Unit dose composition containing midazolam

Abstract

The present invention relates to a unit dose composition comprising midazolam or a pharmaceutically acceptable salt thereof, cyclodextrin, and at least one matrix material, and to the use of the unit dose composition in pharmaceuticals and therapies, particularly in the treatment of febrile seizures, epileptic seizures, e.g., status epilepticus, fear, e.g., preoperative anxiety relief to alleviate fear, and / or agitation, e.g., preoperative agitation.

Description

[Technical Field]

[0001] Field of Invention The present invention relates to a unit dose composition comprising midazolam or a pharmaceutically acceptable salt thereof, cyclodextrin, and at least one matrix material, as well as the use of the unit dose composition in pharmaceuticals and therapeutics. [Background technology]

[0002] background Midazolam is a short-acting hypnotic and sedative with muscle relaxant properties, belonging to the benzodiazepine drug class.

[0003] Midazolam acts on nerve cells in the brain and is used to control convulsions (fit or seizure) in children and adults with epilepsy or other seizure-related disorders, or in children with febrile seizures.

[0004] The brain and nerves are composed of numerous nerve cells that communicate with each other via electrical signals. These signals must be carefully regulated for the brain and nerves to function properly. When abnormally rapid and repetitive electrical signals are induced in the brain, the brain becomes overstimulated, and normal function is disrupted. This results in a seizure (fit or seizure). Midazolam works by enhancing the action of the neurotransmitter GABA in the brain. GABA is involved in the transmission of information between nerve cells and acts as a natural "nerve sedative." It helps to suppress and maintain the balance of nerve activity in the brain, and is involved in inducing drowsiness, reducing anxiety, and relaxing muscles.

[0005] Midazolam is commercially available in the form of its hydrochloride salt, for example, as a glycerin-based syrup containing 2.5 mg / mL of midazolam sold under the trade name VERSED®. Midazolam is also commercially available in the form of its maleate salt, for example, as tablets containing 7.5 mg or 15 mg per tablet under the brand name DORMICUM®. Products formulated for administration via the buccal route are EPISTATUS® (liquid form of midazolam 10 mg / mL) and BUCCOLAM® (liquid form of midazolam 2.5 mg / 0.5 mL, 5 mg / mL, 7.5 mg / mL, or 10 mg / mL).

[0006] Compositions of midazolam for oral administration (e.g., tablets and syrups) are primarily used for epileptic seizures and other seizures, and are also used as a pre-anesthetic to reduce preoperative fear and agitation. On the other hand, intravenous (IV) formulations of midazolam are used for sedative purposes in the operating room (OR) and intensive care unit (ICU), and for sedation during procedures.

[0007] It is understood that the bioavailability of the oral administration form of midazolam differs from the plasma profile obtained after intravenous administration. With intravenous administration, the plasma concentration immediately reaches therapeutic plasma levels and then decreases according to elimination kinetics, whereas with oral administration, the maximum plasma level (C) is generally reached 1-2 hours after swallowing the tablet. max Furthermore, orally administered midazolam undergoes first-pass metabolism, which reduces the plasma concentration of the drug and decreases its bioavailability.

[0008] Therefore, neither route of administration is suitable for administering midazolam in a preoperative setting. Rather, patients who receive oral midazolam before surgery often exhibit some carryover effect, and the decrease in plasma levels is delayed due to slow drug absorption from the small intestine. As a result, sedation persists due to the plasma levels of midazolam, prolonging the postoperative recovery time and making rapid discharge from the recovery or awakening room almost impossible.

[0009] While IV administration does not exhibit similar limitations, it requires ensuring access to IV fluids and controlling the timing between midazolam administration and the start of surgery or procedure to prevent loss of anxiolytic effect before the start of surgery.

[0010] Therefore, neither intravenous solution nor oral tablet formulations provide an appropriate pharmacokinetic profile for the drug, particularly in patients undergoing short-term procedures or surgeries.

[0011] Midazolam administered buccally exhibits rapid absorption. Furthermore, the plasma levels achieved are sufficient to produce a therapeutic effect in patients. However, given the importance of rapid delivery of midazolam to patients who require it, it is desirable that the drug be delivered in a safer, more convenient, and lower-dose manner. Lowering the dose to achieve the desired therapeutic effect may reduce the frequency and severity of side effects, such as respiratory depression.

[0012] However, to date, a suitable formulation with appropriate dosage and tolerable taste masking is not available. [Overview of the project]

[0013] summary The inventors of the present disclosure have surprisingly found that midazolam or a pharmaceutically acceptable salt thereof can be formulated into a unit dosage composition together with cyclodextrin and at least one matrix material, thereby resulting in rapid absorption of midazolam or a pharmaceutically acceptable salt thereof through the oral mucosa and controlled metabolism and excretion. Furthermore, the typical bitter taste of midazolam or a pharmaceutically acceptable salt thereof that limits the tolerance of midazolam in oral administration can be significantly reduced. Also, the solubility in water is increased by using cyclodextrin together with midazolam, thereby presumably increasing and / or facilitating the absorption of midazolam.

[0014] According to a first aspect, the present disclosure relates to a unit dosage composition in the form of an oral thin film comprising midazolam or a pharmaceutically acceptable salt thereof, cyclodextrin, and at least one matrix material.

[0015] According to a second aspect, the present disclosure is a method for manufacturing the unit dosage composition according to the first aspect of the present disclosure, comprising: a) providing an aqueous solution comprising midazolam or a pharmaceutically acceptable salt thereof, cyclodextrin, and at least one matrix material b) coating the solution onto a liner, and c) drying the solution to form a film The method is related to this.

[0016] According to a third aspect, the present disclosure relates to the unit dosage composition according to the first aspect of the present disclosure for use in the treatment of febrile seizures, epileptic seizures such as status epilepticus, fear such as preoperative anxiety to reduce fear, and / or agitation such as preoperative agitation.

[0017] According to a fourth aspect, the present disclosure relates to a method for treating febrile seizures, epileptic seizures, such as status epilepticus, fear, such as preoperative anxiety alleviation to reduce fear, and / or agitation, such as preoperative agitation, wherein the unit dosage composition according to the first aspect of the present disclosure is administered to a subject.

[0018] According to a fifth aspect, the present disclosure relates to the use of the unit dosage composition according to the first aspect of the present disclosure in the manufacture of a medicament for treating febrile seizures, epileptic seizures, such as status epilepticus, fear, such as preoperative anxiety alleviation to reduce fear, and / or agitation, such as preoperative agitation. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] [Figure 1] Shows the Tmax of midazolam after administration of the oral thin film of Example 1, Dormicum® tablets containing 7.5 mg of midazolam, and midazolam solution. [Figure 2] Shows the Cmax of midazolam after administration of the oral thin film of Example 1, Dormicum® tablets containing 7.5 mg of midazolam, and midazolam solution. [Figure 3] Shows the mean midazolam plasma concentration versus time after administration of the oral thin film "PVA film" according to Example 1, compared with Dormicum® tablets and midazolam B. Braun 5 mg / mL solution for injection / infusion. [Figure 4] Shows the mean midazolam plasma concentration versus time after administration of the oral thin film "PVA film" according to Example 1, compared with Dormicum® tablets and midazolam B. Braun 5 mg / mL solution for injection / infusion. [Figure 5] Shows the mean midazolam plasma concentration versus time after administration of the oral thin film "HPMC film pH 4.0" according to Example 1, compared with Dormicum® tablets and midazolam B. Braun 5 mg / mL solution for injection / infusion. <The mean midazolam plasma concentration versus time after administration of the oral thin film "HPMC Film pH 5.0" according to Example 1 is shown in comparison with Dormicum® tablets and midazolam B. Braun 5 mg / mL solution for injection / infusion. [Modes for carrying out the invention]

[0020] Detailed explanation The inventions of this disclosure are described in more detail below with reference to preferred embodiments and examples. However, it should be understood that the scope of this disclosure is not limited thereto, but is limited only by the appended claims.

[0021] This disclosure relates, from a very general perspective, to five aspects, namely, a first aspect relating to a unit-dose composition; a second aspect relating to a method for manufacturing the unit-dose composition; a third aspect relating to the unit-dose composition for use in the treatment or prevention of febrile seizures, acute seizures, epileptic seizures, e.g., status epilepticus, fear, e.g., preoperative anxiety relief to alleviate fear, and / or agitation, e.g., preoperative agitation; a fourth aspect relating to a method for treating these conditions by administering the unit-dose composition; and a fifth aspect relating to the use of the unit-dose composition for the manufacture of pharmaceuticals.

[0022] Unit Dosage Composition According to a first aspect, the present disclosure relates to a unit dose composition in the form of an oral thin film, comprising midazolam or a pharmaceutically acceptable salt thereof, a cyclodextrin, and at least one matrix material.

[0023] The inventors of this disclosure have, surprisingly, found that a unit dose composition comprising midazolam or a pharmaceutically acceptable salt thereof, cyclodextrin, and at least one matrix material provides rapid absorption of midazolam or a pharmaceutically acceptable salt thereof by the oral mucosa, as well as controlled metabolism and excretion. Furthermore, the typical bitter taste of midazolam or a pharmaceutically acceptable salt thereof—which limits the suitability of midazolam for use in oral mucosal absorption—can be significantly reduced, thereby opening up new avenues for rapid and safe administration using midazolam.

[0024] According to this disclosure, the unit dose composition is in the form of an oral thin film. According to a preferred embodiment of this disclosure, the unit dose composition is in the form of a buccal film. These oral thin films are generally paper-thin polymer films used as carriers for active pharmaceutical ingredients.

[0025] According to a preferred embodiment of the present disclosure, the oral thin film has a thickness of 2,000 μm or less. According to another preferred embodiment of the present disclosure, the oral thin film has a thickness of 1,500 μm or less. According to another preferred embodiment of the present disclosure, the oral thin film has a thickness of 1,000 μm or less. According to another preferred embodiment of the present disclosure, the oral thin film has a thickness of 800 μm or less. According to another preferred embodiment of the present disclosure, the oral thin film has a thickness of 700 μm or less. According to another preferred embodiment of the present disclosure, the oral thin film has a thickness of 600 μm or less. According to a further preferred embodiment of the present disclosure, the oral thin film has a thickness of 500 μm or less. Thinner films are preferred because they are more flexible and easier to apply, and provide a smoother feel or texture in the oral cavity. Furthermore, thinner films generally dissolve faster, and therefore allow for faster absorption. On the other hand, if the film is too thin, it may be more difficult to apply or may even break due to reduced stability.

[0026] According to another preferred embodiment of the present disclosure, the oral thin film has a thickness in the range of about 10 μm to about 1,000 μm. According to another preferred embodiment of the present disclosure, the oral thin film has a thickness in the range of about 30 μm to about 800 μm. According to another preferred embodiment of the present disclosure, the oral thin film has a thickness in the range of about 40 μm to about 700 μm. According to another preferred embodiment of the present disclosure, the oral thin film has a thickness in the range of about 50 μm to about 600 μm. According to a further preferred embodiment of the present disclosure, the oral thin film has a thickness in the range of about 50 μm to about 500 μm.

[0027] Oral thin films are understood to be administered orally, such as on the tongue, sublingually (sublingual administration), or applied to the cheek. Upon contact with saliva, the oral thin film dissolves rapidly, releasing the drug into the oral cavity. In other words, administration of oral thin films does not require water or swallowing.

[0028] In the oral cavity, drugs are absorbed into the bloodstream via the oral mucosa, the mucous membrane that lines the inside of the mouth. The oral mucosal epithelium consists of 40 to 50 layers of cells called mucus, which is composed of carbohydrates and proteins. The thickness of the mucosa on the floor of the mouth, tongue, and gums ranges from 100 to 200 μm.

[0029] According to a preferred embodiment of the present disclosure, the unit dose composition is for oral administration. According to a further preferred embodiment of the present disclosure, the unit dose composition is for buccal administration. According to a further preferred embodiment of the present disclosure, the unit dose composition is for sublingual administration.

[0030] Buccal films and oral thin films (OTFs) are solid dosage forms that conform to the European Pharmacopoeia monograph "Oromucosal preparations," more specifically the section "Orodispersible film" within the same monograph.

[0031] Midazolam is a well-known active pharmaceutical ingredient with sedative, anxiolytic, amnesic, and hypnotic effects. Therefore, midazolam or its pharmaceutically acceptable salts are used to treat anxiety and fear, procedural sedation, preoperative sedation, induction of general anesthesia, sedation in patients receiving mechanical ventilation in the intensive care unit, acute management of agitation (e.g., acute management of schizophrenia with aggressive or uncontrollable behavior; or preoperative situations), the final stages of end-of-life care, and various conditions including seizures such as status epilepticus.

[0032] In all of these situations, oral administration of midazolam is preferred, not only for non-professionals, but especially in the form of buccal film and oral thin film. These forms of administration have the advantage that in emergencies, the patient does not need to swallow a unit dose composition—which is particularly difficult for patients who cannot control muscle function or who are in a severe psychotic state. Instead, it is sufficient to simply place the buccal film or oral thin film in the patient's mouth, where the midazolam is absorbed via the oral mucosa. Thus, the unit dose compositions according to this disclosure not only avoid the first-pass effect but also achieve rapid onset of action.

[0033] Furthermore, the unit-administered compositions according to this disclosure are solid. These solid unit-administered compositions have the advantage over liquid administration forms that the solid unit-administered compositions according to this disclosure cannot be accidentally swallowed. Moreover, unlike liquid compositions such as syrups, these solid unit-administered compositions do not spill out of the mouth once they are placed in the mouth of a patient requiring treatment.

[0034] Midazolam The amount of midazolam may be determined according to the patient's needs and the usual dosage of midazolam. The following amounts of midazolam in the unit dose compositions of this disclosure relate to the amount of midazolam determined based on free midazolam base.

[0035] According to a preferred embodiment of this disclosure, the unit dose composition contains midazolam in an amount ranging from about 0.01 mg to about 50 mg. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam in an amount ranging from about 0.1 mg to about 20 mg. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam in an amount ranging from about 0.5 mg to about 10 mg. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam in an amount ranging from about 1 mg to about 5 mg. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam in an amount ranging from about 1.5 mg to about 4.5 mg. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam in an amount ranging from about 1.8 mg to about 4.3 mg. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam in an amount ranging from about 2.0 mg to about 4.0 mg. According to another preferred embodiment of the present disclosure, the unit dose composition contains midazolam in an amount ranging from about 2.3 mg to about 3.5 mg. According to another preferred embodiment of the present disclosure, the unit dose composition contains midazolam in an amount ranging from about 2.3 mg to about 3.2 mg.

[0036] According to a further preferred embodiment of the present disclosure, the unit dose composition contains midazolam in an amount ranging from about 2 mg to about 4 mg. According to a further preferred embodiment of the present disclosure, the unit dose composition contains midazolam in an amount ranging from about 2.4 mg to about 3.1 mg. According to a further preferred embodiment of the present disclosure, the unit dose composition contains midazolam in an amount ranging from about 2.5 mg to about 3.0 mg. According to a further preferred embodiment of the present disclosure, the unit dose composition contains midazolam in an amount ranging from about 2.6 mg to about 2.9 mg.

[0037] According to another preferred embodiment of this disclosure, the unit dose composition contains about 0.01 mg or more of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 0.1 mg or more of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 0.2 mg or more of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 0.5 mg or more of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 1 mg or more of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 1.5 mg or more of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 1.8 mg or more of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 2.0 mg or more of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 2.3 mg or more of midazolam. According to another preferred embodiment of the present disclosure, the unit dose composition contains about 2.4 mg or more of midazolam. According to another preferred embodiment of the present disclosure, the unit dose composition contains about 2.5 mg or more of midazolam. According to a further preferred embodiment of the present disclosure, the unit dose composition contains about 2.6 mg or more of midazolam.

[0038] According to a further preferred embodiment of the present disclosure, the unit dose composition contains about 2.0 mg or more of midazolam. According to a further preferred embodiment of the present disclosure, the unit dose composition contains about 2.5 mg or more of midazolam.

[0039] According to another preferred embodiment of this disclosure, the unit dose composition contains about 50 mg or less of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 20 mg or less of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 15 mg or less of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 10 mg or less of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 5 mg or less of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 4.5 mg or less of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 4.3 mg or less of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 4.0 mg or less of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 3.5 mg or less of midazolam. According to another preferred embodiment of this disclosure, the unit dose composition contains about 3.2 mg or less of midazolam. According to another preferred embodiment of the present disclosure, the unit dose composition contains midazolam in an amount of about 3.1 mg or less. According to another preferred embodiment of the present disclosure, the unit dose composition contains midazolam in an amount of about 3.0 mg or less. According to another preferred embodiment of the present disclosure, the unit dose composition contains midazolam in an amount of about 2.9 mg or less.

[0040] According to a further preferred embodiment of the present disclosure, the unit dose composition contains midazolam in an amount of about 4 mg or less. According to a further preferred embodiment of the present disclosure, the unit dose composition contains midazolam in an amount of about 3.5 mg or less. According to a further preferred embodiment of the present disclosure, the unit dose composition contains midazolam in an amount of about 3.0 mg or less. According to a further preferred embodiment of the present disclosure, the unit dose composition contains midazolam in an amount of about 2.9 mg or less.

[0041] According to a preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 0.03 μmol to about 153.48 μmol. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 0.31 μmol to about 61.39 μmol. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 0.61 μmol to about 46.04 μmol. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 1.53 μmol to about 30.70 μmol. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 3.07 μmol to about 15.35 μmol. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 4.60 μmol to about 13.81 μmol. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 5.53 μmol to about 13.20 μmol. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 6.14 μmol to about 12.28 μmol. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 7.06 μmol to about 10.74 μmol. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 7.06 μmol to about 9.82 μmol. According to another preferred embodiment of the present disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 7.37 μmol to about 9.52 μmol. According to another preferred embodiment of the present disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 7.67 μmol to about 9.21 μmol.According to another preferred embodiment of the present disclosure, the unit dose composition comprises midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 7.98 μmol to about 8.90 μmol.

[0042] According to yet another preferred embodiment of the present disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 6.14 μmol to about 12.28 μmol. According to yet another preferred embodiment of the present disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 7.06 μmol to about 9.82 μmol. According to yet another preferred embodiment of the present disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 7.67 μmol to about 9.21 μmol. According to yet another preferred embodiment of the present disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount ranging from about 6.98 μmol to about 8.90 μmol.

[0043] According to a preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 0.03 μmol or more. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 0.31 μmol or more. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 0.61 μmol or more. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 1.53 μmol or more. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 3.07 μmol or more. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 4.60 μmol or more. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 5.53 μmol or more. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 6.14 μmol or more. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 7.06 μmol or more. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 7.37 μmol or more. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 7.67 μmol or more. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 7.98 μmol or more.

[0044] According to yet another preferred embodiment of the present disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 6.14 μmol or more. According to yet another preferred embodiment of the present disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 7.06 μmol or more. According to yet another preferred embodiment of the present disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 7.67 μmol or more. According to yet another preferred embodiment of the present disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 6.98 μmol or more.

[0045] According to a preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 153.48 μmol or less. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 61.39 μmol or less. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 46.04 μmol or less. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 30.70 μmol or less. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 15.35 μmol or less. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 13.81 μmol or less. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 13.20 μmol. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 12.28 μmol or less. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 10.74 μmol or less. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 9.82 μmol or less. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 9.52 μmol or less. According to another preferred embodiment of this disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 9.21 μmol or less. According to another preferred embodiment of the present disclosure, the unit dose composition comprises midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 8.90 μmol or less.

[0046] According to yet another preferred embodiment of the present disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 12.28 μmol or less. According to yet another preferred embodiment of the present disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 9.82 μmol or less. According to yet another preferred embodiment of the present disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 9.21 μmol or less. According to yet another preferred embodiment of the present disclosure, the unit dose composition contains midazolam or a pharmaceutically acceptable salt thereof in a molar amount of about 8.90 μmol or less.

[0047] The inventors of this disclosure have surprisingly discovered that even small amounts of midazolam, such as 2.7 mg of midazolam or a pharmaceutically acceptable salt thereof, can be efficiently delivered into the bloodstream and achieve pharmaceutically effective plasma concentrations immediately after administration. As shown in Example 3 and Figures 1-6 of this disclosure, the unit dose compositions of this disclosure yield plasma concentrations of approximately 80 ng / mL to approximately 120 ng / mL when administered to Marshall dogs. Despite the test formulation containing only 3 mg of midazolam hydrochloride, its maximum plasma concentration C max This is the maximum plasma concentration C obtained after administration of Dormicum® tablets containing a much higher dose of midazolam. max It is significantly higher than the maximum plasma concentration C of the unit dose composition of the present disclosure. max This is within a similar range to midazolam administered as a 5 mg / mL solution.

[0048] According to a preferred embodiment of the present disclosure, the unit dose composition comprises midazolam. According to another preferred embodiment of the present disclosure, the unit dose composition comprises midazolam maleate. According to a further preferred embodiment of the present disclosure, the unit dose composition comprises midazolam hydrochloride.

[0049] Cyclodextrin According to a first aspect of this disclosure, the unit dose composition comprises a cyclodextrin. The cyclodextrin may be unmodified or a derivative thereof.

[0050] According to a preferred embodiment of the present disclosure, the cyclodextrin is selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and delta-cyclodextrin. According to another preferred embodiment of the present disclosure, the cyclodextrin is selected from the group consisting of beta-cyclodextrin, gamma-cyclodextrin, and delta-cyclodextrin.

[0051] According to another preferred embodiment of the present disclosure, the cyclodextrin is a beta-cyclodextrin. According to another preferred embodiment of the present disclosure, the cyclodextrin is a gamma-cyclodextrin. According to another preferred embodiment of the present disclosure, the cyclodextrin is a delta-cyclodextrin.

[0052] According to a further preferred embodiment of the present disclosure, the cyclodextrin is permethyl-beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin (HPbCD). According to a further preferred embodiment of the present disclosure, the cyclodextrin is hydroxypropyl-beta-cyclodextrin (HPbCD).

[0053] It is understood that cyclodextrins have the potential to bind other molecules to their quasi-cylindrical interiors.

[0054] The inventors of this disclosure have found that cyclodextrin can act as a solubility enhancer for midazolam or its pharmaceutically acceptable salts by encapsulating at least a portion of the drug molecule within its lipophilic core, thereby reducing its bitter taste. Surprisingly, this encapsulation of midazolam or its pharmaceutically acceptable salts was found not to reduce (see Figure 2) or delay (see Figure 1) the absorption of the drug through the oral mucosa. In contrast, as shown in Figures 2-6, midazolam or its pharmaceutically acceptable salts are rapidly absorbed within about 10 minutes, taken into the systemic circulation, and act pharmacologically there. In other words, midazolam or its pharmaceutically acceptable salts are rapidly released from cyclodextrin in the oral mucosa. Therefore, as shown in Figure 1, the onset of pharmacological action is rapid. While we do not wish to be bound by theory, it is thought that after being released from cyclodextrin, the drug is absorbed directly into the oral mucosa without being dissolved in saliva. In other words, cyclodextrin directly transports midazolam or a pharmaceutically acceptable salt thereof from the unit dose composition to the absorption site.

[0055] According to a further preferred embodiment of the present disclosure, the unit dose composition comprises midazolam hydrochloride and hydroxypropyl-beta-cyclodextrin.

[0056] According to another preferred embodiment of the present disclosure, the mass ratio of free midazolam base to hydroxypropyl-beta-cyclodextrin is in the range of about 1:1 to about 1:10. In other words, a unit dose composition according to the first embodiment of the present disclosure contains hydroxypropyl-beta-cyclodextrin in an amount of about 1 to 10 times the mass of free midazolam base. The mass ratio of free midazolam base to hydroxypropyl-beta-cyclodextrin does not depend on the counterion of midazolam, for example, the chloride anion in midazolam hydrochloride.

[0057] According to another preferred embodiment of the present disclosure, the mass ratio of free midazolam base to hydroxypropyl-beta-cyclodextrin is in the range of about 1:2 to about 1:8. According to another preferred embodiment of the present disclosure, the mass ratio of free midazolam base to hydroxypropyl-beta-cyclodextrin is in the range of about 1:3 to about 1:6. According to another preferred embodiment of the present disclosure, the mass ratio of free midazolam base to hydroxypropyl-beta-cyclodextrin is in the range of about 1:4 to about 1:5.

[0058] According to a further preferred embodiment of the present disclosure, the mass ratio of free midazolam base to hydroxypropyl-beta-cyclodextrin is about 1:5.2. In other words, a unit dose composition according to the first embodiment of the present disclosure contains hydroxypropyl-beta-cyclodextrin in an amount about 5.2 times the mass of free midazolam base.

[0059] The above ratio of free midazolam base to cyclodextrin is understood to be convertible or recalculated for the corresponding salt of midazolam or other cyclodextrin, depending on their respective masses, i.e., molecular weights.

[0060] According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 0.1 mg or more. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 0.5 mg or more. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 1 mg or more. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 2 mg or more. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 4 mg or more. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 6 mg or more. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 8 mg or more. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 10 mg or more. According to a further preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 12 mg or more.

[0061] According to a preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 150 mg or less. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 120 mg or less. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 100 mg or less. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 80 mg or less. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 60 mg or less. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 50 mg or less. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 40 mg or less. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 30 mg or less. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount of about 25 mg or less. According to a further preferred embodiment of the present disclosure, the unit dose composition comprises cyclodextrin in an amount of about 20 mg or less.

[0062] According to a preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount ranging from about 0.1 mg to about 150 mg. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount ranging from about 0.5 mg to about 120 mg. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount ranging from about 1 mg to about 100 mg. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount ranging from about 2.0 mg to about 80 mg. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount ranging from about 4.0 mg to about 60 mg. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount ranging from about 6.0 mg to about 40 mg. According to another preferred embodiment of this disclosure, the unit dose composition contains cyclodextrin in an amount ranging from about 8.0 mg to about 30 mg. According to a further preferred embodiment of the present disclosure, the unit dose composition comprises cyclodextrin in an amount ranging from about 10 mg to about 25 mg. According to a further preferred embodiment of the present disclosure, the unit dose composition comprises cyclodextrin in an amount ranging from about 12 mg to about 20 mg.

[0063] From Examples 2 and 3 of this disclosure, it can be concluded that the presence of cyclodextrin in the unit dose composition of this disclosure and the inclusion of midazolam surprisingly do not negatively affect the release of midazolam from the unit dose composition. The rapid release of midazolam from the dose form is supported by the high bioavailability of midazolam in animal studies, as shown in Example 3 and Figures 2-6. In other words, although a negative effect was expected from the cyclodextrin in the buccal film, since it needs to be released from the cyclodextrin complex before the drug is absorbed, it did not have any negative effect on drug absorption via the oral mucosa. Generally, cyclodextrins are not significantly absorbed by passive diffusion through the oral mucosa because they are highly hydrophilic and bulky. For example, the oral bioavailability of hydroxypropyl-beta-cyclodextrin in humans has been reported to be in the range of about 0.5 to about 3.3%.

[0064] Matrix materials According to a first aspect of this disclosure, the unit dose composition comprises at least one matrix material.

[0065] It is understood that at least one matrix material acts as a film-forming agent and determines the solubility properties of the oral thin film.

[0066] According to preferred embodiments of the present disclosure, at least one matrix material is selected from the group consisting of cellulose, cellulose derivatives, acrylic polymers, acrylic copolymers, and mixtures thereof.

[0067] According to preferred embodiments of the present disclosure, at least the matrix material is selected from the group consisting of ethylcellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose salt, microcrystalline cellulose, croscarmellose, cellulose acetate, polyvinylpyrrolidone, polyvinyl alcohol (PVA), polyethylene oxide, and mixtures thereof.

[0068] According to another preferred embodiment of the present disclosure, at least the matrix material is selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose salt, polyvinylpyrrolidone, polyvinyl alcohol (PVA), and mixtures thereof.

[0069] According to further preferred embodiments of the present disclosure, at least the matrix material is selected from the group consisting of hydroxypropyl methylcellulose, polyvinyl alcohol (PVA), and mixtures thereof.

[0070] According to a further preferred embodiment of the present disclosure, at least the matrix material is hydroxypropyl methylcellulose (HMPC). According to a further preferred embodiment of the present disclosure, at least the matrix material is polyvinyl alcohol (PVA).

[0071] As shown in Tables 3-5, it is understood that at least one matrix material causes rapid disintegration of the oral thin film upon contact with water or saliva. Furthermore, at least one matrix material provides adhesion of the oral thin film to the buccal mucosa.

[0072] According to a preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount of about 5 mg or more. According to another preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount of about 10 mg or more. According to yet another preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount of about 15 mg or more. According to a further preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount of about 20 mg or more.

[0073] According to a preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount of about 200 mg or less. According to another preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount of about 150 mg or less. According to another preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount of about 100 mg or less. According to another preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount of about 80 mg or less. According to another preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount of about 60 mg or less. According to another preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount of about 50 mg or less. According to another preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount of about 40 mg or less. According to a further preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount of about 35 mg or less.

[0074] According to a preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount ranging from about 5 mg to about 200 mg. According to another preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount ranging from about 5 mg to about 150 mg. According to another preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount ranging from about 5 mg to about 100 mg. According to another preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount ranging from about 5 mg to about 60 mg. According to another preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount ranging from about 10 mg to about 50 mg. According to another preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount ranging from about 15 mg to about 40 mg. According to another preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount ranging from about 15 mg to about 35 mg. According to a further preferred embodiment of the present disclosure, the unit dose composition comprises at least one matrix material in an amount ranging from about 20 mg to about 35 mg.

[0075] According to a preferred embodiment, at least one matrix material is a mixture of two matrix materials having different viscosities. This makes it possible to adjust the viscosity of the solution used to produce the final oral thin film and the film itself.

[0076] According to a preferred embodiment, at least one matrix material is a mixture of two matrix materials having different viscosities, selected from materials of the same chemical type.

[0077] According to another preferred embodiment of the present disclosure, the mixture of two matrix materials comprises a first matrix material and a second matrix material, wherein the first matrix material has a viscosity about 1.2 to about 100 times higher than that of the second matrix material. According to another preferred embodiment of the present disclosure, the mixture of two matrix materials comprises a first matrix material and a second matrix material, wherein the first matrix material has a viscosity about 2 to about 50 times higher than that of the second matrix material. According to another preferred embodiment of the present disclosure, the mixture of two matrix materials comprises a first matrix material and a second matrix material, wherein the first matrix material has a viscosity about 5 to about 20 times higher than that of the second matrix material.

[0078] A mixture of two matrix materials with different viscosities is thought to improve the manufacturability of oral thin films.

[0079] Further ingredients According to a preferred embodiment of the first aspect of the present disclosure, the unit dose composition further comprises at least one sweetener.

[0080] According to another preferred embodiment of the present disclosure, at least one sweetener is selected from the group consisting of sucralose, sodium saccharin, and mixtures thereof.

[0081] According to a further preferred embodiment of the present disclosure, at least one sweetener is sucralose. According to a further preferred embodiment of the present disclosure, at least one sweetener is sodium saccharin.

[0082] According to a preferred embodiment of the present disclosure, the unit dose composition contains at least one sweetener in an amount of about 20 mg or less. According to another preferred embodiment of the present disclosure, the unit dose composition contains at least one sweetener in an amount of about 15 mg or less. According to another preferred embodiment of the present disclosure, the unit dose composition contains at least one sweetener in an amount of about 10 mg or less.

[0083] According to a preferred embodiment of the present disclosure, the unit dose composition contains at least one sweetener in an amount of about 1 mg or more. According to another preferred embodiment of the present disclosure, the unit dose composition contains at least one sweetener in an amount of about 2 mg or more.

[0084] The presence of at least one sweetener in the unit dose composition according to this disclosure is understood to further improve the comfort of application.

[0085] According to another preferred embodiment of the present disclosure, the unit dose composition of the first aspect of the present disclosure further comprises glycerol.

[0086] According to a preferred embodiment of the present disclosure, the unit dose composition contains glycerol in an amount of about 20 mg or less. According to another preferred embodiment of the present disclosure, the unit dose composition contains glycerol in an amount of about 15 mg or less. According to another preferred embodiment of the present disclosure, the unit dose composition contains glycerol in an amount of about 12 mg or less.

[0087] According to a preferred embodiment of the present disclosure, the unit dose composition contains glycerol in an amount of about 1 mg or more. According to another preferred embodiment of the present disclosure, the unit dose composition contains glycerol in an amount of about 3 mg or more. According to another preferred embodiment of the present disclosure, the unit dose composition contains glycerol in an amount of about 5 mg or more.

[0088] The presence of glycerol is understood to act as a plasticizer in the unit dose compositions of this disclosure. In other words, glycerol softens and makes the oral thin film flexible, thus preventing breakage. The amount of glycerol can be adjusted as needed.

[0089] According to another preferred embodiment of this disclosure, the unit dose composition has a pH in the range of about 2.0 to about 8.0. According to another preferred embodiment of this disclosure, the unit dose composition has a pH in the range of about 2.5 to about 7.0. According to another preferred embodiment of this disclosure, the unit dose composition has a pH in the range of about 3.0 to about 6.0. According to a further preferred embodiment of this disclosure, the unit dose composition has a pH in the range of about 3.5 to about 5.0.

[0090] The pH of the unit dose composition can be adjusted during manufacturing using any pharmaceutically acceptable acid or base. It is preferable to adjust the pH using citric acid.

[0091] Manufacturing method According to a second aspect, the present disclosure is a method for producing a unit dose composition according to a first aspect of the present disclosure, a) A step of providing an aqueous solution comprising midazolam or a pharmaceutically acceptable salt thereof, cyclodextrin, and at least one matrix material. b) A step of coating the liner with the solution, c) A step of drying the solution to form a film. The method, including the method described herein.

[0092] According to a preferred embodiment of the present disclosure, a method for producing a unit dose composition according to a first aspect of the present disclosure further includes a step of adjusting the pH and / or foaming the solution before coating.

[0093] Pharmaceutical use According to a third aspect, the Disclosure relates to a unit dose composition according to a first aspect of the Disclosure for use in the treatment or prevention of febrile seizures, epileptic seizures, e.g., status epilepticus, fear, e.g., preoperative anxiety relief to reduce fear, and / or agitation, e.g., preoperative agitation.

[0094] According to a preferred embodiment, the Disclosure relates to a unit-dose composition according to a first aspect of the Disclosure for use in the treatment of febrile seizures. According to another preferred embodiment, the Disclosure relates to a unit-dose composition according to a first aspect of the Disclosure for use in the treatment of epileptic seizures, such as status epilepticus. According to a further preferred embodiment, the Disclosure relates to a unit-dose composition according to a first aspect of the Disclosure for use in the treatment of status epilepticus. According to another preferred embodiment, the Disclosure relates to a unit-dose composition according to a first aspect of the Disclosure for use in the treatment of preoperative fear. According to a further preferred embodiment, the Disclosure relates to a unit-dose composition according to a first aspect of the Disclosure for use in methods of preoperative anxiety relief to reduce fear. According to another preferred embodiment, the Disclosure relates to a unit-dose composition according to a first aspect of the Disclosure for use in the treatment of agitation, such as preoperative agitation. According to a further preferred embodiment, the Disclosure relates to a unit-dose composition according to a first aspect of the Disclosure for use in the treatment of preoperative agitation.

[0095] According to a preferred embodiment, the Disclosure relates to a unit-dose composition according to a first embodiment of the Disclosure for use in a treatment according to a third embodiment of the Disclosure, wherein the unit-dose composition is administered orally to a subject, and a therapeutically effective concentration of midazolam in the subject's blood is achieved in less than approximately 30 minutes. According to another preferred embodiment, the Disclosure relates to a unit-dose composition according to a first embodiment of the Disclosure for use in a treatment according to a third embodiment of the Disclosure, wherein the unit-dose composition is administered orally to a subject, and a therapeutically effective concentration of midazolam in the subject's blood is achieved in less than approximately 20 minutes. According to a preferred embodiment, the Disclosure relates to a unit-dose composition according to a first embodiment of the Disclosure for use in a treatment according to a third embodiment of the Disclosure, wherein the unit-dose composition is administered orally to a subject, and a therapeutically effective concentration of midazolam in the subject's blood is achieved in less than approximately 15 minutes. In a further preferred embodiment, the Disclosure relates to a unit dose composition according to the first aspect of the Disclosure for use in a treatment according to a third aspect of the Disclosure, wherein the unit dose composition is administered orally to a subject and a therapeutically effective concentration of midazolam in the subject's blood is achieved in less than about 10 minutes.

[0096] In a preferred embodiment, the Disclosure relates to a unit-dose composition according to the First Embodiment of the Disclosure for use in a treatment according to a Third Embodiment of the Disclosure, wherein the unit-dose composition is administered orally to a subject, and a therapeutically effective concentration of midazolam in the subject's blood is maintained for more than about 10 minutes, and up to about 120 minutes. In another preferred embodiment, the Disclosure relates to a unit-dose composition according to the First Embodiment of the Disclosure for use in a treatment according to a Third Embodiment of the Disclosure, wherein the unit-dose composition is administered orally to a subject, and a therapeutically effective concentration of midazolam in the subject's blood is maintained for more than about 20 minutes, and up to about 90 minutes. In a further preferred embodiment, the Disclosure relates to a unit-dose composition according to the First Embodiment of the Disclosure for use in a treatment according to a Third Embodiment of the Disclosure, wherein the unit-dose composition is administered orally to a subject, and a therapeutically effective concentration of midazolam in the subject's blood is maintained for more than about 30 minutes, and up to about 90 minutes.

[0097] According to a preferred embodiment, the Disclosure relates to a unit-dose composition according to a first embodiment of the Disclosure for use in a treatment according to a third embodiment of the Disclosure, wherein the unit-dose composition is administered orally to a subject and maintains a therapeutically effective concentration of midazolam in the subject's blood for more than about 10 minutes. According to another preferred embodiment, the Disclosure relates to a unit-dose composition according to a first embodiment of the Disclosure for use in a treatment according to a third embodiment of the Disclosure, wherein the unit-dose composition is administered orally to a subject and maintains a therapeutically effective concentration of midazolam in the subject's blood for more than about 20 minutes. According to a further preferred embodiment, the Disclosure relates to a unit-dose composition according to a first embodiment of the Disclosure for use in a treatment according to a third embodiment of the Disclosure, wherein the unit-dose composition is administered orally to a subject and maintains a therapeutically effective concentration of midazolam in the subject's blood for more than about 30 minutes.

[0098] According to another preferred embodiment, the Disclosure relates to a unit-dose composition according to the First Embodiment of the Disclosure for use in a treatment according to a Third Embodiment of the Disclosure, wherein the unit-dose composition is administered orally to a subject, and a therapeutically effective concentration of midazolam in the subject's blood is maintained for about 120 minutes or less. According to another preferred embodiment, the Disclosure relates to a unit-dose composition according to the First Embodiment of the Disclosure for use in a treatment according to a Third Embodiment of the Disclosure, wherein the unit-dose composition is administered orally to a subject, and a therapeutically effective concentration of midazolam in the subject's blood is maintained for about 90 minutes or less. According to another preferred embodiment, the Disclosure relates to a unit-dose composition according to the First Embodiment of the Disclosure for use in a treatment according to a Third Embodiment of the Disclosure, wherein the unit-dose composition is administered orally to a subject, and a therapeutically effective concentration of midazolam in the subject's blood is maintained for less than about 90 minutes.

[0099] According to another preferred embodiment, the Disclosure relates to a unit dose composition according to the First Embodiment of the Disclosure for use in a treatment according to a Third Embodiment of the Disclosure, wherein the unit dose composition is administered into the oral cavity of a subject, and the half-life of midazolam in the blood of the subject is in the range of about 10 minutes to about 240 minutes. According to another preferred embodiment, the Disclosure relates to a unit dose composition according to the First Embodiment of the Disclosure for use in a treatment according to a Third Embodiment of the Disclosure, wherein the unit dose composition is applied to the oral mucosa of a subject, and the half-life of midazolam in the blood of the subject is in the range of about 20 minutes to about 120 minutes. According to another preferred embodiment, the Disclosure relates to a unit dose composition according to the First Embodiment of the Disclosure for use in a treatment according to a Third Embodiment of the Disclosure, wherein the unit dose composition is applied to the oral mucosa of a subject, and the half-life of midazolam in the blood of the subject is in the range of about 30 minutes to about 90 minutes. In another preferred embodiment, the Disclosure relates to a unit dose composition according to the first aspect of the Disclosure for use in a treatment according to the third aspect of the Disclosure, wherein the unit dose composition is administered orally to a subject, and the half-life of midazolam in the blood of the subject is in the range of about 40 minutes to about 60 minutes.

[0100] In another preferred embodiment, the Disclosure relates to a unit-dose composition according to the First Embodiment of the Disclosure for use in a treatment according to the Third Embodiment of the Disclosure, wherein the unit-dose composition is administered orally to a subject and the clearance in the blood of the subject is in the range of about 0.005 L / (min*kg) to about 0.25 L / (min*kg). In another preferred embodiment, the Disclosure relates to a unit-dose composition according to the First Embodiment of the Disclosure for use in a treatment according to the Third Embodiment of the Disclosure, wherein the unit-dose composition is administered orally to a subject and the clearance in the blood of the subject is in the range of about 0.01 L / (min*kg) to about 0.2 L / (min*kg). In another preferred embodiment, the present disclosure relates to a unit dose composition according to the first aspect of the present disclosure for use in a treatment according to the third aspect of the present disclosure, wherein the unit dose composition is applied to the oral mucosa of a subject, and the clearance in the blood of the subject is in the range of about 0.02 L / (min*kg) to about 0.15 L / (min*kg).

[0101] According to a preferred embodiment, the Disclosure relates to a unit-dose composition according to a first embodiment of the Disclosure for use in a treatment according to a third embodiment of the Disclosure, wherein the unit-dose composition is administered into the oral cavity of a subject and the volume of distribution in the blood of the subject is in the range of about 0.5 L / kg to about 20 L / kg. According to a preferred embodiment, the Disclosure relates to a unit-dose composition according to a first embodiment of the Disclosure for use in a treatment according to a third embodiment of the Disclosure, wherein the unit-dose composition is administered into the oral cavity of a subject and the volume of distribution in the blood of the subject is in the range of about 1 L / kg to about 20 L / kg. According to a preferred embodiment, the Disclosure relates to a unit-dose composition according to a first embodiment of the Disclosure for use in a treatment according to a third embodiment of the Disclosure, wherein the unit-dose composition is administered into the oral cavity of a subject and the volume of distribution in the blood of the subject is in the range of about 2 L / kg to about 10 L / kg.

[0102] In a preferred embodiment, the Disclosure relates to a unit-dose composition according to a first aspect of the Disclosure for use in a treatment according to a third aspect of the Disclosure, wherein the unit-dose composition is administered orally to a subject, and the plasma concentration profile per dose of the subject is not affected by sex.

[0103] Treatment method According to a fourth aspect, the present disclosure relates to a method for treating or preventing febrile seizures, epileptic seizures, e.g., status epilepticus, phobias, e.g., preoperative anxiety relief to reduce phobias, and / or agitation, e.g., preoperative agitation, wherein a unit dose composition according to a first aspect of the present disclosure is administered to the subject.

[0104] Use in the manufacture of pharmaceuticals According to a fifth aspect, the disclosure relates to the use of a unit-dose composition according to a first aspect of the disclosure in the manufacture of a medicament for the treatment of febrile seizures, epileptic seizures, e.g., status epilepticus, fear, e.g., preoperative anxiety relief to reduce fear, and / or agitation, e.g., preoperative agitation.

[0105] Definitions and General Embodiments As used herein, the term “Oral Thin Film,” which may be abbreviated as OTF, refers to a solid dosage form consisting of a single or multilayer sheet of a suitable material, intended to be administered orally for the delivery of an active substance. Oral thin film is also referred to herein as “wafer.”

[0106] As used herein, “intraoral administration” refers to local administration routes including buccal or sublingual administration. In buccal administration, the drug is held or applied to the buccal region and diffuses through the oral mucosa into the bloodstream directly. Generally, the drug is positioned between the gums and the inner mucosa of the cheek.

[0107] As used herein, the term “midazolam” refers to the free base of midazolam, also known as 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-α][1,4]benzodiazepine or CAS number 59467-70-8. Midazolam has the molecular formula C 18 H 13 It contains ClFN3 and has a molecular weight of 325.77 g / mol. The terms "midazolam" and "midazolam free base" are used interchangeably.

[0108] As used herein, the term “pharmaceutically acceptable salt of midazolam” refers to a salt of midazolam that retains the desired biological and pharmacological activity of midazolam, and includes pharmaceutically acceptable acid addition salts. A suitable pharmaceutically acceptable acid addition salt of midazolam may be prepared from an inorganic or organic acid. Examples of these inorganic acids include hydrochloric acid, sulfuric acid, and phosphoric acid. A suitable organic acid may be selected from the organic acid classes of aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic acids, and sulfonic acids, for example, formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, fumaric acid, maleic acid, alkylsulfonic acid, and arylsulfonic acid.

[0109] As used herein, “midazolam hydrochloride” or “midazolam hydrochloride” are used synonymously and are known by CAS number 59467-96-8, and are addition salts of midazolam and hydrochloric acid (HCl).

[0110] As used herein, “midazolam maleate” or “midazolam maleate” is used synonymously and is known by CAS number 59467-94-6, and is an addition salt of midazolam and maleic acid (HO2CCH=CHCO2H). This also includes midazolam hydrogen maleate.

[0111] When used herein, unless otherwise specified, “amount of midazolam” or “~ amount of midazolam” is determined based on the free base of midazolam. “Amount of midazolam” is also referred to as “m(midazolam)”. In other words, when used herein, “amount of midazolam” or “~ amount of midazolam” is the mass of midazolam or a pharmaceutically acceptable salt thereof, expressed as the mass of the corresponding free base of midazolam. Therefore, the mass of the free base of midazolam is “amount of midazolam”. For pharmaceutically acceptable salts of midazolam, “amount of midazolam” is derived from the mass of the pharmaceutically acceptable salt of midazolam, also referred to as “m(midazolam salt)”, by formula (I):

number

[0112] For example, when midazolam hydrochloride is used as the pharmaceutically acceptable salt of midazolam in the unit dose composition according to this disclosure, since the molecular weight M(midazolam hydrochloride) is 362.23 g / mol, the above formula I is simplified as follows:

number

[0113] For example, when midazolam maleate is used as the pharmaceutically acceptable salt of midazolam in the unit dose composition according to this disclosure, since the molecular weight M(midazolam maleate) is 441.84 g / mol, the above formula I is simplified as follows:

number

[0114] As used herein, the term "cyclodextrin" refers to cyclic oligosaccharides consisting of a macrocyclic ring of glucose subunits linked by α-1,4-glycosidic bonds, and their derivatives.

[0115] As used herein, the terms “alpha-cyclodextrin” and “α-cyclodextrin” are used interchangeably and refer to cyclodextrins, which are cyclic oligosaccharides consisting of a macrocyclic ring of six glucose subunits linked by α-1,4-glycosidic bonds, and their derivatives. Alpha-cyclodextrin is also known by CAS number 10016-20-3.

[0116] As used herein, the terms “beta-cyclodextrin” and “β-cyclodextrin” are used interchangeably and refer to cyclodextrins, which are cyclic oligosaccharides consisting of a macrocyclic ring of seven glucose subunits linked by α-1,4-glycosidic bonds, and their derivatives. Beta-cyclodextrin is also known by CAS number 7585-39-9.

[0117] As used herein, the terms “gamma-cyclodextrin” and “γ-cyclodextrin” are used interchangeably and refer to cyclodextrins, which are cyclic oligosaccharides consisting of a macrocyclic ring of eight glucose subunits linked by α-1,4-glycosidic bonds, and their derivatives. Gamma-cyclodextrin is also known by CAS number 17465-86-0.

[0118] As used herein, the terms "cyclodextrin derivative" and "cyclodextrin derivatives" are used interchangeably and refer to cyclodextrins in which at least one hydrogen of each OH group of each glucose subunit contained in cyclodextrin is replaced by unsubstituted or substituted (C1-C 10 ) alkyl. According to a preferred embodiment of the present disclosure, one, two, or three hydrogens of each OH group of each glucose subunit contained in cyclodextrin are replaced by unsubstituted or substituted (C1-C 10 ) alkyl.

[0119] If one hydrogen of each OH group of each glucose subunit contained in cyclodextrin is replaced by unsubstituted or substituted (C1-C 10 ) alkyl, it is preferred that the hydrogen of the OH group on C6 of each glucose subunit contained in cyclodextrin is replaced by unsubstituted or substituted (C1-C 10 ) alkyl.

[0120] For the purposes of the present disclosure, the term "(C1-C 10 ) alkyl", used alone or as part of another group, refers to a straight-chain or branched-chain aliphatic hydrocarbon containing from 1 to 10, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms (i.e., C1-C 10 alkyl), or a straight-chain or branched-chain aliphatic hydrocarbon containing the specified number of carbon atoms (i.e., C1 alkyl such as methyl, C2 alkyl such as ethyl, C3 alkyl such as propyl or isopropyl, etc.). In one embodiment, the alkyl group is selected from straight-chain (C1-C 10 ) alkyl groups. In another embodiment, the alkyl group is a branched-chain (C3-C 10) Selected from alkyl groups. In another embodiment, the alkyl group is selected from linear (C1-C6) alkyl groups. In another embodiment, the alkyl group is selected from branched (C3-C6) alkyl groups. In another embodiment, the alkyl group is selected from linear (C1-C4) alkyl groups. In another embodiment, the alkyl group is selected from branched (C3-C4) alkyl groups. In another embodiment, the alkyl group is selected from linear or branched (C3-C4) alkyl groups. (C1-C) 10 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl. C is a non-limiting example. 1~4 Alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and isobutyl.

[0121] As used herein, the term “unsubstituted” means the absence of substituents or the sole substituent being hydrogen.

[0122] As used herein, the term “substitution” means that the group comprises one or more substituents. Preferably, the substituents are one or more groups independently selected from the group consisting of halogens, =O, =S, -CN, -NO2, -CF3, -OCF3, and -OH. A non-limiting example of substitution (C1~C 10 Alkyl groups include -CH2CH2NO2, -CH2CH2OH, -CH2CH(OH)CH3, and -CH2CH2CH2OH.

[0123] For the purposes of this disclosure, the term "substitution (C1~C 10 The alkyl group is preferably substituted with one or more hydroxyl groups, for example, one, two, or three (C1-C) groups. 10 ) refers to an alkyl group (C1~C 10 ) refers to "hydroxyalkyl". In one embodiment, (C1~C 10)Hydroxyalkyl groups are monohydroxy-(C1~C 10 ) is an alkyl group, that is, it is substituted with one hydroxyl group. In another embodiment, (C1~C 10 )Hydroxyalkyl groups are dihydroxy-(C1~C 10 ) is an alkyl group, that is, substituted with two hydroxyl groups. In another embodiment, the hydroxyalkyl group is selected from (C1-C4) hydroxyalkyl groups. A non-limiting example is (C1-C 10 The hydroxyalkyl groups include hydroxyethyl, hydroxypropyl, and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxypropane-2-yl.

[0124] Non-limiting examples of "cyclodextrin derivatives" include permethyl-beta-cyclodextrin and hydroxypropyl-beta-cyclodextrin.

[0125] As used herein, “permethyl-beta-cyclodextrin” refers to beta-cyclodextrin in which each hydrogen atom of each OH group in the beta-cyclodextrin is substituted with a -CH3 group. Permethyl-beta-cyclodextrin is also known by CAS number 55216-11-0.

[0126] As used herein, "hydroxypropyl-beta-cyclodextrin," which may be abbreviated as "HPbCD," refers to beta-cyclodextrin in which each hydrogen of each OH group on C6 of each glucose subunit contained in beta-cyclodextrin is substituted with -CH2CH(OH)CH3. Hydroxypropyl-beta-cyclodextrin is also known by CAS number 128446-35-5.

[0127] As used herein, "hydroxypropyl methylcellulose," which may be abbreviated as "HPMC," refers to a semi-synthetic, inert, viscoelastic polymer also known by CAS number 9004-65-3 or E464.

[0128] As used herein, "polyvinyl alcohol," which may be abbreviated as "PVA," refers to a synthetic water-soluble polymer also known by CAS number 9002-89-5 or E1203.

[0129] As used herein, "viscosity" is measured by a viscometer.

[0130] When used herein, the “amount of midazolam or a pharmaceutically acceptable salt thereof” is measured by reversed-phase HPLC analysis combined with UV detection. For the mobile phase, a solution of 7.7 g / L ammonium acetate and 10 mL / L of 40% (400 g / L) tetrabutylammonium hydroxide solution was prepared and the pH was adjusted to 5.3 with acetic acid. 49.5 volumes of this solution were mixed with 50.5 volumes of methanol to constitute the mobile phase. For analysis, Weber was dissolved in 10 mL of the mobile phase by stirring in a closed container for at least 30 minutes until Weber was completely dissolved (visually confirmed). The solution was then subjected to HPLC on a “Phenomenex Luna C8(2) 100A, 150 x 4.6 mm, 3 μm” column at a flow rate of 1.0 μL / min. Midazolam was detected at a wavelength of 254 nm after approximately 19 minutes.

[0131] When used herein, "water content" is measured by Karl Fischer titration and colorimetric determination in a gas extraction method using a Karl Fischer coulometer and Karl Fischer oven. Weigh an empty ampoule with a crimped cap, place Weber into the ampoule, airtight seal the ampoule with the crimped cap, and weigh again. Extract the water in a Karl Fischer oven at 120°C.

[0132] When used herein, “collapse time” is a modified USP <701> The measurement is performed by a disintegration test. The time it takes for a Weber to disintegrate in an aqueous medium is measured. A metal clip is attached to the lower end of the Weber, while its upper end is clipped to a basket. The basket is placed in the medium (800 mL of deionized and deaerated water at 37±2°C), and when the Weber disintegrates, the clip settles to the bottom of the basket, and the measurement automatically stops.

[0133] When the term “contains” is used herein and in the claims, it does not exclude other elements. For the purposes of this disclosure, the term “consisting of” is considered a preferred embodiment of the term “contains.” When a group is defined herein as containing at least a certain number of embodiments, this is also understood to disclose a group consisting preferably only of these embodiments. Furthermore, when a composition is defined using the term “contains,” it may additionally contain other elements not expressly enumerated, but not any further amounts of the enumerated elements. For example, when a unit dose composition contains 2.5 mg of midazolam or a pharmaceutically acceptable salt thereof, the unit dose composition may contain elements other than midazolam or a pharmaceutically acceptable salt thereof, but not any additional amounts of midazolam or a pharmaceutically acceptable salt thereof exceeding 2.5 mg.

[0134] The term "approximately" used with a numerical value refers to the normal deviation of that value. It is understood that the term "approximately" may mean a deviation of ±10%, preferably ±5%, and more preferably ±2.5% of the given numerical value.

[0135] Examples Example 1: Manufacturing of oral thin film Unless otherwise noted, all chemicals used in this specification were obtained from commercial suppliers. PVA 4-88 and PVA 40-88 were obtained from Merck KGaA (Germany). Polyvinyl alcohol (PVA) 4-88 was purchased as Mowiol 4-88, with a viscosity (40 g / L in water) of 3.4–4.6 mPa·s (target: 4 mPa·s), and PVA 40-88 had a viscosity of 34–46 mPa·s (target: 40 mPa·s). HPMC 606 and HPMC 60SH50 (both hydroxypropyl methylcellulose 2910) were purchased from Shin-Etsu Chemical Co. Ltd. as Pharmacoat 606 and Metolose 60SH-50, respectively. The viscosity of HPMC grades was measured according to the USP method (hypromellose) in a 2% by weight aqueous solution at 20°C. The results showed that HPMC 606 had a viscosity of 4.8–7.2 mPa·s (target: 6 mPa·s), and HPMC 60SH50 had a viscosity of 40–60 mPa·s (target: 50 mPa·s).

[0136] For the production of oral thin films, coating masses were prepared by dissolving the components of the oral thin film to be produced in water while stirring at 300-800 rpm until a clear, homogeneous solution with the composition shown in Table 1 was formed. For the oral thin film "PVA foam pH 3.5", the stirring speed was increased to 1400 rpm to create foam. The pH of the solution was adjusted with a small amount of citric acid. While the HPMC film was being adjusted to pH 5.0, some of the midazolam reprecipitated, resulting in a homogeneous whitish suspension, which was then processed in the following steps. [Table 1]

[0137] For example, the solution for HPMC-based film was selectively stored for 1 to 2 days.

[0138] Next, the solution was coated onto the process liner using a 500 μm coating gap by casting and placed in a drying oven at 30°C for 10–15 minutes. The temperature was then increased to 60°C over 10–15 minutes until a soft film was formed, and optionally held at 60°C for up to an additional 15 minutes.

[0139] The oral thin film for testing is 5 cm 2 Multiple die-cuts were used to obtain the square-shaped oral thin film, which was then pouched, sealed, and labeled.

[0140] The oral thin films obtained in this way, "PVA foam pH 3.5," "HPMC film pH 4.0," and "HPMC film pH 5.0," were stable, neither brittle nor sticky.

[0141] The amount of midazolam in each oral thin film was measured according to the procedure outlined above. [Table 2]

[0142] Example 2: Stability Test The oral thin films prepared in Example 1 were stored at 40°C and 75% relative humidity. Samples for stability testing were taken after 1.5 months, 3 months, and 6 months of storage and analyzed for appearance, water content, midazolam content, and disintegration time.

[0143] The results of the stability tests are summarized in Tables 3 to 5. [Table 3] [Table 4] [Table 5]

[0144] The film showed no visible changes in appearance over time. Furthermore, no signs of recrystallization of the active ingredient were observed, as confirmed by XRPD measurements.

[0145] The film's water content, midazolam content, and in vitro decay time did not change significantly over a 6-month storage period.

[0146] Furthermore, in all oral thin films stored at 40°C / 75%RH for 3 months, more than 80% of the drug was released within 3 minutes.

[0147] In conclusion, all oral thin films appear to be stable enough to be introduced into preclinical trials.

[0148] Example 3: Pharmacokinetic evaluation of oral thin film To investigate the local tolerability and pharmacokinetics of four oral thin films prepared according to Example 1, oral thin films containing 3.0 mg of midazolam HCl (equivalent to 2.7 mg of free midazolam base) were sequentially administered to six non-naive Marshall Beagle dogs (three males weighing 8.6–11 kg and three females weighing 7.5–8.1 kg), with at least three days of washout between treatments. Dormicum® 7.5 mg tablets and midazolam 5 mg / mL injection / infusion solution (obtained from B. Braun) were used as reference. The dogs were fasted before administration and throughout the study period. On treatment days, the animals were given their first meal of the day after blood sample collection two hours after administration, and their second meal of the day after blood sample collection six hours after administration.

[0149] No oral tissue reactions were observed at the application site.

[0150] Blood samples were collected from dogs before the procedure and at 2, 5, 10, 30, 60, 120, and 360 minutes after the procedure. Approximately 2 mL of blood sample was collected from the saphenous vein. The blood was collected in a vacuum tank containing lithium heparin as an anticoagulant. The vacuum tank was placed in ice water until centrifugation (10 minutes, 1270 G, +4°C). Each plasma sample was divided into two aliquots of at least 0.4 mL each, transferred to Nunc cryotubes (internal threaded polypropylene tubes), and frozen at -18°C or below within 90 minutes of collection.

[0151] Midazolam concentrations in blood samples were measured using a validated liquid chromatography-mass spectrometry (LC-MS / MS) method. The calibration range was 0.1–1000 ng / mL. Briefly, each analytical batch sequence consisted of a plasma calibrator including blank and zero samples covering the assay range of 0.100 ng / mL–1000 ng / mL for the matrix. Study samples were assayed with animal-specific profiles. The performance of the method was ensured by co-assaying quality control (QC) samples at three concentration levels (0.5, 250, and 800 ng / mL) in the matrix in duplicate. The concentration of the analyte in unknown samples was calculated using the analyte / internal standard area ratio. Linear regression was applied to construct calibration curves, using a weighting of 1 / x2. All instrument control, data acquisition, peak area integration, and storage were performed using Analyst ver.1.7.2 (AB Sciex). Test samples were prepared by aliquoting 40 μl of plasma and 5 μl of IS and precipitating with 200 μl of acetonitrile. It was thoroughly mixed and centrifuged at 14000 g at 8°C for 10 minutes. The supernatant (190 μl) was transferred to an HPLC vial. 190 μl of mobile phase-eluent A was added. It was thoroughly mixed, and the sample was analyzed using LC-MS / MS. [Table 6] [Table 7] [Table 8] [Table 9]

[0152] The results of the pharmacokinetic analysis are summarized in Table 10 and Figures 1-6.

[0153] Maximum exposure (T max The half-life was faster in all buccal films compared to the reference tablet (10 minutes vs. 30 minutes), while the half-life was similar for the tablet and buccal formulation. Furthermore, the buccal film of Example 1 showed a maximum plasma concentration (C) of midazolam equivalent to or very similar to that of the reference solution. max ) showed the C of all buccal films. max and AUC inf The clearance was significantly higher than that of the comparison drug, Dormicum® tablets. Clearance was higher with Dormicum® tablets than with all buccal film formulations.

[0154] No significant differences in pharmacokinetic profiles were observed among the four buccal film formulations. [Table 10]

[0155] item This application is also related to the following numbered items. 1. A unit dose composition in the form of an oral thin film, comprising midazolam or a pharmaceutically acceptable salt thereof, cyclodextrin, and at least one matrix material. 2. The unit dose composition according to item 1, wherein the amount of midazolam is in the range of about 0.01 mg to about 50 mg, preferably in the range of about 0.1 mg to about 20 mg, preferably in the range of about 0.2 mg to about 15 mg, preferably in the range of about 0.5 mg to about 10 mg, preferably in the range of about 1 mg to about 5 mg, more preferably in the range of about 1.5 mg to about 4.5 mg, even more preferably in the range of about 1.8 mg to about 4.3 mg, even more preferably in the range of about 2.0 mg to about 4 mg, even more preferably in the range of about 2.3 mg to about 3.5 mg, even more preferably in the range of about 2.3 mg to about 3.2 mg, even more preferably in the range of about 2.4 mg to about 3.1 mg, still even more preferably in the range of about 2.5 mg to about 3.0 mg, and more preferably in the range of about 2.6 mg to about 2.9 mg, where the amount of midazolam is determined based on the free base of midazolam. 3. The unit dose composition according to item 1 or 2, wherein the pharmaceutically acceptable salt of midazolam is selected from the group consisting of midazolam hydrochloride and midazolam maleate, and preferably the pharmaceutically acceptable salt of midazolam is midazolam hydrochloride. 4. The cyclodextrin is selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and delta-cyclodextrin. Preferably, the cyclodextrin is selected from the group consisting of beta-cyclodextrin, gamma-cyclodextrin, and delta-cyclodextrin. More preferably, the cyclodextrin is beta-cyclodextrin. More preferably, the cyclodextrin is permethyl-beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin (HpbCD), Most preferably, the cyclodextrin is hydroxypropyl-beta-cyclodextrin. A unit dose composition as described in any one of items 1 to 3. 5. The mass ratio of midazolam free base to hydroxypropyl-beta-cyclodextrin is in the range of about 1:1 to about 1:10, preferably in the range of about 1:2 to about 1:8, preferably in the range of about 1:3 to about 1:6, and preferably in the range of about 1:4 to about 1:5. Most preferably, the mass ratio of midazolam free base to hydroxypropyl-beta-cyclodextrin is about 1:5.2. The unit dose composition described in item 3 or 4. 6. At least the matrix material is selected from the group consisting of cellulose, cellulose derivatives, acrylic polymers, acrylic copolymers, and mixtures thereof. Preferably, at least the matrix material is selected from the group consisting of ethylcellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose salt, microcrystalline cellulose, croscarmellose, cellulose acetate, polyvinylpyrrolidone, polyvinyl alcohol (PVA), polyethylene oxide, and mixtures thereof. More preferably, the matrix material is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), and mixtures thereof. Unit dose compositions as described in items 1 to 5. 7. At least one matrix material is a mixture of two matrix materials having different viscosities. Preferably, the mixture of two matrix materials consists of a first matrix material and a second matrix material. Here, the first matrix material has a viscosity about 1.2 to about 100 times higher than the second matrix material, preferably the first matrix material has a viscosity about 2 to about 50 times higher than the second matrix material, and more preferably the first matrix material has a viscosity about 5 to about 20 times higher than the second matrix material. Here, viscosity is measured by a viscometer. A unit dose composition as described in any one of items 1 to 6. 8. A unit dose composition according to any one of claims 1 to 7, further comprising at least one sweetener selected from the group consisting of sucralose and sodium saccharin. 9. A unit dose composition according to any one of items 1 to 8, further comprising glycerol. 10. The unit dose composition has a pH in the range of approximately 2.0 to approximately 8.0. Preferably, the oral thin film has a pH in the range of about 2.5 to about 7.0. Preferably, the oral thin film has a pH in the range of about 3.0 to about 6.0. More preferably, the oral thin film has a pH in the range of about 3.5 to about 5.0 A unit dose composition as described in any one of items 1 to 9. 11. A unit dose composition according to any one of items 1 to 10 for oral administration, for example, for buccal or sublingual administration, preferably for buccal or sublingual administration. 12. A unit dose composition according to any one of the preceding paragraphs for use in the treatment or prevention of febrile seizures, acute seizures, epileptic seizures, e.g., status epilepticus, fear, e.g., preoperative anxiety relief to reduce fear, and / or agitation, e.g., preoperative agitation. 13. The unit dose composition is administered orally to the subject, and the therapeutically effective concentration of midazolam in the subject's blood is achieved in less than approximately 30 minutes, preferably less than approximately 20 minutes, preferably less than approximately 15 minutes. More preferably, the oral thin film is applied to the target oral mucosa, and the therapeutically effective concentration of midazolam in the target blood is achieved in less than approximately 10 minutes. Unit dose composition for use as described in item 12. 14. The unit dose composition is administered orally to the subject, and the therapeutically effective concentration of midazolam in the subject's blood is maintained for more than approximately 10 minutes, and for a maximum of approximately 120 minutes. Preferably, the therapeutically effective concentration of midazolam in the subject's blood is maintained for more than approximately 20 minutes, and for a maximum of approximately 90 minutes. More preferably, the therapeutically effective concentration of midazolam in the subject's blood is maintained for more than approximately 30 minutes and less than approximately 90 minutes. A unit dose composition for use as described in item 12 or 13. 15. The unit dose composition is administered orally to the subject, and the half-life of midazolam in the subject's blood is in the range of about 10 minutes to about 240 minutes, preferably in the range of about 20 minutes to about 120 minutes, preferably in the range of about 30 minutes to about 90 minutes. More preferably, the oral thin film is applied to the target oral mucosa, and the half-life of midazolam in the target blood is in the range of approximately 40 minutes to approximately 60 minutes. A unit dose composition for use as described in any one of items 12 to 14. 16. The unit dose composition is administered into the oral cavity of the subject, and the clearance in the subject's blood is in the range of approximately 0.005 L / (min*kg) to approximately 0.25 L / (min*kg), preferably in the range of approximately 0.01 L / (min*kg) to approximately 0.2 L / (min*kg). More preferably, the oral thin film is applied to the target oral mucosa, and the clearance in the target blood is in the range of approximately 0.01 L / (min*kg) to approximately 0.15 L / (min*kg). A unit dose composition for use as described in any one of items 12 to 15. 17. The unit dose composition is administered into the oral cavity of the subject, and the volume of distribution in the subject's blood is in the range of approximately 0.5 L / kg to approximately 20 L / kg. Preferably, the volume of distribution in the blood of the subject is in the range of approximately 1 L / kg to approximately 15 L / kg. More preferably, the volume of distribution in the blood of the subject is in the range of approximately 2 L / kg to approximately 10 L / kg. A unit dose composition for use as described in any one of items 12 to 16. 18. A unit dose composition for use according to any one of claims 12 to 17, wherein the unit dose composition is administered orally to the subject, and the plasma concentration profile per dose of the subject is not affected by sex. 19. A method for treating or preventing febrile seizures, acute seizures, epileptic seizures, e.g., status epilepticus, phobias, e.g., preoperative anxiety relief to reduce phobias, and / or agitation, e.g., preoperative agitation, wherein a unit dose composition described in any one of items 1 to 11 is administered to the subject. 20. Use of the unit dose compositions described in any one of items 1 to 11 for the manufacture of a medicament for the treatment or prevention of preoperative anxiety relief to alleviate febrile seizures, acute seizures, epileptic seizures, such as status epilepticus, and / or preoperative fear and agitation.

Claims

1. A unit dose composition in the form of an oral thin film, comprising midazolam or a pharmaceutically acceptable salt thereof, cyclodextrin, and at least one matrix material.

2. The unit dose composition according to claim 1, wherein the amount of midazolam is in the range of about 0.01 mg to about 50 mg, preferably in the range of about 0.1 mg to about 20 mg, preferably in the range of about 0.2 mg to about 15 mg, preferably in the range of about 0.5 mg to about 10 mg, preferably in the range of about 1 mg to about 5 mg, more preferably in the range of about 1.5 mg to about 4.5 mg, even more preferably in the range of about 1.8 mg to about 4.3 mg, even more preferably in the range of about 2.0 mg to about 4 mg, even more preferably in the range of about 2.3 mg to about 3.5 mg, even more preferably in the range of about 2.3 mg to about 3.2 mg, even more preferably in the range of about 2.4 mg to about 3.1 mg, still even more preferably in the range of about 2.5 mg to about 3.0 mg, and more preferably in the range of about 2.6 mg to about 2.9 mg, where the amount of midazolam is determined based on the free base of midazolam.

3. The unit dose composition according to claim 1 or 2, wherein the pharmaceutically acceptable salt of midazolam is selected from the group consisting of midazolam hydrochloride and midazolam maleate, and preferably the pharmaceutically acceptable salt of midazolam is midazolam hydrochloride.

4. Cyclodextrin is selected from the group consisting of alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and delta-cyclodextrin. Preferably, the cyclodextrin is selected from the group consisting of beta-cyclodextrin, gamma-cyclodextrin, and delta-cyclodextrin. More preferably, the cyclodextrin is beta-cyclodextrin. More preferably, the cyclodextrin is permethyl-beta-cyclodextrin or hydroxypropyl-beta-cyclodextrin (HpbCD), Most preferably, the cyclodextrin is hydroxypropyl-beta-cyclodextrin. A unit dose composition according to any one of claims 1 to 3.

5. The mass ratio of midazolam free base to hydroxypropyl-beta-cyclodextrin is in the range of about 1:1 to about 1:10, preferably in the range of about 1:2 to about 1:8, preferably in the range of about 1:3 to about 1:6, and preferably in the range of about 1:4 to about 1:

5. Most preferably, the mass ratio of midazolam free base to hydroxypropyl-beta-cyclodextrin is about 1:5.

2. The unit dose composition according to claim 3 or 4.

6. At least the matrix material is selected from the group consisting of cellulose, cellulose derivatives, acrylic polymers, acrylic copolymers, and mixtures thereof. Preferably, at least the matrix material is selected from the group consisting of ethylcellulose, methylcellulose, hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose salt, microcrystalline cellulose, croscarmellose, cellulose acetate, polyvinylpyrrolidone, polyvinyl alcohol (PVA), polyethylene oxide, and mixtures thereof. More preferably, the matrix material is selected from the group consisting of hydroxypropyl methylcellulose (HPMC), polyvinyl alcohol (PVA), and mixtures thereof. and / or At least one matrix material is a mixture of two matrix materials having different viscosities. Preferably, the mixture of two matrix materials consists of a first matrix material and a second matrix material, and Here, the first matrix material has a viscosity about 1.2 to about 100 times higher than the second matrix material, preferably the first matrix material has a viscosity about 2 to about 50 times higher than the second matrix material, and more preferably the first matrix material has a viscosity about 5 to about 20 times higher than the second matrix material. Here, viscosity is measured by a viscometer. The unit dose composition according to claims 1 to 5.

7. The sweetener further comprises at least one selected from the group consisting of sucralose and sodium saccharin; and / or Contains glycerol A unit dose composition according to any one of claims 1 to 6.

8. The unit dose composition has a pH in the range of approximately 2.0 to approximately 8.

0. Preferably, the oral thin film has a pH in the range of about 2.5 to about 7.

0. Preferably, the oral thin film has a pH in the range of about 3.0 to about 6.

0. More preferably, the oral thin film has a pH in the range of about 3.5 to about 5.0 A unit dose composition according to any one of claims 1 to 7.

9. A unit dose composition according to any one of claims 1 to 8 for oral administration, for example, for buccal or sublingual administration, preferably for buccal or sublingual administration.

10. A unit dose composition according to any one of the claims for use in the treatment or prevention of febrile seizures, acute seizures, epileptic seizures, e.g., status epilepticus, fear, e.g., preoperative anxiety relief to reduce fear, and / or agitation, e.g., preoperative agitation.

11. The unit dose composition is administered orally to the subject, and a therapeutically effective concentration of midazolam in the subject's blood is achieved in less than approximately 30 minutes, preferably less than approximately 20 minutes, and preferably less than approximately 15 minutes. More preferably, the oral thin film is applied to the oral mucosa of the subject, and a therapeutically effective concentration of midazolam in the subject's blood is achieved in less than about 10 minutes; and / or The unit dose composition is administered orally to the subject, and the therapeutically effective concentration of midazolam in the subject's blood is maintained for more than approximately 10 minutes, and for a maximum of approximately 120 minutes. Preferably, the therapeutically effective concentration of midazolam in the subject's blood is maintained for more than approximately 20 minutes, and for a maximum of approximately 90 minutes. More preferably, the therapeutically effective concentration of midazolam in the subject's blood is maintained for more than approximately 30 minutes and less than approximately 90 minutes. A unit dose composition for use according to claim 10.

12. The unit dose composition is administered orally to the subject, and the half-life of midazolam in the subject's blood is in the range of about 10 minutes to about 240 minutes, preferably in the range of about 20 minutes to about 120 minutes, preferably in the range of about 30 minutes to about 90 minutes. More preferably, the oral thin film is applied to the target oral mucosa, and the half-life of midazolam in the target blood is in the range of approximately 40 minutes to approximately 60 minutes. A unit dose composition for use according to any one of claims 10 or 11.

13. The unit dose composition is administered into the oral cavity of the subject, and the clearance in the subject's blood is in the range of about 0.005 L / (min*kg) to about 0.25 L / (min*kg), preferably in the range of about 0.01 L / (min*kg) to about 0.2 L / (min*kg). More preferably, the oral thin film is applied to the target oral mucosa, and the clearance in the target blood is in the range of approximately 0.01 L / (min*kg) to approximately 0.15 L / (min*kg). A unit dose composition for use according to any one of claims 10 to 12.

14. The unit dose composition is administered into the oral cavity of the subject, and the volume of distribution in the subject's blood is in the range of approximately 0.5 L / kg to approximately 20 L / kg. Preferably, the volume of distribution in the blood of the subject is in the range of approximately 1 L / kg to approximately 15 L / kg. More preferably, the volume of distribution in the blood of the subject is in the range of approximately 2 L / kg to approximately 10 L / kg. A unit dose composition for use according to any one of claims 10 to 13.

15. A unit-dose composition for use according to any one of claims 10 to 14, wherein the unit-dose composition is administered into the oral cavity of the subject, and the plasma concentration profile per dose of the subject is not affected by sex.

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