the levels of the degradation products CNS 7054 (in samples without the water absorbent) and CNS 7084 are known to be lower than those obtained from equivalent samples stored at 60 °C for 2 weeks (extrapolated according to Arrhenius). In this regard, it is expected that the degradation curve of samples stored with a water absorbent at 25 °C for 2 years will show fewer degradation products than implied by the 9-week / 60 °C data in this stress stability study. However, it is necessary to show the official shelf life of the stability study (e.g., storage temperatures of 25 °C and 40 °C according to ICH) to determine the specific shelf life of each formulation.

[0338] At relevant concentrations, for different unknown impurities that are known to be partly formed by oxidation reactions and thus temperature-induced, lower degradation curves are expected under long-term conditions compared to equivalent sampling time points at 60 °C.

[0339] Example 2b showed high degradation after 2 weeks at 60 °C for both conditions (with and without desiccant), using sucralose, sodium saccharin, and ascorbic acid as sweetener and antioxidant, respectively. The high degradation was accompanied by a very distinct and intense color change from brown to dark beige. Although CNS 7054 was very low and the formation of unknown impurities was completely suppressed in the samples with desiccant after 2 weeks, the concentration of CNS 7084 was significantly higher, which may be related to the incompatibility of the sweetener and / or antioxidant contained. The effect of the antioxidant ascorbic acid could not be demonstrated with Example 2b.

[0340] Mucosal Permeation Study

[0341] To study the potential effect of pH on permeation, a permeation study was conducted to evaluate the pH-dependent permeation of remimazolam besylate (RMZ besylate) through the mucosa. In the second run, the performance of the remimazolam lyophilized product (RMZ besylate) compared to the oral mucosal delivery system was also evaluated.

[0342] The permeation settings are summarized in Table 18. The samples used for permeation run 1 are defined in Table 19.

[0343] Table 18

[0344]

[0345] Table 19

[0346]

[0347] According to the OECD guidelines (adopted on April 13, 2004 ©), the permeation amount and the corresponding mucosal permeation rate of the oral mucosal delivery system prepared according to Example 2a were determined by in vitro experiments using porcine mucosa (esophageal mucosa) with a thickness of 400 μm. The donor solution was prepared by dissolving the sample film of Example 2a with a size of 5.75 cm 2 in 5 ml of artificial saliva or 5 ml of 0.9% NaCl. Remimazolam besylate was dissolved in artificial saliva such that the applied dose of RMZ was equivalent to the oral mucosal delivery system containing 50 mg of remimazolam in 500 μL of medium, and the pH of the mixture was adjusted as indicated in Table 19. The pH was measured using a pH electrode. The permeation donor solution was directly applied to the mucosa (diffusion area of 4.524 cm 2)。The permeation of remimazolam in the receptor medium (phosphate buffer solution pH 7.4) was measured at a temperature of 37 °C ± 1 °C, and the corresponding mucosal permeation rate was calculated. The results are shown in Table 20 and Figure 6a in.

[0348] Table 20

[0349]

[0350] In the permeation experiment of RMZ dissolved in artificial saliva with different pH values (pH 2, 3, 4.5, 6), an obvious dependence between solubility and pH value was confirmed, which indicates that the decrease of pH leads to the increase of permeability. At pH 4.5 and pH 6, due to the low solubility of RMZ, the permeation rate is poor.

[0351] At pH 2, RMZ was completely dissolved. In this run, due to the impairment of the barrier function of one pore caused by mucosal contraction, only 2 out of 3 pores could be analyzed. The permeation values of the remaining samples differed greatly from each other, so it can be assumed that the barrier function of the highly permeable mucosa was also impaired. From the results, it is currently impossible to determine whether a significant decrease in pH leads to an improvement in permeation. However, due to the harsh acidic pH 2, adjusting the pH to this low value in the oral mucosal delivery system sample is disadvantageous in the in vivo situation.

[0352] Due to the high variability in permeation run 1 (n = 3), a second permeation experiment was conducted with more repetitions (n = 6) to expand the data base. The permeation settings are summarized in Table 21. The samples used are defined in Table 15. The example 2a and the lyophilized product were dissolved in artificial saliva and 0.9% NaCl, respectively. Due to the pH adjustment in the lyophilized product / drug product, the resulting pH (pH 3.14 and pH 3.09) was slightly lower than that of the un - pH - adjusted example 2a (pH 3.67 and pH 3.50). The RMZ sample set at pH 3 served as a control.

[0353] Table 21

[0354]

[0355] As outlined above, the permeation amount and the corresponding mucosal permeation rate of the oral mucosal delivery system prepared according to example 2a were determined. The permeation of remimazolam in the receptor medium (phosphate buffer solution pH 7.4) was measured at a temperature of 37 °C ± 1 °C, and the corresponding mucosal permeation rate was calculated. The results are shown in Table 22 and Figure 6b in.

[0356] Table 22

[0357]

[0358] Mucosal penetration data (see Figure 6b ) showed no significant difference between Example 2a and the lyophilized drug product samples (both 0.9% NaCl and artificial saliva).

[0359] The RMZ sample at pH 3 in artificial saliva showed no significant difference from Example 2a and the lyophilized drug product samples (both 0.9% NaCl and artificial saliva).

[0360] Example 2C - 2K

[0361] Preparation of the coating composition (active agent-containing layer) and coating of the coating composition

[0362] The formulations of Examples 2c – 2j (foam preparations) are summarized in Table 24.

[0363] For Examples 2c, 2f, the corresponding sweetener and purified water were charged into a beaker. The mixture was manually stirred until the sweetener was dissolved. Remimazolam besylate was added and the mixture was manually stirred again until the mixture was homogeneous. For Example 2f, since the mixture was inhomogeneous after manual stirring, the mixture was treated twice in an ultrasonic bath for 30 seconds each time after manual stirring. Then Kollicoat IR was added, followed by manual stirring until the mixture was homogeneous. Then PVA 40 - 88 mixed with purified water was added, and the newly formed mixture was stirred until the mixture was homogeneous. The mixture was stirred at 200 rpm for 15 minutes and then foamed by stirring at 2000 rpm for 5 minutes.

[0364] The active agent-containing composition was coated on Polyslik 111 / 80 (silylated on one side) and dried at 70 °C for 25 minutes.

[0365] For Example 2c, the corresponding sweetener and purified water were charged into a beaker. The mixture was stirred at 230 rpm for 10 minutes. Remimazolam besylate was added and the mixture was stirred and mixed at 230 rpm for 5 minutes. Then Kollicoat IR was added, followed by stirring at 230 rpm for 5 minutes. Then PVA 40 - 88 mixed with purified water was added, and the newly formed mixture was manually stirred until the mixture was homogeneous. The mixture was stirred at 200 rpm for 15 minutes and then foamed by stirring at 2000 rpm for 4.5 minutes.

[0366] The active agent-containing composition was coated on Polyslik 111 / 80 (silylated on one side) and dried at 70 °C for 25 minutes.

[0367] For Example 2e, load the corresponding sweetener and purified water into a beaker. Treat the mixture in an ultrasonic bath for 10 minutes until the sweetener dissolves. Add remimazolam besylate, and manually stir the mixture, then treat the mixture in the ultrasonic bath twice, 30 seconds each time. Then add Kollicoat IR, and subsequently manually stir until the mixture is homogeneous. Add PVA 40-88 mixed with purified water, and manually stir the newly formed mixture until the mixture is homogeneous. Stir the mixture at 200 rpm for 15 minutes, and then form foam by stirring at 2000 rpm for 4.5 minutes.

[0368] Coat the active agent-containing composition on Polyslik 111 / 80 (silylated on one side) and dry at 70 °C for 25 minutes.

[0369] For Examples 2g – 2i, load the corresponding sweetener and purified water into a beaker. Manually stir the mixture, then treat in an ultrasonic bath for 10 minutes in the case of Example 2g; treat in an ultrasonic bath twice, 30 seconds each time, with manual stirring between ultrasonic treatments, in the case of Example 2h; and treat in an ultrasonic bath for 20 seconds in the case of Example 2i. Add remimazolam besylate, and manually stir the mixture, then treat the mixture in the ultrasonic bath twice, 30 seconds each time, with manual stirring between ultrasonic treatments. Then add Kollicoat IR, and subsequently manually stir until the mixture is homogeneous. Add PVA 40-88 mixed with purified water, and manually stir the newly formed mixture until the mixture is homogeneous. Stir the mixture at 200 rpm for 15 minutes, and then form foam by stirring at 2000 rpm for 4.5 minutes (2g -2h) and 3.75 minutes (2i).

[0370] Coat the active agent-containing composition on Polyslik 111 / 80 (silylated on one side) and dry at 70 °C for 25 minutes.

[0371] For Example 2j, load the corresponding sweetener and purified water into a beaker. Add remimazolam besylate, and manually stir the mixture, then treat the mixture in the ultrasonic bath twice, 30 seconds each time. Then add Kollicoat IR, and subsequently manually stir until the mixture is homogeneous. Add PVA 40-88 mixed with purified water, and manually stir the newly formed mixture until the mixture is homogeneous. Stir the mixture at 200 rpm for 15 minutes, and then form foam by stirring at 2000 rpm for 5 minutes.

[0372] Coat the active agent-containing composition on Polyslik 111 / 80 (silylated on one side) and dry at 70 °C for 25 minutes.

[0373] The formulation of Example 2k (hot melt formulation) is summarized in Table 23.

[0374] For Example 2k, Polyox N10, RMZ benzenesulfonate, neotame, and mixed fruits were loaded into a mortar and the solids were triturated to obtain a homogeneous powder. The resulting powder was weighed (171.85 mg for each system) and transferred to a vacuum compression molding (VCM) tool. The VCM tool was heated until a homogeneous hot melt oral mucosal delivery system was obtained.

[0375] Preparation of the oral mucosal delivery system (relating to all examples)

[0376] Then, the individual oral mucosal delivery systems were sealed together with two absorbent patches (DesiMax) into a moisture-proof and vapor-proof Surlyn® sachet.

[0377] Table 23

[0378]

[0379] Stability study for evaluating the stability of remimazolam benzenesulfonate in Examples 2C - 2K

[0380] Since RMZ is incompatible with one or both of the sweeteners (sucralose and sodium saccharin) in the formulation of Example 2b, a second short-term stress stability study was conducted to verify the compatible sweeteners for the RMZ - oral mucosal delivery system formulation.

[0381] The stress stability study for Examples 2C - 2K was carried out at 60 °C. The time points were measured at 2 weeks (2W) and 6 weeks (6W) for Examples 2c - 2j, and at 2 weeks (2W), 6 weeks (6W), and 9 weeks (9W) for Example 2k.

[0382] The results of the stress stability study for Examples 2c - 2j are summarized in Table 25.

[0383] The results of the stress stability study for Example 2k are summarized in Table 26.

[0384] Table 24

[0385]

[0386]

[0387] Table 25

[0388]

[0389] n.t. = not tested

[0390] *Known degradation product

[0391] **Including process / method-related impurities and isolated intermediates

[0392] Sweeteners neotame and advantame, as well as orange essence and mixed fruit essence, provide good options for further formulation development of the foam oral mucosa delivery system. The degradation curves of the corresponding foam formulations (2f, 2e, 2i, and 2j respectively) did not show significant differences from the reference formulation of Example 2a.

[0393] Table 26

[0394]

[0395] *Known degradation products

[0396] **Including process / method-related impurities and isolated intermediates

[0397] The hot melt formulation based on Polyox N80 is less stable. Example 2k shows that CNS 7084 increases over time and several unknown degradation products are formed (still at low levels after 6 weeks).

[0398] Examples 3A - 3B

[0399] Preparation of the coating composition (with active agent layer) and coating of the coating composition

[0400] The formulations of Examples 3a and 3b are summarized in Table 27.

[0401] Table 27

[0402]

[0403] For Examples 3a and 3b, load neotame and mixed fruit into a beaker, and use an Ultra Turrax IKA® T25 digital to mix the excipient with purified water at low speed until the excipient is completely dissolved. Add remimazolam besylate, and then add purified water. After manual stirring, use an Ultra Turrax KA® T25 digital to start homogenizing the mixture at low speed in an N2 atmosphere and gradually increase to 20000 rpm for 60 seconds. Add Kollicoat IR, and manually stir the mixture with a 4 - blade stirrer, then stir at low speed in an N2 atmosphere for at least 15 minutes until homogeneous. Then add PVA 40 - 88 pre - dissolved in purified water, and manually stir the mixture with a 4 - blade stirrer at low to medium speed in an N2 atmosphere for 30 minutes until the mixture is homogeneous. Then stir the mixture at 160 rpm for 25 minutes, and then stir at 100 rpm in an N2 atmosphere for 30 minutes.

[0404] To form the foam, a foam device was used, which had the following settings for Example 3a:

[0405] - Feed rate (peristaltic pump): 150 mL / min (peristaltic hose type: SPT 3350, inner diameter 6.4 mm, wall thickness 2.4 mm; calibrated with water)

[0406] - N2 - flow rate: 40 mln / min

[0407] - Rotor speed of the foaming head: 7600 rpm

[0408] To form the foam, a foam device was used, which had the following settings for Example 3b:

[0409] - Feed rate (peristaltic pump): 110 mL / min (peristaltic hose type: SPT 3350, inner diameter 6.4 mm, wall thickness 2.4 mm; calibrated with water)

[0410] - N2 - flow rate: 55 mln / min

[0411] - Rotor speed of the foaming head: 8500 rpm

[0412] The first foam stream of each foaming step was discarded. Four foaming sequences were carried out for Examples 3a and 3b. Between the foaming sequences, the foam coating composition was stirred at a low speed and the preparation container was covered.

[0413] The foam coating composition containing the active agent was coated on Polyslik 111 / 80 (silylated on one side) and dried at 70 °C for 25 minutes.

[0414] Preparation of the oral mucosa delivery system

[0415] Then, single oral mucosa delivery systems with dimensions of 1.5 cm², 3 cm², and 6 cm² were punched out from the active agent-containing layer. Then, the oral mucosa delivery systems were sealed into waterproof and vapor-permeable Surlyn® pouches as follows:

[0416] I. Place the system inside the folded inner liner

[0417] - 1.5 cm² system: 1 desiccant label (DesiMax ® ) on the outer side of the folded inner liner

[0418] - 3 cm² system: 1 desiccant label (DesiMax ® ) on the outer side of the folded inner liner

[0419] - 6 cm² system: 2 desiccant labels (DesiMax on the outer side of the folded inner liner® )

[0420] II. Insert a folded liner with an oral mucosa delivery system and one or more desiccant labels into the sachet with the opening facing downwards.

[0421] The present invention particularly relates to the following further embodiments:

[0422] 1. An oral mucosa delivery system for transmucosal delivery of an active agent, said oral mucosa delivery system comprising an active agent-containing layer, said active agent-containing layer comprising:

[0423] i) remimazolam, a pharmaceutically acceptable salt thereof or any other form as the active agent, and

[0424] ii) a film-forming agent.

[0425] 2. The oral mucosa delivery system according to embodiment 1,

[0426] wherein the active agent-containing layer comprises

[0427] at least 20 wt-%, at least 25 wt-% or at least 30 wt-% of said active agent, and / or

[0428] less than or equal to 60 wt-%, less than or equal to 55 wt-%, or less than or equal to 50 wt-% of said active agent, and / or

[0429] 20 wt-% to 60 wt-%, 25 wt-% to 55 wt-% or 30 wt-% to 50 wt-% of said active agent.

[0430] 3. The oral mucosa delivery system according to embodiment 1 or 2,

[0431] wherein the active agent-containing layer comprises

[0432] at least 4 mg / cm 2 、at least 6 mg / cm 2 or at least 8 mg / cm 2 of said active agent, and / or

[0433] less than or equal to 15 mg / cm 2 、less than or equal to 13 mg / cm 2 、or less than or equal to 11 mg / cm 2 of said active agent, and / or

[0434] 4 to 15 mg / cm 2 、6 to 13 mg / cm 2 or 8 to 11 mg / cm2 the active agent described above

[0435] 4. The oral mucosa delivery system according to any one of Embodiments 1 to 3,

[0436] wherein the oral mucosa delivery system comprises:

[0437] at least 5 mg, at least 10 mg or at least 15 mg of the active agent, and / or

[0438] less than or equal to 80 mg, less than or equal to 70 mg, or less than or equal to 60 mg of the active agent, and / or

[0439] 5 to 80 mg, 10 to 70 mg or 15 to 60 mg of the active agent.

[0440] 5. The oral mucosa delivery system according to any one of Embodiments 1 to 4,

[0441] wherein the active agent is remimazolam, a pharmaceutically acceptable salt of remimazolam or any mixture thereof.

[0442] 6. The oral mucosa delivery system according to Embodiment 5,

[0443] wherein the active agent is remimazolam besylate or remimazolam tosylate.

[0444] 7. The oral mucosa delivery system according to any one of Embodiments 1 to 6,

[0445] wherein the active agent in the active agent-containing layer is dissolved or dispersed, or in the form of non-micronized particles.

[0446] 8. The oral mucosa delivery system according to any one of Embodiments 1 to 7, comprising an active agent-containing layer, the active agent-containing layer comprising:

[0447] i) remimazolam, a pharmaceutically acceptable salt thereof or any other form thereof as the active agent,

[0448] ii) a film-forming agent, and

[0449] iii) a plasticizer.

[0450] 9. The oral mucosa delivery system according to Embodiment 8,

[0451] wherein the plasticizer is selected from the group consisting of linear or branched, saturated or unsaturated alcohols having 6 to 20 carbon atoms, triglycerides, polyethylene glycols or polyvinyl alcohol-polyethylene glycol graft copolymers.

[0452] 10. The oral mucosal delivery system according to embodiment 8 or 9,

[0453] wherein the plasticizer is polyethylene glycol or a polyvinyl alcohol - polyethylene glycol graft copolymer.

[0454] 11. The oral mucosal delivery system according to any one of embodiments 8 to 10,

[0455] wherein the active agent-containing layer comprises

[0456] at least 5 wt-%, at least 15 wt-% or at least 20 wt-% of the plasticizer,

[0457] less than or equal to 50 wt-%, less than or equal to 40 wt-%, or less than or equal to 35 wt-% of the plasticizer, and / or

[0458] 5 wt-% to 50 wt-%, 15 wt-% to 40 wt-% or 20 wt-% to 35 wt-% of the plasticizer.

[0459] 12. The oral mucosal delivery system according to embodiment 11,

[0460] wherein the active agent-containing layer comprises

[0461] at least 10 wt-%, at least 13 wt-% or at least 15 wt-% of the film-forming agent,

[0462] less than or equal to 75 wt-%, less than or equal to 50 wt-%, or less than or equal to 30 wt-% of the film-forming agent, and / or

[0463] 10 wt-% to 75 wt-%, 13 wt-% to 50 wt-% or 15 wt-% to 30 wt-% of the film-forming agent.

[0464] 13. The oral mucosal delivery system according to any one of embodiments 8 to 12,

[0465] wherein the active agent-containing layer comprises the total amount of the film-forming agent and the plasticizer, and the total amount is

[0466] at least 30 wt-%, at least 35 wt-% or at least 40 wt-% of the active agent-containing layer

[0467] less than or equal to 80 wt-%, less than or equal to 60 wt-%, or less than or equal to 45 wt-% of the active agent-containing layer, and / or

[0468] 30 wt-% to 80 wt-%, 35 wt-% to 60 wt-%, or 40 wt-% to 45 wt-% of the active agent-containing layer.

[0469] 14. The oral mucosal delivery system according to any one of embodiments 1 to 13,

[0470] wherein the film-forming agent is a polymer selected from the group consisting of: polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyethylene oxide, polyvinylpyrrolidone, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol, hydroxypropyl methylcellulose, or any mixture thereof.

[0471] 15. The oral mucosal delivery system according to embodiment 14,

[0472] wherein the film-forming agent is polyvinyl alcohol.

[0473] 16. The oral mucosal delivery system according to embodiment 15,

[0474] wherein the film-forming agent is polyvinyl alcohol having a molecular weight in the range of 10,000 to 250,000, or a mixture of two or more polyvinyl alcohols, each polyvinyl alcohol having a molecular weight in the range of 10,000 to 250,000.

[0475] 17. The oral mucosal delivery system according to any one of embodiments 1 to 7 and 14 to 16,

[0476] wherein the active agent-containing layer does not contain a plasticizer and contains

[0477] at least 50 wt-%, at least 60 wt-%, or at least 65 wt-% of the film-forming agent,

[0478] less than or equal to 85 wt-%, less than or equal to 75 wt-%, or less than or equal to 70 wt-% of the film-forming agent, and / or

[0479] 50 wt-% to 85 wt-%, 60 wt-% to 75 wt-%, or 65 wt-% to 70 wt-% of the film-forming agent, and / or

[0480] wherein the active agent-containing layer consists essentially of (i) the active agent and (ii) the film-forming agent.

[0481] 18. The oral mucosal delivery system according to any one of embodiments 1 to 17,

[0482] wherein the active agent-containing layer further comprises one or more excipients selected from the group consisting of sweeteners, flavoring agents, antioxidants, and pH regulators, and / or

[0483] wherein the active agent-containing layer does not contain a pH regulator.

[0484] 19. The oral mucosal delivery system according to embodiment 18,

[0485] wherein the sweetener is selected from the group consisting of sucralose, acesulfame potassium, N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-α-L-aspartyl]-L-phenylalanine 1-methyl ester, N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester, aspartame, thaumatin, and / or

[0486] wherein the flavoring agent is a natural or synthetic flavoring agent, such as a flavoring composition selected from the group consisting of a combination of linalool, α-pinene, citral, δ-3-carene, β-pinene, and myrcene, and a combination of geranyl acetate, vanillin, limonene, and allyl hexanoate.

[0487] 20. The oral mucosal delivery system according to embodiment 19,

[0488] wherein the flavoring agent is a combination of linalool, α-pinene, citral, δ-3-carene, β-pinene, and myrcene, or a combination of geranyl acetate, vanillin, limonene, and allyl hexanoate.

[0489] 21. The oral mucosal delivery system according to embodiment 19,

[0490] wherein the sweetener is N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester or N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-α-L-aspartyl]-L-phenylalanine-1-methyl ester or a mixture thereof.

[0491] 22. The oral mucosal delivery system according to any one of embodiments 18 to 21,

[0492] wherein the active agent-containing layer comprises

[0493] at least 0.05 wt-% or at least 0.5 wt-% of a sweetener,

[0494] less than or equal to 2 wt-% or less than or equal to 1 wt-% of a sweetener, and / or

[0495] 0.05 wt-% to 2 wt-% or 0.5 wt-% to 1 wt-% of a sweetening agent.

[0496] 23. The oral mucosal delivery system according to any one of embodiments 18 to 22,

[0497] wherein the active agent-containing layer comprises

[0498] at least 0.05 wt-% or at least 0.5 wt-% of a flavoring agent,

[0499] less than or equal to 5 wt-% or less than or equal to 2 wt-% of a flavoring agent, and / or

[0500] 0.05 wt-% to 5 wt-% or 0.5 wt-% to 2 wt-% of a flavoring agent.

[0501] 24. The oral mucosal delivery system according to any one of embodiments 1 to 23, wherein the oral mucosal delivery system is free of preservatives.

[0502] 25. The oral mucosal delivery system according to any one of embodiments 1 to 24,

[0503] wherein the oral mucosal delivery system is in the form of a film.

[0504] 26. The oral mucosal delivery system according to embodiment 25,

[0505] wherein the film has a size of at least 0.5 cm 2 or less than or equal to 10 cm 2 or about 1.5 cm 2 about 3 cm 2 or about 6 cm 2 and / or

[0506] wherein the film has an areal weight of at least 100 g / m², at least 110 g / m² or at least 120 g / m², or has an areal weight of less than or equal to 400 g / m², less than or equal to 300 g / m² or less than or equal to 250 g / m², and / or

[0507] wherein the film has an areal weight of 100 g / m² to less than or equal to 230 g / m², or 300 g / m² to less than or equal to 400 g / m².

[0508] 27. The oral mucosal delivery system according to any one of embodiments 1 to 26,

[0509] wherein the active agent-containing layer is in the form of a flexible foam or a flexible single-piece film.

[0510] 28. The oral mucosa delivery system according to any one of embodiments 1 to 27,

[0511] wherein the active agent-containing layer contains water in an amount less than or equal to 3 wt-%, less than or equal to 2 wt-%, less than or equal to 1 wt-%, or less than or equal to 0.5 wt-%.

[0512] 29. The oral mucosa delivery system according to any one of embodiments 1 to 28,

[0513] wherein the active agent-containing layer initially contains remimazolam-related degradation substances in a total amount less than or equal to 0.4 wt-%, less than or equal to 0.3 wt-%, or less than or equal to 0.2 wt-%, and / or

[0514] wherein when subjected to a storage stability test and stored at 60 °C for up to 6 weeks, the active agent-containing layer contains remimazolam-related degradation substances in a total amount less than or equal to 0.5 wt-% or less than or equal to 0.4 wt-%.

[0515] 30. The oral mucosa delivery system according to any one of embodiments 1 to 29,

[0516] wherein the active agent-containing layer contains a plasticizer,

[0517] wherein the film-forming agent is polyvinyl alcohol, and

[0518] wherein the ratio of polyvinyl alcohol to the plasticizer is at least 20:80, or less than or equal to 50:50, or 20:80 to 50:50, or about 25:75 or about 40:60.

[0519] 31. The oral mucosa delivery system according to any one of embodiments 1 to 30,

[0520] wherein the oral mucosa delivery system is in the form of a thin film, and

[0521] wherein, when a sample thin film of the oral mucosa delivery system having a size of 5.75 cm 2 is dissolved in 5 mL of artificial saliva or 0.9% NaCl solution, the pH of the resulting solution measured by a pH electrode is in the range of pH 3.0 to pH 3.7.

[0522] 32. The oral mucosa delivery system according to any one of embodiments 1 to 31, wherein the oral mucosa delivery system provides, after a single administration to the buccal mucosa of a human subject,

[0523] Based on c maxA bioavailability greater than 10% or greater than 20% based on AUC,

[0524] a c equal to or greater than 0.3 µg / mL max , and / or

[0525] a t of 10 to 40 minutes, preferably 10 to 20 minutes max .

[0526] 33. The oral mucosal delivery system according to any one of embodiments 1 to 32, which is used for producing sedation, producing hypnosis, producing anti-anxiety, producing muscle relaxation, treating convulsions or inducing amnesia of perioperative events.

[0527] 34. The oral mucosal delivery system for sedation according to embodiment 33,

[0528] wherein the sedation is procedural sedation, such as sedation for dental procedures or for diagnostic procedures, preoperative sedation and / or conscious sedation.

[0529] 35. The oral mucosal delivery system for sedation according to embodiment 33 or 34,

[0530] wherein sedation is induced before and / or during endoscopic examination, colonoscopy or other diagnostic or surgical procedures.

[0531] 36. The oral mucosal delivery system for sedation according to any one of embodiments 33 to 35,

[0532] wherein mild sedation, moderate sedation, deep sedation or general anesthesia is achieved, which preferably has a duration of 5 to 30 minutes, 8 to 20 minutes or 10 to 15 minutes.

[0533] 37. The oral mucosal delivery system for sedation according to any one of embodiments 33 to 36,

[0534] wherein the oral mucosal delivery system is administered by applying the active agent-containing layer to the mucosa of the oral cavity of a human patient, and in particular to the buccal mucosa, sublingual mucosa, gingival mucosa or palatal mucosa and maintaining it on the mucosa until it dissolves.

[0535] 38. A method for producing sedation, producing hypnosis, producing anti-anxiety, producing muscle relaxation, treating convulsions or inducing amnesia of perioperative events,

[0536] wherein the oral mucosal delivery system according to any one of embodiments 1 to 32 is administered to a subject.

[0537] 39. The sedation method according to embodiment 38,

[0538] wherein the sedation is procedural sedation, preoperative sedation, sedation for dental procedures, sedation for diagnostic procedures, and / or conscious sedation.

[0539] 40. The method of sedation according to embodiment 38 or 39,

[0540] wherein sedation is induced before and / or during an endoscopic examination, colonoscopy, or other diagnostic or surgical procedure.

[0541] 41. The method of sedation according to any one of embodiments 38 to 40,

[0542] wherein mild sedation, moderate sedation, deep sedation, or general anesthesia is achieved, preferably having a duration of 5 to 30 minutes, 8 to 20 minutes, or 10 to 15 minutes.

[0543] 42. The method of sedation according to any one of embodiments 38 to 41,

[0544] wherein the oral mucosal delivery system is administered by applying the active agent-containing layer to the mucosa of the oral cavity of a human patient, and particularly to the buccal mucosa, sublingual mucosa, gingival mucosa, or palatal mucosa, and maintaining it on the mucosa until dissolution.

[0545] 43. Use of the oral mucosal delivery system according to any one of embodiments 1 to 32 in the preparation of a medicament for producing sedation, producing hypnosis, producing anxiolysis, producing muscle relaxation, treating convulsions, or inducing amnesia of perioperative events.

[0546] 44. Use of the oral mucosal delivery system according to embodiment 43 in the preparation of a medicament for producing sedation,

[0547] wherein the sedation is procedural sedation, preoperative sedation, sedation for dental procedures, sedation for diagnostic procedures, and / or conscious sedation.

[0548] 45. Use of the oral mucosal delivery system according to embodiment 43 or 44 in the preparation of a medicament for producing sedation,

[0549] wherein sedation is induced before and / or during an endoscopic examination, colonoscopy, or other diagnostic or surgical procedure.

[0550] 46. Use of the oral mucosal delivery system according to any one of embodiments 43 to 45 in the preparation of a medicament for producing sedation,

[0551] wherein mild sedation, moderate sedation, deep sedation, or general anesthesia is achieved, preferably having a duration of 5 to 30 minutes, 8 to 20 minutes, or 10 to 15 minutes.

[0552] 47. A pharmaceutical product comprising

[0553] a package, and

[0554] one or more unit doses of an oral mucosal delivery system according to any one of embodiments 1 to 32.

[0555] 48. The pharmaceutical product according to embodiment 47,

[0556] wherein the package is in the form of a sachet.

[0557] 49. The pharmaceutical product according to embodiment 48,

[0558] wherein the sachet is made of a multilayer film material comprising an outer-facing paper layer, an intermediate polyethylene layer, and an inner-facing aluminum layer, and / or

[0559] wherein the sachet is sealed with a sealant selected from the group consisting of ethylene copolymers, polyethylene terephthalate copolymers, and cycloolefin copolymers.

[0560] 50. The pharmaceutical product according to embodiment 48 or 49,

[0561] wherein the sachet contains one or more desiccants or does not contain a desiccant.

[0562] 51. The pharmaceutical product according to embodiment 50,

[0563] wherein the sachet contains one or more desiccants, and the desiccants include silica gel, 4Å molecular sieve, and / or 4Å zeolite molecular sieve as desiccants, and / or

[0564] wherein the desiccant is in the form of an adhesive film.

[0565] 52. The pharmaceutical product according to any one of embodiments 47 to 51,

[0566] which further comprises a folded polyethylene terephthalate foil, wherein the one or more unit doses of the oral mucosal delivery system are surrounded by the folded polyethylene terephthalate foil, and the folded polyethylene terephthalate foil is folded up and protects the one or more unit doses from further contact with the package.

[0567] 53. The pharmaceutical product according to embodiment 51 or 52,

[0568] wherein the sachet contains one or more desiccants in the form of an adhesive film, which is attached to the inner-facing side of the sachet or, when present, to the outer-facing side of the folded polyethylene terephthalate foil, so as to avoid contact with the oral mucosal delivery system.

[0569] 54. A pharmaceutical product according to any one of embodiments 47 to 53,

[0570] wherein the sachet is filled with nitrogen.

[0571] 55. A method for manufacturing an active agent-containing layer as defined in any one of embodiments 1 to 32, the manufacturing method comprising the steps of:

[0572] i. combining at least (i) remimazolam, its pharmaceutically acceptable salts or any other form as the active agent with (ii) a film-forming agent to obtain a mixture; and

[0573] ii. forming the active agent-containing layer.

[0574] 56. The manufacturing method according to embodiment 55,

[0575] wherein the method is a hot melt method, and the hot melt method

[0576] is any one of the following:

[0577] a hot melt extrusion method comprising step ii. as follows:

[0578] a. introducing a mixture containing an active agent and a film-forming agent (with or without other excipients) into an extruder;

[0579] b. heating the mixture to at least the softening temperature of the mixture; and

[0580] c. extruding the heated mixture containing the film-forming agent and the active agent into a film form to obtain an active agent-containing layer,

[0581] or

[0582] a vacuum compression molding method comprising step ii. as follows:

[0583] a. introducing a mixture containing an active agent and a film-forming agent (with or without excipients) into a sample chamber; and

[0584] b. compacting the mixture while applying a vacuum and heating the mixture to at least the softening temperature of the mixture to obtain an active agent-containing layer.

[0585] 57. The manufacturing method according to embodiment 55,

[0586] wherein the method is a coating method comprising the following steps:

[0587] i. dispersing or dissolving an active agent in a solution of a film-forming agent with or without other excipients to obtain a coating composition; and

[0588] ii. a. coating the coating composition on a coated substrate; and

[0589] b. drying the laminated section in an oven to obtain an active agent-containing layer in the form of a flexible single-piece film.

[0590] 58. The manufacturing method according to embodiment 55,

[0591] wherein the method is a foam formation method comprising the following steps:

[0592] i. dispersing or dissolving the active agent in an aqueous solution of the film-forming agent with or without other excipients to obtain a coating composition; and

[0593] ii. a. foaming the coating composition to obtain a foam coating composition;

[0594] b. coating the foam coating composition on a coated substrate; and

[0595] c. drying the laminated section in an oven to obtain the active agent-containing layer in the form of a foam.

[0596] 59. The manufacturing method according to embodiment 58,

[0597] wherein the foaming is carried out by introducing nitrogen into the composition while stirring.

[0598] 60. A manufacturing method of an oral mucosa delivery system according to any one of embodiments 1 to 32, the oral mucosa delivery system comprising an active agent-containing layer, the active agent-containing layer comprising (i) remimazolam, a pharmaceutically acceptable salt thereof or any other form as an active agent, and (ii) a film-forming agent, the manufacturing method comprising the following steps:

[0599] i. combining at least the active agent and the film-forming agent to obtain a mixture; and

[0600] ii. forming the active agent-containing layer

[0601] as defined in any one of embodiments 50 to 59.

[0602] 61. An oral mucosa delivery system obtainable by the method according to embodiment 60.

[0603] 62. The oral mucosa delivery system according to embodiment 1, wherein the active agent-containing layer comprises

[0604] i) 55 wt-% to 60 wt-% of remimazolam besylate;

[0605] ii) 10 wt-% to 15 wt-% of polyvinyl alcohol as a film-forming agent,

[0606] iii) 30 wt-% to 35 wt-% of a polyvinyl alcohol-polyethylene glycol graft copolymer,

[0607] iv) 0.05 wt-% to 1 wt-% of one or more sweeteners, and

[0608] v) 0.5 wt-% to 2 wt-% of a flavoring agent

[0609] wherein

[0610] the areal weight of the active agent-containing layer is less than or equal to 200 g / m².

[0611] 63. The oral mucosa delivery system according to embodiment 1, wherein the active agent-containing layer comprises

[0612] i) 55 wt-% to 60 wt-% of remimazolam besylate;

[0613] ii) 15 wt-% to 20 wt-% of polyvinyl alcohol as a film-forming agent

[0614] iii) 20 wt-% to 26 wt-% of a polyvinyl alcohol-polyethylene glycol graft copolymer,

[0615] iv) 0.05 wt-% to 1 wt-% of one or more sweeteners, and

[0616] v) 0.5 wt-% to 2 wt-% of a flavoring agent

[0617] wherein

[0618] the areal weight of the active agent-containing layer is less than or equal to 200 g / m².

Claims

1. An oral mucosal delivery system for transmucosal delivery of an active agent, the oral mucosal delivery system comprising an active agent-containing layer, the active agent-containing layer comprising: i) Remimazolam, a pharmaceutically acceptable salt thereof or any other form, as the active agent, and ii) a film-forming agent, wherein the oral mucosal delivery system is in the form of a thin film.

2. The oral mucosal delivery system according to claim 1, wherein the active agent-containing layer comprises at least 20 wt-%, at least 25 wt-% or at least 30 wt-% of the active agent, and / or less than or equal to 60 wt-%, less than or equal to 55 wt-% or less than or equal to 50 wt-% of the active agent, and / or 20 wt-% to 60 wt-%, 25 wt-% to 55 wt-% or 30 wt-% to 50 wt-% of the active agent.

3. The oral mucosal delivery system according to claim 1 or 2, wherein the active agent is remimazolam besylate or remimazolam tosylate.

4. The oral mucosal delivery system according to any one of claims 1 to 3, which comprises an active agent-containing layer, the active agent-containing layer comprising: i) Remimazolam, a pharmaceutically acceptable salt thereof or any other form, as the active agent, ii) a film-forming agent, and iii) a plasticizer.

5. The oral mucosal delivery system according to any one of claims 1 to 4, wherein the plasticizer is polyethylene glycol or a polyethylene glycol-polyvinyl alcohol graft copolymer, and / or wherein the film-forming agent is a polymer selected from the group consisting of: polyvinyl alcohol, a polyethylene glycol-polyvinyl alcohol graft copolymer, polyethylene oxide, polyvinylpyrrolidone, a polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol, hydroxypropyl methylcellulose or any mixture thereof.

6. The oral mucosal delivery system according to any one of claims 1 to 5, wherein the film-forming agent is polyvinyl alcohol having a molecular weight in the range of 10,000 to 250,000, or a mixture of two or more polyvinyl alcohols, each polyvinyl alcohol having a molecular weight in the range of 10,000 to 250,000.

7. The oral mucosal delivery system according to any one of claims 1 to 6, wherein the active agent-containing layer further comprises one or more excipients selected from the group consisting of: sweeteners, flavoring agents, antioxidants and pH regulators, and / or wherein the active agent-containing layer does not contain a pH regulator.

8. The oral mucosal delivery system according to claim 7, wherein the sweetener is selected from the group consisting of: sucralose, acesulfame potassium, N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-α-L-aspartyl]-L-phenylalanine 1-methyl ester, N-[N-(3,3-dimethylbutyl)-L-α-aspartyl]-L-phenylalanine 1-methyl ester, aspartame, thaumatin, and / or Wherein the flavoring agent is a natural or synthetic flavoring agent, such as a flavoring composition selected from the group consisting of: a combination of linalool, α-pinene, citral, δ-3-carene, β-pinene and myrcene, and a combination of geranyl acetate, vanillin, limonene and allyl hexanoate.

9. The oral mucosal delivery system according to any one of claims 1 to 8, wherein the active agent-containing layer is in the form of a flexible foam or a flexible single-piece film.

10. The oral mucosal delivery system according to any one of claims 1 to 9, wherein the oral mucosal delivery system is in the form of a film, and Among them, When a sample film of the oral mucosa delivery system having a size of 5.75 cm 2 is dissolved in 5 mL of artificial saliva or 0.9% NaCl solution, the pH of the resulting solution as measured by a pH electrode is in the range of pH 3.0 to pH 3.

7.

11. The oral mucosal delivery system according to any one of claims 1 to 10, wherein the oral mucosal delivery system provides, after a single administration to the buccal mucosa of a human subject's oral cavity, Based on c max A bioavailability greater than 10% or based on AUC greater than 20% c equal to or greater than 0.3 µg / mL max , and / or t of 10 to 40 minutes or 10 to 20 minutes max 。 12. The oral mucosal delivery system according to any one of claims 1 to 11, which is used for producing sedation, producing hypnosis, producing anti-anxiety, producing muscle relaxation, treating convulsions or inducing amnesia of perioperative events.

13. A pharmaceutical product, which comprises packaging, and one or more unit doses of the oral mucosal delivery system according to any one of claims 1 to 11.

14. The pharmaceutical product according to claim 13, wherein the packaging is in the form of a sachet, wherein the sachet contains one or more desiccants.

15. A method for manufacturing an active agent-containing layer as defined in any one of claims 1 to 11, the manufacturing method comprising the following steps: i. Combining at least (i) remimazolam, its pharmaceutically acceptable salt or any other form as the active agent with (ii) a film-forming agent to obtain a mixture; and ii. Forming the active agent-containing layer.

16. The manufacturing method according to claim 15, wherein the method is a foam-forming method comprising the following steps: i. Dispersing or dissolving the active agent in an aqueous solution of the film-forming agent with or without other excipients to obtain a coating composition, and ii. a. Foaming the coating composition to obtain a foam coating composition; b. Coating the foam coating composition on a coating substrate; and c. Drying the laminated section in an oven to obtain the active agent-containing layer in the form of a foam.

17. A method for manufacturing an oral mucosal delivery system according to any one of claims 1 to 11, the oral mucosal delivery system comprising an active agent-containing layer, the active agent-containing layer comprising (i) remimazolam, its pharmaceutically acceptable salt or any other form as the active agent, and (ii) a film-forming agent, the manufacturing method comprising the following steps: i. Combining at least the active agent and the film-forming agent to obtain a mixture; and ii. Forming the active agent-containing layer as defined in claim 15 or 16.

18. An oral mucosal delivery system capable of being obtained by the method according to claim 17.

19. The oral mucosal delivery system according to claim 1, wherein the active agent-containing layer comprises i) 55 wt-% to 60 wt-% of remimazolam besylate; ii) 10 wt-% to 15 wt-% of polyvinyl alcohol as a film-forming agent, iii) 30 wt-% to 35 wt-% of a polyvinyl alcohol-polyethylene glycol graft copolymer, iv) 0.05 wt-% to 1 wt-% of one or more sweeteners, and v) 0.5 wt-% to 2 wt-% of a flavoring agent wherein the areal weight of the active agent-containing layer is less than or equal to 200 g / m².

20. The oral mucosal delivery system according to claim 1, wherein the active agent-containing layer comprises i) 55 wt-% to 60 wt-% of remimazolam besylate; ii) 15 wt-% to 20 wt-% of polyvinyl alcohol as a film-forming agent iii) 20 wt-% to 26 wt-% of a polyvinyl alcohol-polyethylene glycol graft copolymer, iv) 0.05 wt-% to 1 wt-% of one or more sweeteners, and v) 0.5 wt-% to 2 wt-% of a flavoring agent wherein the areal weight of the active agent-containing layer is less than or equal to 200 g / m².

Images