United States Patent (19) 11 Patent Number: 4,950,664 Goldberg 45 Date of Patent: Aug
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United States Patent (19) 11 Patent Number: 4,950,664 Goldberg 45 Date of Patent: Aug. 21, 1990 (54) NASAL ADMINISTRATION OF (56) References Cited 4,244,945 l/1981 Wilkinson ........................... 424/177 75) Inventor: Arthur H. Goldberg, Montclair, N.J. 4,284,648 8/1981 Hussain et al. ...................... 424/330 4,786,647 11/1988 Simpkins et al. ................... 514/355 73 Assignee: Rugby-Darby Group Companies, Inc., 4,789,667 12/1988 Makino et al. ...................... 514/16 Rockville Centre, N.Y. Primary Examiner-John Kight, III Assistant Examiner-Carlos Azpura 21 Appl. No.: 245,031 Attorney, Agent, or Firm-Philip M. French 22 Filed: Sep. 16, 1988 57 ABSTRACT Nasal administration of benzodiazepines is described as 51) Int. Cl. ....................... A61K9/08; A61K 47/22; providing improved therapeutic effects as compared to C07D 243/10; C07D 243/20 conventional delivery techniques. The compositions 52 U.S. Cl. .................................... 514/219; 514/159; comprise a benzodiazepine hypnotic in a pharmaceuti 514/161; 514/218 cally acceptable nasal carrier. 58 Field of Search ................ 424/177, 260; 514/159, 514/161, 218, 219 16 Claims, 3 Drawing Sheets Ca MeAN (ser) PASMa Concentration of 4 Dogs (Po vs Nasal) o Pe.Nissal o O. O 4o eo ed to to 40 (as so lo to Ao to zero aco so so so tre (MIN) U.S. Patent Aug. 21, 1990 Sheet 1 of 3 4,950,664 (NIIN)31-IL (hu/en onco livnozviewlisvg U.S. Patent Aug. 21, 1990 Sheet 3 of 3 4,950,664 [NivD=LJIL 8 O (l/en) orio live32veson visv 4,950,664 2 NASALADMNSTRATION OF SUMMARY OF INVENTION BENZODIAZEPINE HYPNOTICS It has been discovered that certain known hypnotic drugs can normally be effectively administered to mam BACKGROUND OF THE INVENTION 5 mals, and especially to humans, in novel compositions. More specifically, these compositions are ones which FIELD OF THE INVENTION contain a benzodiazepine hypnotic adapted for nasal The present invention relates to a novel form of cer administration and comprise a solution, suspension, tain hypnotic drugs and to their administration to mam ointment, gel or other useful nasal form. These nasal mals. They may be employed for any of the conven 10 compositions may be employed for any of the known tional purposes for which hypnotics are known, but therapeutic purposes for which such hypnotics are especially for improving sleep. known. Hypnotic drugs are a class of therapeutic agents The utilization of a nasal form of these hypnotic which are commonly employed to induce and/or to drugs greatly facilitates administration. As compared prolong sleep. They may also be utilized to alleviate 5 with parenteral administration, for example, a simple sleep disorders. Terms such as sedative, anti-anxiety aerosol container or a dropper will suffice for delivery. agent, minor tranquilizer and anxiolytic are sometimes From a therapeutic standpoint, nasal administration used somewhat interchangeably for such drugs because, often provides a hypnotic effect of improved duration. in appropriate dosages, these hypnotics can produce It may also be more efficiently and precisely controlled similar effects. 20 than through conventional means and permits a more There are a wide variety of hypnotic drugs. This term rapid onset of activity. These and additional advantages includes both barbiturates and non-barbiturates. Typical of the present invention will become evident from the barbiturate hypnotics are aprobarbital and pentobarbi description and examples which follow. tal. Non-barbiturates recognized for their hypnotic ac tivity include benzodiazepines; antihistamines having 25 BRIEF DESCRIPTION OF THE DRAWINGS pronounced side effects such as diphenhydramine; sero The invention and particularly the Examples and tonin initiators such as L-tryptophane; and various Tables, will be more clearly understood when consid other drugs including ethinamate, chloral hydrate, eth ered with the accompanying drawings in which: chlorvynol, methyprylon and glutethimide. Their hyp FIG. 1 is a graphic depiction of the comparative notic effect is commonly attributed to a neurological 30 results of Example l; mechanism involving depression of the central nervous FIG. 2 is a graphic depiction of the comparative system. That effect is also frequently accompanied by a results of Example 2; and mild reduction in such physiological functions as blood FIG. 3 is a graphic depiction of the comparative pressure and respiration. results of Example 3. 35 PRIOR ART DETAILED DESCRIPTION OF THE Numerous hypnotic drugs are already known. Many, INVENTION for example, are listed in the Physicians Desk Reference Any benzodiazepine drug capable of exhibiting a (PDR) published by Medical Economics Company, hypnotic activity may be employed in accordance with Inc. They are widely used therapeutically to improve the present invention. These particularly include diaze sleep. Administration is generally performed either pam, triazolam, midazolam, temazepam and fluraze parenterally or, more usually, orally by means of pills, pam; although other, less common benzodiazepines may tablets and capsules. Their various uses are likewise also be utilized. well known. Any pharmaceutically acceptable form of these ben Unfortunately, these drugs commonly exhibit a num 45 Zodiazepine drugs may be utilized in accordance with ber of drawbacks when conventionally administered. the present invention. Generally the selected therapeu Some have undesirable side effects. Many are ineffi tic agent is provided in the chemical form which has ciently and variably absorbed from their current dosage previously been found most efficacious for oral or par forms. Further, the onset of their pharmacological ac enteral delivery. Most commonly, this comprises either tivity is often delayed and/or the duration of that activ SO the free base or a pharmaceutically acceptable salt of ity limited pursuant to ordinary oral, subcutaneous and the hypnotic agent. Aor intra-muscular administration. A peculiar facet of the present invention lies in the Unlike the broad applicability of conventional routes discovery of the uniqueness of this class of hypnotics. of administration, the nasal delivery of therapeutic Despite the recognized equivalence of benzodiazepines agents is a relatively recently discovered technique. It is 55 with other subclasses of hypnotics, they do not provide also recognized only for specific agents. Representative the many advantages enjoyed through the nasal admin disclosures of nasal administration of drugs include: istration of benzodiazepines. In fact, it has been discov U.S. Pat. No. 4,454,140 of Goldberg et al; U.S. Pat. ered that many of these non-benzodiazepine hypnotics No's. 4,428,883; 4,284,648; and 4,394,390 of Hussain and fail to exhibit that therapeutic activity when they are U.S. Pat. No. 4,624,965 of Wenig. administered nasally, instead of by conventional While nasal administration has become an accepted method. route of administration, the foregoing disclosures limit In the formulation of the present hypnotic composi that mode of delivery to the specific drugs described. tions, a relatively water soluble form of the benzodiaze Moreover, it has been observed that many therapeutic pine is usually employed. Use of a fully dissolved form agents cannot be usefully administered by this unusual 65 of the benzodiazepine maximizes its immediate effect. route. Consequently, nasal administration remains a Compositions containing the therapeutic drug in a form technique for which applicability is far from universal having a limited solubility may be employed where and the results unpredictable. sustained release is desired. These compositions, in 4,950,664 3 4. which the therapeutic drug is not totally solubilized in other methods of administration, for example, oral or its dosage form provide a prolonged therapeutic activ rectal. ity. For this purpose, a long chain carboxylic acid salt of As a practical matter, the present therapeutic compo the desired drug is often preferred. The acid portion of sitions will normally be prepared in dosage unit forms to the salt preferably contains from about 10 to about 30 contain a systemic, therapeutically effective amount of carbon atoms. Such salts, including stearates, palmitates the selected hypnotic drug. This can be similar to con and the like, are readily synthesized by known tech ventional dosage amounts of the drug. The drug unit is niques. normally less than 0.2 ml, optimally from 0.05 to 0.1 m1 The dosage forms of the present invention addition in volume. Desirably, nasal dosage units are prepared ally comprise a pharmaceutically acceptable nasal car 10 having a lesser amount of drug, preferably from one rier. Any of the benzodiazepines can be conveniently half to one-tenth of the amount of therapeutic agent administered in such a carrier. These compositions com employed for conventional routes of administration. prise a systemic, therapeutically effective amount of the This is made possible through the improved blood con desired drug together with a pharmaceutically accept centration levels for benzodiazepines which have been able nasal carrier therefore. 15 observed to result from nasal administration. These are Nasal carriers suitable in accordance with the present the most preferred types of compositions. invention will be apparent to those skilled in the art of The present compositions are especially useful for nasal pharmaceutical formulations. Exemplary nasal improving sleep. They may be utilized to more rapidly carriers include saline solutions;