United States Patent:  RE36,744

Assignee:  Ribogene, Inc. (Hayward, CA)

Filed:  March 16, 1994

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.

DETAILED DESCRIPTION OF THE INVENTION

Any benzodiazepine drug capable of exhibiting a hypnotic activity may be employed in accordance with the present invention. These particularly include diazepam, triazolam, midazolam, temazepam and flurazepam; although other, less common benzodiazepines may also be utilized.

Any pharmaceutically acceptable form of these benzodiazepine drugs may be utilized in accordance with the present invention. Generally the selected therapeutic agent is provided in the chemical form which has previously been found most efficacious for oral or parenteral delivery. Most commonly, this comprises either the free base or a pharmaceutically acceptable salt of the hypnotic agent.

A peculiar facet of the present invention lies in the discovery of the uniqueness of this class of hypnotics. Despite the recognized equivalence of benzodiazepines with other subclasses of hypnotics, they do not provide the many advantages enjoyed through the nasal administration of benzodiazepines. In fact, it has been discovered that many of these non-benzodiazepine hypnotics fail to exhibit that therapeutic activity when they are administered nasally, instead of by conventional method.

In the formulation of the present hypnotic compositions, a relatively water soluble form of the benzodiazepine is usually employed. Use of a fully dissolved form of the benzodiazepine maximizes its immediate effect. Compositions containing the therapeutic drug in a form having a limited solubility may be employed where sustained release is desired. These compositions, in which the therapeutic drug is not totally solubilized in its dosage form provide a prolonged therapeutic activity. For this purpose, a long chain carboxylic acid salt of the desired drug is often preferred. The acid portion of the salt preferably contains from about 10 to about 30 carbon atoms. Such salts, including stearates, palmitates and the like, are readily synthesized by known techniques.

The dosage forms of the present invention additionally comprise a pharmaceutically acceptable nasal carrier. Any of the benzodiazepines can be conveniently administered in such a carrier. These compositions comprise a systemic, therapeutically effective amount of the desired drug together with a pharmaceutically acceptable nasal carrier therefore.

Nasal carriers suitable in accordance with the present invention will be apparent to those skilled in the art of nasal pharmaceutical formulations. Exemplary nasal carriers include saline solutions; alcohols such as ethanol; glycols such as propylene glycol; glycol ethers such as polyethylene glycol and combinations of the foregoing with water and/or one another. For still other examples, reference is made to the text entitled "REMINGTON'S PHARMACEUTICAL SCIENCES", 14th edition, 1970.

The choice of a suitable carrier in accordance with the present invention will depend on the exact nature of the particular nasal dosage form required. A therapeutic agent may, for example, be formulated into a nasal solution (for use as drops or as a spray), a nasal suspension, a nasal ointment, a nasal gel or any other nasal form. Preferred nasal dosage forms are solutions, suspensions and gels. These normally contain a major amount of water (preferably purified water) in addition to the active hypnotic ingredient. Minor amounts of other ingredients such as tonicity agents (e.g. NaCl) pH adjusters (e.g., a base such as NaOH), emulsifiers or dispersing agents, buffering agents, preservatives, wetting agents and jelling agents (e.g., methylcellulose) may also be present. Particularly preferred compositions contain various of the foregoing other ingredients so as to be isotonic and/or buffered to the same pH as blood serum.

The present compositions may be administered to any of the subjects recognized as being susceptible to benzodiazepine hypnotics. While therefore generally useful in treatment of a broad spectrum of mammals, the present invention is most desirably employed on human subjects.

The efficacy of a hypnotic drug is most clearly revealed by its concentration in the blood of the subject being treated. In general, hypnotic activity is dependent upon the bioavailability of therapeutic agent evidenced by that concentration. It is therefore particularly significant that the present nasal administration of benzodiazepines is characterized by a significantly faster onset and more pronounced blood concentration of hypnotic than conventional forms of administration. This insures an elevated and more constant hypnotic effect.

Those skilled in the art will be aware that a systemic, therapeutically effective amount of a particular benzodiazepine hypnotic will vary with the particular drug as well as the type, age, size, weight and general physical condition of the subject. The amount will also vary dependent upon the particular therapeutic effect desired. Typically the dosage level will be more similar to the expected dosage level for intravenous administration than to the dosage levels currently employed for other methods of administration, for example, oral or rectal.

As a practical matter, the present therapeutic compositions will normally be prepared in dosage unit forms to contain a systemic, therapeutically effective amount of the selected hypnotic drug. This can be similar to conventional dosage amounts of the drug. The drug unit is normally less than 0.2 ml, optimally from 0.05 to 0.1 ml in volume. Desirably, nasal dosage units are prepared having a lesser amount of drug, preferably from one-half to one-tenth of the amount of therapeutic agent employed for conventional routes of administration. This is made possible through the improved blood concentration levels for benzodiazepines which have been observed to result from nasal administration. These are the most preferred types of compositions.

The present compositions are especially useful for improving sleep. They may be utilized to more rapidly induce and/or to prolong sleep. This use is not, however, exclusive. The present invention may likewise be employed to enhance other known therapeutic utilities of benzodiazepines.

Claim 1 of 16 Claims

1. A composition for the administration of a hypnotic drug comprising a systemically effective amount of a benzodiazepine in a pharmaceutically acceptable aqueous nasal carrier.

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