Nasal administration of benzodiazepine hypnotics

a benzodiazepine and hypnotics technology, applied in the direction of biocide, heterocyclic compound active ingredients, aerosol delivery, etc., can solve the problems of inefficient many drugs exhibit a number of drawbacks, and many are often inefficiently and variably absorbed from current dosage forms, etc., to facilitate administration, improve duration, efficient and precisely control

Inactive Publication Date: 2000-06-20
QUESTCOR PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The utilization of a nasal form of these hypnotic drugs greatly facilitates administration. As compared with parenteral administration, for example, a simple aerosol container or a dropper will suffice for delivery. From a therapeutic standpoint, nasal administration often provides a hypnotic effect of improved duration. It may also be more efficiently and precisely controlled than through conventional means and permits a more rapid onset of activity. These and additional advantages of the present invention will become evident from the description and examples which follow.

Problems solved by technology

Unfortunately, these drugs commonly exhibit a number of drawbacks when conventionally administered.
Some have undesirable side effects.
Many are inefficiently and variably absorbed from their current dosage forms.
Further, the onset of their pharmacological activity is often delayed and / or the duration of that activity limited pursuant to ordinary oral, subcutaneous and / or intra-muscular administration.
While nasal administration has become an accepted route of administration, the foregoing disclosures limit that mode of delivery to the specific drugs described.
Moreover, it has been observed that many therapeutic agents cannot be usefully administered by this unusual route.
Consequently, nasal administration remains a technique for which applicability is far from universal and the results unpredictable.

Method used

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  • Nasal administration of benzodiazepine hypnotics

Examples

Experimental program
Comparison scheme
Effect test

example 1

In two comparative studies separated in time by over one week; four healthy male, 2-3 year old beagle dogs received oral and nasal doses of triazolam. They were fasted overnight before each study and food was withheld until the end of the experiment. They were restrained in a dog sling during the studies while blood (3 ml) was withdrawn from each dog through a cannula inserted into the cephalic vein.

Oral Administration Studies: Two 0.5 mg triazolam tablets were given to each dog with 50 ml of water. Blood samples were taken from the cephalic vein at 0 min before administration and 15, 30, 45, 60, 120, 180, 240, 300, 360 and 420 min after administration. The plasma samples were stored frozen until gas chromotographic assay for triazolam.

Nasal Administration Studies: Thirty milligrams of triazolam powder was dissolved in 5 ml of PEG 400 warmed at 55.degree.-60.degree. C. After the solution was cooled to room temperature, an equal volume of 1% methocel J5MS (Dow Chemical Company, Midla...

example 2

The efficacy of oral versus nasal administration of midazolam was examined using the methodology of Example 1, but modified to allow at least three weeks between studies.

Oral Administration Studies: Five mg equivalent of midazolam free base solution was given to each of four dogs with 50 ml of water. Blood samples were taken from the cephalic vein at 0 min before administration and 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 min after administration. The plasma samples were stored frozen until GC assay for midazolam.

Nasal Administration Studies: 55.6 milligrams of midazolam HCl powder was dissolved in 4 ml of distilled water. One ml of 7.5% methocel J5MS (Dow Chemical Company, Midland, Mich.) solution was mixed with the midazolam solution. Air bubbles generated during mixing were removed by centrifugation. The pH of the solution was 3.62.

Midazolam solution was sprayed, using a meter dose inhaler into both nostrils of the dogs. The dose given to each dog was 7.85, 7.89, 7.22, 5.61 mg...

example 3

The efficacy of oral versus nasal administration was examined using the methodology of Example 2.

Oral Administration Studies: Fifteen mg of flurazepam HCl solution was given to each dog with 50 ml of water. Blood samples were taken from the cephalic vein at 0 min before administration and at 15, 30, 45, 60, 120, 180, 240, 300, 360 min after administration. The plasma samples were stored frozen until GC assay for flurazepam.

Nasal Administration Studies: One hundred and twenty milligrams of flurazepam HCl powder was dissolved in 4 ml of distilled water. One ml of 7.5% methocel J5MS (Dow Chemical Company, Midland, Mich.) solution was mixed with the flurazepam solution. Air bubbles generated during mixing were eliminated by centrifugation. The pH of the solution was 1.82.

Flurazepam solution was sprayed into both nostrils of the dogs. The dose given to the dogs was 14.5, 12.4, 12.1 and 12.5 mg as flurazepam HCl. Blood sampling times were same as in the oral study. The plasma samples were...

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Abstract

Nasal administration of benzodiazepines is described as providing improved therapeutic effects as compared to conventional delivery techniques. The compositions comprise a benzodiazepine hypnotic in a pharmaceutically acceptable nasal carrier.

Description

BACKGROUND OF THE INVENTIONFIELD OF THE INVENTIONThe present invention relates to a novel form of certain hypnotic drugs and to their administration to mammals. They may be employed for any of the conventional purposes for which hypnotics are known, but especially for improving sleep.Hypnotic drugs are a class of therapeutic agents which are commonly employed to induce and / or to prolong sleep. They may also be utilized to alleviate sleep disorders. Terms such as sedative, anti-anxiety agent, minor tranquilizer and anxiolytic are sometimes used somewhat interchangeably for such drugs because, in appropriate dosages, these hypnotics can produce similar effects.There are a wide variety of hypnotic drugs. This term includes both barbiturates and non-barbiturates. Typical barbiturate hypnotics are aprobarbital and pentobarbital. Non-barbiturates recognized for their hypnotic activity include benzodiazepines; antihistamines having pronounced side effects such as diphenhydramine; serotonin...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K9/00A61K31/55
CPCA61K31/55A61K9/0043
Inventor GOLDBERG, ARTHUR H.
Owner QUESTCOR PHARMA
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