Oral mucosal delivery system containing remimazolam

Abstract

The present invention relates to an oral mucosal delivery system for transmucosal administration of an active agent comprising an active agent-containing layer comprising remimazolam, for example, a remimazolam oral mucosal delivery system for producing sedation, a method for producing sedation comprising applying such a remimazolam oral mucosal delivery system, and a process for manufacturing such a remimazolam oral mucosal delivery system.

Description

[Technical Field]

[0001] The present invention relates to an oral mucosal delivery system for transmucosal administration of remimazolam into the systemic circulation, as well as its manufacturing process, methods of treatment and use. [Background technology]

[0002] Remimazolam (methyl 3-{(4S)-8-bromo-1-methyl-6-(pyridin-2-yl)-4 / - / -imidazo[1,2-a][1,4]benzodiazepin-4-yl}propanoate) is a novel benzodiazepine sedative identified as one of the lead compounds in a program initiated in the late 1990s that focused on ester-based benzodiazepine derivatives with a short and predictable duration of action.

[0003] Remimazolam contains an ester group that is rapidly hydrolyzed by tissue esterases (carboxylesterase 1) and converted to the inactive metabolite CNS7054, thus making it an ultrashort-acting drug. [ka]

[0004] Remimazolam exhibits anxiolytic, amnesic, sedative, muscle relaxant, and anticonvulsant properties. These properties make it suitable for use in anesthesiology practice and intensive care, for example for preoperative sedation, anxiolysis, amnesic use for perioperative events, conscious sedation during short-term diagnostic, surgical, or endoscopic procedures, for example as a component for inducing and maintaining general anesthesia before and / or simultaneously with the administration of other anesthetic agents, and during intensive care sedation.

[0005] In particular, two salt forms have been developed: the besylate and the tosylate. Remimazolam besylate is approved for general anesthesia in Japan and South Korea, and for procedural sedation in the United States, China, and Europe. The tosylate salt is approved for procedural sedation in China.

[0006] Remimazolam besylate is manufactured in a lyophilized form for reconstitution. Currently, no ready-to-use formulation is available.

[0007] Regarding the route of administration, oral bioavailability of remimazolam is low (reportedly 1-2%) due to its high initial metabolic excretion mediated by carboxylesterase in the liver. Intranasal administration achieves significantly higher bioavailability (approximately 50%), but may be associated with nasal discomfort / pain in certain cases. Inhalation has been suggested as an alternative.

[0008] Therefore, the primary route considered for remimazolam remains intravenous (IV) administration. In Europe, remimazolam besylate is approved as Byfavo, a 20 mg powder for injectable solution. However, in certain circumstances, alternative IV routes are desirable. The lyophilized form of the drug requires reconstitution of the active ingredient before IV administration. Strict hygiene is required for preparation of the injection, and special care must be taken with needle disposal. Younger patients, in particular, fear the pain associated with injections.

[0009] Therefore, it is desirable to provide an alternative, ready-to-use, non-invasive remimazolam dosage form (which is understood to include remimazolam, its pharmaceutically acceptable salts, or any other form thereof). However, remimazolam is susceptible to hydrolytic degradation, and developing a formulation with sufficient stability to provide an adequate shelf life is difficult. Furthermore, as outlined above, due to low bioavailability, the classical oral route, for which extensive knowledge of formulation technology is available, does not appear to be useful. Therefore, developing a suitable parenteral drug delivery route that is patient-acceptable, has a rapid onset of action, and provides adequate pharmacokinetic properties may be considered a very difficult task.

[0010] It is therefore not surprising that there appear to be no current, viable available dosage forms of remimazolam other than the IV formulation, and no ongoing / recent research or investigations into alternative dosage forms of remimazolam other than those described above are known to the applicant.

[0011] Therefore, there is a need for alternative dosage forms of remimazolam that overcome the drawbacks of low bioavailability associated with oral administration and the drawbacks associated with intravenous administration. Summary of the Invention

[0012] It is an object of the present invention to provide a remimazolam dosage form that overcomes one or more of the above-mentioned drawbacks of current remimazolam administration.

[0013] An alternative object of the present invention is to provide a remimazolam dosage form that is non-invasive, patient-friendly, and / or based on a ready-to-use formulation.

[0014] It is also an alternative object of the present invention to provide a remimazolam dosage form that provides high bioavailability, especially when compared to oral administration.

[0015] A further alternative object of the present invention is to provide a remimazolam dosage form that provides a rapid and / or reliable onset of action, especially when compared to oral administration.

[0016] It is also a further alternative object of the present invention to provide a remimazolam dosage form that provides a permeation rate high enough to achieve a therapeutically effective dose of remimazolam.

[0017] It is a further alternative object of the present invention to provide a remimazolam dosage form that has an extended duration of action compared to a single dose of IV remimazolam.

[0018] Another alternative object of the present invention is to provide a remimazolam dosage form in which the remimazolam is stable and can be stored, for example, at room temperature.

[0019] It is also another alternative object of the present invention to provide a remimazolam dosage form that does not induce a tingling sensation at the administration site.

[0020] Yet another alternative object of the present invention is to provide a remimazolam dosage form that conforms to convenient application and handling needs, provides good patient compliance, and / or is simple and cost-effective to manufacture.

[0021] One or more of the above objects and other objects are achieved by the present invention, in accordance with one aspect, which relates to an oral mucosal delivery system for transmucosal delivery of an active agent comprising an active agent-containing layer, said active agent-containing layer comprising: i) as an active agent, remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof; ii) a film-forming agent.

[0022] According to another aspect of the invention, the oral mucosal delivery system according to the invention is for use in producing sedation, producing hypnosis, producing anxiolysis, producing muscle relaxation, treating convulsions, or inducing amnesia for perioperative events.

[0023] According to another aspect, the present invention also relates to a method for producing sedation, producing hypnosis, producing anxiolysis, producing muscle relaxation, treating convulsions, or inducing amnesia for a perioperative event, wherein an oral mucosal delivery system is administered to a subject.

[0024] 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 anxiolysis, producing muscle relaxation, treating convulsions, or inducing amnesia for perioperative events.

[0025] According to yet another aspect, the present invention relates to a pharmaceutical product comprising packaging and one or more unit doses of an oral mucosal delivery system.

[0026] According to a further aspect, the present invention relates to a process for manufacturing an active agent-containing layer, said process comprising: i. combining at least (i) as an active agent, remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof, and (ii) a film-forming agent to obtain a mixture; ii. forming an active agent-containing layer.

[0027] According to a further aspect, the present invention relates to a process for the manufacture of an oral mucosal delivery system comprising an active agent-containing layer comprising (i) as an active agent, remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof, and (ii) a film-forming agent, said process comprising: i. combining at least the active agent and a film-forming agent to obtain a mixture; ii. forming an active agent-containing layer.

[0028] According to a further aspect, the present invention relates to an oral mucosal delivery system obtainable by such a process.

[0029] According to certain embodiments, the present invention also relates to an oral mucosal delivery system for transmucosal administration of remimazolam, comprising an active agent-containing layer, said active agent-containing layer comprising: i) 55-60% by weight of remimazolam besylate; ii) 10-15 wt. % polyvinyl alcohol as a film former; iii) 30 to 35% by weight of a polyvinyl alcohol-polyethylene glycol graft copolymer; iv) 0.05 to 1% by weight of one or more sweeteners; v) 0.5 to 2% by weight of a flavoring agent; where: The area weight of the active agent-containing layer is 200 g / m 2 The following is the result.

[0030] According to certain embodiments, the present invention also relates to an oral mucosal delivery system for transmucosal administration of remimazolam, comprising an active agent-containing layer, said active agent-containing layer comprising: i) 55-60% by weight of remimazolam besylate; ii) 15 to 20% by weight of polyvinyl alcohol as a film former; iii) 20 to 26 wt % of a polyvinyl alcohol-polyethylene glycol graft copolymer; iv) 0.05 to 1% by weight of one or more sweeteners; v) 0.5 to 2% by weight of a flavoring agent; where: The area weight of the active agent-containing layer is 200 g / m 2 The following is the result.

[0031] Within the meaning of the present invention, the term "oral mucosal therapeutic system" refers to a system in which an active agent (remimazolam, its pharmaceutically acceptable salt, or any other form) is administered to the systemic circulation via transmucosal delivery by application to the mucous membrane of the oral cavity, and specifically refers to an entire individual dosage unit that is applied to the patient's mucous membrane and contains a therapeutically effective amount of remimazolam, its pharmaceutically acceptable salt, or any other form in an active agent-containing layer. The oral mucosal delivery system consists of one or more thin layers that are applied to and adhere to the mucous membrane of the oral cavity to deliver the active agent. Dosage forms in the form of thin films for application in the oral cavity are sometimes called "oral thin films" or OTFs, although OTFs are not necessarily intended to adhere to the mucous membrane. In oral mucosal delivery systems, the active agent is contained in a dissolvable layer, and due to the film adhering to the mucosa, active delivery is achieved primarily by a combination of local active release from the oral mucosal delivery system to the mucosa (i.e., the active is dissolved from the system and released directly onto the underlying mucosa) and "indirect" active delivery due to the active, once dissolved in saliva, traveling from the administration site to other parts of the oral cavity.

[0032] Within the meaning of the present invention, the term "oral mucosal therapeutic system" refers in particular to a system that is mucoadhesive and provides passive transmucosal delivery, excluding active substance transport similar to methods involving microporation. Also, in contrast to certain oral thin films (sometimes called "flash wafers") that are not necessarily mucoadhesive and are intended to disintegrate very quickly in saliva, enteral delivery is not intended for oral mucosal delivery systems, but is not excluded (e.g., due to unintentional swallowing of saliva).

[0033] Within the meaning of the present invention, the term "active agent-containing layer" refers to a layer comprising an active agent and a film-forming agent, the film-forming agent forming a matrix with the active agent that disintegrates upon contact with saliva, releasing the active agent. The active agent-containing layer may be mucoadhesive (in the form of a mucoadhesive layer), or the oral mucosal delivery system may comprise an additional mucocontact layer that is mucoadhesive to provide sufficient adhesion. In particular, the active agent-containing layer is a mucoadhesive layer.

[0034] Within the meaning of the present invention, the term "therapeutically effective amount" refers to an amount of active agent in an oral mucosal delivery system sufficient to provide a similar range of sedation and / or remimazolam blood levels (e.g., total maximum plasma concentration c) when administered to a patient, as compared to the sedation and / or blood levels obtained after a single IV administration of 0.01 to 0.5 mg / kg of remimazolam, its pharmaceutically acceptable salt, or any other form. max 189 to 6,960 ng / mL).

[0035] Within the meaning of the present invention, terms such as "active," "active agent," and the like refer to remimazolam and its pharmaceutically acceptable salts or any other forms, specifically its pharmaceutically acceptable chemical and morphological forms and physical states. These forms include, but are not limited to, remimazolam (free base form), protonated or partially protonated remimazolam, remimazolam salts, and specifically acid addition salts formed by the addition of inorganic or organic acids, such as remimazolam besylate or remimazolam tosylate, hydrates, solvates, complexes, and the like, as well as the active agent in the form of crystalline and / or amorphous particles, which may be micronized or preferably not micronized, and any mixture of the aforementioned forms. When contained in a medium such as a solvent, the active agent may be dissolved or dispersed, or may be partially dissolved and partially dispersed.

[0036] When it is stated that an active agent is used in a specific form during the preparation of an oral mucosal delivery system, this does not exclude the interaction, such as salt formation or complexation, between this form of the active agent and other components of the active agent-containing self-adhesive structure in the final oral mucosal delivery system.This means that even if the active agent is contained in its free base form, the active agent may exist in the final oral mucosal delivery system in a protonated or partially protonated form or in the form of an acid addition salt, or if the active agent is contained in a salt form, a portion of it may exist in the final oral mucosal delivery system as a free base.Unless otherwise indicated, the amount of the active agent indicated is calculated based on remimazolam in the form of free base.In particular, the amount of active agent in the active agent-containing layer is related to the amount of active agent contained in the oral mucosal delivery system during the preparation of the oral mucosal delivery system, and is calculated based on remimazolam in the form of free base. For example, if a) 0.1 mmol (equivalent to 43.9 mg) of remimazolam base or b) 0.1 mmol (equivalent to 59.8 mg) of remimazolam besylate is included in the oral mucosal delivery system during manufacture, the amount of active agent in the self-adhesive layer structure will be given within the meaning of the present invention as 0.1 mmol or 43.9 mg in each case.

[0037] The active agent starting material included in the oral mucosal delivery system during its manufacture may be in the form of particles, e.g., the active agent may be present in the mucoadhesive layer structure in the form of particles, e.g., dispersed and / or dissolved.

[0038] Within the meaning of the present invention, the term "particle" refers to a solid particulate material comprising individual particles, the dimensions of which are negligible compared to the material. In particular, particles are solids, including plastic / deformable solids, including amorphous and crystalline materials.

[0039] Within the meaning of the present invention, the term "dispersing" refers to a step or combination of steps in which the starting material (e.g., remimazolam) is not completely dissolved. Dispersion within the meaning of the present invention includes dissolving a portion of the starting material (e.g., remimazolam particles) depending on the solubility of the starting material (e.g., the solubility of remimazolam in the coating composition).

[0040] With respect to the active agent content of the oral mucosal therapeutic system and with respect to the film-forming agent when cast into a film, terms such as "dissolution," "solubility," "dissolving," etc., are to be understood very broadly and do not have the strict scientific meaning of chemically dissolving molecules in a solvent. Any transformation of the relevant layer from a solid state to a liquid state, such as dispersion, formation of a suspension, gelation of a film, and disintegration of the gel into smaller pieces, must be considered "dissolution" within the meaning of the present invention, as long as the "dissolved" material is freely mobile in a liquid (e.g., saliva). In preferred embodiments, this meaning is limited to the ordinary chemical meaning of dissolving molecules in a solvent. It should be noted that the term "dissolving" with respect to the substance itself, such as the active agent remimazolam or any excipient, continues to be used in the ordinary chemical sense of dissolving molecules in a solvent. For example, remimazolam in a dissolved form obviously does not include remimazolam in a dispersed form. The film-forming agent itself may be present in the coating composition during manufacture of the oral mucosal therapeutic system in a dissolved form in the general chemical sense (e.g., undispersed, in the form of a small gel, etc.), but when the film-forming agent is cast into a film, "dissolving" such a film also includes gelling of the film and the disintegration of the gel into smaller gel portions.

[0041] Within the meaning of the present invention, the term "mucoadhesive" refers in particular to a material that adheres to and upon contact with the mucosa, but is preferably non-sticky when dry, and can be touched with a finger, for example, and manipulated for application to the oral cavity without unintentionally adhering to the skin of the finger. The mucoadhesive layer is "self-adhesive" when in contact with the mucosa, i.e., it provides adhesion to the mucosa so that no further assistance is typically required for fixation. The adhesive strength is preferably so strong that typical movements within the oral cavity are not sufficient to displace the mucoadhesive layer adhered to the mucosa.

[0042] Within the meaning of the present invention, the term "areal weight" means g / m 2Refers to the dry weight of a particular layer, e.g., an active agent-containing layer, provided in units. Area weight values ​​are subject to a tolerance of ±10%, preferably ±7.5%, due to manufacturing variations.

[0043] Unless otherwise indicated, "%" refers to % by weight.

[0044] Within the meaning of the present invention, the term "polymer" refers to any substance consisting of so-called repeating units obtained by polymerizing one or more monomers, including homopolymers consisting of one type of monomer and copolymers consisting of two or more types of monomers. Polymers can be of any structure, such as linear polymers, star polymers, comb polymers, or brush polymers, and in the case of copolymers, can be of any monomer arrangement, such as alternating, statistical, block copolymers, or graft polymers. The minimum molecular weight varies depending on the type of polymer and is known to those skilled in the art. Polymers can have a molecular weight of, for example, more than 2,000 daltons, preferably more than 5,000 daltons, and more preferably more than 10,000 daltons. Correspondingly, compounds having a molecular weight of less than 2,000 daltons, preferably less than 5,000 daltons, or more preferably less than 10,000 daltons are usually called oligomers.

[0045] The oral mucosal delivery system according to the present invention can be characterized by certain parameters measured in an in vitro permeation test.

[0046] In vitro permeation tests are performed using human or animal mucosa, preferably explanted split-thickness porcine mucosa with a thickness of 400 μm and intact barrier function, and using phosphate buffer pH 5.5 or 7.4 as the receptor medium (37°C), with or without the addition of up to 40% by volume of organic solvents, such as ethanol, acetonitrile, isopropanol, dipropylene glycol, PEG 400, so that the receptor medium can contain, for example, 60% by volume of phosphate buffer (pH 5.5), 30% by volume of dipropylene glycol, and 10% by volume of acetonitrile.

[0047] Unless otherwise indicated, in vitro permeation tests are performed using excised split-thickness porcine mucosa (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 permeated into the receptor medium is determined at regular intervals using an HPLC method with a UV photometric detector by taking sample volumes. The measured amount of active substance permeated relates to the amount permeated between the last two sample collection times, not the total amount permeated up to that point. Within the meaning 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 sodium hydrogen phosphate dihydrate, adjusted to a pH of 7.0 + / - 0.05 using 1N NaOH.

[0048] Therefore, within the meaning of the present invention, the parameter "permeation amount" is expressed in μg / cm 2 It is provided in units and relates to the amount of active agent permeated over a particular elapsed time sample interval per area of ​​release. For example, in an in vitro permeation test as described above, in which the amount of active agent permeated into a receptor medium is measured at, e.g., 0, 2, 4, 8, 12, and 24 minutes, the "permeation amount" of active agent may be provided over, e.g., 8-12 minute sample intervals, corresponding to the measurement at 12 minutes.

[0049] The permeation amount may also be given as a "cumulative permeation amount" which corresponds to the cumulative amount of active substance permeated at a particular time point. For example, in an in vitro permeation test as described above in which the amount of active substance permeated into a receptor medium is measured at, for example, 0, 2, 4, 8, 12, and 24 minutes, the "cumulative permeation amount" of active substance at 12 minutes corresponds to the sum of the permeation amounts from 0 to 2 minutes, from 2 to 4 minutes, from 4 to 8 minutes, and from 8 to 12 minutes.

[0050] Within the meaning of the present invention, the parameter "mucosal permeation rate" for a particular sample interval at a particular elapsed time is expressed as μg / (cm 2The "mucosal permeation rate" is provided in units of 0, 2, 4, 8, 12, and 24 minutes and is calculated by dividing the amount of permeation at the sample interval, as measured by an in vitro permeation test as described above in μg / cm², by the fraction of the sample interval. For example, in an in vitro permeation test as described above, the amount of active agent that has permeated into a receptor medium is measured at, for example, 0, 2, 4, 8, 12, and 24 minutes, the "mucosal permeation rate" at 12 minutes is calculated as the amount of permeation at the sample interval from 8 minutes to 12 minutes divided by 4 minutes.

[0051] The "cumulative mucosal permeation rate" can be calculated from each cumulative permeation amount by dividing the cumulative permeation amount by the elapsed time. For example, in an in vitro permeation test as described above, in which the amount of active substance permeated into the receptor medium is measured at, for example, 0, 2, 4, 8, 12, and 24 minutes, the "cumulative mucosal permeation rate" at 12 minutes is calculated as the cumulative permeation amount at 12 minutes (see above) divided by 12 minutes.

[0052] Within the meaning of the present invention, the above parameters of 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.

[0053] The oral mucosal delivery systems according to the present invention can also be characterized by certain parameters measured in in vivo non-clinical or clinical studies.

[0054] Within the meaning of the present invention, the term "administration" refers to the application of the dosage form, i.e., the oral mucosal delivery system, to the oral mucosa of a patient, where it is then maintained on the mucosa until the active agent-containing layer structure dissolves.

[0055] Within the meaning of the present invention, the term "room temperature" refers to the unaltered temperature found in the laboratory where the experiment is performed, which is usually in the range of 15 to 35°C, preferably about 18 to 25°C.

[0056] Within the meaning of the present invention, the term "patient" refers to a subject who presents with clinical signs of a particular symptom(s) indicating the need for therapy or treatment, in particular the need for sedation, a subject being treated preventatively or prophylactically for a condition, or a subject diagnosed with a treatable condition requiring sedation.

[0057] Within the meaning of the present invention, the term "pharmacokinetic parameters" refers to the plasma curves, e.g., C, obtained in clinical studies, e.g., by single or multiple administration of an oral mucosal delivery system to healthy human subjects. max , C t and AUC t1-t2 The pharmacokinetic parameters of an individual subject are the arithmetic and geometric means, e.g., mean C max , average AUC t , and average AUC INF , and additional statistics such as the respective standard deviations and standard errors, minimum and maximum values, and, if the list of values ​​is ranked, the mean value (median). In the context of the present invention, pharmacokinetic parameters, such as C max , C t and AUC t1-t2 " refers to arithmetic mean value or geometric mean value, preferably refers to geometric mean value.In clinical research, it cannot be excluded that the absolute mean value obtained for a specific oral mucosal delivery system will differ to some extent from study to study.In order to enable the comparison of absolute mean values ​​between studies, a reference formulation, for example, any product based on the present invention in the future, can be used as an internal standard.By using the comparison of the AUC per release area of ​​each reference product in the previous study and the later study, a correction factor can be obtained to take into account the difference between studies.

[0058] 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 total amount of active agent absorbed into the blood circulation and is therefore a measure of bioavailability.

[0059] Within the meaning of the present invention, "AUC t1-t2The parameter " is given in (ng / ml)h and is calculated by the linear trapezoidal method for the area under the plasma concentration-time curve from time t1 to time t2.

[0060] Within the meaning of the present invention, "C max The parameter " is provided in (ng / ml) and relates to the maximum observed plasma concentration of the active agent.

[0061] Within the meaning of the present invention, "C t The parameter " is provided in (ng / mL) and relates to the plasma concentration of the active agent observed at time t.

[0062] Within the meaning of the present invention, "t max The parameter is given in hours (h) and C max It relates to the time at which a value is reached. In other words, t max is the time point of maximum observed plasma concentration.

[0063] Within the meaning of the present invention, the term "mean plasma concentration" is given in (ng / ml) and is the average of the individual plasma concentrations of the active agent, e.g., remimazolam, at each time point. Within the meaning of the present invention, "bioavailability" is expressed in %, i.e., the C after IV administration. max vs. dose-normalized C after oromucosal administration max or the dose-normalized ratio of dose-normalized AUC after IV administration to dose-normalized AUC after oromucosal administration.

[0064] Within the meaning of the present invention, the term "coating composition" refers to a composition that contains all the ingredients of the active agent-containing layer in a solvent.

[0065] Within the meaning of the present invention, the term "dissolving" in the context of preparing a coating composition, e.g., dissolving a component of the coating composition, such as an active agent, refers to the process of obtaining a solution that is clear and does not contain any particles when seen with the naked eye.

[0066] Within the meaning of the present invention, the term "foam" refers to a state of liquid or solid material that encapsulates relatively large amounts of gas pockets separated by relatively thin layers of material, whereas a "monolithic film" refers to a homogeneous film composed of one continuous phase that is substantially free of large amounts of pores or trapped gas pockets.

[0067] 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, thereby reducing the water level.

[0068] 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, methylene chloride, hexane, n-heptane, heptane, toluene and mixtures thereof.

[0069] Within the meaning of the present invention, unless otherwise specified, the term "about" refers to an amount of ±10% of the disclosed amount. In some embodiments, the term "about" refers to an amount of ±5% of the disclosed amount. In some embodiments, the term "about" refers to an amount of ±2% of the disclosed amount. [Brief explanation of the drawings]

[0070] [Figure 1] 1 illustrates a cross section of a pharmaceutical product of the present invention comprising a unit dose of an oral mucosal delivery system of the present invention in a pouch with a folded polyethylene terephthalate foil in the primary packaging. [Figure 2A] 1 illustrates the levels of sedation determined during an in vivo study for a placebo buccal delivery system. [Figure 2B] 1 illustrates the level of sedation determined during an in vivo study of an oral mucosal delivery system prepared according to Example 1c. [Figure 2C] 1 illustrates the level of sedation determined during an in vivo study of an oral mucosal delivery system prepared according to Example 1d. [Figure 2D] 1 illustrates the level of sedation determined during an in vivo study following IV administration of remimazolam besylate. [Figure 3A] 1 shows the plasma concentrations of remimazolam obtained in an in vivo study on an oral mucosal delivery system prepared according to Example 1c. [Figure 3B] 1 shows the plasma concentrations of CNS7054 obtained in an in vivo study on an oral mucosal delivery system prepared according to Example 1c. [Figure 4A] 1 shows the plasma concentrations of remimazolam obtained in an in vivo study on an oral mucosal delivery system prepared according to Example 1d. [Figure 4B] 1 shows the plasma concentrations of CNS7054 obtained in an in vivo study on an oral mucosal delivery system prepared according to Example 1d. [Figure 5A] 1 illustrates the plasma concentrations of remimazolam obtained in an in vivo study after IV administration of remimazolam besylate. [Figure 5B] 1 illustrates the plasma concentrations of CNS7054 obtained in an in vivo study after IV administration of remimazolam besylate. [Figure 6A] 1 illustrates the mucosal permeation of remimazolam from an oral mucosal delivery system prepared according to Example 2a dissolved in artificial saliva or dissolved in 0.9% NaCl, or remimazolam besylate dissolved in artificial saliva and adjusted to a pH of 2, 3, 4.5, or 6.0, respectively. [Figure 6B] 1 illustrates the mucosal permeability of remimazolam for an oral mucosal delivery system prepared according to Example 2a dissolved in artificial saliva or 0.9% NaCl, or for a lyophilized product of remimazolam besylate dissolved in artificial saliva or 0.9% NaCl, or for remimazolam besylate dissolved in artificial saliva. DETAILED DESCRIPTION OF THE INVENTION

[0071] Oral mucosal delivery system The present invention relates to an oral mucosal delivery system for transmucosal administration of an active agent, comprising an active agent-containing layer containing remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof, as the active agent.

[0072] The active agent-containing layer comprises i) remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof as the active agent, and ii) a film-forming agent.

[0073] Thus, an oral mucosal delivery system for transmucosal administration of an active agent comprises an active agent-containing layer, which layer comprises: i) as an active agent, remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof; ii) a film-forming agent.

[0074] This oral mucosal administration route is a relatively new form of drug delivery, which means that there is limited knowledge about formulation technology.Therefore, it is difficult to formulate a suitable dosage form for transmucosal delivery by oral mucosal dosage form.As further explained above, the oral mucosal delivery system of the present invention surprisingly provides suitable transmucosal drug delivery, avoiding the first-pass effect associated with intestinal delivery, and has been shown to achieve high bioavailability, as demonstrated by the preclinical results further shown below.

[0075] Oromucosal dosage forms are non-invasive, simple and ready to use, and in this respect address the needs and shortcomings of IV formulations.

[0076] As outlined above, the oral mucosal delivery system is composed of one or more thin layers, and thus in certain embodiments, the oral mucosal delivery system is in the form of a film. Such films may have a circular, rectangular or square shape, or any other shape.

[0077] The film has a certain thickness; otherwise, it is difficult to incorporate the required amount of active substance, and very thin films are not easy to manufacture, especially with regard to providing a uniform thickness. Thus, in certain embodiments, the oral mucosal delivery system is in the form of a thin film, and the film has a thickness of at least 100 g / m 2 , at least 110g / m 2 , or at least 120 g / m 2 or 400 g / m 2 Below 300g / m 2 or less, or 250g / m 2 and / or the film has an area weight of 100 g / m 2 ~230g / m 2 or less, or 300g / m 2 ~400g / m 2 It has the following area weight:

[0078] In certain embodiments of the present invention, the oral mucosal delivery system is in the form of a film, the film having a thickness of at least 0.5 cm 2 , or 10cm 2 Less than or equal to 1.5cm 2 , about 3cm 2 or about 6 cm 2 It has a size of

[0079] In some embodiments, the oral mucosal delivery system for transmucosal administration of an active agent according to the present invention does not contain a preservative.

[0080] Active agent-containing layer As outlined in more detail above, the oral mucosal delivery system according to the present invention comprises an active agent-containing layer comprising remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof as an active agent, and a film-forming agent.

[0081] As outlined above, and without wishing to be bound by theory, it is believed that a sufficient amount of active agent contained in the oral mucosal delivery system is necessary to achieve certain advantageous characteristics of the oral mucosal delivery system according to the present invention, such as good in vitro permeation. On the other hand, a thick layer may not only cause discomfort in the oral cavity, but also be difficult to manufacture and may result in the layer taking too long to dissolve for the desired release profile. Furthermore, too much active substance may lead to undesirable storage stability issues, such as recrystallization of the active agent when it is present in a dissolved form, as well as a potentially irritating sensation in the oral cavity due to too high a drug concentration.

[0082] The amount of active agent contained in the oral mucosal delivery system can be controlled in two ways by adjusting the concentration and / or area weight of the active agent-containing layer. Thus, in certain embodiments of the present invention, the active agent-containing layer contains at least 20%, at least 25%, or at least 30% by weight of active agent, and / or up to 60%, up to 55%, or up to 50% by weight of active agent, and / or 20-60%, 25-55%, or 30-50% by weight of active agent.

[0083] In certain embodiments of the present invention, the active agent-containing layer has a density of at least 4 mg / cm 2 , at least 6 mg / cm 2 , or at least 8 mg / cm 2 of active agent, and / or 15 mg / cm 2 Below, 13mg / cm 2 or less than 11 mg / cm 2 The following active agents and / or 4-15 mg / cm 2 , 6-13 mg / cm 2 , or 8-11 mg / cm 2 Contains an active agent.

[0084] In terms of active amount, the oral mucosal delivery system may contain at least 5 mg, at least 10 mg, or at least 15 mg of active agent, and / or up to 80 mg, up to 70 mg, or up to 60 mg of active agent, and / or up to 5-80 mg, 10-70 mg, or 15-60 mg of active agent.

[0085] As outlined above, the amounts of active agent provided herein are defined with respect to the free base form of remimazolam, i.e., if the buccal delivery system contains at least 10 mg of remimazolam, this corresponds to at least 13.6 mg of remimazolam besylate as described above.

[0086] The correct dissolution behavior of the active agent-containing layer is important for controlling the delivery route. The faster the oral mucosal delivery system disintegrates, the more likely dissolution in saliva will be preferred over direct delivery to the mucosa at the attachment site. In particular, indirect delivery, which can utilize the entire mucosa for drug delivery, is important to achieve high permeation rates. This means that the oral mucosal delivery system should disintegrate relatively quickly.

[0087] Since it is preferable that the active agent-containing layer can be directly attached to the mucosa, in certain preferred embodiments of the present invention, the active agent-containing layer is mucoadhesive.As will be outlined in more detail below, tactility is an important aspect for oral mucosal delivery systems.Therefore, in certain embodiments, the active agent-containing layer is in the form of a foam or a plastic monolithic film.Such an active agent-containing layer in foam form or plasticity provides a more comfortable mouthfeel and is therefore beneficial in this sense.

[0088] In certain embodiments of the invention, the active agent-containing layer comprises no more than 3% by weight, no more than 2% by weight, no more than 1% by weight, or no more than 0.5% by weight of water.

[0089] Even more surprisingly, it has been found that the mucosal permeation rate of the oral mucosal delivery system of the present invention is advantageous at certain pH levels. Thus, in some embodiments of the present invention, the oral mucosal delivery system is in the form of a film and has a permeation rate of 5, 75 cm 2 A sample film of the oral mucosal delivery system of size 1 is dissolved in 5 mL of artificial saliva or 0.9% NaCl solution, and the pH of the resulting solution is in the range of pH 3.0 to pH 3.7 as measured with a pH electrode.

[0090] activator According to the present invention, the active agent-containing layer contains as the active agent remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof, specifically in a therapeutically effective amount.

[0091] According to the present invention, the active agent may be present in the oral mucosal delivery system, particularly in the active agent-containing layer, in any form, for example, in free base form, in the form of a pharmaceutically acceptable salt, or any mixture thereof, and it is preferred that remimazolam is present in the form of a pharmaceutically acceptable salt.

[0092] That is, in some particular 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.

[0093] Furthermore, 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.

[0094] 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, so that the active agent is present in dispersed form. Of course, if the active agent is present in dispersed form, the active agent-containing layer may still contain the active agent in dissolved form, depending on the solubility (e.g., saturated or supersaturated) of the active substance in the active agent-containing layer.

[0095] In a preferred embodiment, the active agent is completely dissolved, e.g., 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 is free of active agent crystals.

[0096] As outlined above, the amount of active agent in the oral mucosal delivery system is believed to be important for successful release of the active agent and can be adjusted, for example, by the active agent concentration. Thus, in certain embodiments, the concentration of active agent in the active agent-containing layer is in the range of 20-60%, 25-55%, or 30-50% by weight of the active agent-containing layer.

[0097] The oral mucosal delivery systems according to the present invention advantageously exhibit improved stability with respect to active agent content as well as active agent degradation.

[0098] Thus, in certain embodiments, the active agent-containing layer initially (i.e., immediately after manufacture, e.g., 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 active agent contained in the active agent-containing layer, the theoretical amount being calculated from the amount of active agent used in the coating composition and the (actual) areal weight of the coated and dried active agent-containing layer of the tested oral mucosal delivery system.

[0099] The active agent-containing layer may also initially contain no more than 0.4 wt. %, no more than 0.3 wt. %, or no more than 0.2 wt. % remimazolam-related decomposition substances in total.

[0100] In certain other embodiments, the oral mucosal delivery systems according to the present invention are stable upon storage, i.e., they may maintain their initial remimazolam content value or exhibit small amounts of degradation products, as follows:

[0101] In one such embodiment, the active agent-containing layer contains remimazolam in an amount of 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 after storage at 60°C for up to 6 or 9 weeks.

[0102] The active agent-containing layer may also be subjected to storage stability testing and may contain less than or equal to 0.5% by weight, or less than or equal to 0.4% by weight, of total remimazolam-related decomposition substances after storage at 60°C for up to 6 weeks.

[0103] The method for determining the remimazolam content and the total amount of remimazolam-related degradation substances is preferably performed by validated HPLC-UV as described in the Examples section.

[0104] Film-forming agents As outlined above, the oral mucosal delivery system according to the present invention comprises an active agent-containing layer containing remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof as an active agent, and a film-forming agent.

[0105] The film-forming agent forms a matrix and provides sufficient adhesion of the active agent-containing layer as long as it is kept dry. According to certain embodiments, the film-forming agent may also provide sufficient adhesion to the mucosa once wetted, i.e., upon contact with the mucosa. In such embodiments, but also generally, the film-forming agent may be selected from mucoadhesive polymers.

[0106] The film-forming agent is the primary control over the dissolution / disintegration behavior of the active agent-containing layer. By selecting an appropriate film-forming agent, the adhesion to the mucosa and disintegration behavior can be appropriately adjusted, for example, not only with respect to disintegration time, but also with respect to the integrity of the oral mucosal delivery system.

[0107] Suitable film formers according to the present invention are, for example, 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® 250L from Ashland Industries), hydroxypropylcellulose (commercially available as Klucel® from Ashland Industries), hydroxypropylmethylcellulose (also known as hypromellose and commercially available as Pharmacoat® from Shin-Etsu), sodium carboxymethylcellulose (the non-crosslinked sodium salt of carboxymethylcellulose, also known as CMC or carmellose and commercially available from Ashland Industries), and the like. Industries as Blanose®), polyethylene glycol-polyvinyl acetate- and polyvinyl caprolactam-based graft copolymers (BASF as Soluplus®), polyvinyl alcohol (Merck as Emprove®), polyvinyl alcohol-polyethylene glycol copolymers (BASF as Kollicoat® IR), polyvinylpyrrolidone-polyvinyl acetate copolymers (also known as copovidone, BASF as Kollidon® VA64), polyethylene oxide, polyethylene glycol, methacrylic acid-methyl methacrylate copolymers (Eudragit® L100, Eudragit® L12, 5, Eudragit® S100, and Eudragit® S12, from Evonik),5), and methacrylic acid-ethyl methacrylate copolymers (available from Evonik as Eudragit® L100-55 and Eudragit® L30D55), as well as natural film-forming agents such as shellac, pectin, gelatin, alginates, pullulan, and starch derivatives, and mixtures thereof. Commercially available mixtures include, for example, Kollidon® SR (a physical mixture of 80% polyvinyl acetate and 19% povidone (Kollidon® 30), containing approximately 0.8% sodium lauryl sulfate and approximately 0.2% silica used as a stabilizer) and Kollicoat® Protect (a mixture containing 55-65% polyvinyl alcohol-polyethylene glycol graft copolymer, 35-45% polyvinyl alcohol, and 0.1-0.3% silicon dioxide as a processing aid).

[0108] The film-forming agent should not only provide sufficient adhesion to the active agent-containing layer, but also preferably provide a film that is not sticky in the dry state so that a patient can touch and manipulate the active agent-containing layer, for example, by applying the oral mucosal delivery system including the active agent-containing layer to the oral mucosa without sticking it to their fingers. In addition, since the film-forming agent is the primary control over the dissolution behavior of the active agent-containing layer, which must not be too fast or too slow, the dissolvable film-forming agent is preferably soluble, dispersible, or otherwise disintegrable in an aqueous medium, specifically saliva, or simply water. On the other hand, film-forming agents that are soluble in other solvents, such as C1-C3 alcohols, for example, ethanol, are also preferred for ease of manufacturing and to enable a water-free manufacturing process (which is advantageous in terms of the stability of the active agent).

[0109] The present inventors have surprisingly found that, in view of the above, polymers such as polyvinyl alcohol, polyvinyl alcohol-polyethylene glycol graft copolymer, polyethylene oxide, polyvinylpyrrolidone, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol, hydroxypropyl methylcellulose, or mixtures thereof are preferred as dissolvable film-forming agents.

[0110] Preferred film-forming agents are polyvinyl alcohol and polyvinyl alcohol-polyethylene glycol graft copolymers, especially polyvinyl alcohol. Polyvinyl alcohol-polyethylene glycol graft copolymers are commercially available from BASF under the name Kollicoat® IR. Kollicoat® IR is particularly preferred, a polymer consisting of 75% polyvinyl alcohol units and 25% polyethylene glycol units, further containing approximately 0.3% colloidal silica to improve flow properties, and having a MW of 45,000 AMU. Polyvinyl alcohol is commercially available from Kuraray under the brand name Mowiol and from Merck under the brand names Parteck® MXP and Emprove®, and is offered in several grades with different degrees of hydrolysis and molecular weights. 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 with a molecular weight in the range of 10,000 to 250,000. The molecular weights are determined as weight averages of the molar masses Mw by gel permeation chromatography (GPC) combined with static light scattering (absolute method) on reacetylated standards.

[0111] Mowiol partially hydrolyzed grades vary in molecular weight MW as follows: PVA 3-83 has a MW of approximately 14,000; PVA4-88 has a MW of approximately 31,000; PVA5-88 has a MW of approximately 37,000; PVA8-88 has a MW of approximately 67,000; PVA18-88 has a MW of approximately 130,000; PVA23-88 has a MW of approximately 150,000; PVA26-88 has a MW of approximately 160,000; PVA40-88 has a MW of approximately 205,000. On the other hand, Mowiol fully hydrolyzed grades have different molecular weights MW, as follows: PVA3-98 has a MW of approximately 16,000; PVA4-98 has a MW of approximately 27,000; PVA6-98 has a MW of approximately 47,000; PVA10-98 has a MW of approximately 67,000; PVA20-98 has a MW of approximately 130,000; PVA56-98 has a MW of approximately 150,000; PVA28-99 has a MW of approximately 160,000 Parteck® MXP4-88 grade PVA has a MW of 32,000, and Parteck® MXP3-82 grade PVA has a MW of 47,000. In these grade designations, the first number indicates the apparent viscosity (mPa·s) of a 4% aqueous solution at 20°C, and the second number indicates the hydrolysis grade as a percentage. Thus, Parteck® MXP3-82 indicates a viscosity of 3 mPa·s and a hydrolysis grade of 82%, while Parteck® MXP 4-88 indicates a viscosity of 4 mPa·s and a hydrolysis grade of 88%.

[0112] A certain amount of dissolvable film-forming agent should be included to provide sufficient adhesion to the active-agent-containing layer. Thus, in certain preferred embodiments, the active-agent-containing layer comprises at least 10%, at least 13%, or at least 15% by weight of film-forming agent, up to 75%, up to 50%, or up to 30% by weight of said film-forming agent, and / or 10-75%, 13-50%, or 15-30% by weight of said film-forming agent.

[0113] However, the amount of film-forming agent will need to be adapted depending on the presence of further excipients in the formulation. As outlined in the next section, the above figures take into account that certain amounts of plasticizers may be present.

[0114] In other embodiments, the active-agent-containing layer is plasticizer-free and comprises at least 50%, at least 60%, or at least 65% by weight of film-forming agent, up to 85%, up to 75%, or up to 70% by weight of film-forming agent, and / or 50-85%, 60-75%, or 65-70% by weight of said film-forming agent. The active-agent-containing layer may also consist essentially of the active agent and the film-forming agent.

[0115] Film-forming agents such as those described above may be present as film-forming agents in the active agent-containing layer, but may also be contained in any further (optional) layer or optional overlayer.

[0116] plasticizer The active agent-containing layer of the oral mucosal delivery system according to the present invention comprises remimazolam, its pharmaceutically acceptable salt, or any other form thereof, as an active agent, and a film-forming agent. Depending on factors such as the type and amount of film-forming agent, the form and amount of the active agent, and other components of the formulation or the manufacturing process, it may be beneficial to incorporate a plasticizer. The plasticizer improves the plasticity of the active agent-containing layer, thereby reducing the risk of the layer becoming brittle over time. The plasticizer can also improve the tactile sensation of the oral mucosal delivery system upon administration to the oral mucosa, i.e., provide a pleasant tactile sensation in the mouth.

[0117] Thus, in some embodiments of the present invention, the active-agent-containing layer may further comprise a plasticizer.

[0118] In other words, in some particular embodiments, the active agent-containing layer comprises: i) as an active agent, remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof; ii) a film former; and iii) a plasticizer.

[0119] The plasticizer is selected from the group consisting of linear or branched saturated or unsaturated alcohols having 6 to 20 carbon atoms, triglycerides, polyethylene glycol, or polyvinyl alcohol-polyethylene glycol graft copolymers. Particularly preferred are polyethylene glycol and polyvinyl alcohol-polyethylene glycol graft copolymers. In a more preferred embodiment, polyvinyl alcohol-polyethylene glycol graft copolymers are used as the plasticizer, and the film former is polyvinyl alcohol (grades 4-88 and 40-88), preferably having a molecular weight of 31,000 or 205,000, or a mixture thereof.

[0120] 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% plasticizer, no more than 50 wt%, no more than 40 wt%, or no more than 35 wt% plasticizer, and / or 5-50 wt%, 15-40 wt%, or 20-35 wt% plasticizer.

[0121] In order to provide a good balance between the amount of film former and plasticizer, which on the one hand provide the matrix of the active agent-containing layer, and the amount of active agent, it is useful to maintain the total amount of film former and plasticizer within a certain range or to provide the two components in a specific ratio.

[0122] Thus, in some specific embodiments of the present invention, the active-agent-containing layer comprises a total amount of film-forming agent and plasticizer, the total amount being at least 30%, at least 35%, or at least 40% by weight of the active-agent-containing layer, 80% or less, 60% or less, or 45% or less by weight of the active-agent-containing layer, and / or 30-80%, 35-60%, or 40-45% by weight of the active-agent-containing layer. Also, in certain embodiments, the active-agent-containing layer comprises a plasticizer, the film-forming agent is polyvinyl alcohol, and the ratio of polyvinyl alcohol to plasticizer is at least 20:80, or not more than 50:50, or 20:80 to 50:50, or about 25:75, or about 40:60.

[0123] In certain embodiments of the present invention, the active-agent-containing layer is plasticizer-free and comprises at least 50%, at least 60%, or at least less than 65% by weight of a film-forming agent, 85% or less, 75% or less, or 70% or less by weight of a film-forming agent, and / or 50-85%, 60-75%, or 65-70% by weight of a film-forming agent, and / or the active-agent-containing layer consists essentially of (i) the active agent and (ii) the film-forming agent.

[0124] Further excipients The active agent-containing layer of the oral mucosal delivery system according to the present invention may contain additional excipients common in the art, such as fatty acids, sweeteners, flavoring agents, coloring agents, permeation enhancers, solubilizers, plasticizers, humectants, disintegrants, emulsifiers, antioxidants, stabilizers, buffering agents and additional film-forming agents.

[0125] In certain embodiments, the active agent-containing layer further comprises one or more excipients selected from the group consisting of sweeteners, flavoring agents, antioxidants, and pH adjusters. As outlined above, the active agent is preferably present in the form of a besylate or tosylate addition salt, which can provide the desired pH value. Thus, the presence of a pH adjuster does not always seem to be necessary. That is, in certain embodiments, the active agent-containing layer does not comprise a pH adjuster.

[0126] The excipients may be present in the active agent-containing layer in an amount of 0.001 to 15% by weight of the active agent-containing layer per excipient. In certain embodiments, the total amount of all additives is 0.001 to 25% by weight of the active agent-containing layer. When a range of amounts for a particular additive is provided below, such range refers to the amount per individual additive.

[0127] It should be noted that in pharmaceutical formulations, formulation components are categorized according to their physicochemical and physiological properties and according to their functions. This means, in particular, that substances or compounds classified as one category of formulation components are not excluded from classification in another category. In such cases, for purposes of calculation in the patent claims (e.g., for determining weight percentages, ratios, etc.), such substances or compounds are preferably assigned to the appropriate category first mentioned in the respective claim. For example, certain polymers, such as polyvinyl alcohol-polyethylene glycol graft copolymers, can be plasticizers but can also be film-forming agents. Some substances, for example, can be typical emollients and simultaneously act as permeation enhancers. Those skilled in the art can determine to which category(ies) of formulation components a particular substance or compound belongs based on their general knowledge. Details of excipients and additives are provided below, but these should not be understood as being exclusive. Other substances not explicitly listed herein may also be used in accordance with the present invention, and substances and / or compounds explicitly listed as one category of formulation components are not excluded from use as another formulation component within the meaning of the present invention.

[0128] Particularly preferred as excipients are substances that can mask or modify the taste, or that can otherwise mitigate any potential unpleasant effects of remimazolam.

[0129] 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. In certain preferred embodiments, the active agent-containing layer comprises one or more natural or artificial sweeteners that may be 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 glycoside, thaumatin, 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, thaumatin, 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., when the active agent-containing layer comprises one or more natural or artificial sweeteners, the active agent-containing layer comprises at least 0.05% by weight or at least 0.5% by weight of sweetener, no more than 2% by weight or no more than 1% by weight of sweetener, and / or between 0.05% by weight and 2% by weight or between 0.5% by weight and 1% by weight of sweetener.

[0130] In a preferred embodiment, the active-agent-containing layer contains one or more natural or artificial flavors selected from the group consisting of vanillin, methyl salicylate, menthol, manzanate, diacetyl, acetylpropionyl, acetoin, isoamyl acetate, benzaldehyde, cinnamaldehyde, ethyl propionate, methyl anthranilate, limonene, ethyl decadienoate, allyl hexanoate, ethyl maltol, 2,4-dithiapentane, ethyl vanillin, and eucalyptol, as well as flavor compositions such as peppermint flavor and MANE flavor, e.g., MANE orange flavor or MANE Tutti Frutti Flavor. Preferred flavor compositions include MANE orange flavor, which is a combination of linalool, alpha-pinene, citral, delta-3 carene, beta-pinene, and myrcene, and MANE Tutti Frutti Flavor, which is a combination of geranyl acetate, vanillin, limonene, and allyl hexanoate. In such embodiments, i.e., when the active agent-containing layer includes one or more flavoring agents, the active agent-containing layer includes at least 0.05% by weight or at least 0.5% by weight of flavoring agent, no more than 5% by weight or no more than 2% by weight of flavoring agent, and / or between 0.05% by weight and 5% by weight or between 0.5% by weight and 2% by weight of flavoring agent.

[0131] Suitable flavoring agents are also commercially available from Mane Company, and any of those identified by flavorings such as apple, caramel, chocolate, lemon, mint, etc. may be used as flavoring agents in the present invention.

[0132] The active agent-containing layer according to the present invention may contain a pH adjuster as described above. The pH adjuster may be selected from, for example, mono- and polytropic acids, mono-, di-, and tri-basic acids, buffers containing a mixture of a weak acid and its conjugate base, amine derivatives, inorganic alkali derivatives, and polymers with basic and acidic functionality. The active agent-containing layer according to the present invention may also contain an antioxidant. Suitable antioxidants include, for example, ascorbic acid, α-tocopherol, ascorbyl palmitate, and sodium metabisulfite.

[0133] Pharmaceuticals As outlined above, according to one embodiment, the present invention relates to a pharmaceutical product comprising packaging and one or more unit doses of an oral mucosal delivery system.

[0134] In certain embodiments, the packaging is in the form of a pouch. The pouch may be made of a multilayer film material including an outer paper layer, a middle polyethylene layer, and an inner aluminum layer. The pouch may be sealed with a sealant to protect the contained unit dose of the oral mucosal delivery system from, for example, moisture or oxygen. In certain embodiments, the sealant is selected from the group consisting of ethylene copolymers (modified ionomers, such as those commercially available as Surlyn®), or polyethylene terephthalate copolymers and cyclic olefin copolymers.

[0135] In certain embodiments, the pouch is filled with nitrogen as an additional protection against moisture and the associated degradation of the active agent. The pouch may also include one or more desiccants, but does not necessarily include a desiccant. In certain embodiments, the desiccant includes silica gel, molecular sieve 4Å, and / or zeolite molecular sieve 4Å as a drying agent and / or is in the form of an adhesive film. The adhesive film can be attached to the inward-facing side of the pouch. Such adhesive desiccants are commercially available as DesiMax.

[0136] In further embodiments, the pharmaceutical product comprises a folded polyethylene terephthalate foil within the primary packaging, and one or more unit dose(s) of the oral mucosal delivery system are enclosed by the folded polyethylene terephthalate foil, which is folded around to protect the unit dose(s) from further contact with the packaging. In such cases, the pouch may comprise one or more desiccant(s) in the form of an adhesive film attached to the outward 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 comprise such a folded polyethylene terephthalate foil.

[0137] Methods for producing sedation and other methods According to a particular aspect of the present invention, the oral mucosal delivery system according to the present invention is for use in producing sedation, hypnosis, anxiolysis, muscle relaxation, treatment of convulsions, or inducing amnesia for perioperative events. According to another aspect, the present invention relates to a method for producing sedation, hypnosis, anxiolysis, muscle relaxation, treatment of convulsions, or inducing amnesia for perioperative events, wherein the oral mucosal delivery system is administered to a subject, preferably a human patient. According to 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, anxiolysis, muscle relaxation, treatment of convulsions, or inducing amnesia for perioperative events.

[0138] As explained above, remimazolam is a very promising ultra-short acting sedative approved for both procedural sedation and general anesthesia.

[0139] Thus, in certain embodiments, the sedation referred to in the different aspects above is procedural sedation, such as sedation for dental procedures or sedation for diagnostic procedures, preoperative sedation, and / or conscious sedation. Sedation may 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 for the performance of an endoscopy (preferably an upper gastrointestinal endoscopy or colonoscopy), a dental procedure, a diagnostic procedure, imaging, or a brief, uncomfortable procedure (e.g., changing a wound dressing or manipulating a catheter, e.g., removing a central catheter).

[0140] Regarding the sedative effect, in certain embodiments, mild sedation, moderate sedation, deep sedation, or general anesthesia is achieved. In certain embodiments, the duration of sedation or general anesthesia achieved is 5 to 30 minutes, 8 to 20 minutes, or 10 to 15 minutes.

[0141] To achieve soothing, in certain embodiments, the oral mucosal delivery system is administered by applying the active agent-containing layer to the mucosa, particularly the buccal, sublingual, gingival, or palatal mucosa of the oral cavity of a human patient, and remaining on the mucosa until dissolving.

[0142] As outlined above, transmucosal delivery avoids the first-pass effect, and therefore the oral mucosal delivery system according to the present invention has a low risk of any unintended effects, such as those caused by hepatic metabolism, and is advantageous in terms of patient acceptability compared to IV administration.Therefore, there is no limitation regarding the patient group.The subject may be a human patient with or without liver impairment, including the elderly and children.

[0143] Manufacturing Process The present invention further relates to a process for manufacturing an active agent-containing layer for use in an oral mucosal delivery system, as well as the corresponding active agent-containing layer and the corresponding oral mucosal delivery system.

[0144] According to the present invention, the manufacturing process of the active agent-containing layer comprises the following steps: i. combining at least (i) as an active agent, remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof, and (ii) a film-forming agent to obtain a mixture; ii. forming an active agent-containing layer.

[0145] In such a process, suitable film-forming agents are the same as those described above.

[0146] Step ii. forming an active agent-containing layer can be performed by any known method. In certain embodiments, the process is a hot melt process, a coating process, or a foam-forming process.

[0147] The hot melt process may be a hot melt extrusion process or a vacuum compression molding process, wherein: The hot melt extrusion process comprises the following steps: a. introducing the mixture comprising the active agent and the film former, with or without additional excipients, into an extruder; b. heating the mixture to at least the softening temperature of the mixture; 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; on the other hand, The vacuum compression molding process comprises the following steps: a. introducing the mixture comprising the active agent and a film-forming agent, with or without an excipient, into a sample chamber; b. compressing 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.

[0148] Meanwhile, the coating process consists of the following steps: i. dispersing or dissolving the active agent in a solution of the film-forming agent, with or without additional excipients, to obtain a coating composition; ii.a. coating the coating composition onto a coating substrate; b. drying the laminated segment in a drying oven to obtain the active-agent-containing layer in the form of a plastic monolithic film.

[0149] Finally, the foam forming process involves the following steps: i. dispersing or dissolving the active agent in an aqueous solution of the film-forming agent, with or without additional excipients, to obtain a coating composition; ii.a. foaming the coating composition to obtain a foam coating composition; b. coating the foam coating composition onto a coating substrate; c. drying the laminated segment in a drying oven to obtain the active-agent-containing layer in the form of a foam.

[0150] In such embodiments, foaming can be achieved by stirring while introducing nitrogen gas into the composition, which may be particularly fast and / or may use a foaming device that includes a foaming head equipped with a dispersion unit.

[0151] According to a further aspect, the present invention relates to a process for the manufacture of an oral mucosal delivery system comprising an active agent-containing layer comprising (i) as an active agent, remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof, and (ii) a film-forming agent, said process comprising: i. combining at least the active agent and a film-forming agent to obtain a mixture; ii. forming an active agent-containing layer.

[0152] According to a further aspect, the present invention relates to an oral mucosal delivery system obtainable by such a process.

[0153] According to certain embodiments, one or more unit doses of the oral mucosal delivery system may be packaged in a primary package to provide the pharmaceutical product. In such embodiments, the primary package may be in the form of a pouch, as further described above. The packaging step may be performed under a nitrogen atmosphere to obtain a nitrogen-filled pouch that protects from environmental moisture. [Example]

[0154] The present invention will now be more fully described with reference to the accompanying examples. However, it should be understood that the following description is illustrative only and should not be construed as limiting the invention in any way. The numerical values ​​provided in the examples regarding the amounts or area weights of components in the compositions may vary slightly due to manufacturing variations. Examples 1A to 1H Preparation of coating composition (active agent-containing layer) and coating of the coating composition

[0155] The formulations of Examples 1a-1h are summarized in Tables 1-6. In these tables and below, "Amt [g]" refers to the amount in grams. The active agent, remimazolam besylate, was ground using a pestle.

[0156] In Example 1a, remimazolam besylate (hereinafter also referred to as RMZ) was added to a beaker. Purified water was then added, and the mixture was stirred at 1000 rpm for 1 minute. PEG 300 was then added, and the mixture was again stirred at 1000 rpm for 1 minute. Kollicoat® Protect was added while stirring at 1000-2000 rpm. After the final addition, stirring was continued at 2000 rpm for 5 minutes.

[0157] The resulting active agent-containing foam coating composition was coated onto polyethylene terephthalate (thickness: 100 μm) and dried at 70° C. for 45 minutes. The coating thickness was 232 g / m2 This resulted in an area weight of

[0158] [Table 1]

[0159] For Example 1b, remimazolam besylate was charged to a beaker, and PEG 300 and 199.61 g of purified water were added. The beaker was swirled, and then 26.2 g of a solution of 14.48 g of Methocel E3LV and 8.07 g of Methocel E50LV in 127.55 g of purified water was added. The mixture was stirred at 1000 rpm for 10 minutes, followed by stirring at 2000 rpm for 5 minutes, and then stirring at 100 rpm for 5 minutes.

[0160] The obtained active agent-containing coating composition was coated onto polyethylene terephthalate (thickness: 100 μm) and dried at 70° C. for 45 minutes. The coating thickness was 103 g / m 2 This resulted in an area weight of

[0161] [Table 2]

[0162] For Example 1c, remimazolam besylate was placed in a beaker and 87.7 g of a solution of PEG 300 and 1300.1 g of purified water with 700 g of PVA 4-88 was added. The mixture was stirred until the remimazolam besylate was dispersed in the mixture and a foam formed.

[0163] The resulting active agent-containing foam coating composition was coated onto Polysik 111 / 80 (one side siliconized) and dried at 70°C for 15 minutes. The coating thickness was 181 g / m 2 This resulted in an area weight of

[0164] [Table 3]

[0165] For Example 1d, the heating jacket was preheated to 150°C. Polyox N10 was added to a beaker, which was then placed in the preheated heating jacket. The Polyox N10 was stirred at 57 rpm for 45 minutes, then at 150 rpm for 65 minutes, and then at 250 rpm for 130 minutes. The temperature of the Polyox N10 was 136°C. Remimazolam besylate was added with stirring at 300 rpm. Stirring was continued at 520 rpm for 15 minutes. The temperature at this point was 135°C.

[0166] The resulting active agent-containing coating composition was coated onto polyethylene terephthalate (100 μm thick) using a hot melt coater with both the top and bottom rollers heated to 150° C. and a gap width of 405 mm. The coating thickness was 355 g / m 2 This resulted in an area weight of

[0167] [Table 4]

[0168] For Examples 1e and 1g, purified water was added to a beaker and the film former (Kollidon VA64 or Soluplus) was added while stirring at 1500 rpm. Stirring was continued at 250 rpm for 1.25 hours, followed by overnight swelling. The next day, remimazolam besylate was added to the beaker. PEG300 was added, followed by hand mixing. The swollen mixture of film former in purified water was then added, followed by stirring the newly formed mixture at 250 rpm for 45 minutes.

[0169] The resulting active agent-containing coating composition was coated onto Polysik (one side siliconized) and dried at 70°C for 25 minutes. The coating thickness was 244 g / m 2 (1e) or 123g / m 2 This resulted in an area weight of (1 g).

[0170] For Examples 1f and 1h, remimazolam besylate was placed in a beaker and methanol was added until the remimazolam besylate was dissolved. Then, the film former (Kollidon VA64 or Soluplus) was added under stirring, followed by PEG300 to the mixture.

[0171] The active agent-containing coating composition was coated onto Polysik 111 / 80 (one side siliconized) and dried at 70°C for 30 minutes. The coating thickness was 63 g / m 2 This resulted in an area weight of

[0172] [Table 5]

[0173] [Table 6]

[0174] Preparation of Oral Mucosal Delivery Systems (for all Examples) Individual oral mucosal delivery systems were then punched out from the active agent-containing layer. The oral mucosal delivery systems were then sealed in moisture-proof Surlyn™ pouches. In Example 1D, the oral mucosal delivery system was sealed in a Surlyn® pouch along with two moisture-absorbing patches (DesiMax).

[0175] Stability studies to assess the stability of remimazolam besylate in different formulations The prepared buccal delivery systems according to Examples 1a-1h were sealed in Surlyn® packaging and stored at 25°C / 60% RH and 40°C / 75% RH for 2, 4, and 8 weeks. Samples were analyzed to obtain a rapid stability assessment of potential API-excipient-solvent interactions that may lead to any instability resulting in the formation of new impurities and / or degradation products (e.g., via hydrolysis). Tests for remimazolam content and degradation products were performed after 2, 4, and 8 weeks of storage.

[0176] At predetermined intervals, as shown in Table 7, samples were taken and tested for assay and degradation products of remimazolam. Therefore, 20.0 mL of diluent (HO / ACN 3:1 (v / v)) was added to each sample and stirred for approximately 45 minutes. Aliquots of the resulting sample solutions were then centrifuged at 10,000 rpm for 10 minutes (approximately 5°C) and analyzed by a validated HPLC-UV method. A drug-free matrix sample served as a reference to allow for the assignment of potential interferences due to the excipients used. The results are shown in Table 8.

[0177] [Table 7]

[0178] [Table 8]

[0179] The degradation products CNS7054 (hydrolysis) and CNS7084 were measured in varying amounts in all formulations. Additionally, an unknown impurity was detected in varying amounts in all formulations.

[0180] The PVA4-88 based foam (Example 1c) and Polyox™ N10 based hot melt (Example 1d) formulations showed acceptable levels of degradation products, but unknown impurities were detected in both formulations. All other approaches showed high levels of degradation (especially hydrolysis) and unknown impurities.

[0181] In vivo studies in Examples 1c and 1d using Göttingen minipigs An in vivo study was conducted using Göttingen minipigs (female, approximately 3 months old, weighing 7 kg at the start of the study) to evaluate the pharmacokinetic profile and efficacy of buccally administered oral mucosal delivery systems containing remimazolam besylate. Three minipigs were used. A single oral mucosal delivery system of Example 1c (foam) or 1d (hot melt), prepared as described above with a nominal dose of 20 mg of remimazolam (formulated as a nominal dose of 27.2 mg of remimazolam besylate), was used per animal (excluding Animal No. 3 in Phase 1, in which 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.

[0182] [Table 9]

[0183] The formulations of the placebo systems corresponding to Examples 1c (foam) and 1d (hot melt) are summarized below in Table 10. Coating compositions were prepared as described for Examples 1c and 1d above.

[0184] [Table 10]

[0185] Doses were given via buccal administration (oral mucosal delivery systems; hot melt and foam) or IV administration (10 mg of remimazolam formulated as remimazolam besylate according to the treatment schedule shown in Table 9). Doses were spaced at least 48 hours apart to allow for adequate cleaning. Treatment with the oral mucosal delivery system was administered as follows: 1. Animals were anesthetized by mask with isoflurane to achieve a depth of anesthesia sufficient to facilitate placement of the oromucosal delivery system without stressing the animals. The duration and concentration of isoflurane anesthesia were similar for all animals. 2. The oral mucosal delivery system was placed on the buccal mucosa. A small amount of saline was applied to the mucosa to facilitate the dissolution process in phase 1. 3. The minipig's mouth was closed for 1-2 minutes and then opened to confirm complete dissolution of the oral mucosal delivery system. If the oral mucosal delivery system did not dissolve, further testing was performed at 1-2 minute intervals as needed. 4. Isoflurane treatment was discontinued as soon as the oromucosal delivery system dissolved.

[0186] To assess bioavailability, animals were also given a single intravenous (IV) dose, which was administered as a bolus over a period of approximately 1 minute.

[0187] RMZ IV dose formulations were prepared in glass containers. To prepare the above formulations at a nominal 5 mg / mL (stock solution), a drug product vial (50 mg of RZM powder) was reconstituted with 10 mL of 0.9% (w / v) sodium chloride solution. The reconstituted RMZ solution was clear and colorless to slightly yellow. The reconstituted RMZ drug product was used within 24 hours.

[0188] No local reactions were observed at the administration site 90 minutes after dosing.

[0189] Reflexes and depth of sedation were monitored and recorded every 5 minutes from the end of isoflurane administration until the animal was fully awake. In Phase 1, the time from induction to full recovery from isoflurane sedation was recorded. Depth of sedation was scored as shown in Table 11 below.

[0190] [Table 11]

[0191] Reflexes and depth of anesthesia were monitored every 5 minutes for at least 1 hour, and the depth of sedation was characterized as described in Table 11. The monitoring data for different animals are shown in Table 12, and the sedation profiles are shown in Figures 2a-2c. Only the first phase, in which animals received placebo, shows that the effect of isoflurane dissipates within 5-10 minutes. Therefore, any sedation observed after 10 minutes is considered related to this test item.

[0192] [Table 12-1] [Table 12-2]

[0193] With IV administration, the effects of the test item directly followed those of isoflurane, i.e., there was no decrease in sedation followed by an increase. High inter-animal variability was observed with the hot-melt oromucosal delivery system. Two of the three animals experienced an effect, with animal number 2 showing no sedation by 10 minutes, the time at which the isoflurane effect ended. The two animals that showed RMZ-related effects had maximum sedation scores of 1 and 3, with no full recovery observed before 35 and 60 minutes, respectively. Less inter-animal variability was observed with the foam oromucosal delivery system compared to the hot-melt variant. All three animals experienced an effect, with two animals reaching a maximum score of 2 and one animal reaching a score of 1. Three animals showed full recovery from RMZ-related effects by 35, 40, and 60 minutes after placement of the oromucosal delivery system.

[0194] Blood samples were collected from all animals after each dose in Phases 2-4. After application of the oromucosal delivery system, blood samples were collected at eight time points: pre-treatment and 2, 5, 10, 20, 40, 60, and 90 minutes post-treatment.

[0195] Concentrations of RMZ and CNS7054 in minipig plasma were determined using a validated liquid-liquid extraction followed by LC-MS / MS. All samples taken before treatment initiation were measured to be below the limit of quantification (0.100 ng / mL).

[0196] The individual plasma concentrations are listed in Table 13 and shown graphically in Figures 3a-5b. Additionally, the maximum plasma concentration (c max ), and the time it takes to reach it (t max ), and area under the curve (AUC 0-t Basic pharmacokinetic parameters, such as exposure, defined as the mean pharmacokinetic (MDR) of RMZ and CNS7054, and for individual animals following administration of either IV or the two oral mucosal delivery system formulations, are summarized in Table 13.

[0197] [Table 13-1] [Table 13-2]

[0198] These two oral mucosal delivery system formulations were compared to evaluate the plasma pharmacokinetics (PK) and c max The hot melt formulation of Example 1d shows higher variability in the PK profile of RMZ, which is in part driven by the results observed in Animal No. 1, with higher c at later time points. max The foam formulation of the oral mucosal delivery system has a faster release (t max The PK profile of CNS7054, the major metabolite of RMZ, was consistent with that observed for RMZ, with the foam formulation of the oral mucosal delivery system showing a slightly faster release rate than the hot melt formulation (20-40 min for the hot melt compared with 10-20 min for the foam) and a more uniform PK profile. However, this conclusion is based only on small animal numbers. The PK profile of CNS7054, the major metabolite of RMZ, was consistent with that observed for RMZ, with the foam formulation of the oral mucosal delivery system showing a slightly faster release rate than the hot melt formulation of the oral mucosal delivery system. max This is a slightly higher c maxThis, combined with the fact that the dose reaches 100 mg / kg / day, tends to result in higher exposure to metabolites when a foam formulation of an oral mucosal delivery system is administered, as well as when a hot melt formulation of an oral mucosal delivery system is administered.

[0199] To assess bioavailability (BA), dose-normalized c values ​​were measured for two oral mucosal delivery system formulations of RMZ and CNS7054. max (c max / D) and dose-normalized AUC (AUC 0-t / D) was determined. The results are summarized in Table 14.

[0200] [Table 14]

[0201] RMZ's c max The base BA ranged from 6 to 25% for the hot-melt oral mucosal delivery system formulation of Example 1d and from 9 to 25% for the foam oral mucosal delivery system formulation of Example 1c. The corresponding results for AUC-based BA were 16 to 51% and 24 to 41%. While mean exposure parameters were similar for the two RMZ oral mucosal delivery system formulations, the greater variability observed after application of the hot-melt oral mucosal delivery system formulation of Example 1d may indicate a lower likelihood of adhesion to the oral mucosa, which may lead to film detachment from the application site and accidental and unpredictable drug swallowing. As a result, a decrease in BA may be observed due to significant first-pass elimination of the swallowed dose portion. Relative exposure to CNS7054 was generally higher after administration of the oral mucosal delivery system foam formulation of Example 1c, consistent with its faster uptake compared to the oral mucosal delivery system hot-melt formulation of Example 1d. Taken together, the PK results indicate a very promising bioavailability (BA) of remimazolam when administered as an oromucosal delivery system. Examples 2A to 2B Preparation of coating composition (active agent-containing layer) and coating of the coating composition

[0202] The formulations of Examples 2a-2b are summarized in Table 15.

[0203] In Example 2a, remimazolam besylate and purified water were added to a beaker. The mixture was manually stirred until homogeneous. Kollicoat IR was then added, and the mixture was manually stirred again until homogeneous. PVA40-88 and purified water were added to the mixture, and the mixture was manually stirred until homogeneous, followed by stirring at 220 rpm for 50 minutes and then at 2000 rpm for 4 minutes to foam the mixture.

[0204] The resulting active agent-containing composition was coated onto Polysik 111 / 80 and dried at 70° C. for 25 minutes.

[0205] In Example 2b, ascorbic acid, sucralose, saccharin-Na, and purified water were added to a beaker. The mixture was stirred until all sweeteners were dissolved, and then remimazolam besylate was added. The mixture was manually stirred until homogeneous, followed by the addition of Kollicoat IR and manually stirring until homogeneous. A mixture of PVA40-88 and purified water was added, and the composition was manually stirred until homogeneous, followed by stirring at 220 rpm for 50 minutes and at 2000 rpm for 4 minutes to foam the mixture.

[0206] The resulting active agent-containing composition was coated onto Polysik 111 / 80 and dried at 70° C. for 25 minutes.

[0207] [Table 15]

[0208] Preparation of Oral Mucosal Delivery System (for Examples 2a and 2b) Individual oral mucosal delivery systems were then die-cut from the active agent-containing layer. The oral mucosal delivery systems were then sealed in water vapor-proof Surlyn® pouches, either without a moisture absorbent patch or with two moisture absorbent patches (DesiMax). Stability studies to assess the stability of remimazolam besylate in different formulations

[0209] The stress stability studies of Examples 2a and 2b were conducted at 60° C. with measurement time points of 2 weeks (2W), 6 weeks (6W), and 9 weeks (9W), with 9W set to extrapolate to 2 years in real time under Arrhenius kinetics assumptions.

[0210] For each measurement time point, a total of nine samples were provided, including three samples for the determination of water content by Karl Fischer method and six samples (test n=3) for the analysis and assay of degradation products (three of these samples were used as backups).

[0211] The results of the stability studies of Examples 2a and 2b are shown in Tables 16 and 17.

[0212] [Table 16]

[0213] [Table 17]

[0214] Stress stability studies showed that Example 2a (basic formulation without sweeteners and antioxidants) produced via a water-based manufacturing process was stable with respect to degradation only when pouched with a water-absorbing agent. Arrhenius kinetics was assumed; all samples of the basic formulation pouched with a water-absorbing agent could be stable for at least 2 years at 25°C.

[0215] This assumption can be supported by the results obtained for samples stored at 25°C for 5 and 6 months, since the levels of the known degradation products CNS7054 (samples without water absorbent) and CNS7084 were lower (after Arrhenius extrapolation) than those obtained for equivalent samples stored at 60°C for 2 weeks. In this regard, the degradation profile of samples stored at 25°C with a water absorbent for 2 years is expected to show fewer degradation products than the 9-week / 60°C data of the present stress stability study imply. However, official shelf life indications from stability studies (e.g., storage temperatures at 25°C and 40°C following ICH) are needed to determine the specific shelf life of each formulation.

[0216] For different unknown impurities that are known to be formed in relevant concentrations in part by oxidation reactions and therefore temperature induced, a lower degradation profile is expected at long-term conditions compared to the equivalent sampling time point at 60°C.

[0217] Example 2b, using sucralose, saccharin-Na, and ascorbic acid as sweetener and antioxidant, respectively, showed high degradation in both conditions (with and without absorbent) after 2 weeks at 60°C. The high degradation was accompanied by a very pronounced and strong brown to dark beige discoloration. CNS7054 was very low and the formation of unknown impurities was completely suppressed in the absorbent-containing sample after 2 weeks, whereas the concentration of CNS7084 was significantly higher, which may be related to incompatibility with the included sweeteners and / or antioxidants. The effect of the antioxidant ascorbic acid could not be demonstrated in Example 2b.

[0218] Mucosal permeation research To investigate the potential effect of pH on permeation, a permeation study was conducted to evaluate the permeation of remimazolam besylate (RMZ besylate) through mucosal membranes as a function of pH. In a second study, the performance of the remimazolam lyophilizate product (RMZ besylate) in an oral mucosal delivery system was also evaluated.

[0219] The transmission settings are summarized in Table 18. The samples used for Transmission Run 1 are defined in Table 19.

[0220] [Table 18]

[0221] [Table 19]

[0222] The permeation amount and corresponding mucosal permeation rate of the oral mucosal delivery system prepared according to Example 2a were determined by in vitro experiments using 400 μm thick porcine mucosa (esophageal mucosa) according to OECD guidelines (adopted April 13, 2004). The donor solution was applied to a 5.75 cm 2 A sample film of Example 2a measuring 1.5 mm in size was prepared by dissolving it in either 5 ml of artificial saliva or 5 ml of 0.9% NaCl. Remimazolam besylate was dissolved in the artificial saliva, and the pH of the mixture was adjusted as shown in Table 19, so that the applied dose of RMZ was equivalent to a mucosal delivery system containing 50 mg of remimazolam in 500 μL of vehicle. The pH was measured using a pH electrode. The permeation donor solution was applied directly to the mucosa (spreading area 4.524 cm). 2 The amount of remimazolam permeated through the receptor medium (phosphate buffer, pH 7.4) at a temperature of 37±1°C was measured, and the corresponding mucosal permeation rate was calculated. The results are shown in Table 20 and Figure 6a.

[0223] [Table 20]

[0224] Permeation experiments using RMZ dissolved in artificial saliva at different pH values ​​(pH 2, 3, 4.5, and 6) confirmed a clear dependence between solubility and pH value, indicating that a decrease in pH resulted in an increase in permeability. At pH 4.5 and pH 6, the permeation rate was low due to the low solubility of RMZ.

[0225] At pH 2, RMZ was completely dissolved. In this experiment, only two of the three wells could be analyzed because the barrier function of one well was impaired due to mucosal contraction. The permeation values ​​of the remaining samples diverged significantly from each other, so it can be assumed that the barrier function of the highly permeable mucosa was also impaired. It is currently not possible to determine from the results whether a strong decrease in pH would lead to improved permeation. However, due to the strongly acidic pH of 2, adjusting the pH to that low in oral mucosal delivery system samples is not desirable in an in vivo situation.

[0226] Due to the high variability in Permeation Run 1 (n=3), a second permeation experiment was performed with more replicates (n=6) to expand the data base. The permeation settings are summarized in Table 21. The samples used are defined in Table 15. Example 2a and the lyophilisate were dissolved in artificial saliva and 0.9% NaCl, respectively. Due to the pH adjustment of the lyophilisate / drug, the resulting pH was slightly lower (pH 3.14 and pH 3.09) than Example 2a without pH adjustment (pH 3.67 and pH 3.50). The RMZ sample set at pH 3 served as a control.

[0227] [Table 21]

[0228] The permeation amount and corresponding mucosal permeation rate of the oral mucosal delivery system prepared according to Example 2a were determined as outlined above. The permeation amount of remimazolam in the receptor medium (phosphate buffer pH 7.4) at a temperature of 37±1°C was measured, and the corresponding mucosal permeation rate was calculated. The results are shown in Table 22 and Figure 6a.

[0229] [Table 22]

[0230] Mucosal permeation data (see Figure 6b) show no significant differences between Example 2a and the lyophilized drug product samples (both 0.9% NaCl and artificial saliva). The RMZ sample at pH 3 in artificial saliva shows no significant difference from Example 2a and the lyophilized pharmaceutical sample (both 0.9% NaCl and artificial saliva).

[0231] Examples 2C-2K Preparation of coating composition (active agent-containing layer) and coating of the coating composition

[0232] The formulations of Examples 2c-2j (foam formulations) are summarized in Table 24. For Examples 2c and 2f, a beaker was charged with the corresponding sweetener and purified water. 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 uniform. In Example 2f, the mixture was not homogeneous after manual stirring, so it was manually stirred and then treated in an ultrasonic bath twice for 30 seconds. Next, Kollicoat IR was added, followed by manual stirring until the mixture was uniform. Next, PVA 40-88 mixed with purified water was added, and the newly formed mixture was stirred until the mixture was uniform. The mixture was stirred at 200 rpm for 15 minutes, followed by stirring at 2000 rpm for 5 minutes to form a foam.

[0233] The active agent-containing coating composition was coated onto Polysik 111 / 80 (one side siliconized) and dried at 70° C. for 25 minutes.

[0234] For Example 2d, a beaker was charged with the corresponding sweetener and purified water. The mixture was stirred at 230 rpm for 10 minutes. Remimazolam besylate was added, and the mixture was stirred at 230 rpm for 5 minutes. Kollicoat IR was then added, followed by stirring at 230 rpm for 5 minutes. PVA 40-88 mixed with purified water was then added, and the newly formed mixture was manually stirred until the mixture was homogeneous. The mixture was stirred at 200 rpm for 15 minutes, followed by stirring at 2000 rpm for 4.5 minutes to form a foam.

[0235] The active agent-containing coating composition was coated onto Polysik 111 / 80 (one side siliconized) and dried at 70° C. for 25 minutes.

[0236] For Example 2e, a beaker was charged with the corresponding sweetener and purified water. The mixture was treated in an ultrasonic bath for 10 minutes until the sweetener was dissolved. Remimazolam besylate was added, and the mixture was manually stirred, followed by treating the mixture twice in an ultrasonic bath for 30 seconds. Next, Kollicoat IR was added, followed by manually stirring until the mixture was uniform. PVA 40-88 mixed with purified water was added, and the newly formed mixture was manually stirred until the mixture was uniform. The mixture was stirred at 200 rpm for 15 minutes, followed by stirring at 2000 rpm for 4.5 minutes to form a foam.

[0237] The active agent-containing coating composition was coated onto Polysik 111 / 80 (one side siliconized) and dried at 70° C. for 25 minutes.

[0238] For Examples 2g-2i, a beaker was charged with the corresponding sweetener and purified water. The mixture was manually stirred and then treated in an ultrasonic bath for 10 minutes in the case of Example 2g, two 30-second periods with manual stirring between sonications in the case of Example 2h, and 20 seconds in the case of Example 2i. Remimazolam besylate was added, the mixture was manually stirred, and the mixture was then treated in an ultrasonic bath for two 30-second periods with manual stirring between sonications. Kollicoat IR was then added, followed by manual stirring until the mixture was uniform. PVA 40-88 mixed with purified water was added, and the newly formed mixture was manually stirred until the mixture was uniform. The mixture was stirred at 200 rpm for 15 minutes, followed by 4.5 minutes (2g-2h) and 3.75 minutes (2i) at 2000 rpm to form a foam.

[0239] The active agent-containing composition was coated onto Polysik 111 / 80 (one side siliconized) and dried at 70° C. for 25 minutes.

[0240] For Example 2j, a beaker was charged with the corresponding sweetener and purified water. Remimazolam besylate was added, and the mixture was manually stirred. The mixture was then treated twice in an ultrasonic bath for 30 seconds. Kollicoat IR was then added, and the mixture was manually stirred until uniform. PVA 40-88 mixed with purified water was added, and the newly formed mixture was manually stirred until uniform. The mixture was stirred at 200 rpm for 15 minutes, followed by stirring at 2000 rpm for 5 minutes to form a foam.

[0241] The active agent-containing composition was coated onto Polysik 111 / 80 (one side siliconized) and dried at 70° C. for 25 minutes.

[0242] The formulation of Example 2k (hot melt formulation) is summarized in Table 23.

[0243] For Example 2k, Polyox N10, RMZ besylate, neotam, and Tutti Frutti were added to a mortar and the solids were ground to obtain a homogeneous powder. The resulting powder was weighed (171.85 mg per 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. Preparation of Oral Mucosal Delivery Systems (for all Examples)

[0244] Each individual buccal delivery system was then sealed in a water vapor proof Surlyn® pouch along with two moisture absorbent patches (DesiMax).

[0245] [Table 23]

[0246] Stability Studies to Evaluate the Stability of Remimazolam Besylate in Examples 2C-2K Because RMZ was incompatible with one or both sweeteners (sucralose and saccharin-Na) in the formulation of Example 2b, a second short-term stress stability study was conducted to examine sweeteners that were compatible with the RMZ-oral mucosal delivery system formulation.

[0247] Stress stability studies for Examples 2C-2K were conducted at 60°C at 2-week (2W) and 6-week (6W) measurement time points for Examples 2c-2j, and at 2-week (2W), 6-week (6W), and 9-week (9W) measurement time points for Example 2k.

[0248] The results of the stress stability studies for Examples 2c-2j are summarized in Table 25.

[0249] The results of the stress stability study for Example 2k are summarized in Table 26.

[0250] [Table 24-1] [Table 24-2]

[0251] [Table 25-1] [Table 25-2]

[0252] The sweeteners neotame and advantame, and the flavors orange and Tutti Frutti, represent good options for further formulation development of foam oromucosal delivery systems. The degradation profiles of each foam formulation (2f, 2e, 2i, and 2j, respectively) did not deviate significantly from the reference formulation of Example 2a.

[0253] [Table 26]

[0254] Polyox N80-based hot melt formulations showed poor stability: Example 2k showed a steady increase in CNS7084 over time and the formation of some unknown degradation products (still at low levels after 6 weeks). Examples 3A to 3B Preparation of coating composition (active agent-containing layer) and coating of the coating composition

[0255] The formulations of Examples 3a and 3b are summarized in Table 27.

[0256] [Table 27]

[0257] For Examples 3a and 3b, Neotam and Tutti Frutti were added to a beaker, and the excipients were mixed with purified water using an Ultra Turrax IKA® T25 digital mixer at low speed until the excipients were completely dissolved. Remimazolam besylate was added, followed by the addition of purified water. After manual stirring, the mixture was homogenized using an Ultra Turrax KA® T25 digital mixer, starting at low speed and gradually increasing to a maximum of 20,000 rpm for 60 seconds under a N2 atmosphere. Kollicoat IR was added, and the mixture was manually stirred with a four-blade mixer, followed by slow stirring under a N2 atmosphere for at least 15 minutes until homogenous. Next, PVA 40-88, pre-dissolved in purified water, was added, and the mixture was manually stirred with a four-blade mixer at low to medium speed for 30 minutes under a N2 atmosphere until the mixture was homogenous. The mixture was then stirred at 160 rpm for 25 minutes, followed by stirring at 100 rpm for 30 minutes under a N2 atmosphere.

[0258] A foaming device was used for foam formation, which had the following settings for Example 3a: - Feed rate (hose pump): 150 mL / min (hose type: SPT3350, inner diameter 6.4 mm, wall thickness 2.4 mm; calibration with water) -N2-Flow rate: 40mln / min - Foam head rotor speed: 7600 rpm

[0259] A foaming device was used for foam formation, which had the following settings for Example 3b: - Feed rate (hose pump): 110 mL / min (hose type: SPT3350, inner diameter 6.4 mm, wall thickness 2.4 mm; calibration with water) -N 2- Flow rate: 55mln / min - Foam head rotor speed: 8500 rpm

[0260] The initial foam stream of every foaming step was discarded. For Examples 3a and 3b, four foaming sequences were performed. The foam coating composition was stirred at low speed between foaming sequences and the preparation vessel was covered.

[0261] The active agent-containing foam coating composition was coated onto Polysik 111 / 80 (one side siliconized) and dried at 70°C for 25 minutes. Preparation of oral mucosal delivery system

[0262] The individual buccal delivery systems were then placed 1.5 cm from the active agent-containing layer. 2 , 3cm 2 , and 6 cm 2 The buccal delivery systems were then sealed in water vapor proof Surlyn® pouches as follows: I. Place the system inside the folding liner -1.5cm 2 System: One desiccant label (DesiMax®) on the outside of the folded liner -3cm 2 System: One desiccant label (DesiMax®) on the outside of the folded liner -6cm 2 System: Two desiccant labels (DesiMax®) on the outside of the folded liner II. Insert the folded liner with the intraluminal mucosal delivery system and desiccant label(s) into the pouch with the opening facing downwards.

[0263] The present invention relates in particular to the following further embodiments: 1. An oral mucosal delivery system for transmucosal delivery of an active agent, comprising an active agent-containing layer, said layer comprising: i) as an active agent, remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof; ii) a film-forming agent.

[0264] 2. The oral mucosal delivery system of embodiment 1, wherein the activator-containing layer is at least 20%, at least 25%, or at least 30% by weight of said active agent; and / or 60% by weight or less, 55% by weight or less, or 50% by weight or less of said active agent; and / or The oral mucosal delivery system comprises 20-60% by weight, 25-55% by weight, or 30-50% by weight of the active agent.

[0265] 3. The oral mucosal delivery system of embodiment 1 or 2, wherein the activator-containing layer is At least 4 mg / cm 2 , at least 6 mg / cm 2 , or at least 8 mg / cm 2 and / or 15 mg / cm 2 Below, 13mg / cm 2 or less than 11 mg / cm 2 the active agent(s) below, and / or 4-15 mg / cm 2 , 6-13 mg / cm 2 or 8-11 mg / cm 2 The oral mucosal delivery system comprises the active agent of

[0266] 4. The oral mucosal delivery system according to any one of embodiments 1 to 3, wherein the oral mucosal delivery system comprises: at least 5 mg, at least 10 mg, or at least 15 mg of the active agent; and / or 80 mg or less, 70 mg or less, or 60 mg or less of said active agent; and / or The oral mucosal delivery system comprises 5 to 80 mg, 10 to 70 mg, or 15 to 60 mg of the active agent.

[0267] 5. The oral mucosal delivery system according to any one of embodiments 1 to 4, The oral mucosal delivery system, wherein the active agent is remimazolam, a pharmaceutically acceptable salt of remimazolam, or any mixture thereof.

[0268] 6. The oral mucosal delivery system of embodiment 5, The oral mucosal delivery system, wherein the active agent is remimazolam besylate or remimazolam tosylate.

[0269] 7. The oral mucosal delivery system according to any one of embodiments 1 to 6, The oral mucosal delivery system, wherein the active agent in the active agent-containing layer is dissolved, dispersed, or in the form of non-micronized particles.

[0270] 8. The oral mucosal delivery system according to any one of embodiments 1 to 7, comprising an active agent-containing layer, i) as an active agent, remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof; ii) a film former; and iii) a plasticizer.

[0271] 9. The oral mucosal delivery system according to embodiment 8, An oral mucosal delivery system, 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 glycol, or polyvinyl alcohol-polyethylene glycol graft copolymers.

[0272] 10. The oral mucosal delivery system according to embodiment 8 or 9, The oral mucosal delivery system, wherein the plasticizer is polyethylene glycol or a polyvinyl alcohol-polyethylene glycol graft copolymer.

[0273] 11. The oral mucosal delivery system according to any one of embodiments 8 to 10, wherein the activator-containing layer is at least 5 wt. %, at least 15 wt. %, or at least 20 wt. % of said plasticizer; 50% by weight or less, 40% by weight or less, or 35% by weight or less of said plasticizer; and / or The oral mucosal delivery system comprises 5 to 50 wt %, 15 to 40 wt %, or 20 to 35 wt % of the plasticizer.

[0274] 12. The oral mucosal delivery system according to embodiment 11, wherein the activator-containing layer is at least 10%, at least 13%, or at least 15% by weight of said film former; 75% by weight or less, 50% by weight or less, or 30% by weight or less of said film-forming agent; and / or The oral mucosal delivery system comprises 10 to 75 wt %, 13 to 50 wt %, or 15 to 30 wt % of the film-forming agent.

[0275] 13. The oral mucosal delivery system according to any one of embodiments 8 to 12, the active-agent-containing layer comprises a total amount of a film-forming agent and a plasticizer, the total amount being: at least 30 wt. %, at least 35 wt. %, or at least 40 wt. % of the active-agent-containing layer; 80% by weight or less, 60% by weight or less, or 45% by weight or less of the active agent-containing layer; and / or The oral mucosal delivery system, wherein the active agent-containing layer is 30 to 80 wt %, 35 to 60 wt %, or 40 to 45 wt %.

[0276] 14. The oral mucosal delivery system according to any one of embodiments 1 to 13, The oral mucosal delivery system, 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, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol, hydroxypropyl methylcellulose, or a mixture thereof.

[0277] 15. The oral mucosal delivery system according to embodiment 14, The oral mucosal delivery system, wherein the film-forming agent is polyvinyl alcohol.

[0278] 16. The oral mucosal delivery system according to embodiment 15, 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 having a molecular weight in the range of 10,000 to 250,000.

[0279] 17. The oral mucosal delivery system according to any one of embodiments 1-7 and 14-16, the active-agent-containing layer does not contain a plasticizer; and at least 50%, at least 60%, or at least 65% by weight of said film former; 85% by weight or less, 75% by weight or less, or 70% by weight or less of a film-forming agent; and / or and / or comprising 50-85 wt. %, 60-75 wt. %, or 65-70 wt. % of said film-forming agent; and / or The oral mucosal delivery system, wherein the active agent-containing layer consists essentially of (i) the active agent and (ii) the film-forming agent.

[0280] 18. The oral mucosal delivery system according to any one of embodiments 1 to 17, the active-agent-containing layer further comprises one or more excipients selected from the group consisting of sweeteners, flavoring agents, antioxidants, and pH adjusters; and / or The oral mucosal delivery system, wherein the active agent-containing layer does not contain a pH adjuster.

[0281] 19. The oral mucosal delivery system according to embodiment 18, 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 flavor composition selected from the group consisting of a combination of linalool, alpha pinene, citral, delta 3 carene, beta pinene, and myrcene, and a combination of geranyl acetate, vanillin, limonene, and allyl hexanoate.

[0282] 20. The oral mucosal delivery system according to embodiment 19, The oral mucosal delivery system, wherein the flavoring agent is a combination of linalool, alpha pinene, citral, delta 3 carene, beta pinene, and myrcene, or a combination of geranyl acetate, vanillin, limonene, and allyl hexanoate.

[0283] 21. The oral mucosal delivery system according to embodiment 19, The oral mucosal delivery system, 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.

[0284] 22. The oral mucosal delivery system according to any one of embodiments 18 to 21, wherein the activator-containing layer is at least 0.05% by weight or at least 0.5% by weight of a sweetener; not more than 2% by weight or not more than 1% by weight of sweeteners, and / or The oral mucosal delivery system comprises 0.05% to 2% by weight or 0.5 to 1% by weight of a sweetener.

[0285] 23. The oral mucosal delivery system according to any one of embodiments 18 to 22, wherein the activator-containing layer is at least 0.05% by weight or at least 0.5% by weight of a flavoring agent; not more than 5% by weight or not more than 2% by weight of flavorings, and / or The oral mucosal delivery system comprises 0.05% to 5% by weight or 0.5 to 2% by weight of a flavoring agent.

[0286] 24. The oral mucosal delivery system of any one of embodiments 1 to 23, wherein the oral mucosal delivery system does not contain a preservative.

[0287] 25. The oral mucosal delivery system according to any one of embodiments 1 to 24, The oral mucosal delivery system, wherein the oral mucosal delivery system is in the form of a film.

[0288] 26. The oral mucosal delivery system according to embodiment 25, The film is at least 0.5 cm 2 , or 10cm 2 Less than or equal to 1.5cm 2 , about 3cm 2 , or about 6 cm 2 and / or The film has a thickness of at least 100 g / m 2 , at least 110g / m 2 , or at least 120 g / m 2or 400 g / m 2 Below 300g / m 2 or less, or 250g / m 2 and / or The film has a thickness of 100 g / m 2 ~230g / m 2 or less, or 300 g / m 2 ~400g / m 2 The oral mucosal delivery system has an area weight of:

[0289] 27. The oral mucosal delivery system according to any one of embodiments 1 to 26, The oral mucosal delivery system, wherein the active agent-containing layer is in the form of a plastic foam or a plastic monolithic film.

[0290] 28. The oral mucosal delivery system according to any one of embodiments 1 to 27, The oral mucosal delivery system, wherein the active agent-containing layer comprises no more than 3% by weight, no more than 2% by weight, no more than 1% by weight, or no more than 0.5% by weight of water.

[0291] 29. The oral mucosal delivery system according to any one of embodiments 1 to 28, the active agent-containing layer initially contains no more than 0.4 wt.%, no more than 0.3 wt.%, or no more than 0.2 wt.% total remimazolam-related decomposition substances; and / or The oral mucosal delivery system, wherein the active agent-containing layer has been subjected to a storage stability test and contains a total amount of remimazolam-related decomposition substances of 0.5% by weight or less, or 0.4% by weight or less, after being stored at 60°C for up to 6 weeks.

[0292] 30. The oral mucosal delivery system according to any one of embodiments 1 to 29, wherein the active agent-containing layer contains a plasticizer, the film-forming agent is polyvinyl alcohol; and The oral mucosal delivery system, wherein the ratio of polyvinyl alcohol to plasticizer is at least 20:80, or not more than 50:50, or between 20:80 and 50:50, or about 25:75 or about 40:60.

[0293] 31. The oral mucosal delivery system according to any one of embodiments 1 to 30, the oral mucosal delivery system is in the form of a film; and Here, 5.75 cm 2 When a sample film of the oral mucosal delivery system having a size of 100 μm is dissolved in 5 mL of artificial saliva or 0.9% NaCl solution, the pH of the resulting solution is in the range of pH 3.0 to pH 3.7 as measured by a pH electrode.

[0294] 32. The oral mucosal delivery system according to any one of embodiments 1 to 31, wherein after a single administration to the buccal mucosa of the oral cavity of a human subject: c max bioavailability based on the AUC of greater than 10% or bioavailability based on the AUC of greater than 20%; 0.3 μg / mL or more max and / or 10 to 40 minutes, preferably 10 to 20 minutes max The oral mucosal delivery system provides

[0295] 33. An oral mucosal delivery system according to any one of embodiments 1 to 32 for use in producing sedation, producing hypnosis, producing anxiolysis, producing muscle relaxation, treating convulsions, or inducing amnesia for perioperative events.

[0296] 34. An oral mucosal delivery system for use in sedation according to embodiment 33, comprising: wherein the sedation is procedural sedation, such as sedation for dental procedures or sedation for diagnostic procedures, preoperative sedation, and / or conscious sedation.

[0297] 35. An oral mucosal delivery system for use in sedation according to embodiment 33 or 34, comprising: The oral mucosal delivery system wherein sedation is induced before and / or during endoscopy, colonoscopy, or other diagnostic or surgical procedure.

[0298] 36. An oral mucosal delivery system for use in sedation according to any one of embodiments 33 to 35, The oral mucosal delivery system achieves mild sedation, moderate sedation, deep sedation, or general anesthesia, which preferably has a duration of 5 to 30 minutes, 8 to 20 minutes, or 10 to 15 minutes.

[0299] 37. An oral mucosal delivery system for use in sedation according to any one of embodiments 33 to 36, comprising: The oral mucosal delivery system, wherein the active agent-containing layer is administered by application to a mucosa, particularly the buccal, sublingual, gingival or palatal mucosa of the oral cavity of a human patient, and is maintained on the mucosa until it dissolves.

[0300] 38. A method for producing sedation, producing hypnosis, producing anxiolysis, producing muscle relaxation, treating convulsions, or inducing amnesia for a perioperative event, comprising: The method, wherein the oral mucosal delivery system of any one of embodiments 1 to 32 is administered to the subject.

[0301] 39. The sedation method of embodiment 38, Here, the sedation method is procedural sedation, preoperative sedation, sedation for dental procedures, sedation for diagnostic procedures, and / or conscious sedation.

[0302] 40. The sedation method according to embodiment 38 or 39, The method of sedation, wherein sedation is induced before and / or during an endoscopy, colonoscopy, or other diagnostic or surgical procedure.

[0303] 41. The sedation method according to any one of embodiments 38 to 40, The sedation method achieves mild sedation, moderate sedation, deep sedation, or general anesthesia, which preferably has a duration of 5 to 30 minutes, 8 to 20 minutes, or 10 to 15 minutes.

[0304] 42. The sedation method according to any one of embodiments 38 to 41, The method of soothing, wherein the active agent-containing layer is administered by application to a mucosa, particularly the buccal, sublingual, gingival or palatal mucosa of the oral cavity of a human patient, and is maintained on the mucosa until dissolved.

[0305] 43. Use of an 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 for perioperative events.

[0306] 44. Use of an oral mucosal delivery system in the preparation of a medicament for producing sedation according to embodiment 43, comprising: wherein the sedation is procedural sedation, preoperative sedation, sedation for dental procedures, sedation for diagnostic procedures, and / or conscious sedation.

[0307] 45. Use of an oral mucosal delivery system in the preparation of a medicament for producing sedation according to embodiment 43 or 44, The above uses wherein sedation is induced before and / or during an endoscopy, colonoscopy, or other diagnostic or surgical procedure.

[0308] 46. ​​Use of an oral mucosal delivery system in the preparation of a medicament for producing sedation according to any one of embodiments 43 to 45, The use achieves mild sedation, moderate sedation, deep sedation, or general anesthesia, which preferably has a duration of 5 to 30 minutes, 8 to 20 minutes, or 10 to 15 minutes.

[0309] 47. A pharmaceutical product, Packaging and and one or more unit doses of the oral mucosal delivery system according to any one of embodiments 1 to 32.

[0310] 48. The pharmaceutical product according to embodiment 47, The pharmaceutical product, wherein the packaging is in the form of a pouch.

[0311] 49. The pharmaceutical product according to embodiment 48, the pouch is made from a multi-layer film material including an outer paper layer, a middle polyethylene layer, and an inner aluminum layer; and / or The pharmaceutical product, wherein the pouch is sealed with a sealant selected from the group consisting of ethylene copolymers, polyethylene terephthalate copolymers, and cyclic olefin copolymers.

[0312] 50. A pharmaceutical product according to any one of embodiments 48 or 49, The pharmaceutical product, wherein the pouch contains one or more desiccants or no desiccants.

[0313] 51. The pharmaceutical product according to embodiment 50, the pouch contains one or more desiccants, the desiccants including silica gel, molecular sieve 4Å and / or zeolite molecular sieve 4Å as desiccants; and / or The pharmaceutical product, wherein the desiccant is in the form of an adhesive film.

[0314] 52. The pharmaceutical product according to any one of embodiments 47 to 51, The pharmaceutical product further comprises a folded polyethylene terephthalate foil, wherein one or more unit doses of the oral mucosal delivery system are encapsulated by the folded polyethylene terephthalate foil that is folded around to protect the unit dose(s) from further contact with the packaging.

[0315] 53. A pharmaceutical product according to any one of embodiments 51 or 52, The pharmaceutical product, wherein the pouch comprises one or more desiccants in the form of an adhesive film, the desiccants being attached to the inward facing side of the pouch or, if present, to the outward facing side of the folded polyethylene terephthalate foil to avoid contact with the oral mucosal delivery system.

[0316] 54. A pharmaceutical product according to any one of embodiments 47 to 53, The pharmaceutical product, wherein the pouch is nitrogen-filled.

[0317] 55. A process for manufacturing an active-agent-containing layer as defined in any one of embodiments 1-32, comprising the steps of: i. combining at least (i) as an active agent, remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof, and (ii) a film-forming agent to obtain a mixture; ii. forming the active agent-containing layer.

[0318] 56. A manufacturing process according to embodiment 55, comprising: the process is a hot melt process; This can be one of the following: A hot melt extrusion process comprising the following step ii: a. introducing the mixture comprising the active agent and the film former, with or without additional excipients, into an extruder; b. heating the mixture to at least the softening temperature of the mixture; 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; or a vacuum compression molding process comprising the following step ii: a. introducing the mixture comprising the active agent and the film-forming agent, with or without an excipient, into a sample chamber; b. compressing 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.

[0319] 57. A manufacturing process according to embodiment 55, comprising: The process is a coating process, the coating process comprising the following steps: i. dispersing or dissolving the active agent in a solution of the film-forming agent, with or without additional excipients, to obtain a coating composition; ii.a. coating the coating composition onto a coating substrate; b. drying the laminated segment in a drying oven to obtain the active-agent-containing layer in the form of a plastic monolithic film.

[0320] 58. A manufacturing process according to embodiment 55, comprising: The process is a foam forming process, the forming process comprising the steps of: i. dispersing or dissolving the active agent in an aqueous solution of the film-forming agent, with or without additional excipients, to obtain a coating composition; ii.a. foaming the coating composition to obtain a foam coating composition; b. coating the foam coating composition onto a coating substrate; c. drying the laminated segment in a drying oven to obtain the active-agent-containing layer in the form of a foam.

[0321] 59. A manufacturing process according to embodiment 58, comprising: The manufacturing process wherein foaming is carried out by stirring while introducing nitrogen gas into the composition.

[0322] 60. A process for manufacturing an oral mucosal delivery system comprising an active agent-containing layer comprising (i) as an active agent, remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof, and (ii) a film-forming agent according to any one of embodiments 1 to 32, said process comprising the following steps: i. combining at least the active agent and a film-forming agent to obtain a mixture; ii. forming the active agent-containing layer. The manufacturing process, wherein the layer is as defined in any one of embodiments 50 to 59.

[0323] 61. An oral mucosal delivery system obtainable by the process according to embodiment 60.

[0324] 62. The oral mucosal delivery system of embodiment 1, wherein the active agent-containing layer comprises: i) 55-60% by weight of remimazolam besylate; ii) 10-15 wt. % polyvinyl alcohol as a film former; iii) 30 to 35% by weight of a polyvinyl alcohol-polyethylene glycol graft copolymer; iv) 0.05 to 1% by weight of one or more sweeteners; v) 0.5 to 2% by weight of a flavoring agent; where: The area weight of the active agent-containing layer is 200 g / m 2 The oral mucosal delivery system, which is:

[0325] 63. The oral mucosal delivery system of embodiment 1, wherein the active agent-containing layer comprises: i) 55-60% by weight of remimazolam besylate; ii) 15 to 20% by weight of polyvinyl alcohol as a film former; iii) 20 to 26 wt % of a polyvinyl alcohol-polyethylene glycol graft copolymer; iv) 0.05 to 1% by weight of one or more sweeteners; v) 0.5 to 2% by weight of a flavoring agent; where: The area weight of the active agent-containing layer is 200 g / m 2 The oral mucosal delivery system, which is:

Claims

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

2. 10. The oral mucosal delivery system of claim 1, wherein the activator-containing layer is at least 20%, at least 25%, or at least 30% by weight of said active agent; and / or 60% by weight or less, 55% by weight or less, or 50% by weight or less of said active agent; and / or The oral mucosal delivery system comprises 20-60% by weight, 25-55% by weight, or 30-50% by weight of the active agent.

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

4. 4. The oral mucosal delivery system of claim 1, comprising an active agent-containing layer, i) as an active agent, remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof; ii) a film former; and iii) a plasticizer.

5. The oral mucosal delivery system according to any one of claims 1 to 4, the plasticizer is polyethylene glycol or a polyvinyl alcohol-polyethylene glycol graft copolymer; and / or The oral mucosal delivery system, 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, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyethylene glycol, hydroxypropyl methylcellulose, or a mixture thereof.

6. The oral mucosal delivery system according to any one of claims 1 to 5, wherein the film-forming agent is a 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.

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

8. 8. The oral mucosal delivery system of claim 7, 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 flavor composition selected from the group consisting of a combination of linalool, alpha pinene, citral, delta 3 carene, beta 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, The oral mucosal delivery system, wherein the active agent-containing layer is in the form of a plastic foam or a plastic monolithic film.

10. The oral mucosal delivery system according to any one of claims 1 to 9, the oral mucosal delivery system is in the form of a film; and Here, 5.75 cm ２ When a sample film of the oral mucosal delivery system having a size of 100 μm is dissolved in 5 mL of artificial saliva or 0.9% NaCl solution, the pH of the resulting solution is in the range of pH 3.0 to pH 3.7 as measured by a pH electrode.

11. 11. The oral mucosal delivery system of any one of claims 1 to 10, which, after a single administration to the buccal mucosa of the oral cavity of a human subject, c ｍａｘ or a bioavailability based on AUC of greater than 20%; 0.3 μg / mL or more ｍａｘ and / or 10 to 40 minutes or 10 to 20 minutes ｍａｘ The oral mucosal delivery system provides

12. 12. The oral mucosal delivery system of any one of claims 1 to 11 for use in producing sedation, producing hypnosis, producing anxiolysis, producing muscle relaxation, treating convulsions, or inducing amnesia for perioperative events.

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

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

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

16. 16. The manufacturing process of claim 15, The process is a foam forming process, the forming process comprising the steps of: i. dispersing or dissolving the active agent in an aqueous solution of the film-forming agent, with or without additional excipients, to obtain a coating composition; ii. a. foaming the coating composition to obtain a foam coating composition; b. coating the foam coating composition onto a coating substrate; c) drying the laminated segment in a drying oven to obtain the active agent-containing layer in the form of a foam; The manufacturing process comprising:

17. (i) as an active agent, remimazolam, a pharmaceutically acceptable salt thereof, or any other form thereof; and (ii) 12. A process for manufacturing an oral mucosal delivery system comprising an active agent-containing layer comprising the film-forming agent of any one of claims 1 to 11, said process comprising the steps of: i. combining at least the active agent and a film former to obtain a mixture; ii. forming the active agent-containing layer; 17. The manufacturing process as claimed in claim 15 or 16.

18. An oral mucosal delivery system obtainable by the process of claim 17.

19. 10. The oral mucosal delivery system of claim 1, wherein the active agent-containing layer comprises: i) 55-60% by weight of remimazolam besylate; ii) 10-15% by weight of polyvinyl alcohol as a film former; iii) 30 to 35 wt. % of a polyvinyl alcohol-polyethylene glycol graft copolymer; iv) 0.05 to 1% by weight of one or more sweeteners; v) 0.5 to 2% by weight of a flavoring agent; where: The area weight of the active agent-containing layer is 200 g / m 2 The oral mucosal delivery system, which is:

20. 10. The oral mucosal delivery system of claim 1, wherein the active agent-containing layer comprises: i) 55-60% by weight of remimazolam besylate; ii) 15-20% by weight of polyvinyl alcohol as a film former; iii) 20 to 26 wt. % of a polyvinyl alcohol-polyethylene glycol graft copolymer; iv) 0.05 to 1% by weight of one or more sweeteners; v) 0.5 to 2% by weight of a flavoring agent; where: The area weight of the active agent-containing layer is 200 g / m 2 The oral mucosal delivery system, which is:

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