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JP-2026076153-A - Administration of benzodiazepine compositions

JP2026076153AJP 2026076153 AJP2026076153 AJP 2026076153AJP-2026076153-A

Abstract

[Problem] To provide 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. [Selection Diagram] Figure 1

Inventors

  • カート，スティーブ
  • メデイロス，デイビッド
  • グヴォーズ，ギャリー，トーマス
  • ロクスレー，アンドリュー
  • ミッチニック，マーク
  • ヘイル，デイビッド
  • マッジオ，エドワード，ティー．

Assignees

  • ニューレリス、インク．

Dates

Publication Date
20260511
Application Date
20251223
Priority Date
20110614

Claims (20)

  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 an amount of approximately 10% to approximately 70% (w/w), and (d) alkyl glycosides, 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 approximately 30% to approximately 95% (w/w) of one or more natural or synthetic tocopherols or tocotrienols, or any combination thereof, and approximately 10% to approximately 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 by containing approximately 1 to approximately 20% (w/v) of benzodiazepines.
  6. The drug solution according to claim 5, characterized by containing approximately 1 to approximately 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 pharmaceutical solution according to claim 1, characterized by containing two or more alcohols.
  10. The pharmaceutical solution according to claim 1, characterized by containing ethanol (1-25% (w/v)) and benzyl alcohol (1-25% (w/v)).
  11. The pharmaceutical solution according to claim 1, characterized by containing 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 approximately 20 mg/mL to approximately 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 approximately 15% to approximately 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 approximately 25% to approximately 40% (w/w).
  17. The pharmaceutical 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 pharmaceutically acceptable formulation is characterized by containing at least about 0.01% (w/w) of an alkyl glycoside, as described in claim 1.
  19. The pharmaceutically acceptable formulation is characterized by containing approximately 0.01% to 1% (w/w) of an alkyl glycoside such as dodecyl maltoside, as described in claim 18.
  20. The pharmaceutical solution according to claim 1, characterized in that it essentially consists of diazepam, vitamin E, ethanol, benzyl alcohol, and dodecyl maltoside.

Description

<Cross-references to related applications> This application claims priority to U.S. Provisional Application No. 61/497,017, filed on 14 June 2011, and U.S. Provisional Application No. 61/570,110, filed on 13 December 2011, both of which are incorporated herein by reference in their entirety. This application relates to the intranasal administration of benzodiazepine drugs and combinations thereof. To name just a few, the benzodiazepine family includes drugs such as diazepam, lorazepam, and midazolam. Drugs within this family have been observed to possess sedative, tranquilizing, and muscle-relaxing properties. They are often classified as anxiolytics and skeletal muscle relaxants. They are considered useful in preventing, treating, or improving symptoms of anxiety, insomnia, agitation, seizures (including those caused by epilepsy), muscle spasms and rigidity, withdrawal from the continued abuse of central nervous system depressants, and symptoms of exposure to nerve gases. Benzodiazepines are thought to act by binding to GABAA receptors in nerve cells, altering the shape of the receptors and making them more accessible to gamma-aminobutyric acid (GABA). GABA is an inhibitory neurotransmitter that, when bound to the GABAA receptor, promotes the influx of Cl- ions into the nerve cell to which the receptor binds. This increase in Cl- ions hyperpolarizes the nerve cell membrane, completely or substantially reducing the nerve cell's ability to carry action potentials. Targeting this receptor is particularly useful in treating many disorders, such as tetanus and epilepsy, which can result from too many action potentials traversing the nervous system. Current formulations of benzodiazepine drugs can be administered orally, rectally, or parenterally. The availability of these and other types of formulations is often significantly limited by solubility challenges. The oral route of administration may be considered suboptimal due to several drawbacks. For example, it may take more than one hour for orally administered benzodiazepine drugs to reach therapeutically relevant concentrations in plasma. Furthermore, significant amounts of the drug can be metabolized as it crosses the liver. Therefore, high doses may be required to achieve therapeutic plasma levels. Additionally, the seizure and muscle-spastic nature of benzodiazepines can make oral administration difficult for patients or caregivers, and caregivers may hesitate to put their hands in the patient's mouth. 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. Additionally, 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. Benzodiazepine suppository formulations can have a rapid onset of action. However, the difficulty with rectally administered drugs lies in their obvious impairment when administered by someone other than the patient's close acquaintances and the patient's professional medical donors. Several embodiments of the present invention may be further recognized by consideration of the accompanying drawings: 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.Table 11-2 shows a semi-logarithmic plot of the arithmetic mean plasma concentration of diazepam 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.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.This is a flowchart relating to one embodiment of the process for producing a diazepam solution according to the present invention.This is a flowchart relating to one embodiment of the process for producing a diazepam suspension according to the present invention. This specification provides pharmaceutical compositions of one or more benzodiazepine drugs and methods for using such pharmaceutical compositions. Such pharmaceutical compositions are administered intranasally. In some embodiments, the pharmaceutical composition comprises a benzodiazepine drug; one or more natural or synthetic tocopherols or tocotrienols, or