Administration of benzodiazepine compositions

Abstract

The present invention provides a pharmaceutical composition containing a benzodiazepine drug. [Solution] A drug solution for intranasal administration is provided, comprising: (a) a benzodiazepine drug; (b) one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 30% to about 95% (w / w); (c) one or more alcohols or glycols, or any combination thereof, in an amount of about 10% to about 70% (w / w); and (d) an alkyl glycoside.

Description

Technical Field

[0001] <Cross - Reference to Related Applications> This application claims priority to U.S. Provisional Application No. 61 / 497,017, filed on Jun. 14, 2011, and U.S. Provisional Application No. 61 / 570,110, filed on Dec. 13, 2011, each of which is hereby incorporated by reference in its entirety.

Background Art

[0002] This application relates to the nasal administration of benzodiazepine drugs and combinations thereof.

[0003] By way of non - limiting example, the benzodiazepine family consists of drugs such as diazepam, lorazepam, and midazolam. Drugs within this family have been observed to possess sedative, anxiolytic, and muscle - relaxant properties. They are often classified as anxiolytics and skeletal muscle relaxants. They are said to be useful for preventing, treating, or ameliorating symptoms of anxiety, insomnia, agitation, seizures (such as those caused by epilepsy), muscle cramps and rigidity, drug withdrawal related to the continuous abuse of central nervous system depressants, and symptoms of exposure to nerve gas. [[ID=2�]]

[0004] Benzodiazepines are said to act by binding to the GABA A receptors of nerve cells, altering the shape of the receptor and making it more accessible to gamma - aminobutyric acid (GABA).

[0005] GABA is an inhibitory neurotransmitter that promotes the flow of Cl A ions into the nerve cells to which the receptor is bound. Cl - ions. The increase in Cl - ions hyperpolarizes the membrane of the nerve cell. This reduces the ability of the nerve cell to carry action potentials either completely or substantially. Targeting this receptor is particularly useful for treating many disorders such as tetanus and epilepsy, which can result from too many action potentials passing through the nervous system.

[0006] Current formulations of benzodiazepine drugs can be administered orally, rectally, or parenterally. The availability of these and other types of formulations is, in many cases, significantly limited by solubility challenges.

[0007] The oral route of administration may be considered suboptimal due to several drawbacks. For example, it may take more than an hour for orally administered benzodiazepine drugs to reach therapeutically relevant concentrations in plasma. Furthermore, as benzodiazepine drugs cross the liver, a significant amount of the drug may be metabolized. Therefore, high doses may be required to achieve therapeutic plasma levels. In addition, the seizure and muscle-spastic nature of benzodiazepine drugs can make oral administration difficult for patients or caregivers, and caregivers may hesitate to put their hands in the patient's mouth.

[0008] Intravenous administration may offer a faster route of administration. However, intravenous administration is generally limited to trained healthcare professionals in a well-controlled clinical setting. Furthermore, sterility must be maintained. In addition, administering any drug intravenously may be painful and may be impractical for patients suffering from needle phobia. Moreover, intravenous administration of benzodiazepines is associated with respiratory depression. Therefore, the use of intravenous benzodiazepines is limited to professional healthcare settings.

[0009] Benzodiazepine suppository formulations can have a rapid onset of action. However, the difficulty with rectally administered drugs is that they are administered by someone other than the patient's close acquaintances and the patient's professional medical donors, which is a significant obstacle. [Overview of the project] [Means for solving the problem]

[0010] In some embodiments, a pharmaceutically acceptable (non-aqueous) drug solution for nasal administration is provided, comprising (a) a benzodiazepine drug, (b) one or more natural or synthetic tocopherols or tocotrienols, or a combination thereof, in an amount of about 30% to about 95% (w / w), (c) one or more alcohols or glycols, or any combination thereof, in an amount of about 10% to about 70% (w / w), and (d) an alkyl glycoside. In some embodiments, the benzodiazepine drug is dissolved in one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 30% to about 95% (w / w); and one or more alcohols or glycols, or any combination thereof, in an amount of about 10% to about 70% (w / w). In some embodiments, the benzodiazepine drug is selected from the group consisting of alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, chlorazepam, demoxazepam, diazepam, flumazenil, flurazepam, harazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically acceptable salt thereof, and any combination thereof. In some embodiments, the benzodiazepine drug is diazepam or a pharmaceutically acceptable salt thereof. In some embodiments, the solution contains about 1 to about 20% (w / v) of benzodiazepine, for example, about 1 to about 20% (w / v) of diazepam. In some embodiments, one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocophersolane, any isomer thereof, any ester thereof, any analog or derivative thereof, and any combination thereof. In some embodiments, one or more alcohols are selected from the group consisting of ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomer thereof, or any combination thereof.In some embodiments, the solution contains two or more alcohols, such as ethanol (1-25% w / v) and benzyl alcohol (1-25% w / v), or ethanol (10-22.5% w / v) and benzyl alcohol (7.5-12.5% ​​w / v). In some embodiments, the benzodiazepine is present in the pharmaceutical composition at a concentration of about 20 mg / mL to about 200 mg / mL. In some embodiments, one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, are present in an amount of about 45% to about 85% w / w. In some embodiments, one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, are present in an amount of about 50% to about 75% w / w. In some embodiments, one or more alcohols or glycols, or any combination thereof, are present in an amount of about 15% to about 55% (w / w), for example, about 25% to about 40% (w / w). In some embodiments, the solution consists of diazepam (5-15% (w / v)), alkyl glycoside (0.01-1% (w / v)), vitamin E (45-65% (w / v)), ethanol (10-25% (w / v)), and benzyl alcohol (5-15% (w / v)). In some embodiments, the solution contains at least about 0.01% (w / w) of an alkyl glycoside, such as dodecyl maltoside, for example, about 0.01% to 1% (w / w) of the alkyl glycoside.In some embodiments, the solution consists of diazepam (5-15% (w / v)), dodecyl maltoside (0.01-1% (w / v)), vitamin E (45-65% (w / v)), ethanol (10-25% (w / v)), and benzyl alcohol (5-15% (w / v)), and in particular, the solution consists of diazepam (9-11% (w / v)), dodecyl maltoside (0.1-0.5% (w / v)), and vitamin E (50%). The solution may consist of -60% (w / v), ethanol (15-22.5% (w / v)), and benzyl alcohol (7.5-12.5% ​​(w / v)), and more specifically, the solution may consist of diazepam (10% (w / v)), dodecyl maltoside (0.15-0.3% (w / v)), vitamin E (50-60% (w / v)), ethanol (17-20% (w / v)), and benzyl alcohol (10-12% (w / v)).

[0011] Several embodiments described herein provide a method for treating a patient having a disorder that may be treatable with a benzodiazepine drug, the method comprising administering a drug solution for intranasal administration to one or more nasal mucosa of a patient, comprising about 30% to about 95% (w / w) of one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, about 10% to about 70% (w / w) of one or more alcohols or glycols, or any combination thereof, and an alkyl glycoside. In some embodiments, the benzodiazepine drug is dissolved in about 30% to about 95% (w / w) of one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, and about 10% to about 70% (w / w) of one or more alcohols or glycols, or any combination thereof. In some embodiments, the benzodiazepine drug is selected from the group consisting of alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, chlorazepam, demoxazepam, diazepam, flumazenil, flurazepam, harazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically acceptable salt thereof, and any combination thereof. In some embodiments, the benzodiazepine drug is diazepam or a pharmaceutically acceptable salt thereof. In some embodiments, the solution contains about 1 to 20% (w / v) of benzodiazepine, for example, about 1 to about 20% (w / v) of diazepam. In some embodiments, one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocophersolane, any isomer thereof, any ester thereof, any analog or derivative thereof, and any combination thereof.In some embodiments, one or more alcohols are selected from the group consisting of ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomer thereof, or any combination thereof. In some embodiments, the solution contains two or more alcohols, such as ethanol (1-25% (w / v)) and benzyl alcohol (1-25% (w / v)), or ethanol (10-22.5% (w / v)) and benzyl alcohol (7.5-12.5% ​​(w / v)). In some embodiments, benzodiazepines are present in the pharmaceutical composition at a concentration of about 20 mg / mL to about 200 mg / mL. In some embodiments, one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, are present in an amount of about 45% to about 85% (w / w). In some embodiments, one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, are present in an amount of about 50% to about 75% (w / w). In some embodiments, one or more alcohols or glycols, or any combination thereof, are present in an amount of about 15% to about 55% (w / w), for example, about 25% to about 40% (w / w). In some embodiments, the solution consists of diazepam (5-15% (w / v)), alkyl glycoside (0.01-1% (w / v)), vitamin E (45-65% (w / v)), ethanol (10-25% (w / v)), and benzyl alcohol (5-15% (w / v)). In some embodiments, the solution contains at least about 0.01% (w / w) of alkyl glycoside, such as dodecyl maltoside, for example, about 0.01% to 1% (w / w) of alkyl glycoside.In some embodiments, the solution consists of diazepam (5-15% w / v), dodecyl maltoside (0.01-1% w / v), vitamin E (45-65% w / v), ethanol (10-25% w / v), and benzyl alcohol (5-15% w / v), and in particular, the solution consists of diazepam (9-11% w / v), dodecyl maltoside (0.1-0.5% w / v), and vitamin E (50-6%). The solution may consist of 0% (w / v), ethanol (15-22.5% (w / v)), and benzyl alcohol (7.5-12.5% ​​(w / v)), and more specifically, the solution may consist of diazepam (10% (w / v)), dodecyl maltoside (0.15-0.3% (w / v)), vitamin E (50-60% (w / v)), ethanol (17-20% (w / v)), and benzyl alcohol (10-12% (w / v)). In some embodiments, the patient is human. In some embodiments, the benzodiazepine is administered in a therapeutically effective dose of about 1 mg to about 20 mg. In some embodiments, the benzodiazepine is administered in a dose volume of about 10 μL to about 200 μL. In some embodiments, the administration of the pharmaceutical composition includes spraying at least a portion of a therapeutically effective dose of benzodiazepine into at least one nostril. In some embodiments, administration of the pharmaceutical composition includes spraying at least a portion of a therapeutically effective amount of benzodiazepine into each nostril. In some embodiments, administration of the pharmaceutical composition includes spraying a first amount of the pharmaceutical composition into a first nostril, spraying a second amount of the pharmaceutical composition into a second nostril, and spraying a third amount of the pharmaceutical composition into the first nostril after a optionally pre-selected time delay. In some embodiments, the method includes administering at least a fourth amount of the pharmaceutical composition into the second nostril after a optionally pre-selected time delay. In some embodiments, intranasal administration of the pharmaceutical composition begins at any time before or after the onset of symptoms of a disorder that may be treatable by the pharmaceutical composition. In some embodiments, the treatment achieves a bioavailability of about 80–125% (e.g., about 90–110%, or, in particular, about 92.5–107.5%) achieved by the same benzodiazepine administered intravenously.For example, in this context, bioavailability is intended to be measured by appropriate pharmacokinetic methods, such as a comparison of the area under the plasma concentration curve (AUC) for drugs administered intranasally and intravenously. Percent bioavailability of a benzodiazepine administered intranasally may be measured by comparing the area under the plasma concentration curve obtained with one dose of the benzodiazepine (e.g., 10 mg of nasal diazepam) with another dose of the same benzodiazepine administered intravenously (e.g., 5 mg of iv diazepam), and it is further understood that dose differences are taken into account. Therefore, for illustrative purposes, a dose of 10 mg of nasal diazepam that achieves an AUC that is exactly half the AUC obtained with 5 mg iv would have 100% bioavailability. In some embodiments, the disorder treated is a seizure, such as an epileptic seizure, an uncontrollable seizure, or another seizure. In some embodiments, the solution and treatment with the solution are substantially non-irritating and well-tolerated.

[0012] In some embodiments, the pharmaceutical composition for intranasal administration comprises a benzodiazepine drug in a pharmaceutically acceptable formulation for administration to one or more nasal mucosa of a patient; one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 30% to about 95% (w / w); and one or more alcohols or glycols, or any combination thereof, in an amount of about 5% to about 70% (w / w), preferably 10% to about 70% (w / w). In some embodiments, the benzodiazepine drug is dissolved in one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 30% to about 95% (w / w); and one or more alcohols or glycols, or any combination thereof, in an amount of about 5% to about 70% (w / w), preferably 10% to about 70% (w / w). In some embodiments, the benzodiazepine drug is dissolved in a carrier system. In some embodiments, at least a portion of the benzodiazepine drug is in a form comprising benzodiazepine microparticles, nanoparticles, or a combination thereof. In some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles, or a combination thereof.

[0013] In some embodiments, the benzodiazepine drug is selected from the group consisting of alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, chlorazepam, demoxazepam, diazepam, flumazenil, flurazepam, harazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically acceptable salt thereof, and any combination thereof. In some embodiments, the benzodiazepine drug is diazepam or a pharmaceutically acceptable salt thereof. In some embodiments, the benzodiazepine drug is benzodiazepine microparticles, nanoparticles, or a combination thereof. In some embodiments, the benzodiazepine nanoparticles have an effective average particle size of less than about 5000 nm. In some embodiments, the benzodiazepine drug is substantially free of benzodiazepine microparticles, nanoparticles, or combinations thereof.

[0014] In some embodiments, one or more natural or synthetic tocopherols or tocotrienols are selected from groups consisting of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocophersolane, any isomer thereof, any ester thereof, any analog or derivative thereof, and any combination thereof. In some embodiments, the synthetic tocopherol may include vitamin E TPGS (vitamin E polyethylene glycol succinate). On the other hand, in some embodiments, the synthetic tocopherol excludes tocopherols covalently bonded or linked to a glycol polymer (e.g., by diacidic linking groups), such as polyethylene glycol. Therefore, in some embodiments, the compositions described herein exclude vitamin E TPGS.

[0015] In some embodiments, one or more alcohols are selected from the group consisting of ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomer thereof, or any combination thereof. In some embodiments, one or more glycols are selected from groups consisting of ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomer thereof, and any combination thereof. In some preferred embodiments, glycols are excluded from glycol polymers. In some preferred embodiments, glycols are excluded from glycol polymers having an average molecular weight greater than 200. In some embodiments, glycols are excluded from polyethylene glycols having an average molecular weight greater than about 200.

[0016] In some embodiments, the benzodiazepine drug is present in the carrier system at a concentration of about 1 mg / mL to about 600 mg / mL. In some embodiments, the benzodiazepine drug is present in the carrier system at a concentration of about 10 mg / mL to about 250 mg / mL. In some embodiments, the benzodiazepine is present in the carrier system at a concentration of about 20 mg / mL to about 50 mg / mL.

[0017] In some embodiments, the carrier system contains one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 45% to about 85% (w / w). In some embodiments, the carrier system contains one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 60% to about 75% (w / w). In some embodiments, the carrier system contains one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 70% (w / w).

[0018] In some embodiments, the carrier system contains one or more alcohols or glycols, or any combination thereof, in an amount of about 10% to about 70% (w / w). In some embodiments, the carrier system contains one or more alcohols or glycols, or any combination thereof, in an amount of about 15% to about 55% (w / w). In some embodiments, the carrier system contains one or more alcohols or glycols, or any combination thereof, in an amount of about 25% to about 40% (w / w). In some embodiments, the carrier system contains one or more alcohols or glycols, or any combination thereof, in an amount of about 30% (w / w).

[0019] In some embodiments, the composition comprises at least one additional component selected from the group consisting of pharmaceutical active ingredients; enhancers; excipients; and agents used to adjust pH, buffer the composition, prevent degradation, or improve appearance, aroma, or taste.

[0020] In some embodiments, the composition comprises one or more parahydroxybenzoic acid esters, one or more povidones, and / or one or more additional excipients such as one or more alkyl glycosides.

[0021] The present invention also discloses methods for treating patients with disorders that may be treatable with benzodiazepine drugs. In some embodiments, the patients are human. In some embodiments, the method includes administering a nasal pharmaceutical composition to one or more nasal mucosa of a patient, comprising: a benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 30% to about 95% (w / w); and one or more alcohols or glycols, or any combination thereof, in an amount of about 5% to about 70%, preferably about 10% to about 70% (w / w). In some embodiments, the benzodiazepine is dissolved in one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 30% to about 95% (w / w); and one or more alcohols or glycols, or any combination thereof, in an amount of about 5% to about 70%, preferably about 10% to about 70% (w / w). In some embodiments, the benzodiazepine drug is dissolved in a carrier system. In some embodiments, the benzodiazepine drug is benzodiazepine microparticles, nanoparticles, or a combination thereof. In some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles, or a combination thereof.

[0022] In some embodiments, the benzodiazepine drug is selected from the group consisting of alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, chlorazepam, demoxazepam, diazepam, flumazenil, flurazepam, harazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, or any pharmaceutically acceptable salt thereof, and any combination thereof. In some embodiments, the benzodiazepine drug is diazepam or a pharmaceutically acceptable salt thereof. In some embodiments, the benzodiazepine drug is sufficiently dissolved in a single phase comprising one or more natural or synthetic tocopherols or tocotrienols and one or more alcohols or glycols. In some embodiments, the benzodiazepine drug comprises benzodiazepine microparticles, nanoparticles, or a combination thereof. In some embodiments, the composition further comprises water. In some embodiments, the benzodiazepine nanoparticles have an effective average particle size of less than about 5000 nm. In some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles, or combinations thereof.

[0023] In some embodiments, one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocophersolane, any isomer thereof, any ester thereof, any analog or derivative thereof, and any combination thereof.

[0024] In some embodiments, the one or more alcohols are selected from the group consisting of ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomers thereof, and any combination thereof. In some embodiments, the one or more glycols are selected from the group consisting of ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomers thereof, and any combination thereof. In some embodiments, the alcohol or glycol is free of water (anhydrous, USP). In some embodiments, the alcohol is ethanol (anhydrous, USP).

[0025] In some embodiments, the benzodiazepine drug is present in the carrier system at a concentration of from about 1 mg / mL to about 600 mg / mL. In some embodiments, the benzodiazepine drug is present in the carrier system at a concentration of from about 10 mg / mL to about 250 mg / mL. In some embodiments, the benzodiazepine drug is present in the carrier system at a concentration of from about 20 mg / mL to about 50 mg / mL.

[0026] In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of from about 45% to about 85% (w / w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of from about 60% to about 75% (w / w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 70% (w / w).

[0027] In some embodiments, the carrier system comprises from about 15% to about 55% (w / w) of one or more alcohols or glycols, or any combination thereof. In some embodiments, the carrier system comprises from about 25% to about 40% (w / w) of one or more alcohols or glycols, or any combination thereof. In some embodiments, the carrier system comprises about 30% (w / w) of one or more alcohols or glycols, or any combination thereof.

[0028] In some embodiments, the composition comprises at least one additional component selected from the group consisting of a pharmaceutical active ingredient; an enhancer; an excipient; and an agent used to adjust the pH, buffer the composition, prevent degradation, or improve the appearance, aroma, or taste of the composition.

[0029] In some embodiments, the composition is in a pharmaceutically acceptable spray formulation and further comprises administering the composition to one or more nasal mucosae of a patient. In some embodiments, the therapeutically effective amount is from about 1 mg to about 20 mg of benzodiazepine. In some embodiments, the pharmaceutical composition is in a pharmaceutically acceptable spray formulation having a volume of from about 10 μL to 200 μL.

[0030] In some embodiments, administration of the composition comprises spraying at least a therapeutically effective amount of a portion of the composition into at least one nostril. In some embodiments, administration of the pharmaceutical composition comprises spraying at least a therapeutically effective amount of at least a portion of the benzodiazepine into each nostril. In some embodiments, administration of the pharmaceutical composition comprises spraying a first amount of the pharmaceutical composition into a first nostril, spraying a second amount of the pharmaceutical composition into a second nostril, and optionally spraying a third amount of the pharmaceutical composition into the first nostril after a preselected time delay. In some embodiments, the method comprises optionally administering at least a fourth amount of the pharmaceutical composition into the second nostril after a preselected time delay.

[0031] In some embodiments, administration of the composition begins before the onset of symptoms of a disorder that may be treatable by the composition, or at any time after the onset of symptoms.

[0032] Additional embodiments, uses, and advantages of the present invention will be apparent to those skilled in the art in consideration of the disclosures set forth herein.

[0033] <Incorporation via citation> All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent that each individual publication, patent, or patent application is incorporated by reference. [Brief explanation of the drawing]

[0034] Some embodiments of the present invention may be further recognized by consideration of the accompanying drawings:

[0035] [Figure 1] Linear plots of the arithmetic mean plasma concentration of diazepam over 240 hours are shown for intranasal administration of 10 mg of diazepam as a suspension (Table 11-2), intranasal administration of 10 mg of diazepam as a solution (Table 11-1), and intravenous infusion of 5 mg of diazepam. [Figure 2] Table 11-2 shows a semi-logarithmic plot of the arithmetic mean plasma concentration of diazepam at 240 hours after intranasal administration of 10 mg of diazepam as a suspension, after intranasal administration of 10 mg of diazepam as a solution (Table 11-1), and after intravenous infusion of 5 mg of diazepam. [Figure 3] Linear plots of the arithmetic mean plasma concentration of diazepam over 24 hours are drawn after intranasal administration of 10 mg of diazepam as a suspension (Table 11-2), intranasal administration of 10 mg of diazepam as a solution (Table 11-1), and intravenous administration of 5 mg of diazepam. [Figure 4] This is a flowchart relating to one embodiment of the process for producing a diazepam solution according to the present invention. [Figure 5]This is a flowchart relating to one embodiment of the process for producing a diazepam suspension according to the present invention. [Modes for carrying out the invention]

[0036] Pharmaceutical compositions comprising one or more benzodiazepine drugs and methods for using such pharmaceutical compositions are provided herein. Such pharmaceutical compositions are administered intranasally.

[0037] In some embodiments, the pharmaceutical composition comprises a benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in amounts of about 30% to about 95% (w / w); and one or more alcohols or glycols, or any combination thereof, in amounts of about 10% to about 70% (w / w) in a pharmaceutically acceptable formulation for administration to one or more nasal mucosa of a patient. In some embodiments, the benzodiazepine drug is dissolved in one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in amounts of about 30% to about 95% (w / w); and one or more alcohols or glycols, or any combination thereof, in amounts of about 10% to about 70% (w / w). In some embodiments, the benzodiazepine drug is dissolved in a carrier system. In some embodiments, at least a portion of the benzodiazepine drug is in the form of microparticles, nanoparticles, or combinations thereof. In some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles, or combinations thereof.

[0038] In some embodiments, the pharmaceutical composition for nasal administration comprises a benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 30% to about 95% (w / w); and one or more alcohols or glycols, or any combination thereof, in an amount of about 5% to about 70% (w / w) in a pharmaceutically acceptable formulation for administration to one or more nasal mucosa of a patient. In some embodiments, the benzodiazepine drug is dissolved in one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 30% to about 95% (w / w); and one or more alcohols or glycols, or any combination thereof, in an amount of about 5% to about 70% (w / w). In some embodiments, the benzodiazepine drug is dissolved in a carrier system. In some embodiments, at least a portion of the benzodiazepine drug is in the form of microparticles, nanoparticles, or combinations thereof. In some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles, or combinations thereof.

[0039] In some embodiments, the benzodiazepine drug is selected from the group consisting of alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, chlorazepam, demoxazepam, diazepam, flumazenil, flurazepam, harazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically acceptable salt thereof, and any combination thereof. In some embodiments, the benzodiazepine drug is diazepam or a pharmaceutically acceptable salt thereof. In some embodiments, the benzodiazepine drug comprises benzodiazepine microparticles, nanoparticles, or combinations thereof. In some embodiments, the benzodiazepine nanoparticles have an effective average particle size of less than about 5000 nm. In some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles, or combinations thereof.

[0040] In some embodiments, one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocofersolan, any isomer thereof, any ester thereof, any analog or derivative thereof, and any combination thereof. In some embodiments, the carrier system comprises one or more synthetic tocopherols having a polymer glycol covalently bound or linked to a tocopherol core, such as vitamin E TPGS, described in U.S. Patent No. 6,193,985, incorporated herein by reference in its entirety. In particular, in some particulate suspensions of benzodiazepines in which the benzodiazepine is insoluble in the tocopherol phase, vitamin E TPGS can be a desirable excipient for stabilizing the particulate (fine particles, nanoparticles, or combinations) suspension. On the other hand, in some embodiments, the carrier system specifically excludes synthetic tocopherols having polymer glycols covalently bound or linked to a tocopherol core, such as vitamin E TPGS, which is described in U.S. Patent No. 6,193,985, incorporated herein by reference in its entirety.

[0041] In some embodiments, one or more alcohols are selected from the group consisting of ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomer thereof, or any combination thereof. In some embodiments, the alcohol is ethanol (dehydrated, USP). In some embodiments, one or more glycols are selected from groups consisting of ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomer thereof, and any combination thereof. In some embodiments, the glycol is propylene glycol USP. In some embodiments, the synthetic tocopherol may include vitamin E TPGS (vitamin E polyethylene glycol succinate). On the other hand, in some embodiments, the synthetic tocopherol excludes tocopherols covalently bonded or linked to a glycol polymer such as polyethylene glycol (e.g., by a diacid linking group). Therefore, in some embodiments, the compositions described herein exclude vitamin E TPGS.

[0042] In some embodiments, the benzodiazepine drug is present in a carrier system at a concentration of about 1 mg / mL to about 600 mg / mL. In some embodiments, the benzodiazepine drug is present in a carrier system at a concentration of about 10 mg / mL to about 250 mg / mL. In some embodiments, the benzodiazepine is present in a carrier system at a concentration of about 20 mg / mL to about 50 mg / mL.

[0043] In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 45% to about 85% (w / w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 60% to about 75% (w / w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 70% (w / w). In some embodiments, the synthetic tocopherol may include vitamin E TPGS (vitamin E polyethylene glycol succinate). On the other hand, in some embodiments, the synthetic tocopherol excludes tocopherols covalently bonded or linked to a glycol polymer, such as polyethylene glycol (e.g., by diacid linking groups). Therefore, in some embodiments, the compositions described herein exclude vitamin E TPGS.

[0044] In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combination thereof, in amounts of about 10% to about 55%, about 10% to about 40%, about 10% to about 35%, about 12% to about 55%, about 12% to about 40%, about 12% to about 35%, about 15% to about 55%, about 15% to about 40%, about 15% to about 35%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about 25%, about 27.5%, about 30%, about 32.5%, about 35%, about 37.5%, about 40%, about 42.5%, about 45%, about 47.5%, about 50%, about 52.5%, or about 55% (w / w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combination thereof, in an amount of about 25% to about 40% (w / w). In some embodiments, the carrier system comprises one or more alcohols or glycols, or any combination thereof, in an amount of about 30% (w / w). In some embodiments, the alcohol is ethanol or contains ethanol. In some preferred embodiments, the glycol is excluding glycol polymers. In some preferred embodiments, the glycol is excluding glycol polymers having an average molecular weight greater than 200. In some embodiments, the glycol is excluding polyethylene glycol having an average molecular weight greater than about 200.

[0045] In some embodiments, the carrier system contains one or more alcohols or glycols, or any combination thereof, in an amount of about 15% to about 55% (w / w). In some embodiments, the carrier system contains one or more alcohols or glycols, or any combination thereof, in an amount of about 25% to about 40% (w / w). In some embodiments, the carrier system contains one or more alcohols or glycols, or any combination thereof, in an amount of about 30% (w / w).

[0046] In some embodiments, the composition comprises at least one additional component selected from the group consisting of pharmaceutical active ingredients; enhancers; excipients; and agents used to adjust pH, buffer the composition, prevent degradation, or improve appearance, aroma, or taste.

[0047] In some embodiments, the composition comprises at least one alkyl glycoside. In some embodiments, the at least one alkyl glycoside is described in U.S. Patent No. 5,661,130, which is incorporated herein by reference.

[0048] In some embodiments, the composition comprises a natural or synthetic tocopherol or tocotrienol and a benzodiazepine drug that is well soluble in an alcohol or glycol. In some embodiments, the composition comprises a natural or synthetic tocopherol or tocotrienol and a benzodiazepine drug that is well soluble in a solvent containing an alcohol or glycol, wherein the solution is substantially water-free. (In some embodiments, "substantially water-free" means that the solution contains less than about 1%, less than about 0.5%, less than about 0.25%, or less than about 0.1% water.) In some embodiments, the composition essentially consists of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides. In some embodiments, the composition essentially consists of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides that are well soluble in a solution that is substantially water-free. (In some embodiments, "substantially water-free" means that the solution contains less than about 1%, less than about 0.5%, less than about 0.25%, or less than about 0.1% water.) In some embodiments, the composition comprises a benzodiazepine dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides. In some embodiments, the composition comprises a benzodiazepine dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides, wherein the solution is substantially water-free. (In some embodiments, "substantially water-free" means that the solution contains less than about 1%, less than about 0.5%, less than about 0.25%, or less than about 0.1% water.)

[0049] In some embodiments, the composition comprises a benzodiazepine drug well dissolved in a solvent containing natural or synthetic tocopherols or tocotrienols and alcohols or glycols. Therefore, in some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles or combinations thereof. In some embodiments, the composition comprises a benzodiazepine drug well dissolved in a solvent containing natural or synthetic tocopherols or tocotrienols and alcohols or glycols, wherein the solution is substantially free of water. (In some embodiments, "substantially free of water" means that the solution contains less than about 1%, less than about 0.5%, less than about 0.25%, or less than about 0.1% water.) In some embodiments, the composition is essentially composed of a benzodiazepine well dissolved in a solvent consisting of one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides. In some embodiments, the composition essentially consists of a benzodiazepine drug sufficiently soluble in one or more natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and optionally one or more alkyl glycosides, wherein the solution is substantially water-free. (In some embodiments, “substantially water-free” means that the solution contains less than about 1%, less than about 0.5%, about 0.25%, or less than about 0.1% water.) In some embodiments, the composition consists of a benzodiazepine dissolved in a solvent comprising one or more natural or synthetic tocopherols, one or more alcohols or glycols, and optionally one or more alkyl glycosides. In some embodiments, the composition is dissolved to the extent that one or more natural or synthetic tocopherols, one or more alcohols or glycols, and optionally one or more alkyl glycosides, wherein the solution is substantially water-free. (In some embodiments, “substantially water-free” means that the solution contains less than about 1%, less than about 0.5%, about 0.25%, or less than about 0.1% water.)

[0050] In some embodiments, the composition contains, at least, benzodiazepine drugs in the form of fine particles suspended in a carrier system or glycol, which partially contains natural or synthetic tocopherols or tocotrienols and one or more alcohols. In some embodiments, substantially all benzodiazepine drugs are in the form of fine particles. In some embodiments, at least a portion of the benzodiazepine drugs are in the form of fine particles or nanoparticles. The carrier system is such that the amount of at least one benzodiazepine present in the composition exceeds its solubility in the carrier system. In some embodiments, the carrier system in such a composition contains water. In some embodiments, such a liquid carrier system contains water and one or more excipients. In some embodiments, one or more excipients are dissolved or suspended in the carrier system. In some embodiments, at least one such excipient stabilizes the suspension of benzodiazepine fine particles in the carrier system. In some embodiments, the carrier system may contain different concentrations of para-hydroxybenzoic acid esters (e.g., methylparaben, propylparaben, etc.) and / or a variable amount of one or more surfactants such as povidone (polyvinyl). In some embodiments, the benzodiazepine particulate suspension specifically excludes one or more polymer glycols, such as polyethylene glycol. In some embodiments, the benzodiazepine particulate suspension specifically excludes one or more polymer glycols having a molecular weight greater than about 200 g / mol. In some embodiments, the composition comprises a benzodiazepine drug in a form comprising benzodiazepine microparticles and / or nanoparticles suspended in a carrier system comprising synthetic tocopherol, one or more para-hydroxybenzoic acid esters, one or more alcohols or glycols, one or more surfactants and water. In some embodiments, the composition comprises a benzodiazepine drug in a form comprising benzodiazepine microparticles or nanoparticles suspended in a carrier system comprising vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, povidone and water.In some embodiments, the composition comprises a benzodiazepine drug in a form comprising benzodiazepine microparticles and / or nanoparticles suspended in a carrier system comprising vitamin E TPGS, methylparaben, propylparaben, propylene glycol, povidone, and water. In some embodiments, the composition essentially comprises a benzodiazepine drug in a form comprising benzodiazepine microparticles and / or nanoparticles suspended in a carrier system essentially comprising synthetic tocopherol, one or more para-hydroxybenzoic acid esters, one or more alcohols or glycols, one or more surfactants, and water. In some embodiments, the composition essentially comprises a benzodiazepine drug in a form comprising benzodiazepine microparticles or nanoparticles suspended in a carrier system essentially comprising vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, povidone, and water. In some embodiments, the composition essentially comprises a benzodiazepine drug in a form comprising benzodiazepine microparticles and / or nanoparticles suspended in a carrier system essentially comprising vitamin E TPGS, methylparaben, propylparaben, propylene glycol, povidone, and water. In some embodiments, the composition comprises a benzodiazepine drug in the form of benzodiazepine microparticles and / or nanoparticles suspended in a carrier system comprising synthetic tocopherol, one or more para-hydroxybenzoic acid esters, one or more alcohols or glycols, one or more surfactants, and water. In some embodiments, the composition comprises a benzodiazepine drug in the form of benzodiazepine microparticles or nanoparticles suspended in a carrier system comprising vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, povidone, and water. In some embodiments, the composition comprises a benzodiazepine drug in the form of benzodiazepine microparticles and / or nanoparticles suspended in a carrier system comprising vitamin E TPGS, methylparaben, propylparaben, propylene glycol, povidone, and water.

[0051] In some embodiments, the composition contains a benzodiazepine drug in at least partially particulate form suspended in a carrier system containing natural or synthetic tocopherols or tocotrienols, one or more alcohols or glycols, and alkyl glycosides. In some embodiments, substantially all of the benzodiazepine drugs are in particulate form. In some embodiments, at least a portion of the benzodiazepine drugs are in particulate or nanoparticulate form. The carrier system is such that the amount of at least one benzodiazepine present in the composition exceeds its solubility in the carrier system. In some embodiments, the carrier system in such a composition contains water. In some embodiments, such a liquid carrier system contains water and one or more excipients. In some embodiments, one or more excipients are dissolved or suspended in the carrier system. In some embodiments, at least one such excipient stabilizes the suspension of benzodiazepine microparticles in the carrier system. In some embodiments, the carrier system may contain different concentrations of parahydroxybenzoic acid esters (e.g., methylparaben, propylparaben, etc.) and / or different amounts of one or more surfactants such as povidone (polyvinylpyrrolidone). In some embodiments, the particulate suspension of benzodiazepines specifically excludes one or more polymer glycols, such as polyethylene glycol. In some embodiments, the particulate suspension of benzodiazepines specifically excludes one or more polymer glycols having a molecular weight greater than about 200 g / mol. In some embodiments, the composition comprises a benzodiazepine drug in a form comprising benzodiazepine microparticles and / or nanoparticles suspended in a carrier system comprising synthetic tocopherol, one or more parahydroxybenzoic acid esters, one or more alcohols or glycols, alkyl glucosides and water. In some embodiments, the composition comprises a benzodiazepine drug in a form comprising benzodiazepine microparticles or nanoparticles suspended in a carrier system comprising vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, alkyl glycoside and water.In some embodiments, the composition comprises a benzodiazepine drug in a form comprising benzodiazepine microparticles and / or nanoparticles suspended in a carrier system comprising vitamin E TPGS, methylparaben, propylparaben, propylene glycol, alkyl glycoside, and water. In some embodiments, the composition comprises a benzodiazepine drug in a form comprising benzodiazepine microparticles and / or nanoparticles suspended in a carrier system essentially comprising synthetic tocopherol, one or more para-hydroxybenzoic acid esters, one or more alcohols or glycols, alkyl glycosides, optionally a surfactant, and water. In some embodiments, the composition comprises a benzodiazepine drug in a form comprising benzodiazepine microparticles or nanoparticles suspended in a carrier system essentially comprising vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, alkyl glycoside, optionally povidone, and water. In some embodiments, the composition comprises a benzodiazepine drug in the form of benzodiazepine microparticles and / or nanoparticles suspended in a carrier system comprising vitamin E TPGS, methylparaben, propylparaben, propylene glycol, alkyl glycoside, optionally povidone, and water. In some embodiments, the composition comprises a benzodiazepine drug in the form of benzodiazepine microparticles and / or nanoparticles suspended in a carrier system comprising synthetic tocopherol, one or more para-hydroxybenzoic acid esters, one or more alcohols or glycols, alkyl glycosides, optionally one or more surfactants, and water. In some embodiments, the composition comprises a benzodiazepine drug in the form of benzodiazepine microparticles or nanoparticles suspended in a carrier system comprising vitamin E TPGS, one or both of methylparaben and propylparaben, at least one glycol, alkyl glycoside, optionally povidone, and water. In some embodiments, the composition comprises a benzodiazepine drug in the form of benzodiazepine microparticles and / or nanoparticles suspended in a carrier system comprising vitamin E TPGS methylparaben, propylparaben, propylene glycol, alkyl glycoside, optionally povidone, and water.

[0052] The present invention discloses a method for treating a patient having a disorder that may be treatable with a benzodiazepine drug. In some embodiments, the patient is a human. In some embodiments, the method involves administering a pharmaceutical composition for intranasal administration to one or more nasal mucosa of a patient, comprising: a benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 30% to about 95% (w / w); and one or more alcohols or glycols, or any combination thereof, in an amount of about 5% to about 70% (w / w), preferably about 10% to about 70% (w / w). In some embodiments, the benzodiazepine is dissolved in one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 30% to about 95% (w / w); and one or more alcohols or glycols, or any combination thereof, in an amount of about 5% to about 70% (w / w), preferably about 10% to about 70% (w / w). In some embodiments, the benzodiazepine drug is dissolved in a carrier system. In other embodiments, at least a portion of the benzodiazepine drug is in the form of microparticles, nanoparticles, or a combination thereof. In some embodiments, the composition is substantially free of benzodiazepine microparticles, nanoparticles, or a combination thereof.

[0053] In some embodiments, the benzodiazepine drug is selected from a corpus consisting of alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, chlorazepam, demoxazepam, diazepam, flumazenil, flurazepam, harazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, or any pharmaceutically acceptable salt thereof, and any combination thereof. In some embodiments, the benzodiazepine drug is diazepam or a pharmaceutically acceptable salt thereof. In some embodiments, the benzodiazepine drug is benzodiazepine microparticles, nanoparticles, or a combination thereof. In some embodiments, the benzodiazepine nanoparticles have an effective average particle size of less than about 5000 nm.

[0054] In some embodiments, one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocophersolane, any isomer thereof, any ester thereof, any analog or derivative thereof, and any combination thereof. Synthetic tocopherols may include tocopherols modified to include hydrophilic groups such as polyethylene glycol groups, which are covalently bonded to tocopherol by covalent linking groups such as diacids or which can be linked to tocopherol. Those skilled in the art can envision other synthetic tocopherols having similar diacidic and / or hydrophilic groups, an exemplary synthetic tocopherol of this type being vitamin E polyethylene glycol succinate (vitamin E TPGS).

[0055] In some embodiments, one or more alcohols are selected from the group consisting of ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomer thereof, and any combination thereof. In some embodiments, one or more glycols are selected from the group consisting of ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any isomer thereof, and any combination thereof. In some embodiments, one or more glycols specifically exclude polymer glycols such as polyethylene glycol. In some embodiments, one or more glycols specifically exclude polymer glycols having a molecular weight greater than about 200 g / mol.

[0056] In some embodiments, the benzodiazepine drug is present in the carrier system at a concentration of approximately 1 mg / mL to approximately 600 mg / mL. In some embodiments, the benzodiazepine drug is present in the carrier system at a concentration of approximately 10 mg / mL to approximately 250 mg / mL. In some embodiments, the benzodiazepine drug is present in the carrier system at a concentration of approximately 20 mg / mL to approximately 50 mg / mL.

[0057] In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 45% to about 85% (w / w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 60% to about 75% (w / w). In some embodiments, the carrier system comprises one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 70% (w / w). In some embodiments, a suspension of particulate matter of benzodiazepine drugs in particular is considered, and the composition may comprise tocopherols, particularly synthetic tocopherols having hydrophilic groups covalently linked to tocopherols. In other embodiments, a solution of benzodiazepine drugs in particular is considered, and the tocopherols are substantially or completely free of vitamin E TPGS.

[0058] In some embodiments, the carrier system contains one or more alcohols or glycols, or any combination thereof, in an amount of about 10% to about 55% (w / w). In some embodiments, the carrier system contains one or more alcohols or glycols, or any combination thereof, in an amount of about 25% to about 40% (w / w). In some embodiments, the carrier system contains one or more alcohols or glycols, or any combination thereof, in an amount starting from about 30% (w / w). In some embodiments, the amount of one or more alcohols or glycols in the carrier system is 10% to about 55%, about 10% to about 40%, about 10% to about 35%, about 12% to about 55%, about 12% to about 40%, about 12% to about 35%, about 15% to about 55%, about 15% to about 40%, about 15% to about 35%, about 10%, about 12.5%, about 15%, about 17.5%, about 20%, about 22.5%, about 25%, about 27.5%, about 30%, about 32.5%, about 35%, about 37.5%, about 40%, about 42.5%, about 45%, about 47.5%, about 50%, about 52.5%, or about 55% (w / w).

[0059] In some embodiments, the composition comprises at least one additional component selected from the group consisting of pharmaceutical active ingredients; enhancers; excipients; and agents used to adjust pH, buffer the composition, prevent degradation, or improve appearance, aroma, or taste.

[0060] In some embodiments, the composition comprises a benzodiazepine drug, a natural or synthetic tocopherol or tocotrienol, an alcohol or glycol, and at least one penetration enhancer. In some embodiments, the penetration enhancer is an alkyl glycoside. In some embodiments, as described in U.S. Patent No. 5,661,130, which is incorporated herein by reference in its entirety, an alkyl glycoside refers to any sugar bonded to any hydrophobic alkyl. The hydrophobic alkyl can be of any suitable length, for example, a length of about 9 to about 24 carbons, particularly a length of about 10 to about 14 carbons. The hydrophobic alkyl can be branched and / or partially or fully unsaturated. The alkyl can be bonded to a saccharide core, for example, by a carbonyl group, thereby forming an ester group. A suitable alkyl glycoside has the properties of being non-toxic, non-ionic, and can increase the absorption of benzodiazepines when administered intranasally as described herein. Exemplary sugars that can be covalently bonded to alkyls according to the present invention include glucose, maltose, maltotriose, maltotetrose, sucrose, and trehalose. Exemplary alkyl glycosides that can be used include octyl-, nonyl-, decyl-, undecyl-, dodecyl, tridecyl, tetradecyl, pentadecyl, octadecyl α- or β-D-maltoside, α-glucoside, or scorose. In some embodiments, preferred glycosides include maltose, sucrose, or glycosides linked by glycosidic linkage to an alkyl chain of 9, 10, 12, 14, 16, 18, or 20 carbon atoms. If present, the amount of alkyl glycoside in the composition is sufficient to enhance the absorption of benzodiazepine drugs administered via the intranasal route. In some embodiments, the amount of alkyl glycoside in the composition is selected to enhance the absorption of benzodiazepine drugs while simultaneously not significantly irritating the nasal mucosa. In some embodiments, the amount of alkyl glycoside in the composition is in the range of about 0.01% (w / v) to about 1% (w / v).In some embodiments, the amount of alkyl glycoside in the composition is in the range of about 0.05% (w / v) to about 0.5% (w / v), or about 0.125% (w / v) to about 0.05% (w / v).

[0061] In some embodiments, the composition is a pharmaceutically acceptable spray formulation, further comprising administering the composition to one or more nasal mucosa of a patient. In some embodiments, the therapeutically effective dose is about 1 mg to about 20 mg of benzodiazepine. In some embodiments, the pharmaceutical composition is a pharmaceutically acceptable spray formulation having a volume of about 10 μL to 200 μL.

[0062] In some embodiments, administration of the composition includes spraying at least a therapeutically effective amount of a portion of the composition into at least one nostril. In some embodiments, administration of the composition includes spraying at least a therapeutically effective amount of a portion of the composition into at least each nostril. In some embodiments, administration of the composition includes spraying a first amount of the composition into a first nostril, spraying a second amount of the composition into a second nostril, and spraying a third amount of the composition into the first nostril after a optionally pre-selected time delay. In some embodiments, administration of the composition further includes administering at least a fourth amount of the composition to the second nostril after a optionally pre-selected time delay.

[0063] In some embodiments, administration of the composition begins before or at any time after the onset of symptoms of a disorder that may be treatable by the composition.

[0064] <Definition> As used herein, the phrase “therapeutably effective dose” (more concisely, “effective dose”) includes an amount sufficient to provide a specific therapeutic response when administered to a patient requiring a particular treatment. Experienced clinicians recognize that the therapeutically effective dose of a drug depends on the patient, the efficacy, and the specific drug administered.

[0065] As used herein, the modifying phrase “approximately” is intended to have a regularly recognized approximate meaning. In some embodiments, the term may be interpreted more precisely as meaning within a specific percentage of the value being modified, for example, “approximately” may in some embodiments mean ±20%, ±10%, ±5%, ±2%, or ±1% or less.

[0066] As used herein, the phrase “analog or derivative” includes molecules that are distinct from one another by the exchange of one or more atoms or functional groups with different atoms or functional groups. This may result in molecules that have similar chemical formulas but different chemical and / or biological properties.

[0067] As used herein, the term “isomer” includes molecules that have the same chemical formula but may have different molecular arrangements. These different arrangements may result in molecules with the same chemical formula but different chemical properties. As an example that is not limited, propanol has the chemical formula C3H7OH. It may be found as propano-1-ol, where the -OH is attached to the end carbon. Alternatively, it may be found as propano-2-ol, where the -OH is attached to the second carbon.

[0068] [ka]

[0069] As used herein, the term “seizure” includes commonly recognized types of seizures, including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and atonic seizures. Often, seizures, particularly severe tonic or tonic-clonic seizures, are predicted by one or more auras that are well known to the patient or those close to the patient. Each patient generally experiences different types of auras, which are unique to that patient, but auras can be classified as auditory, visual, olfactory, or tactile sensations that usually or at least often precede the seizure the patient experiences. (Not all patients suffering from seizures experience auras, but it is not uncommon among those suffering from the worst types of seizures, particularly tonic-clonic seizures.)

[0070] As used herein, the term “prevention” refers to prevention, including temporary prevention of the onset of a disorder. In the case of a seizure, this may occur with or without the benefit of warning signs.

[0071] As used herein, the term “treatment” refers to a reduction in the severity and / or duration of a disorder, or a similar effect. The term also encompasses any side effects of such “treatment.”

[0072] As used herein, unless otherwise limited, "a" and "an" can mean one or more things.

[0073] As used herein, the term “including” in all variants is a transitional phrase used in the claims to indicate that the invention includes or contains, but is not limited to, the claims described in particular.

[0074] As used herein, the phrase “essentially consisting of” is a transitional phrase used in a claim to indicate that the list of components, parts or procedure steps described below must be the claimed composition, machine or procedure, but that the claim also applies to components, parts or procedure steps not listed, which do not materially affect the basic and novel characteristics of the invention.

[0075] As used herein, the term "consisting of" is a transitional phrase used in a claim to indicate that the claimed invention includes only the elements described in the claim.

[0076] <Benzodiazepine drugs> In the context of the present invention, the term “benzodiazepine drug” includes any therapeutically effective benzodiazepine compound, or a pharmaceutically acceptable salt, or combination thereof. In some embodiments, benzodiazepines include members of the group consisting of alprazolam, diazepam, flurazepam, lorazepam, medazepam, mexazolam, midazolam, temazepam and pharmaceutically acceptable salts, and combinations thereof.

[0077] Additional benzodiazepine compounds that have previously been considered of little importance or of little therapeutic benefit due to low bioavailability, poor pharmacokinetic properties, or poor pharmacological properties will be found to be used by the present invention, which may result in improved benzodiazepine drug bioavailability, delivery of high concentrations of benzodiazepine drugs via the nasal route, rapid attainment of therapeutic levels of benzodiazepines in plasma, avoidance and incidental avoidance of the hepatic portal vein of the first-pass effect, and / or improved rapid presentation of benzodiazepine drugs to the brain, as will be recognized by those skilled in the art.

[0078] For example, most benzodiazepines are only slightly soluble in water, so a therapeutically effective amount cannot be dissolved in an aqueous solvent suitable for application to mucous membranes. In some embodiments, by using a carrier system of the present invention that provides an improved ability to dissolve benzodiazepine drugs, the present invention enables the administration of benzodiazepine drugs to one or more mucous membranes, including the nasal mucosa. This can enable the administration of drugs without hospitalization or unnecessary discomfort. Additionally, in some embodiments of the present invention, such as intranasal administration, a large portion of the digestive system can be avoided. This latter improvement can result in improved bioavailability, faster delivery of therapeutic levels of benzodiazepines to plasma, avoidance of the hepatic portal vein, and / or incidental avoidance of the first-pass effect.

[0079] Nasal administration of the composition can result in faster delivery of one or more benzodiazepine drugs to the brain due to the proximity of the cell membrane to the brain. Patients experiencing seizures suffer, for example, from stiff muscles and uncontrollable movement. This can make oral and / or intravenous administration difficult or inconvenient. However, the nasal passage remains open and readily available, making it a useful route of administration for the present invention.

[0080] In some embodiments, the pharmaceutical composition is used to treat patients suffering from disorders applicable to treatment or prevention with one or more benzodiazepine drugs in an effective amount. By some, but not limited to, such disorders include symptoms of insomnia, anxiety, seizures, muscle spasms and rigidity, and drug withdrawal.

[0081] In some embodiments, one or more benzodiazepine drugs are used alone or in combination with other anticonvulsants to treat seizures, protect against seizures, reduce or improve the intensity of seizures, reduce or improve the frequency of seizures, and / or prevent the onset or recurrence of seizures.

[0082] Alprazolam (8-chloro-6-phenyl-1-methyl-4H-1,2,4-triazolo[4,3-a][1,4]benzodiazepine)

[0083] [ka]

[0084] Alprazolam is a benzodiazepine drug with sedative, tranquilizer, and muscle relaxant properties. It is classified as an anxiety reliever. Alprazolam has also been shown to be useful in the treatment of panic disorder. The dosage of alprazolam varies depending on the efficacy, but the therapeutic dose is expected to be in the range of about 0.5 to about 4, preferably about 1 to about 2 mg per dose, 1 to 8, preferably 2 to 8, and in some preferred embodiments about 4 to 6 hours per day. Alprazolam may be manufactured using the procedure disclosed in U.S. Patent 3,987,052, which is incorporated herein by reference in its entirety.

[0085] In some embodiments, alprazolam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect, or a combination of the aforementioned effects.

[0086] In some embodiments, alprazolam is used alone or in combination with other anticonvulsants to treat seizures, protect against seizures, reduce or improve the intensity of seizures, reduce or improve the frequency of seizures, and / or prevent the onset or recurrence of seizures. To protect against seizures, alprazolam may be administered by the patient or another person (such as a healthcare worker) while the patient is seizure-free. Even when protection from seizures is not absolute, administration of alprazolam may reduce or improve the intensity of seizures and / or reduce or improve the frequency of seizures. In some embodiments, administration of alprazolam may prevent the onset of seizures. In some embodiments, particularly when the patient is prone to experiencing successive seizures or persistent status epilepticus, administration of alprazolam may help interrupt seizure cycles and thus prevent seizure recurrence. In addition to benzodiazepines (such as diazepam), other anticonvulsant drugs may be combined with alprazolam to provide anticonvulsant or synergistic anticonvulsant effects.

[0087] While a patient is in a seizure state, alprazolam may also be administered to the patient by another person (e.g., an acquaintance or colleague, family member or healthcare professional). Therefore, one of the advantages of the formulations according to the present invention is the ability to be administered, for example, intranasally, in an emergency treatment setting for treating seizure victims. Among the beneficial therapeutic effects that can be provided by emergency administration of benzodiazepine anticonvulsants, such as nasal administration, are a reduction in the severity of the seizure (e.g., overall muscle relaxation, reduction of seizure-inducing anxiety experienced by the patient, and an overall transmission of well-being to the patient), a reduction in the duration of the seizure, a decrease in the likelihood of the patient experiencing repeated seizures, and an increase in the interval between the current seizure and the next seizure. Therefore, the alprazolam formulations of the present invention, and in certain nasal formulations, provide a faster onset of therapeutic effect in some cases less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes. The alprazolam formulations of the present invention, and in specific nasal formulations, also provide a convenient administration of therapeutically beneficial drugs to patients who do not require intravenous or rectal drug administration.

[0088] Often, seizures, particularly severe tonic or tonic-clonic seizures, are predicted by one or more aura events well known to the patient or those close to the patient. These auras, while actually unique to each patient, can generally or typically be classified as auditory, visual, olfactory, or tactile sensations that precede the patient's seizure experience. In some embodiments of the present invention, the method involves rapid administration of a benzodiazepine drug preparation according to the present invention during an aura. In some embodiments, administration of such a benzodiazepine drug during an aura, for example by intranasal administration, prevents or at least improves the effects (intensity, duration, or both) of an impending seizure. Thus, in the context of the present invention, seizure prevention refers to temporarily preemptively preventing the occurrence of a seizure, with or without the presence of warning auras.

[0089] Diazepam (7-chloro-1-methyl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one)

[0090] [ka]

[0091] Diazepam is a benzodiazepine drug having sedative, tranquilizing, and muscle relaxant properties. It is classified as an anxiolytic and a skeletal muscle relaxant. It has anxiety-relieving, anticonvulsant, sedative, skeletal muscle relaxant, and memory-inducing properties. The dosage of diazepam may vary depending on the efficacy, but the therapeutic dose is expected to be in the range of about 1 to about 20 mg per dose, preferably about 2 to about 10 mg, 1 to 8 doses per day, preferably 2 to 8 doses, and in some preferred embodiments about 4 to about 6 doses. Diazepam may be manufactured using the procedures disclosed in one of U.S. Patents 3,371,085, 3,109,843, 3,136,815, or 3,102,116, each of which is incorporated herein by reference in whole.

[0092] In some embodiments, diazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect, or a combination of the aforementioned effects.

[0093] In some embodiments, diazepam is used alone or in combination with other anticonvulsants to treat seizures, protect against seizures, reduce or improve the intensity of seizures, reduce or improve the frequency of seizures, and / or prevent the onset or recurrence of seizures. To protect against seizures, diazepam may be administered by the patient or another person (such as a healthcare worker) while the patient is seizure-free. Even when protection from seizures is not absolute, administration of diazepam may reduce or improve the intensity of seizures and / or reduce or improve the frequency of seizures. In some embodiments, administration of diazepam may prevent the onset of seizures. In some embodiments, particularly when the patient is prone to experiencing consecutive seizures or persistent status epilepticus, administration of diazepam may help interrupt seizure cycles and thus prevent seizure recurrence. In addition to benzodiazepines (such as diazepam), other anticonvulsant drugs may be combined with diazepam to provide anticonvulsant or synergistic anticonvulsant effects.

[0094] While a patient is in a seizure state, diazepam may also be administered to the patient by another person (e.g., an acquaintance or colleague, family member or healthcare professional). Therefore, one of the advantages of the formulations according to the present invention is the ability to be administered, for example, intranasally, in an emergency treatment setting for treating seizure victims. Among the beneficial therapeutic effects that can be provided by emergency administration of benzodiazepine anticonvulsants, such as nasal administration, are a reduction in the severity of the seizure (e.g., overall muscle relaxation, reduction of seizure-inducing anxiety experienced by the patient, and an overall transmission of well-being to the patient), a reduction in the duration of the seizure, a decrease in the likelihood of the patient experiencing repeated seizures, and an increase in the interval between the current seizure and the next seizure. Therefore, the diazepam formulations of the present invention, and in certain nasal formulations, provide a faster onset of therapeutic effect in some cases less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes. The diazepam formulations of the present invention, and in specific nasal formulations, also provide a convenient administration of therapeutically beneficial drugs to patients who do not require intravenous or rectal drug administration.

[0095] Often, seizures, particularly severe tonic or tonic-clonic seizures, are predicted by one or more aura events well known to the patient or those close to the patient. These auras, while actually unique to each patient, can generally or typically be classified as auditory, visual, olfactory, or tactile sensations that precede the patient's seizure experience. In some embodiments of the present invention, the method involves rapid administration of a benzodiazepine drug preparation according to the present invention during an aura. In some embodiments, administration of such a benzodiazepine drug during an aura, for example by intranasal administration, prevents or at least improves the effects (intensity, duration, or both) of an impending seizure. Thus, in the context of the present invention, seizure prevention refers to temporarily preemptively preventing the occurrence of a seizure, with or without the presence of warning auras.

[0096] Flurazepam (7-chloro-5-(2-fluorophenyl)-2,3-dihydro-1-(2-(diethylamino)ethyl)-1H-1,4-benzodiazepine-2-one)

[0097] [ka]

[0098] Flurazepam is a benzodiazepine drug having sedative (particularly sleep-inducing and hypnotic), anxiolytic, anticonvulsant, and muscle relaxant properties. It is classified as sedative and hypnotic. Flurazepam has been shown to be useful in the treatment of insomnia. The dosage of flurazepam may vary depending on the efficacy, but the therapeutic dose is expected to be in the range of about 5 to about 40, preferably about 20 to about 35 mg per dose, 1 to 8, preferably 2 to 8, per day, and in some preferred embodiments, about 4 to about 6 times. Flurazepam may be manufactured using the procedures disclosed in U.S. Patent Nos. 3,567,710 and 3,299,053, each of which is incorporated herein by reference in whole.

[0099] In some embodiments, flurazepam is used alone or in combination with other drugs to provide anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant, amnesic, or a combination of the aforementioned effects.

[0100] In some embodiments, flurazepam is used alone or in combination with other anticonvulsants to treat seizures, protect against seizures, reduce or improve the intensity of seizures, reduce or improve the frequency of seizures, and / or prevent the onset or recurrence of seizures. To protect against seizures, flurazepam may be administered by the patient or another person (such as a healthcare worker) while the patient is seizure-free. Even when protection from seizures is not absolute, administration of flurazepam may reduce or improve the intensity of seizures and / or reduce or improve the frequency of seizures. In some embodiments, administration of flurazepam may prevent the onset of seizures. In some embodiments, particularly when the patient is prone to experiencing consecutive seizures or persistent status epilepticus, administration of flurazepam may help interrupt seizure cycles and thus prevent seizure recurrence. In addition to benzodiazepines (such as diazepam), other anticonvulsant drugs may be combined with flurazepam to provide anticonvulsant or synergistic anticonvulsant effects.

[0101] While a patient is in a seizure state, flurazepam may also be administered to the patient by another person (e.g., an acquaintance or colleague, family member or healthcare professional). Therefore, one of the advantages of the formulations according to the present invention is the ability to be administered, for example, intranasally, in an emergency treatment setting for treating seizure victims. Among the beneficial therapeutic effects that can be provided by emergency administration of benzodiazepine anticonvulsants, such as nasal administration, are a reduction in the severity of the seizure (e.g., overall muscle relaxation, reduction of seizure-inducing anxiety experienced by the patient, and an overall transmission of well-being to the patient), a reduction in the duration of the seizure, a decrease in the likelihood of the patient experiencing repeated seizures, and an increase in the interval between the current seizure and the next seizure. Therefore, the flurazepam formulations of the present invention, and in certain nasal formulations, provide a faster onset of therapeutic effect in some cases less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes. The flurazepam formulations of the present invention, and in specific nasal formulations, also provide a convenient administration of therapeutically beneficial drugs to patients who do not require intravenous or rectal drug administration.

[0102] Often, seizures, particularly severe tonic or tonic-clonic seizures, are predicted by one or more aura events well known to the patient or those close to the patient. These auras, while actually unique to each patient, can generally or typically be classified as auditory, visual, olfactory, or tactile sensations that precede the patient's seizure experience. In some embodiments of the present invention, the method involves rapid administration of a benzodiazepine drug preparation according to the present invention during an aura. In some embodiments, administration of such a benzodiazepine drug during an aura, for example by intranasal administration, prevents or at least improves the effects (intensity, duration, or both) of an impending seizure. Thus, in the context of the present invention, seizure prevention refers to temporarily preemptively preventing the occurrence of a seizure, with or without the presence of warning auras.

[0103] Lorazepam (7-chloro-5-(2-chlorophenyl)-3-hydroxy-1,3-dihydro-2H-1,4-benzodiazepine-2-one)

[0104] [ka]

[0105] Lorazepam is a benzodiazepine drug with sedative, tranquilizer, anticonvulsant, amnesic, and muscle relaxant properties. It is classified as an anxiolytic. Lorazepam has been shown to be useful in the treatment of nausea. The dosage of lorazepam may vary depending on the efficacy, but the therapeutic dose is expected to be in the range of about 0.1 to about 10 mg per dose, preferably about 0.2 to about 1 mg, 1 to 8 doses per day, preferably 2 to 8 doses, and in some preferred embodiments about 4 to about 6 doses. Lorazepam may be manufactured using the procedure disclosed in U.S. Patent No. 3,296,249, which is incorporated herein by reference in its entirety.

[0106] In some embodiments, lorazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect, or a combination of the aforementioned effects.

[0107] In some embodiments, lorazepam is used alone or in combination with other anticonvulsants to treat seizures, protect against seizures, reduce or improve the intensity of seizures, reduce or improve the frequency of seizures, and / or prevent the onset or recurrence of seizures. To protect against seizures, lorazepam may be administered by the patient or another person (such as a healthcare worker) while the patient is seizure-free. Even when protection from seizures is not absolute, administration of lorazepam may reduce or improve the intensity of seizures and / or reduce or improve the frequency of seizures. In some embodiments, administration of lorazepam may prevent the onset of seizures. In some embodiments, particularly when the patient is prone to experiencing consecutive seizures or persistent status epilepticus, administration of lorazepam may help interrupt seizure cycles and thus prevent seizure recurrence. In addition to benzodiazepines (such as diazepam), other anticonvulsant drugs may be combined with lorazepam to provide anticonvulsant or synergistic anticonvulsant effects.

[0108] While a patient is in a seizure state, lorazepam may also be administered to the patient by another person (e.g., an acquaintance or colleague, family member or healthcare professional). Therefore, one of the advantages of the formulations according to the present invention is the ability to be administered, for example, intranasally, in an emergency treatment setting for treating seizure victims. Among the beneficial therapeutic effects that can be provided by emergency administration of benzodiazepine anticonvulsants, such as nasal administration, are a reduction in the severity of the seizure (e.g., overall muscle relaxation, reduction of seizure-inducing anxiety experienced by the patient, and an overall transmission of well-being to the patient), a reduction in the duration of the seizure, a decrease in the likelihood of the patient experiencing repeated seizures, and an increase in the interval between the current seizure and the next seizure. Therefore, the lorazepam formulations of the present invention, and in certain nasal formulations, provide a faster onset of therapeutic effect in some cases less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes. The lorazepam formulations of the present invention, and in specific nasal formulations, also provide a convenient administration of therapeutically beneficial drugs to patients who do not require intravenous or rectal drug administration.

[0109] Often, seizures, particularly severe tonic or tonic-clonic seizures, are predicted by one or more aura events well known to the patient or those close to the patient. These auras, while actually unique to each patient, can generally or typically be classified as auditory, visual, olfactory, or tactile sensations that precede the patient's seizure experience. In some embodiments of the present invention, the method involves rapid administration of a benzodiazepine drug preparation according to the present invention during an aura. In some embodiments, administration of such a benzodiazepine drug during an aura, for example by intranasal administration, prevents or at least improves the effects (intensity, duration, or both) of an impending seizure. Thus, in the context of the present invention, seizure prevention refers to temporarily preemptively preventing the occurrence of a seizure, with or without the presence of warning auras.

[0110] Medazepam ((7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine)

[0111] [ka]

[0112] Medazepam is a benzodiazepine drug with sedative, tranquilizer, anticonvulsant, amnesic, and muscle relaxant properties. It is classified as an anxiolytic. Medazepam has been shown to be useful in the treatment of nausea. The dosage of medazepam may vary depending on the efficacy, but the therapeutic dose is expected to be in the range of about 0.1 to about 10 mg per dose, preferably about 0.2 to about 1 mg, 1 to 8 doses per day, preferably 2 to 8 doses, and in some preferred embodiments about 4 to about 6 doses. Medazepam may be manufactured using the procedure disclosed in U.S. Patent No. 3,243,427, which is incorporated herein by reference in its entirety.

[0113] In some embodiments, medazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect, or a combination of the aforementioned effects.

[0114] In some embodiments, medazepam is used alone or in combination with other anticonvulsants to treat seizures, protect against seizures, reduce or improve the intensity of seizures, reduce or improve the frequency of seizures, and / or prevent the onset or recurrence of seizures. To protect against seizures, medazepam may be administered by the patient or another person (such as a healthcare worker) while the patient is seizure-free. Even when protection from seizures is not absolute, administration of medazepam may reduce or improve the intensity of seizures and / or reduce or improve the frequency of seizures. In some embodiments, administration of medazepam may prevent the onset of seizures. In some embodiments, particularly when the patient is prone to experiencing consecutive seizures or persistent status epilepticus, administration of medazepam may help interrupt seizure cycles and thus prevent seizure recurrence. In addition to benzodiazepines (such as diazepam), other anticonvulsant drugs may be combined with medazepam to provide anticonvulsant or synergistic anticonvulsant effects.

[0115] While a patient is in a seizure state, medazepam may also be administered to the patient by another person (e.g., an acquaintance or colleague, family member or healthcare professional). Therefore, one of the advantages of the formulations according to the present invention is the ability to be administered, for example, intranasally, in an emergency treatment setting for treating seizure victims. Among the beneficial therapeutic effects that can be provided by emergency administration of benzodiazepine anticonvulsants, such as nasal administration, are a reduction in the severity of the seizure (e.g., overall muscle relaxation, reduction of seizure-inducing anxiety experienced by the patient, and an overall transmission of well-being to the patient), a reduction in the duration of the seizure, a decrease in the likelihood of the patient experiencing repeated seizures, and an increase in the interval between the current seizure and the next seizure. Therefore, the medazepam formulations of the present invention, and in certain nasal formulations, provide a faster onset of therapeutic effect in some cases less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes. The medazepam formulations of the present invention, and in specific nasal formulations, also provide a convenient administration of therapeutically beneficial drugs to patients who do not require intravenous or rectal drug administration.

[0116] Often, seizures, particularly severe tonic or tonic-clonic seizures, are predicted by one or more aura events well known to the patient or those close to the patient. These auras, while actually unique to each patient, can generally or typically be classified as auditory, visual, olfactory, or tactile sensations that precede the patient's seizure experience. In some embodiments of the present invention, the method involves rapid administration of a benzodiazepine drug preparation according to the present invention during an aura. In some embodiments, administration of such a benzodiazepine drug during an aura, for example by intranasal administration, prevents or at least improves the effects (intensity, duration, or both) of an impending seizure. Thus, in the context of the present invention, seizure prevention refers to temporarily preemptively preventing the occurrence of a seizure, with or without the presence of warning auras.

[0117] Mexazolam (10-chloro-11b-(2-chlorophenyl)-1,3,7,11b-tetrahydro-3-methyloxazolo[3,2-d][1,4]benzodiazepine-6(5H)-one)

[0118] [ka]

[0119] Mexazolam is a benzodiazepine drug with sedative, tranquilizer, anticonvulsant, amnesic, and muscle relaxant properties. It is classified as an anxiolytic. Mexazolam has been shown to be useful in treating nausea. The dosage of mexazolam may vary depending on the efficacy, but the therapeutic dose is expected to be in the range of about 0.1 to about 10 mg per dose, preferably about 0.2 to about 1 mg, 1 to 8 doses per day, preferably 2 to 8 doses, and in some preferred embodiments about 4 to about 6 doses. Mexazolam may be manufactured using the procedure disclosed in U.S. Patent No. 3,722,371, which is incorporated herein by reference in its entirety.

[0120] In some embodiments, mexazolam is used alone or in combination with other drugs to provide anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant, amnesic, or a combination of the aforementioned effects.

[0121] In some embodiments, mexazolam is used alone or in combination with another anticonvulsant to treat seizures, protect against seizures, reduce or improve the intensity of seizures, reduce or improve the frequency of seizures, and / or prevent the onset or recurrence of seizures. To protect against seizures, mexazolam may be administered by the patient or another person (such as a healthcare worker) while the patient is seizure-free. Even when protection from seizures is not absolute, administration of mexazolam may reduce or improve the intensity of seizures and / or reduce or improve the frequency of seizures. In some embodiments, administration of mexazolam may prevent the onset of seizures. In some embodiments, particularly when the patient is prone to experiencing successive seizures or persistent status epilepticus, administration of mexazolam may help interrupt seizure cycles and thus prevent seizure recurrence. In addition to benzodiazepines (such as diazepam), other anticonvulsant drugs may be combined with medazepam to provide anticonvulsant or synergistic anticonvulsant effects.

[0122] While a patient is in a seizure state, mexazolam may also be administered to the patient by another person (e.g., an acquaintance or colleague, family member or healthcare professional). Therefore, one of the advantages of the formulations according to the present invention is the ability to be administered, for example, intranasally, in an emergency treatment setting for treating seizure victims. Among the beneficial therapeutic effects that can be provided by emergency administration of benzodiazepine anticonvulsants, such as nasal administration, are a reduction in the severity of the seizure (e.g., overall muscle relaxation, reduction of seizure-inducing anxiety experienced by the patient, and an overall transmission of well-being to the patient), a reduction in the duration of the seizure, a decrease in the likelihood of the patient experiencing repeated seizures, and an increase in the interval between the current seizure and the next seizure. Therefore, the mexazolam formulations of the present invention, and in certain nasal formulations, provide a faster onset of therapeutic effect in some cases less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes. The mexazolam formulations of the present invention, and in specific nasal formulations, also provide a convenient administration of therapeutically beneficial drugs to patients who do not require intravenous or rectal drug administration.

[0123] Often, seizures, particularly severe tonic or tonic-clonic seizures, are predicted by one or more aura events well known to the patient or those close to the patient. These auras, while actually unique to each patient, can generally or typically be classified as auditory, visual, olfactory, or tactile sensations that precede the patient's seizure experience. In some embodiments of the present invention, the method involves rapid administration of a benzodiazepine drug preparation according to the present invention during an aura. In some embodiments, administration of such a benzodiazepine drug during an aura, for example by intranasal administration, prevents or at least improves the effects (intensity, duration, or both) of an impending seizure. Thus, in the context of the present invention, seizure prevention refers to temporarily preemptively preventing the occurrence of a seizure, with or without the presence of warning auras.

[0124] Midazolam (8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo(1,5-a)benzodiazepine)

[0125] [ka]

[0126] Midazolam is a tricyclic benzodiazepine drug with anxiolytic, amnesic, hypnotic, anticonvulsant, and skeletal muscle relaxant and sedative properties. Midazolam is thought to be soluble in water with a pH lower than about 4, but is relatively insoluble in most aqueous solutions with a neutral pH (e.g., about 6 to 8). Therefore, in some embodiments, it is desirable for a water-soluble nasal formulation of midazolam to have a pH of about 5.5 or higher, preferably about 6.0 or higher, or about 6.5 or higher. In some preferred embodiments, the pH is between about 6 to 9, or between about 6 to 8. Since lipid-soluble (nearly neutral pH) midazolam is rapidly absorbed across the nasal mucosa, resulting in efficient uptake of midazolam, it is considered that preparations of midazolam are particularly suitable for nasal administration. It is further considered that midazolam may be formulated with non-aqueous delivery means, such as those known in aerosol delivery techniques, such as hydrofluorocarbon propellants and hydrocarbon propellants.

[0127] The dosage of midazolam may vary depending on the efficacy, but the therapeutic dose is expected to be in the range of about 0.1 to about 20, preferably about 0.2 to about 10 mg per dose, 1 to 8, preferably 2 to 8, per day, and in some preferred embodiments, about 4 to about 6 times. Midazolam may be manufactured using the procedures disclosed in one of U.S. Patent Nos. 4,280,957 and 5,831,089, each of which is incorporated herein by reference in whole.

[0128] In some embodiments, midazolam is used alone or in combination with other drugs to provide anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant, amnesic, or a combination of the aforementioned effects.

[0129] In some embodiments, midazolam is used alone or in combination with other anticonvulsants to treat seizures, protect against seizures, reduce or improve the intensity of seizures, reduce or improve the frequency of seizures, and / or prevent the onset or recurrence of seizures. To protect against seizures, midazolam may be administered by the patient or another person (such as a healthcare worker) while the patient is seizure-free. Even when protection from seizures is not absolute, administration of midazolam may reduce or improve the intensity of seizures and / or reduce or improve the frequency of seizures. In some embodiments, administration of midazolam may prevent the onset of seizures. In some embodiments, particularly when the patient is prone to experiencing consecutive seizures or persistent status epilepticus, administration of midazolam may help interrupt seizure cycles and thus prevent seizure recurrence. In addition to benzodiazepines (such as diazepam), other anticonvulsant drugs may be combined with midazolam to provide a synergistic anticonvulsant effect.

[0130] While a patient is in a seizure state, midazolam may also be administered to the patient by another person (e.g., an acquaintance or colleague, family member or healthcare professional). Therefore, one of the advantages of the formulations according to the present invention is the ability to be administered, for example, intranasally, in an emergency treatment setting for treating seizure victims. Among the beneficial therapeutic effects that can be provided by emergency administration of benzodiazepine anticonvulsants, such as nasal administration, are a reduction in the severity of the seizure (e.g., overall muscle relaxation, reduction of seizure-inducing anxiety experienced by the patient, and an overall transmission of well-being to the patient), a reduction in the duration of the seizure, a decrease in the likelihood of the patient experiencing repeated seizures, and an increase in the interval between the current seizure and the next seizure. Therefore, the midazolam formulations of the present invention, and in certain nasal formulations, provide a faster onset of therapeutic effect in some cases less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes. The midazolam formulations of the present invention, and in specific nasal formulations, also provide a convenient administration of therapeutically beneficial drugs to patients who do not require intravenous or rectal drug administration.

[0131] Often, seizures, particularly severe tonic or tonic-clonic seizures, are predicted by one or more aura events well known to the patient or those close to the patient. These auras, while actually unique to each patient, can generally or typically be classified as auditory, visual, olfactory, or tactile sensations that precede the patient's seizure experience. In some embodiments of the present invention, the method involves rapid administration of a benzodiazepine drug preparation according to the present invention during an aura. In some embodiments, administration of such a benzodiazepine drug during an aura, for example by intranasal administration, prevents or at least improves the effects (intensity, duration, or both) of an impending seizure. Thus, in the context of the present invention, seizure prevention refers to temporarily preemptively preventing the occurrence of a seizure, with or without the presence of warning auras.

[0132] Temazepam (7-chloro-1-methyl-5-phenyl-3-hydroxy-1,3-dihydro-2H-1,4-benzodiazepine-2-one)

[0133] [ka]

[0134] Temazepam is a benzodiazepine drug having sedative, tranquilizer, anticonvulsant, amnesic, hypnotic, anticonvulsant, and muscle relaxant properties. It is classified as an anxiolytic. Temazepam has been shown to be useful in the treatment of nausea. The dosage of temazepam may vary depending on the efficacy, but the therapeutic dose is expected to be in the range of about 1 to about 50 mg per dose, preferably about 5 to about 30 mg, 1 to 8 times per day, preferably 2 to 8 times, and in some preferred embodiments about 4 to about 6 times. Temazepam may be manufactured using the procedures disclosed in U.S. Patents 3,340,253 and 3,374,225, each of which is incorporated herein by reference in whole.

[0135] In some embodiments, temazepam is used alone or in combination with other drugs to provide an anxiolytic effect, an anticonvulsant effect, a sedative effect, a skeletal muscle relaxant effect, an amnesic effect, or a combination of the aforementioned effects.

[0136] In some embodiments, temazepam is used alone or in combination with other anticonvulsants to treat seizures, protect against seizures, reduce or improve the intensity of seizures, reduce or improve the frequency of seizures, and / or prevent the onset or recurrence of seizures. To protect against seizures, temazepam may be administered by the patient or another person (such as a healthcare worker) while the patient is seizure-free. Even when protection from seizures is not absolute, administration of temazepam may reduce or improve the intensity of seizures and / or reduce or improve the frequency of seizures. In some embodiments, administration of temazepam may prevent the onset of seizures. In some embodiments, particularly when the patient is prone to experiencing consecutive seizures or persistent status epilepticus, administration of temazepam may help interrupt seizure cycles and thus prevent seizure recurrence. In addition to benzodiazepines (such as diazepam), other anticonvulsant drugs may be combined with temazepam to provide a synergistic anticonvulsant effect.

[0137] While a patient is in a seizure state, temazepam may also be administered to the patient by another person (e.g., an acquaintance or colleague, family member or healthcare professional). Therefore, one of the advantages of the formulations according to the present invention is the ability to be administered, for example, intranasally, in an emergency treatment setting for treating seizure victims. Among the beneficial therapeutic effects that can be provided by emergency administration of benzodiazepine anticonvulsants, such as nasal administration, are a reduction in the severity of the seizure (e.g., overall muscle relaxation, reduction of seizure-inducing anxiety experienced by the patient, and an overall transmission of well-being to the patient), a reduction in the duration of the seizure, a decrease in the likelihood of the patient experiencing repeated seizures, and an increase in the interval between the current seizure and the next seizure. Therefore, the temazepam formulations of the present invention, and in certain nasal formulations, provide a faster onset of therapeutic effect in some cases less than about 30 minutes, less than about 15 minutes, less than about 10 minutes, and in some cases less than about 5 minutes. The temazepam formulations of the present invention, and in specific nasal formulations, also provide a convenient administration of therapeutically beneficial drugs to patients who do not require intravenous or rectal drug administration.

[0138] Often, seizures, particularly severe tonic or tonic-clonic seizures, are predicted by one or more aura events well known to the patient or those close to the patient. These auras, while actually unique to each patient, can generally or typically be classified as auditory, visual, olfactory, or tactile sensations that precede the patient's seizure experience. In some embodiments of the present invention, the method involves rapid administration of a benzodiazepine drug preparation according to the present invention during an aura. In some embodiments, administration of such a benzodiazepine drug during an aura, for example by intranasal administration, prevents or at least improves the effects (intensity, duration, or both) of an impending seizure. Thus, in the context of the present invention, seizure prevention refers to temporarily preemptively preventing the occurrence of a seizure, with or without the presence of warning auras.

[0139] <Pharmacologically acceptable salts> Benzodiazepines generally have the basic structure of formula I:

[0140] [ka]

[0141] Here, R1-R5 are substituents. In certain embodiments, R1 is an optionally substituted alkyl or forms a ring having R4, R2 is a halogen (e.g., Cl, Br), R3 is an optionally substituted aryl (e.g., 2-chloro or 2-fluorophenyl), R5 is H or OH, R4 and R4' together form a carbonyl (C=O) at the carbon to which they are attached, or R4 and R1 together form an optionally substituted heterocycle with the diazepam ring atom to which they are each attached, and R3' and R6 together form a double bond or form an optionally substituted heterocycle along the diazepam ring atom to which they are each attached. Such basic compounds can form acid addition salts with pharmaceutically acceptable acids such as pharmaceutically acceptable mineral acids and pharmaceutically acceptable organic acids.

[0142] Pharmaceutically acceptable mineral acids include HCl, H2SO4, H2SO3, H3PO4, H3PO3, and others, as recognized by those skilled in the art. Pharmaceutically acceptable organic acids include acetic acid, benzoic acid, tartaric acid, citric acid, oxalic acid, maleic acid, malonic acid, and others. Therefore, in some embodiments, pharmaceutically acceptable acids include 1-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor-10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, and formic acid fumaric acid. Acids, galactaric acid, gentisic acid, glucoheptonic acid (D), gluconic acid (D), glucuronic acid (D), glutamic acid, glutaric acid, glycerophosphate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (DL), lactobionic acid, lauric acid, maleic acid, malic acid (-L), malonic acid, mandelic acid (DL), methanesulfonic acid, benzenesulfonic acid (besylic acid (besylic acid (besylic Acids can be selected from the group consisting of naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, propionic acid, pyroglutamic acid (-L), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+L), thiocyanic acid, toluenesulfonic acid (p), and undecylenic acid. Other pharmaceutically acceptable acids may be pharmaceutically acceptable acidic (nonionic) polymers or pharmaceutically acceptable amphoteric polymers. Those skilled in the art will recognize that other basic pharmaceutically active ingredients may be combined with the aforementioned acids to produce acid addition salts. Similarly, those skilled in the art will recognize that in some embodiments, it may be advantageous that some or all of the added acids are pharmaceutically active ingredients themselves.

[0143] In some embodiments, the present invention provides nasal compositions comprising one or more acidic pharmaceutical active ingredients. It is well considered within the usual art to determine which of the compounds set forth above is acidic. Such compounds can be prepared as base addition salts by, for example, the addition of one or more mineral bases (e.g., NaOH, KOH, NaHCO3, Na2CO3, NH3) or organic bases. It is considered within the art to select pharmaceutically acceptable bases.

[0144] Known benzodiazepine compounds have anxiolytic, anticonvulsant, sedative, and / or skeletal muscle relaxant effects. The term “anticonvulsant” includes treatment of seizures, protection from seizures, reduction or improvement of seizure intensity, reduction or improvement of seizure frequency, and / or prevention of seizure onset or recurrence. In this regard, treatment of seizures includes stopping an ongoing seizure, reducing the severity of an ongoing seizure, and reducing the duration of an ongoing seizure. Protection from seizures includes preventing an impending seizure.

[0145] <Carrier system> Vitamin E is a class of lipid-soluble methylated phenols. This class comprises at least eight naturally occurring compounds, namely α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol, all of which can be used in the compositions and methods of the present invention. Each of these compounds has multiple isomers, all of which can be used in the compositions and methods of the present invention. Each of these compounds, including tocophersolane, also has multiple esters, all of which can be used in the compositions and methods of the present invention. As used herein, vitamin E refers to either natural or synthetic tocopherols, tocotrienols, any of their isomers, any of their esters, any of their analogs or derivatives, or any combination thereof.

[0146] [ka]

[0147] <α-tocopherol> Compounds containing vitamin E are antioxidants. There is also evidence that they can prevent, delay the onset of, or improve the symptoms of heart disease, cancer, cataracts, macular degeneration, glaucoma, Alzheimer's disease, and Parkinson's disease. The inventors found that vitamin E can provide an effective carrier for benzodiazepine drugs. In some embodiments, the benzodiazepine is soluble or partially soluble in vitamin E. In some embodiments, vitamin E may exist as fine particles, nanoparticles, or any combination thereof. Furthermore, the use of vitamin E has the additional benefit of avoiding irritation of sensitive mucous membranes and / or soothing irritated mucous membranes.

[0148] Vitamin E is generally classified as hydrophobic and, when used as a carrier, may be limited to formulations as emulsions. However, emulsions can have several drawbacks. For example, they may be difficult to produce and can be quite unstable. Furthermore, they may leave an oily film on the surface of the skin. Therefore, to avoid the drawbacks of emulsions, some embodiments of the present invention include a solution of one or more benzodiazepine drugs and one or more lower alkyl alcohols or one or more lower alkyl glycols in vitamin E, or any combination thereof.

[0149] A lower alkyl alcohol is an alkyl alcohol having 6 or fewer carbon atoms. Therefore, ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any of their isomers, or any combination thereof can be used.

[0150] A lower alkyl glycol is an alkyl glycol having 6 or fewer carbon atoms. Therefore, any of ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, any of their isomers, or any combination thereof can be used.

[0151] <Additional excipients> In some embodiments, the composition comprises a benzodiazepine drug, a natural or synthetic tocopherol or tocotrienol, and an alcohol or glycol, in addition to at least one penetration enhancer. In some embodiments, the penetration enhancer is at least one alkyl glycoside. In some embodiments, the alkyl glycoside refers to any sugar bonded to any hydrophobic alkyl, as described in U.S. Patent No. 5,661,130, which is incorporated herein by reference in whole. The hydrophobic alkyl may be of any suitable length, e.g., about 9 to about 24 carbon atoms, particularly about 10 to about 14 carbon atoms. The hydrophobic alkyl may be branched and / or partially or entirely unsaturated. The alkyl may be bonded to the sugar core, for example, via a carbonyl group, thereby forming an ester group. A suitable alkyl glycoside, when administered intranasally as described herein, will have properties that are non-toxic, non-ionic, and can increase the absorption of benzodiazepines. Typical sugars that can be covalently bonded to alkyls according to the present invention include glucose, maltose, maltotriose, maltotetrose, sucrose, and trehalose. Typical alkyl glycosides that may be used include octyl-, nonyl-, decyl-, undecyl-, dodecyl, tridecyl, tetradecyl, pentadecyl, octadecyl α- or β-D-maltoside, α-glucoside, or sucrose. In some embodiments, preferred glycosides include maltose, sucrose, or glucose linked by glycosidic bonds to an alkyl chain of 9, 10, 12, 14, 16, 18, or 20 carbon atoms. Specific excipients that may be used in nasal compositions according to the present invention include alkyl sugars, dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and / or combinations of two or more thereof. Alkyl glycosides that are particularly useful in embodiments of the present invention include those marketed under the name Intravail® by Aegis Therapeutics, LLC, San Diego, CA.Other alkyl glycosides may be selected from those having a hydrophilic-lipophilic ratio (HLB) value of about 10–20, particularly about 11–15. The HLB value may be determined as specified in Publication US2009 / 0047347, published on 19 February 2009, the whole therein, and in particular paragraphs

[0075] –

[0079] , are incorporated herein by reference. If present, the amount of alkyl glycoside in the composition is sufficient to enhance the absorption of benzodiazepine drugs administered via the intranasal route. In some embodiments, the amount of alkyl glycoside in the composition is selected to enhance the absorption of benzodiazepine drugs, while at the same time not irritating the nasal mucosa too much. In some embodiments, the amount of alkyl glycoside in the composition is in the range of about 0.01% (w / v) to about 1% (w / v). In some embodiments, the amount of alkyl glycoside in the composition is in the range of about 0.05% (w / v) to about 0.5% (w / v), or about 0.125% (w / v) to about 0.5% (w / v).

[0152] The term “penetration enhancer” refers to any substance that acts to increase absorption across mucous membranes and / or increase bioavailability. In some embodiments, such substances include mucolytics, enzyme inhibitors, and compounds that increase the permeability of mucosal cell membranes. Whether a given compound is an “enhancer” can be determined in vivo or in excellent model studies by comparing two formulations containing unrelated, small polar molecules as a drug, with or without the enhancer, and by measuring whether the absorption of the drug is increased to a clinically significant degree. Enhancers do not pose problems with regard to chronic toxicity because, in vivo, enhancers should be non-irritating and / or rapidly metabolized to become components of normal cells without serious irritant effects.

[0153] In some embodiments, the preferred promoter is lysophosphatidylcholine, which is available from lysophospholipids, such as egg or soy lecithin. In addition to different acyl groups, other lysophosphatidylcholines may be used, including lyso compounds produced from phosphatidylethanolamine and phosphatidic acid, which have similar membrane-modifying properties but modify their properties. Acylcarnitines (e.g., palmitoyl-dl-carnitine chloride) are alternatives. In some embodiments, suitable concentrations are 0.02 to 20% (w / v).

[0154] In some embodiments, suitable accelerators include chelating agents (EGTA, EDTA, arginates), surfactants (especially nonionic substances), acylglycerols, fatty acids and salts (listed in SIGMA Catalog, 1988, pages 316-321 (which is incorporated herein by reference)), tyroxapole, and biological detergents. Agents that modify the fluidity and permeability of the membrane include suitable agents such as enamines (e.g., phenylalanine enamine of ethyl acetoacetate), malonates (e.g., diethyleneoxymethylene malonate), salicylates, bile salts, and their analogs and fusidic acids. Suitable concentrations are up to 20% (v / v).

[0155] Accordingly, in some embodiments, the present invention provides pharmaceutical compositions for intranasal administration in pharmaceutically acceptable formulations for administration to one or more nasal mucosa of a patient, the pharmaceutical compositions comprising a benzodiazepine drug, one or more natural or synthetic tocopherols or tocotrienols in amounts of about 30% to about 95% (w / w), or any combination thereof; one or more alkyl glycosides; and one or more alcohols or glycols in amounts of about 10% to about 70% (w / w), or any combination thereof. In some embodiments, the alkyl glycoside is an alkyl glycoside of the trademark Intravail®. In some embodiments, the alkyl glycoside is dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and / or two or more combinations thereof. In some embodiments, the alkyl glycoside is dodecyl maltoside. In some embodiments, the alkyl glycoside is tetradecyl maltoside. In some embodiments, the alkyl glycoside is sucrose dodecanoate. In some embodiments, the alkyl glycoside is sucrose monostearate. In some embodiments, the alkyl glycoside is sucrose distearate. In some embodiments, the alkyl glycoside is a combination of two or more of dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, or sucrose distearate.

[0156] Accordingly, in some embodiments, the present invention provides pharmaceutical compositions for intranasal administration in pharmaceutically acceptable formulations for administration to one or more nasal mucosa of a patient, the pharmaceutical compositions comprising a benzodiazepine drug comprising fine particles, nanoparticles or both; one or more natural or synthetic tocopherols or tocotrienols in an amount of about 30% to about 95% (w / w); one or more alkyl glycosides; and one or more alcohols or glycols in an amount of about 10% to about 70% (w / w); or any combination thereof. In some embodiments, the alkyl glycoside is an alkyl glycoside of the trademark Intravail®. In some embodiments, the alkyl glycoside is dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and / or two or more combinations thereof. In some embodiments, the alkyl glycoside is dodecyl maltoside. In some embodiments, the alkyl glycoside is tetradecyl maltoside. In some embodiments, the alkyl glycoside is sucrose dodecanoate. In some embodiments, the alkyl glycoside is sucrose monostearate. In some embodiments, the alkyl glycoside is sucrose distearate. In some embodiments, the alkyl glycoside is a combination of two or more of dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, or sucrose distearate.

[0157] <Mucosal Membrane Preparations> Mucosal preparations are generally administered by metered-release sprays with doses of less than 250 μL, preferably less than 150 μL, and ideally between 25 and 100 μL. Although not prohibited in this invention, administering amounts greater than approximately 300 μL per dose usually exceeds the absorption capacity of the membrane. As a result, a large portion of the pharmaceutically active ingredients are lost.

[0158] The dosage of the compounded medication, especially the nasal compound, is preferably in the range of 25 to 100 μL. Any dose exceeding this range bypasses the sinuses and flows down the back of the pharynx, where the excess volume is swallowed.

[0159] <Alprazolam> The dosage of alprazolam varies depending on the efficacy, but the therapeutic dose is expected to be in the range of 1 to 8 doses per day, preferably 2 to 8 doses, and in some preferred embodiments, about 4 to 6 doses, with each dose being about 0.5 to 4, preferably 1 to 2 mg. Alprazolam may be manufactured using the process disclosed in U.S. Patent No. 3,987,052, which is incorporated herein by reference in whole.

[0160] As a nasal preparation, alprazolam may be administered in a metered-dose spray of 25 to 250 μL. In some preferred embodiments, alprazolam is administered in a metered-dose spray of 50 to 150 μL, particularly about 100 μL.

[0161] <Diazepam> The dosage of diazepam varies depending on the efficacy, but the therapeutic dose is expected to be in the range of 1 to 8, preferably 2 to 8, per day, and about 4 to about 6 times, with each dose being about 1 to about 20, preferably about 2 to about 10 mg. Diazepam may be manufactured using the processes disclosed in one of U.S. Patents 3,371,085, 3,109,843, 3,136,815, or 3,102,116, each of which is incorporated herein by reference in whole.

[0162] As a nasal preparation, diazepam may be administered in a metered-dose spray of 25 to 250 μL. In some preferred embodiments, diazepam is administered in a metered-dose spray of 50 to 150 μL, particularly about 100 μL.

[0163] <Flurazepam> The dosage of flurazepam varies depending on the efficacy, but the therapeutic dose is expected to be in the range of 1 to 8, preferably 2 to 8, per day, and in some preferred embodiments, about 4 to about 6 doses, with each dose being about 5 to 40, preferably about 20 to about 35 mg. Flurazepam may be manufactured using the processes disclosed in U.S. Patent No. 3,567,710 or No. 3,299,053, each of which is incorporated herein by reference in whole.

[0164] As a nasal preparation, flurazepam may be administered in a metered-dose spray of 25 to 250 μL. In some preferred embodiments, flurazepam is administered in a metered-dose spray of 50 to 150 μL, particularly about 100 μL.

[0165] <Lorazepam> The dosage of lorazepam varies depending on the efficacy, but the therapeutic dose is expected to be in the range of 1 to 8 doses per day, preferably 2 to 8 doses, and in some preferred embodiments, about 4 to about 6 doses, with each dose being about 0.1 to about 10 mg, preferably about 0.2 to about 1 mg. Lorazepam may be manufactured using the process disclosed in U.S. Patent No. 3,296,249, which is incorporated herein by reference in whole.

[0166] As a nasal preparation, lorazepam may be administered in a metered-dose spray of 25 to 250 μL. In some preferred embodiments, lorazepam is administered in a metered-dose spray of 50 to 150 μL, particularly about 100 μL.

[0167] <Medazepam> The dosage of medazepam varies depending on the efficacy, but the therapeutic dose is expected to be in the range of 1 to 8 doses per day, preferably 2 to 8 doses, and in some preferred embodiments, about 4 to about 6 doses, with each dose being about 0.1 to about 10, preferably about 0.2 to about 1 mg. Medazepam may be manufactured using the process disclosed in U.S. Patent No. 3,243,427, which is incorporated herein by reference in whole.

[0168] As a nasal preparation, medazepam may be administered in a metered-dose spray of 25 to 250 μL. In some preferred embodiments, medazepam is administered in a metered-dose spray of 50 to 150 μL, particularly about 100 μL.

[0169] <Mexazolam> The dosage of mexazolam varies depending on the efficacy, but the therapeutic dose is expected to be in the range of 1 to 8 doses per day, preferably 2 to 8 doses, and in some preferred embodiments, about 4 to about 6 doses, with each dose being about 0.1 to about 10 mg, preferably about 0.2 to about 1 mg. Mexazolam may be manufactured using the process disclosed in U.S. Patent No. 3,722,371, which is incorporated herein by reference in whole.

[0170] As a nasal preparation, mexazolam may be administered in a metered-dose spray of 25 to 250 μL. In some preferred embodiments, mexazolam is administered in a metered-dose spray of 50 to 150 μL, particularly about 100 μL.

[0171] <Midazolam> The dosage of midazolam varies depending on the efficacy, but the therapeutic dose is expected to be in the range of 1 to 8 doses per day, preferably 2 to 8 doses, and in some preferred embodiments, about 4 to about 6 doses, with each dose being about 0.1 to about 20 mg, preferably about 0.2 to about 10 mg. Midazolam may be manufactured using the processes disclosed in either U.S. Patent No. 4,280,957 or No. 5,831,089, each of which is incorporated herein by reference in whole.

[0172] As a nasal preparation, midazolam may be administered in a metered-dose spray of 25 to 250 μL. In some preferred embodiments, midazolam is administered in a metered-dose spray of 50 to 150 μL, particularly about 100 μL.

[0173] <Temazepam> The dosage of temazepam varies depending on the efficacy, but the therapeutic dose is expected to be in the range of 1 to 8 doses per day, preferably 2 to 8 doses, and in some preferred embodiments, about 4 to 6 doses, with each dose being about 1 to 50 mg, preferably about 5 to 30 mg. Temazepam may be manufactured using the processes disclosed in U.S. Patent No. 3,340,253 or No. 3,374,225, each of which is incorporated herein by reference in whole.

[0174] As a nasal preparation, temazepam may be administered in a metered-dose spray of 25 to 250 μL. In some preferred embodiments, temazepam is administered in a metered-dose spray of 50 to 150 μL, particularly about 100 μL.

[0175] <Pharmaceutical Products> Some embodiments include administering a therapeutically effective amount of one or more benzodiazepine drugs, or pharmaceutically acceptable salts thereof, to one or more mucous membranes of a patient. Some embodiments of the compositions disclose compositions containing one or more benzodiazepine drugs or pharmaceutically acceptable salts thereof at concentrations up to about 600 mg / mL. Other compositions disclose compositions containing one or more benzodiazepine drugs or pharmaceutically acceptable salts thereof at concentrations from about 10 mg / mL to about 250 mg / mL. Furthermore, some embodiments disclose compositions containing one or more benzodiazepine drugs or pharmaceutically acceptable salts thereof at concentrations from about 20 mg / mL to about 50 mg / mL.

[0176] Some embodiments disclose a carrier system comprising about 50% to about 90% (w / w) of vitamin E and about 10% to about 50% (w / w) of a lower alcohol or lower alkyl glycol, or any combination thereof. Some embodiments disclose a carrier system comprising about 65% to about 75% (w / w) of vitamin E and about 25% to about 35% (w / w) of a lower alkyl alcohol or lower alkyl glycol, or any combination thereof. Furthermore, some embodiments disclose a carrier system comprising about 70% (w / w) of vitamin E and about 30% (w / w) of a lower alkyl alcohol or lower alkyl glycol, or any combination thereof.

[0177] Some embodiments of the present invention provide a method for administering a benzodiazepine drug composition to a patient. Preferred embodiments involve the use of diazepam. Some embodiments of the method disclose dose levels of diazepam ranging from about 1.0 mg to about 20.0 mg until the desired result is achieved. Other dose levels disclose dose levels ranging from about 2.0 mg to about 15.0 mg until the desired result is achieved. Some embodiments disclose dose levels ranging from about 5.0 mg to about 10.0 mg until the desired result is achieved.

[0178] In some embodiments of the method, the dose ranges from about 10 μL to about 200 μL. In some embodiments, the dose ranges from about 20 μL to about 180 μL. Furthermore, some embodiments disclose a dose of about 50 μL to about 140 μL. In some embodiments, the dose is 50 μL, 75 μL, or 100 μL per nostril.

[0179] <Formulation Process> In some embodiments, the nasal administration composition is substantially free of benzodiazepine microparticles, nanoparticles, or combinations thereof. In some embodiments, the composition is made by slowly warming and heating vitamin E until it is liquefied. Then, one or more benzodiazepine drugs are added. The mixture is stirred and heated until one or more benzodiazepine drugs are dissolved or substantially dissolved. Then, one or more alcohols or glycols, or any combination thereof, are added to the composition. The composition is stirred until a less viscous composition is achieved.

[0180] The formulation process may be modified to accommodate changes in the formulation. For example, as depicted in Figure 4, a formulation containing both benzyl alcohol and ethanol may be formulated by first combining vitamin E, benzyl alcohol and ethanol (e.g., anhydrous alcohol, USP) and mixing until the components are homogeneous, heating the mixture to 45°C (±2°C), adding an alkyl glycoside and mixing until the alkyl glycoside is dissolved and the solution is homogeneous, adding a benzodiazepine (e.g., diazepam) while maintaining the mixture at approximately 45°C, cooling the solution to 25°C (±2°C), adding ethanol (sufficient amount) to achieve the final target weight of the solution, and mixing thoroughly to ensure homogeneity. The solution produced by this process may be formulated with different concentrations of diazepam. For example, some embodiments of the present invention include diazepam formulations summarized in the following table. Although diazepam is used as an example in Figure 4 and the table below, any benzodiazepine may also be used, such as alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, chlorazepam, demoxazepam, diazepam, flumazenil, flurazepam, harazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically acceptable salt thereof, and any combination thereof.

[0181] Quantitative composition of NRL-1. In some embodiments, the pharmaceutical formulation is a formulation for intranasal administration.

[0182] [Table 1]

[0183] In some embodiments, the aforementioned formulation is a sterile solution having a bacterial count of 10 per 1 mL, which is below an acceptable level. Furthermore, it is preferable that pathogens are absent. In some embodiments, the solution is self-preserving, self-sterile, or both.

[0184] In some embodiments, benzodiazepine drugs are formulated as suspensions of benzodiazepine microparticles and / or nanoparticles. The formulation of benzodiazepines in microparticle and nanoparticle form can be achieved by methods such as milling. Such methods are known to those skilled in the art.

[0185] Figure 5 illustrates one embodiment of the process for producing a benzodiazepine suspension according to the present invention. First, a benzodiazepine (e.g., diazepam) is sieved to produce a micronized benzodiazepine (e.g., diazepam). The micronized benzodiazepine (e.g., diazepam) is then split into two intermediate products: diazepam A (high pressure) having a small particle size (average particle size < 2000 nm) and diazepam B (low pressure) having a large particle size (average particle diameter > 2000 nm). After testing during the process, the two intermediate products are combined in the correct proportions with one or more excipients to yield a suspension of bimodal particles having a pre-selected average particle diameter (which, in some embodiments, is greater than 2000 nm). In some embodiments, the excipient is prepared according to the second column in Figure 5, for example, by first combining polyethylene glycol succinate of propylene glycol, water, and vitamin E to form a mixture, heating the mixture until the components are dissolved, then adding methylparaben, propylparaben, and Intravail® (alkyl glycoside) to the mixture, mixing until the newly added components are dissolved, and finally cooling the mixture to, for example, 25°C ± 2°C. The excipient is then combined with pulverized diazepam A and pulverized diazepam B, vigorously mixed to disperse the pulverized diazepam and form a suspension. Next, povidone is added to the mixture and mixed until fully dissolved. Finally, the suspension is brought to its final target weight with purified water, thoroughly mixed, and homogeneity is achieved. The final product can then be filled into a suitable container. In some embodiments, 3 mL may be filled into a 4 mL amber glass vial having PTFE-lined phenolic closures, but other containers are also possible and will be considered within the scope of the present invention.As diazepam is depicted in Figure 5 as a typical benzodiazepine, any benzodiazepine, and any combination thereof, such as alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, chlorazepam, demoxazepam, diazepam, flumazenil, flurazepam, harazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, and any pharmaceutically acceptable salts thereof, may also be used.

[0186] In some embodiments, the formulation described above is a sterile suspension having a total bacterial count of 10 or less per ml, below an acceptable level. Furthermore, pathogens are preferably not included. In some embodiments, the suspension is self-preserving, self-sterile, or both.

[0187] In some embodiments, benzodiazepine drugs are formulated as solutions. In what is considered an embodiment of the present invention, the use of benzodiazepine drugs in particulate and / or nanoparticle form during the formulation preparation process can improve the overall solubility of the benzodiazepine drug in the solvent system.

[0188] <Additional active and inactive ingredients> Furthermore, some embodiments of the composition and methods of using the composition include additional components in the composition selected from the active ingredients. Such active ingredients include, but are not limited to, insulin, calcitonin (e.g., from pigs, humans, salmon, chickens, or eels) and its synthetic modifications, enkephalins, LHRH and its analogues (nafarelin, buserelin, Zolidex), GHRH (growth hormone-releasing hormone), nifedipine, THF (thymic humor factor), CGRP (calcitonin gene-related peptide), atrial natriuretic peptide, antibiotics, metoclopramide, ergotamine, pizotizin, nasal vaccines (especially HIV vaccine, measles, rhinovirus type 13, and syncytial viruses of the respiratory system), pentamidine, CCK (cholecystikinin), DDVAP, interferon, and growth hormone (solatotropir peptide). This includes butylates or their derivatives (preferably having molecular weights from 1,000 to 300,000), secretin, bradykinin antagonists, GRF (growth hormone-releasing factor), THF, TRH (thyroid-stimulating hormone-releasing hormone), ACTH analogs, IGF (insulin-like growth factor), CGRP (calcitrin gene-related peptide), atrial natriuretic peptide, vasopressin and its analogs (DDAVP, repressin), metoclopramide, treatment of migraines (dihydroergotamine, ergometrine, ergotamine, pizotidine), intranasal vaccines (especially AIDS vaccines), factor VIII, colony-stimulating factor, G-colony-stimulating factor (granulocyte colony-stimulating factor), EPO (erythropoietin), PTH (parathyroid hormone), or pharmaceutically acceptable salts or combinations thereof.

[0189] Furthermore, several embodiments of the composition and methods of using the composition include additional components in the composition selected from other anticonvulsants. Examples of such active components, though not limited, include: paraaldehydes; aromatic allyl alcohols (e.g., stiripentol); barbiturates (e.g., phenobarbitol, primidone, methylphenobarbital, metalbital, and barbexacron); bromides (e.g., potassium bromide); carbamates (e.g., felbamate); carboxamides (e.g., carbamazepine and oxcarbazepine); fatty acids (e.g., valproic acid, sodium valproate, and divalproex sodium, vigabatrin, progavid, thiagabin); fructose, topiramates; Gaba analogs (e.g., gabapentin and pregabalin); hydantoins (e.g., etotoin, phenytoin, mephenytoin, and fosphenytoin); oxazo This includes lysine diones (paramethadione, trimethadione, etadione, etc.); propionates (e.g., beclamide), pyrimidine diones (e.g., primidone), pyrrolidines (e.g., brivalacetam, levetiracetam, and seletracetam); succinimide (e.g., ethosuximide, fenxuximide, and mesuximide); sulfonamides (e.g., acetazolamide, sultium, metazolamide, and zonisamide); triazines (e.g., lamotrigine); ureas (e.g., phenetulide, phenasemide); valproylamides (e.g., valbromide and valnoctamide); and other anticonvulsants or their pharmaceutically acceptable salts or combinations.

[0190] Furthermore, some embodiments of the composition and methods of using the composition include additional components in the composition selected from other anticonvulsants. Examples of unrestricted active ingredients include antibiotics and antibacterial agents such as tetracycline hydrochloride, leucomycin, penicillin, penicillin derivatives, erythromycin, gentamicin, sulfathiazole, and nitrofurazone; local anesthetics such as benzocaine; vasoconstrictors such as phenylephrine hydrochloride, tetrahydrozoline hydrochloride, naphazoline nitrate, oxymetazoline hydrochloride, and tramazoline hydrochloride; cardiac stimulants such as digitalis and digoxin; vasodilators such as nitroglycerin and papaverine hydrochloride; disinfectants such as chlorhexidine hydrochloride, hexylresorcinol, decalinium chloride, and acrinol; enzymes such as lysozyme chloride and dextranase; bone metabolism regulators such as vitamin D, active vitamin D, and vitamin C; sex hormones; antihypertensives; sedatives; antitumor drugs, hydrocortisone, prednisone, fluticasone, prednisolone, triamcinolone acetone This includes steroidal anti-inflammatory agents such as nitrate, dexamethasone, betamethasone, beclomethasone, and beclomethasone dipropionate; nonsteroidal anti-inflammatory agents such as acetaminophen, aspirin, aminopyrine, phenylbutazone, medamic acid, ibuprofen, diclofenac sodium, indomethacin, colchicine, and probenocid; enzyme anti-inflammatory agents such as chymotrypsin and bromelain seratiopeptidase; antihistamines such as diphenhydramine salt chain, chloropheniramine maleate, and clemastine; antiallergic drugs such as sodium caromoglycate, codeine phosphate, and isoproterenol hydrochloride, and antitussive expectorant antiasthmatic drugs, or pharmaceutically acceptable salts or combinations thereof.

[0191] Furthermore, some embodiments of the composition and methods of using the composition include additional inert components in the composition. Non-limiting examples include small amounts of components such as stabilizers, colorants, pH adjusters, buffers, preservatives (including those that may prevent decomposition), humectants, and flavorings. Examples of colorants include β-carotene, Red No. 2, and Blue No. 1. Examples of preservatives include stearic acid, ascorbic acid stearate, and ascorbic acid. Examples of flavorings include menthol and citrus perfumes.

[0192] In some embodiments, the drug delivery system of the present invention may conveniently include an absorption enhancer. The term “enhancer” means any material that acts to increase absorption throughout the mucosa and / or enhance bioavailability. In some embodiments, such materials include mucolytics, degradable enzyme inhibitors, and compounds that increase the permeability of mucosal cell membranes. Whether a given compound is an “enhancer” is determined by comparing two formulations containing an unrelated small polar molecule as a drug, with and without the enhancer, in an in vivo or excellent model study, and by measuring whether the absorption of the drug is enhanced to a clinically significant degree. Since the in vivo enhancer should be non-irritating and / or rapidly metabolized into normal cellular components without any irritating effects, the enhancer should not create any problems from the standpoint of chronic toxicity.

[0193] In some embodiments, preferred reinforcing materials are lysophospholipids, such as lysophosphatidylcholine, which can be obtained from egg or soy lecithin. Other lysophosphatidylcholines having different acyl groups may be used, as well as lyso compounds produced from phosphatidylethanolamine and phosphatidic acid, which have similar membranes with modified properties. Acylcarnitines (e.g., palmitoyl-di-carnitine chloride) are alternatives. In some embodiments, suitable concentrations are 0.02 to 20% (w / v).

[0194] In some embodiments, suitable accelerators include chelating agents (EGTA, EDTA, arginates), surfactants (especially nonionic materials), acylglycerols, fatty acids and salts, tyroxapole and biological detergents (as enumerated in the SIGMA catalog, 1988, pp. 316-321, incorporated herein by reference). Suitable agents modifying membrane fluidity and permeability include enamines (e.g., phenylalanine enamine of ethyl acetoacetate), malonates (e.g., diethyleneoxymethylene malonate), salicylic acid, bile salts, and analogs and fusidic acid. Suitable concentrations are up to 20% (v / v).

[0195] In some embodiments, the present invention utilizes the delivery of drugs incorporated into bioadhesive microspheres, along with additional pharmaceutical adjuvant applied to systems containing active drugs and mucolytics, peptidase inhibitors, or non-drug polypeptide substrates, either alone or in combination. Preferably, the mucolytics are thiol-containing compounds such as N-acetylcysteine ​​and its derivatives. Peptide inhibitors include actinonine, amastatin, bestatin, chloroacetyl-HOLeu-Ala-Gly-NH.sub.2 diprotin A and B, ebelactone A and B, E-64, leupeptin, pepstatin A, phosphoramidon, H-Thr-(tBu)-Phe-Pro-OH, aprotinin, kallikrein, chymostatin, benzamidine, chymotrypsin, and trypsin. The appropriate concentration is 0.01 to 10% (w / v). Those skilled in the art can easily determine whether or not an enhancer should be included.

[0196] <Administration> In some embodiments, administration of the composition includes administering at least a portion of a therapeutically effective amount of the composition to at least one mucous membrane. In some embodiments, administration of the composition includes spraying at least a portion of a therapeutically effective amount of the composition into at least one nostril. In some embodiments, administration of the composition includes spraying at least a portion of a therapeutically effective amount of the composition into each nostril. In some embodiments, administration of the composition includes spraying a first amount of the composition into a first nostril, spraying a second amount of the composition into a second nostril, and spraying a third amount of the composition into the first nostril after a optionally pre-selected time delay. In some embodiments, administration of the composition further includes administering at least a fourth amount of the composition into the second nostril after a optionally pre-selected time delay.

[0197] <Alprazolam> The dosage of alprazolam varies depending on the symptoms, however, the therapeutic dose is expected to be in the range of about 0.5 to about 4 mg per dose, preferably 1 to about 2 mg per dose, 1 to 8 times per day, preferably 2 to 8 times per day, and in some preferred embodiments, about 4 to 6 times per day. Alprazolam may be manufactured using the process disclosed in U.S. Patent 3,987,052, which is incorporated herein by reference in its adjective form.

[0198] As a nasal preparation, alprazolam may be administered in 25 to 250 μL metered sprays. In preferred embodiments, alprazolam is administered in 50 to 150 μL, particularly about 100 μL metered sprays. In some embodiments, the first metered spray is applied to the first nostril, and if necessary, the second metered spray is applied to the second nostril. In optional embodiments, the third metered spray is applied to the first nostril. In some embodiments, the fourth metered spray is applied to the second nostril. In some embodiments, additional metered sprays are applied alternately to the nostrils until a sufficient targeted therapeutic dose is administered to the patient. In some embodiments, there is a time increment of a few seconds to 5 minutes, preferably 10 seconds to about 1 minute, between applying the benzodiazepine drug to the same nostril. This allows time for the drug to cross the nasal mucosa and enter the bloodstream. Multiple applications of a metered-dose spray to each nostril, separated at arbitrary time intervals, allow for complete absorption of benzodiazepine drugs into the bloodstream, enabling the administration of a total therapeutic dose with only slight increases in dosage sufficient to prevent the drug from being lost in the back of the throat.

[0199] <Diazepam> The dosage of diazepam may vary depending on the symptoms, but the therapeutic dose is expected to be in the range of about 1 to about 20 mg per dose, preferably 2 to about 10 mg per dose, 1 to 8 times per day, preferably 2 to 8 times per day, and in some preferred embodiments, about 4 to 6 times per day. Diazepam may be manufactured using the processes disclosed in one of U.S. Patents 3,371,085, 3,109,843, 3,136,815, or 3,102,116, which are incorporated herein by reference.

[0200] As a nasal formulation, diazepam may be administered in 25 to 250 μL of metered-dose spray. In some preferred embodiments, diazepam is administered in 50 to 150 μL, particularly 100 μL of metered-dose spray. In some embodiments, the first metered-dose spray is applied to the first nostril, and if necessary, the second metered-dose spray is applied to the second nostril. In optional embodiments, the third metered-dose spray is applied to the first nostril. In some embodiments, the fourth metered-dose spray is applied to the second nostril. In some embodiments, additional metered-dose sprays are applied alternately to the nostrils until a sufficient targeted therapeutic dose is administered to the patient. In some embodiments, there is a time increment of several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applying the benzodiazepine drug to the same nostril. This allows time for the drug to cross the nasal mucosa and enter the bloodstream. Multiple applications of a metered-dose spray to each nostril, separated at arbitrary time intervals, allow for complete absorption of benzodiazepine drugs into the bloodstream, enabling the administration of a total therapeutic dose with only slight increases in dosage sufficient to prevent the drug from disappearing into the back of the throat.

[0201] <Flurazepam> The dosage of flurazepam varies depending on the symptoms, but the therapeutic dose is expected to range from about 5 to about 40 mg per dose, preferably 20 to about 35 mg per dose, 1 to 8 times per day, preferably 2 to 8 times per day, and in some preferred embodiments, about 4 to 6 times per day. Flurazepam may be manufactured using the processes disclosed in U.S. Patents 3,567,710 or 3,299,053, which are incorporated herein by reference.

[0202] As a nasal formulation, flurazepam may be administered in 25 to 250 μL of metered-dose spray. In some preferred embodiments, flurazepam is administered in 50 to 150 μL, particularly 100 μL of metered-dose spray. In some embodiments, the first metered-dose spray is applied to the first nostril, and if necessary, the second metered-dose spray is applied to the second nostril. In optional embodiments, the third metered-dose spray is applied to the first nostril. In some embodiments, the fourth metered-dose spray is applied to the second nostril. In some embodiments, additional metered-dose sprays are applied alternately to the nostrils until a sufficient targeted therapeutic dose is administered to the patient. In some embodiments, there is a time increment of several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applying the benzodiazepine drug to the same nostril. This allows time for the drug to cross the nasal mucosa and enter the bloodstream. Multiple applications of a metered-dose spray to each nostril, separated at arbitrary time intervals, allow for complete absorption of benzodiazepine drugs into the bloodstream, enabling the administration of a total therapeutic dose with only slight increases in dosage sufficient to prevent the drug from disappearing into the back of the throat.

[0203] <Lorazepam> The dosage of lorazepam varies depending on the symptoms, but the therapeutic dose is expected to range from about 0.1 to about 10 mg per dose, preferably 0.2 to about 1 mg per dose, 1 to 8 times per day, preferably 2 to 8 times per day, and in some preferred embodiments, about 4 to 6 times per day. Lorazepam may be manufactured using the process disclosed in U.S. Patent 3,296,249, which is incorporated herein by reference.

[0204] As a nasal formulation, lorazepam may be administered in 25 to 250 μL of metered-dose spray. In some preferred embodiments, lorazepam is administered in 50 to 150 μL, particularly 100 μL of metered-dose spray. In some embodiments, the first metered-dose spray is applied to the first nostril, and if necessary, the second metered-dose spray is applied to the second nostril. In optional embodiments, the third metered-dose spray is applied to the first nostril. In some embodiments, the fourth metered-dose spray is applied to the second nostril. In some embodiments, additional metered-dose sprays are applied alternately to the nostrils until a sufficient targeted therapeutic dose is administered to the patient. In some embodiments, there is a time increment of several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applying the benzodiazepine drug to the same nostril. This allows time for the drug to cross the nasal mucosa and enter the bloodstream. Multiple applications of a metered-dose spray to each nostril, separated at arbitrary time intervals, allow for complete absorption of benzodiazepine drugs into the bloodstream, enabling the administration of a total therapeutic dose with only slight increases in dosage sufficient to prevent the drug from disappearing into the back of the throat.

[0205] <Medazepam> The dosage of medazepam varies depending on the symptoms, but the therapeutic dose is expected to range from about 0.1 to about 10 mg per dose, preferably 0.2 to about 1 mg per dose, 1 to 8 times per day, preferably 2 to 8 times per day, and in some preferred embodiments, about 4 to 6 times per day. Medazepam may be manufactured using the process disclosed in U.S. Patent 3,243,427, which is incorporated herein by reference.

[0206] As a nasal formulation, medazepam may be administered in 25 to 250 μL of metered-dose spray. In some preferred embodiments, medazepam is administered in 50 to 150 μL, particularly 100 μL of metered-dose spray. In some embodiments, the first metered-dose spray is applied to the first nostril, and if necessary, the second metered-dose spray is applied to the second nostril. In optional embodiments, the third metered-dose spray is applied to the first nostril. In some embodiments, the fourth metered-dose spray is applied to the second nostril. In some embodiments, additional metered-dose sprays are applied alternately to the nostrils until a sufficient targeted therapeutic dose is administered to the patient. In some embodiments, there is a time increment of several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applying the benzodiazepine drug to the same nostril. This allows time for the drug to cross the nasal mucosa and enter the bloodstream. Multiple applications of a metered-dose spray to each nostril, separated at arbitrary time intervals, allow for complete absorption of benzodiazepine drugs into the bloodstream, enabling the administration of a total therapeutic dose with only slight increases in dosage sufficient to prevent the drug from disappearing into the back of the throat.

[0207] <Mexazolam> The dosage of mexazolam varies depending on the symptoms, but the therapeutic dose is expected to be in the range of about 0.1 to about 10 mg per dose, preferably 0.2 to about 1 mg per dose, 1 to 8 times per day, preferably 2 to 8 times per day, and in some preferred embodiments, about 4 to 6 times per day. Mexazolam may be manufactured using the process disclosed in U.S. Patent 3,722,371, which is incorporated herein by reference.

[0208] As a nasal formulation, mexazolam may be administered in 25 to 250 μL of metered-dose spray. In some preferred embodiments, mexazolam is administered in 50 to 150 μL, particularly 100 μL of metered-dose spray. In some embodiments, the first metered-dose spray is applied to the first nostril, and if necessary, the second metered-dose spray is applied to the second nostril. In optional embodiments, the third metered-dose spray is applied to the first nostril. In some embodiments, the fourth metered-dose spray is applied to the second nostril. In some embodiments, additional metered-dose sprays are applied alternately to the nostrils until a sufficient targeted therapeutic dose is administered to the patient. In some embodiments, there is a time increment of several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applying the benzodiazepine drug to the same nostril. This allows time for the drug to cross the nasal mucosa and enter the bloodstream. Multiple applications of a metered-dose spray to each nostril, separated at arbitrary time intervals, allow for complete absorption of benzodiazepine drugs into the bloodstream, enabling the administration of a total therapeutic dose with only slight increases in dosage sufficient to prevent the drug from disappearing into the back of the throat.

[0209] <Midazolam> The dosage of midazolam varies depending on the symptoms, but the therapeutic dose is expected to be in the range of about 0.1 to about 20 mg per dose, preferably 0.2 to about 10 mg per dose, 1 to 8 times per day, preferably 2 to 8 times per day, and in some preferred embodiments, about 4 to 6 times per day. Midazolam may be manufactured using the process disclosed in one of U.S. Patents 4,280,957 or 5,831,089, which are incorporated herein by reference.

[0210] As a nasal formulation, midazolam may be administered in 25 to 250 μL of metered-dose spray. In some preferred embodiments, midazolam is administered in 50 to 150 μL, particularly 100 μL of metered-dose spray. In some embodiments, the first metered-dose spray is applied to the first nostril, and if necessary, the second metered-dose spray is applied to the second nostril. In optional embodiments, the third metered-dose spray is applied to the first nostril. In some embodiments, the fourth metered-dose spray is applied to the second nostril. In some embodiments, additional metered-dose sprays are applied alternately to the nostrils until a sufficient targeted therapeutic dose is administered to the patient. In some embodiments, there is a time increment of several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applying the benzodiazepine drug to the same nostril. This allows time for the drug to cross the nasal mucosa and enter the bloodstream. Multiple applications of a metered-dose spray to each nostril, separated at arbitrary time intervals, allow for complete absorption of benzodiazepine drugs into the bloodstream, enabling the administration of a total therapeutic dose with only slight increases in dosage sufficient to prevent the drug from disappearing into the back of the throat.

[0211] <Temazepam> The dosage of temazepam varies depending on the symptoms, but the therapeutic dose is expected to range from about 1 to about 50 mg per dose, preferably about 5 to about 30 mg per dose, 1 to 8 times per day, preferably 2 to 8 times per day, and in some preferred embodiments, about 4 to 6 times per day. Temazepam may be manufactured using the process disclosed in one of U.S. Patents 3,340,253 or 3,374,225, which are incorporated herein by reference.

[0212] As a nasal formulation, temazepam may be administered in 25 to 250 μL of metered-dose spray. In some preferred embodiments, temazepam is administered in 50 to 150 μL, particularly 100 μL of metered-dose spray. In some embodiments, the first metered-dose spray is applied to the first nostril, and if necessary, the second metered-dose spray is applied to the second nostril. In some optional embodiments, the third metered-dose spray is applied to the first nostril. In some embodiments, the fourth metered-dose spray is applied to the second nostril. In some embodiments, additional metered-dose sprays are applied alternately to the nostrils until a sufficient targeted therapeutic dose is administered to the patient. In some embodiments, there is a time increment of several seconds to 5 minutes, preferably about 10 seconds to about 1 minute, between applying the benzodiazepine drug to the same nostril. This allows time for the drug to cross the nasal mucosa and enter the bloodstream. Multiple applications of a metered-dose spray to each nostril, separated at arbitrary time intervals, allow for complete absorption of benzodiazepine drugs into the bloodstream, enabling the administration of a total therapeutic dose with only slight increases in dosage sufficient to prevent the drug from disappearing into the back of the throat.

[0213] Those skilled in the art will notice that the systematically therapeutically effective amount of benzodiazepine drug for treating the aforementioned diseases varies depending on the patient's age, size, weight, and general health condition, as well as the severity of the disease. The frequency of administration also varies depending on the formulation of the composition, and the frequency can be adjusted so that an appropriate number of doses per day is used.

[0214] <Examples> The present invention is illustrated herein in relation to the following exemplary, non-limiting embodiments.

[0215] <Example 1> A pharmaceutical composition containing diazepam is prepared. It is formulated as a solution delivered by a nasal delivery device. The composition is used to treat or prevent seizures associated with epilepsy in adults. The treatment is administered before or after the onset of a seizure. If the patient is having a seizure, it is administered as one puff from any nasal delivery device (5.0 mg / puff (5.0 mg / 0.1 puff, and 0.1 mL / puff)) every 5 minutes until the seizure subsides. However, it can also be administered as one puff per nostril (2.5 mg / puff (5.0 mg / 0.1 mL, and 0.05 mL / puff)) every 5 minutes until the seizure subsides. The composition according to this example is described in the table below.

[0216] [Table 2]

[0217] <Example 2> A pharmaceutical composition containing diazepam is prepared. It is formulated as a solution delivered by a nasal delivery device. The composition is used to treat or prevent seizures associated with epilepsy in children. The treatment is administered before or after the onset of a seizure. When the patient is having a seizure, it is administered in one puff from any nasal delivery device (2.0 mg / puff (2.0 mg / 0.1 mL and 0.1 mL / puff in one puff)). If the seizure does not stop, another dose may be administered after 5 minutes. However, it can be given as one puff per nostril (two puffs at 1.0 mg / puff (2.0 mg / 0.1 mL and 0.05 mL / puff)). If the seizure does not stop, another dose may be administered after 5 minutes. The composition according to this embodiment is described in the following table.

[0218] [Table 3]

[0219] <Example 3 - Formulation of diazepam solution> Generally, a benzodiazepine solution may be formulated by combining one or more natural or synthetic tocopherols or tocotrienols with one or more lower alcohols or glycols, mixing them until a homogeneous mixture is formed, adding the benzodiazepine drug to the homogeneous mixture, heating and mixing the components until the benzodiazepine is completely dissolved in the homogeneous mixture, cooling the mixture, and bringing the mixture to its final mass or volume containing the lower alcohol or glycol.

[0220] Two different diazepam solutions were formulated by the process described above. Vitamin E USP and anhydrous ethanol USP were combined and mixed in the amounts described in the table below to form a homogeneous mixture. The amount of diazepam specified in the table below was then added to the homogeneous mixture. The mixture was heated to 40-45°C while stirring the ingredients until the diazepam was fully dissolved. The solution was cooled to 20-25°C, and then the solution was thoroughly mixed with anhydrous ethanol USP to its final target weight and to ensure homogeneity. A sample of the solution was then taken for the ongoing test and placed in a 3 mL amber glass vial.

[0221] [Table 4]

[0222] Additional diazepam solutions of various concentrations can be prepared in a similar manner by varying the amount of diazepam and the relative amounts of vitamin E and ethanol. Other benzodiazepine solutions can be prepared by using one or more benzodiazepines instead of diazepam. Other components, such as alkyl glycosides, can be added at appropriate steps in the process (e.g., before or at the same time as the addition of benzodiazepines).

[0223] <Example 4> -- Formulation of diazepam suspension Generally, benzodiazepine suspensions are formulated by micronizing the benzodiazepine and combining it with a carrier. The carrier is prepared by combining one or more lower alcohols or glycols with water, adding natural or synthetic tocopherols or tocotrienols, heating the mixture until the tocopherols or tocotrienols dissolve, adding one or more parabens, mixing until the parabens dissolve, and then cooling the carrier. Once the benzodiazepines are added to the carrier, additional excipients such as surfactants can be optionally added and dissolved within the carrier. The suspension is then prepared with water to its final mass or volume.

[0224] Two different diazepam suspensions were formulated by the general process described above. Two different diazepam particle sizes were prepared: A: small particle size prepared by micronization under high pressure, and B: large particle size prepared by micronization under low pressure. A carrier was prepared by combining propylene glycol USP and purified water USP, then adding vitamin E polyethylene glycol succinate NF, and then mixing the combined components and heating to approximately 45°C. Mixing was continued until the vitamin E polyethylene glycol succinate was fully dissolved. The carrier was then cooled to 20-25°C. Micronized diazepam (A and B) was added to the carrier with vigorous mixing until the diazepam was fully dispersed in the carrier. Polyvinylpyrrolidone povidone USP / NF was then added to the mixture and mixed until fully dissolved. The suspension was then adjusted to the weight of purified water USP. The suspension was then mixed until homogenized, and a sample was taken for ongoing testing and placed in a 3 mL amber glass bottle.

[0225] [Table 5]

[0226] Additional suspensions of diazepam at various concentrations can be prepared in a similar manner by varying the amounts of diazepam and, optionally, other excipients. Other benzodiazepine suspensions can be prepared by using one or more benzodiazepines instead of diazepam. Other components, such as alkyl glycosides, can be added at appropriate steps in the process. For example, alkyl glycosides may be added to the carrier while the carriers are being mixed, or added to the suspension mixture simultaneously with or after the addition of povidone.

[0227] <Example 5> -- Stability of diazepam solution and suspension Solutions 00 and 02 (<Example 3>) and suspensions 01 and 03 (<Example 4>) were set to be stable at 25°C / 60%RH, 30°C / 65%RH, and 40°C / 75%RH. In addition to the corresponding actuators, one batch of each of the four different formulations, contained in 3 ml vials with screw-top sealed containers, was set to three storage conditions. They are listed in Table 1 along with the first sample control numbers of the corresponding particle sciences.

[0228] [Table 6]

[0229] Samples were tested for uniformity of spray content, spray volume, diazepam contents, diazepam-related substances, and assays for methylparaben and propylparaben (suspension samples only). Unit weights are USP <755> It was decided accordingly.

[0230] A summary of the average analytical values ​​and all other results is given in Tables 5-4, 5-5, 5-6, and 5-7. The results at the initial, 1-month, and 3-month points are also shown for comparison. The results for the uniformity of individual spray content are given in Tables 5-8, 5-9, 5-10, 5-11, 5-12, 5-13, 5-14, and 5-15.

[0231] In general, all assay and other results are similar to the initial data, with the exception of diazepam-related compounds A and B.

[0232] Related compound A did not even meet the specification of (NMT) 0.01% in some samples (see Table 2). Related compound A increased with time and temperature.

[0233] [Table 7]

[0234] Related compound B also increases with time and temperature, failing to meet the NMT 0.1% specification at 40°C for both the suspension and one solution formulation. Only formulation 2602 meets all impurity specifications.

[0235] [Table 8]

[0236] [Table 9]

[0237] [Table 10]

[0238] [Table 11]

[0239] [Table 12]

[0240] [Table 13]

[0241]

Table 14

[0242]

Table 15

[0243]

Table 16

[0244]

Table 17

[0245]

Table 18

[0246]

Table 19

[0247]

Table 20

[0248] <Example 6> All of the solutions and suspensions described in Examples 3 and 4 are formulated as described in Examples 3 and 4 by adding an appropriate amount of alkyl glycoside as described herein, such as dodecyl maltoside, tetradecyl maltoside, sucrose dodecanoate, sucrose monostearate, sucrose distearate, and / or a combination of two or more thereof, or as sold under the trade name Intravail® by Aegis Therapeutics of San Diego, California. Thereafter, the solutions and suspensions containing the added alkyl glycoside may be set to the stability as described in Example 5.

[0249] <Example 7> The solutions and suspensions of Examples 3, 4, and 6 are evaluated for pharmacokinetics in appropriate animal models such as mice, rats, rabbits, or dogs. First, each animal (e.g., rabbits) is administered a benzodiazepine drug dose intravenously. The amount of benzodiazepine drug administered intravenously is selected to be less than (e.g., about half) the amount considered to be an effective dose administered nasally. For example, the intravenous dose of diazepam administered to rabbits is about 0.05 to about 0.2 mg / kg, for example, about 0.1 mg / kg. Blood is collected immediately before administration and at specific time points after administration. Plasma blood concentrations of the drug are assayed for each blood sample. After a drug-free period of at least one day, each animal is administered intranasally in amounts of the solutions or suspensions described in Examples 3, 4, and 6. Blood is collected immediately before administration and at approximately the same specific time points as after the IV administration. Pharmacokinetic curves (plasma concentration of drug versus time) are constructed for intravenous administration, and for solutions and suspensions administered via nasal administration.

[0250] Toxicity is assessed by known methods. In particular, histological samples are collected, especially from the nasal mucosal tissue of test animals. Similarly, other toxicological methods are used as appropriate.

[0251] <Example 8> The solutions and suspensions of Examples 3, 4, and 6 are evaluated for their ability to deliver drugs across the blood-brain barrier in suitable animal models such as mice, rats, rabbits, or dogs. Each animal is administered intranasally in the amounts of the solutions or suspensions described in Examples 3, 4, and 6, and the solutions or suspensions optionally contain contrast agents, such as dyes, which may be used as surrogates to measure the ability of the drug to cross the blood-brain barrier. The drug or contrast agent is detected at a selected time point after administration of the suspension or solution to measure the extent to which the suspension or solution crosses the blood-brain barrier. These results may be compared to similar results obtained with intravenous solutions containing the drug or contrast agent.

[0252] <Example 9> The above-described solutions and / or suspensions can be evaluated for pharmacokinetics in humans. Normal, healthy human subjects are administered the drug intravenously. The amount chosen for intravenous administration may be any amount, but it is preferable that it be a dose considered effective in treating human seizures. For example, the IV dose of diazepam administered to humans ranges from 1 to 15 mg, and may be, for example, about 7.5 mg. Blood is collected immediately before administration and at selected time points after administration. Plasma blood concentrations of the drug are assayed for each blood sample. After a drug-free period of at least one day, each subject is administered intranasally in amounts of the solutions or suspensions described herein. Blood is collected immediately before administration and at substantially the same time points as for intravenous administration after administration. Pharmacokinetic curves (plasma concentration of the drug versus time) are constructed for the intravenous and intranasal administration routes.

[0253] <Example 10> The above solution and / or suspension can be evaluated for efficacy in a suitable animal model. Briefly, for each dose of the suspension or solution being tested, the test animals are stimulated by a stimulus that induces seizures. The stimulus may be light, sound, a chemical stimulus, or other stimuli effective in inducing seizures in the model animal. Once the animal begins to suffer from seizures, a solution or suspension as described herein is administered intranasally to the animal. The efficacy of the dose of the solution and / or suspension is evaluated based on the animal's response to the test dose. This procedure is repeated with sufficient replicates and a sufficient number of administrations to confirm a dose that is considered effective in treating seizures by intranasal administration of the drug.

[0254] <Example 11> A pharmaceutical composition containing diazepam was prepared as a composition formulated as a solution to be delivered by a nasal delivery device. The solution was prepared according to the procedure outlined in the flowchart of Figure 4. The components used in the 100 mg / mL diazepam solution are described in Table 11-1 below. <000,0954> [Table 21]

[0256] One portion of the solution of Table 11-1 was prepared and subjected to a stability test at 25°C / 60% R.H. for 12 months. The following table measures the stability of this one portion at the initial, 3-month, 6-month, and 12-month time points.

[0257] [Table 22]

[0258] One portion of the solution of Table 11-1 was prepared and subjected to a stability test (early conditions) at 30°C / 65% R.H. for 12 months. The following table measures the stability of this one portion at the initial, 1-month, and 12-month time points.

[0259] [Table 23]

[0260] A single dose of the solution shown in Table 11-1 was prepared and subjected to stability testing (early conditions) at 40°C / 75%RH for 12 months. The following table measures the stability of this single dose at initial, 3-month, 6-month, and 12-month intervals.

[0261] [Table 24]

[0262] Suspension formulations are described in Table 11-2 below.

[0263] [Table 25]

[0264] The single-dose suspensions shown in Table 11-2 were prepared and subjected to stability testing at 25°C / 60%RH for 3 months. The following table measures the stability of this single dose at initial and 3-month intervals.

[0265] [Table 26]

[0266] A single-batch suspension from Table 11-2 was prepared and subjected to stability testing (early conditions) at 30°C / 65% RH for one month. The following table measures the stability of this batch at initial and one month.

[0267] [Table 27]

[0268] The single-dose suspensions shown in Table 11-2 were prepared and subjected to stability testing (early conditions) at 40°C / 75% RH for 3 months. The following table measures the stability of this single dose at initial, 1-month, and 3-month intervals.

[0269] [Table 28]

[0270] Three period, three treatments, six sequences, and a randomized crossover study were conducted in healthy volunteers. For each dose, each volunteer remained stationary for 12 hours prior to each administration and for 24 hours after pharmacokinetic sampling was collected. The 100 μL single-dose pharmaceutical compositions described in Tables 11-1 and 11-2 were administered to each volunteer as one 100 μL spray into the left nostril. Pharmacokinetic samples were collected at 22 time points over 10 days (PK time points: 2.5, 5, 10, 15, 20, 30, and 45 minutes, 1, 1.5, 2, 4, 12, 24, 36, 48, 72, 96, 144, 192, and 240 hours after each administration). No serious adverse events were observed. PK data were compared to those obtained with 5 mg of diazepam administered intravenously. The PK data is summarized in Table 11-3 and Figure 1-3.

[0271] The solutions in Table 11-1 and the suspensions in Table 11-2 were found to be sufficiently tolerable to only the reported mild adverse events. The solutions in Table 11-1 were further found to have similar bioavailability to intravenous administration of diazepam (96% of iv). The nasal formulations in Table 11-1 showed a Tmax of 1.5 hours and a Cmax of approximately 272 nanograms / mL. These results are comparable to those reported in the literature for commercially available diazepam gel (Diastat®).

[0272] Solutions similar to those described in Table 11-1 include diazepam (5-15% (w / v)), dodecyl maltoside (0.01-1% (w / v)), vitamin E (45-65% (w / v)), ethanol (10-25% (w / v)), and benzyl alcohol (5-15% (w / v)); diazepam (9-11% (w / v)), dodecyl maltoside (0.1-0.5% (w / v)), vitamin E (50-60%). It can be prepared to consist of %(w / v)), ethanol (15-22.5%(w / v)), and benzyl alcohol (7.5-12.5%(w / v)); or diazepam (10%(w / v)), dodecyl maltoside (0.15-0.3%(w / v)), vitamin E (50-60%(w / v)), ethanol (17-20%(w / v)), and benzyl alcohol (10-12%(w / v)).

[0273] Solutions similar to those described in Table 11-1 achieve bioavailability of approximately 80–125% of the bioavailability achieved by the same benzodiazepine administered intravenously, for example, approximately 90–110% of the bioavailability achieved by the same benzodiazepine administered intravenously, or approximately 92.5–107.5% of the bioavailability achieved by the same benzodiazepine administered intravenously. Such solutions may be used in methods of treating patients with benzodiazepine-treated diseases such as seizures, epileptic seizures and / or sudden seizures. In some embodiments, the solutions described herein may be used to treat diseases such as those treated with Diastat® diazepam gel.

[0274] A summary of the pharmacokinetic data obtained for diazepam in solution and suspension forms is shown below in Table 11-3.

[0275] [Table 29]

[0276] The data collected in the study are further illustrated in Figures 1-3. Table 1 is a uniformly scaled plot of the arithmetic mean of plasma diazepam concentrations after intranasal (IN) administration of 10 mg of diazepam as a suspension (Table 11-2) and after IN administration of 10 mg of diazepam as a solution (Table 11-1), compared to intravenous (IV) administration of 5 mg of diazepam (Table 11-1). Figure 2 is a semi-logarithmic plot of the same data shown in Figure 1. Figure 3 shows the first 24 hours of data from Figure 1 on a uniform scale.

[0277] Preferred embodiments of the present invention are shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided only as examples. It will be understood that numerous modifications, changes, and substitutions are possible without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used in carrying out the invention. The following claims define the scope of the present invention, and methods and structures within the scope of these claims and their equivalents are intended to be included thereby.

Claims

1. A pharmaceutically acceptable formulation for administration to one or more nasal mucosa of a patient, (a) Benzodiazepine drugs, (b) One or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in amounts ranging from approximately 30% to approximately 95% (w / w), (c) One or more alcohols or glycols, or any combination thereof, in amounts ranging from approximately 10% to approximately 70% (w / w), and (d) alkyl glycoside, A drug solution for nasal administration consisting of the following components.

2. The drug solution according to claim 1, characterized in that the benzodiazepine drug is dissolved in about 30% to about 95% (w / w) of one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, and in about 10% to about 70% (w / w) of one or more alcohols or glycols, or any combination thereof.

3. The drug solution according to claim 2, characterized in that the benzodiazepine drug is selected from the group consisting of alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, chlorazepam, demoxazepam, diazepam, flumazenil, flurazepam, harazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, any pharmaceutically acceptable salt thereof, and any combination thereof.

4. The drug solution according to claim 3, characterized in that the benzodiazepine drug is diazepam or a pharmaceutically acceptable salt thereof.

5. The drug solution according to claim 1, characterized in that it contains about 1 to about 20% (w / v) of benzodiazepines.

6. The drug solution according to claim 5, characterized in that it contains about 1 to about 20% (w / v) of diazepam.

7. The pharmaceutical solution according to claim 1, characterized in that one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocofersolan, any isomer thereof, any ester thereof, any analog or derivative thereof, and any combination thereof.

8. The pharmaceutical solution according to claim 1, characterized in that one or more alcohols are selected from the group consisting of ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomer thereof, or any combination thereof.

9. The drug solution according to claim 1, characterized in that it contains two or more alcohols.

10. The pharmaceutical solution according to claim 1, characterized in that it contains ethanol (1-25% (w / v)) and benzyl alcohol (1-25% (w / v)).

11. The pharmaceutical solution according to claim 1, characterized in that it contains ethanol (10-22.5% (w / v)) and benzyl alcohol (7.5-12.5% ​​(w / v)).

12. The drug solution according to claim 11, characterized in that the benzodiazepine is present in the drug solution at a concentration of about 20 mg / mL to about 200 mg / mL.

13. The pharmaceutical solution according to claim 1, characterized in that one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, is present in an amount of about 45% to about 85% (w / w).

14. The pharmaceutical solution according to claim 13, characterized in that one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, is present in an amount of about 50% to about 75% (w / w).

15. The pharmaceutical solution according to claim 1, characterized in that one or more alcohols or glycols, or any combination thereof, are present in an amount of about 15% to about 55% (w / w).

16. The pharmaceutical solution according to claim 15, characterized in that one or more alcohols or glycols, or any combination thereof, are present in an amount of about 25% to about 40% (w / w).

17. The drug solution according to claim 1, characterized by comprising diazepam (5-15% (w / v)), alkyl glycoside (0.01-1% (w / v)), vitamin E (45-65% (w / v)), ethanol (10-25% (w / v)), and benzyl alcohol (5-15% (w / v)).

18. The pharmaceutical solution according to claim 1, characterized in that a pharmaceutically acceptable formulation contains at least about 0.01% (w / w) of an alkyl glycoside.

19. The pharmaceutical solution according to claim 18, characterized in that the pharmaceutically acceptable formulation contains about 0.01% to 1% (w / w) of an alkyl glycoside such as dodecyl maltoside.

20. The pharmaceutical solution according to claim 1, characterized in that it essentially consists of diazepam, vitamin E, ethanol, benzyl alcohol, and dodecyl maltoside.

21. The drug solution according to claim 20, characterized by comprising diazepam, vitamin E, ethanol, benzyl alcohol, and dodecyl maltoside.

22. The drug solution according to claim 21, characterized by comprising approximately 56.47% (w / v) vitamin E, approximately 10.5% (w / v) benzyl alcohol, approximately 10% (w / v) diazepam, approximately 0.25% (w / v) dodecyl maltoside, and a sufficient amount of anhydrous ethanol.

23. A method for treating patients with diseases treatable with benzodiazepine drugs, The aforementioned method, A method characterized by comprising the step of administering a drug solution for intranasal administration to one or more nasal mucosa of a patient, comprising about 30% to about 95% (w / w) of a benzodiazepine drug, one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, about 10% to about 70% (w / w) of one or more alcohols or glycols, or any combination thereof, and an alkyl glycoside.

24. The method according to 23, characterized in that the benzodiazepine drug is dissolved in about 30% to about 95% (w / w) of one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, and in about 10% to about 70% (w / w) of one or more alcohols or glycols, or any combination thereof.

25. The method according to 24, characterized in that the natural or synthetic tocopherol or tocotrienol is vitamin E.

26. The method according to 23, characterized in that the benzodiazepine drug is selected from the group consisting of alprazolam, brotizolam, chlordiazepoxide, clobazam, clonazepam, chlorazepam, demoxazepam, diazepam, flumazenil, flurazepam, harazepam, midazolam, nordazepam, medazepam, nitrazepam, oxazepam, lorazepam, prazepam, quazepam, triazolam, temazepam, loprazolam, or any pharmaceutically acceptable salt thereof, and any combination thereof.

27. The method according to 26, characterized in that the benzodiazepine drug is diazepam or a pharmaceutically acceptable salt thereof.

28. The method according to 23, characterized in that the drug solution contains about 1 to about 20% (w / v) of benzodiazepines.

29. The method according to 28, characterized in that the drug solution contains about 1 to about 20% (w / v) of diazepam.

30. The method according to 23, characterized in that one or more natural or synthetic tocopherols or tocotrienols are selected from the group consisting of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol, δ-tocotrienol, tocophersolane, any isomer thereof, any ester thereof, any analog or derivative thereof, and any combination thereof.

31. The method according to 23, characterized in that one or more alcohols are selected from the group consisting of ethanol, propyl alcohol, butyl alcohol, pentanol, benzyl alcohol, any isomer thereof, and any combination thereof.

32. The method according to 23, characterized in that the drug solution contains two or more alcohols.

33. The method according to 23, characterized in that the drug solution contains ethanol (1-25% (w / v)) and benzyl alcohol (1-25% (w / v)).

34. The method according to 33, characterized in that the benzodiazepine drug is present in the drug solution at a concentration of about 10 mg / mL to about 250 mg / mL.

35. The method according to 34, characterized in that the benzodiazepine drug is present in the drug solution at a concentration of about 20 mg / mL to about 50 mg / mL.

36. The method according to 23, characterized in that the drug solution contains one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 45% to about 85% (w / w).

37. The method according to 36, characterized in that the drug solution contains one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, in an amount of about 60% to about 75% (w / w).

38. The method according to 23, characterized in that the drug solution contains one or more alcohols or glycols, or any combination thereof, in an amount of about 15% to about 55% (w / w).

39. The method according to 38, characterized in that the drug solution contains one or more alcohols or glycols, or any combination thereof, in an amount of about 25% to about 40% (w / w).

40. The method according to 23, characterized in that the drug solution comprises ethanol (10-22.5% (w / v)) and benzyl alcohol (7.5-12.5% ​​(w / v)).

41. The method according to 23, characterized in that the drug solution is a pharmaceutically acceptable spray formulation.

42. The method according to 41, characterized in that the benzodiazepine is administered in a therapeutically effective dose of about 1 mg to about 20 mg.

43. The method according to 42, characterized in that the drug solvent is a pharmaceutically acceptable spray formulation having a volume of about 10 μL to about 200 μL.

44. The method according to 43, characterized in that the administration of the drug solution includes the step of spraying at least a portion of a therapeutically effective amount of benzodiazepine into at least one nostril.

45. The method according to 43, characterized in that the administration of the drug solution includes the step of spraying at least a portion of a therapeutically effective amount of benzodiazepine into each nostril.

46. The method according to 45, characterized in that the administration of the drug solution includes the steps of spraying a first amount of the drug solution into a first nostril, spraying a second amount of the drug solution into a second nostril, and optionally, spraying a third amount of the drug solution into the first nostril after a predetermined time delay.

47. The method according to 46, characterized by comprising the step of optionally administering at least a fourth amount of drug solution into a second nostril after a predetermined time delay.

48. The method according to 46, characterized in that the nasal administration of the drug solution is initiated at any time before or after the onset of symptoms of the disease treatable by the drug solution.

49. The method according to 23, characterized in that the drug solution contains at least about 0.01% (w / w) of an alkyl glycoside.

50. The method according to 50, characterized in that the drug solution contains about 0.01% to 1% (w / w) of an alkyl glycoside.

51. The method according to 50, characterized in that the drug solution contains about 0.01% to 1% (w / w) of dodecyl maltoside.

52. The method according to 23, characterized in that the drug solution essentially consists of diazepam, vitamin E, ethanol, benzyl alcohol, and dodecyl maltoside.

53. The method according to 23, characterized in that the drug solution comprises diazepam, vitamin E, ethanol, benzyl alcohol, and dodecyl maltoside.

54. The method according to 23, characterized in that the drug solution consists of approximately 56.47% (w / v) vitamin E, approximately 10.5% (w / v) benzyl alcohol, approximately 10% (w / v) diazepam, approximately 0.25% (w / v) dodecyl maltoside, and a sufficient amount of anhydrous ethanol.

55. The method according to one of 23-54, characterized in that the drug solution comprises diazepam, alkyl glycoside, vitamin E, ethanol, and benzyl alcohol.

56. The method according to one of 23-54, characterized in that the drug solution comprises diazepam (5-15% (w / v)), dodecyl maltoside (0.01-1% (w / v)), vitamin E (45-65% (w / v)), ethanol (10-25% (w / v)), and benzyl alcohol (5-15% (w / v)).

57. The drug solution according to claim 17, characterized in that it comprises diazepam (5-15% (w / v)), dodecyl maltoside (0.01-1% (w / v)), vitamin E (45-65% (w / v)), ethanol (10-25% (w / v)), and benzyl alcohol (5-15% (w / v)).

58. The drug solution according to claim 17, characterized in that it comprises diazepam (9-11% (w / v)), dodecyl maltoside (0.1-0.5% (w / v)), vitamin E (50-60% (w / v)), ethanol (15-22.5% (w / v)), and benzyl alcohol (7.5-12.5% ​​(w / v)).

59. The drug solution according to claim 17, characterized by comprising diazepam (10% (w / v)), dodecyl maltoside (0.15-0.3% (w / v)), vitamin E (50-60% (w / v)), ethanol (17-20% (w / v)), and benzyl alcohol (10-12% (w / v)).

60. The method according to 23, characterized in that the drug solution comprises diazepam (5-15% (w / v)), dodecyl maltoside (0.01-1% (w / v)), vitamin E (45-65% (w / v)), ethanol (10-25% (w / v)), and benzyl alcohol (5-15% (w / v)).

61. The method according to 23, characterized in that the drug solution consists of diazepam (9-11% (w / v)), dodecyl maltoside (0.1-0.5% (w / v)), vitamin E (50-60% (w / v)), ethanol (15-22.5% (w / v)), and benzyl alcohol (7.5-12.5% ​​(w / v)).

62. The method according to 23, characterized in that the drug solution comprises diazepam (10% (w / v)), dodecyl maltoside (0.15-0.3% (w / v)), vitamin E (50-60% (w / v)), ethanol (17-20% (w / v)), and benzyl alcohol (10-12% (w / v)).

63. The method according to one of 23-56 or 60-62, characterized in that the procedure achieves a bioavailability of about 80-125% of the bioavailability achieved by the same benzodiazepine administered intravenously.

64. The method according to 63, characterized in that the treatment achieves a bioavailability of about 90–110% of the bioavailability achieved by the same benzodiazepine administered intravenously.

65. The method according to 64, characterized in that the procedure achieves a bioavailability of approximately 92.5–107.5% of the bioavailability obtained with the same benzodiazepine administered intravenously.

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