A novel method of vehicle modulated administration of an anticonvulsive agent to the mucous membranes of humans and animals is disclosed. The vehicle system is an aqueous pharmaceutical carrier comprising an aliphatic alcohol (10 80%) or a glycol (10 80%), and their combinations with a biological surfactant such as a bile salt or a lecithin. The pharmaceutical composition provides a means to control and promote the rate and extent of transmucosal permeation and absorption of the medicaments via a single and multiple administration. Nasal administration of the pharmaceutical preparation produces a high plasma concentration of the anticonvulsant nearly as fast as intravenous administration. Such compositions are particularly suitable for a prompt and timely medication of patients in the acute and/or emergency treatment of status epilepticus and other fever-induced seizures.

FIELD OF THE INVENTION

The present invention is directed to pharmaceutical compositions for transmucosal delivery of biologically active agents. More particularly, this invention relates to a novel method for controlling and promoting the rate and extent of transmucosal permeation and absorption of an anticonvulsive agent by coadministration of the medicament with a pharmaceutically acceptable co-solvent system comprising an aliphatic alcohol, a glycol, and water, and their combinations with a biological surfactant such as a bile salt or a lecithin. Even more particularly, this invention relates to the pharmaceutical compositions to provide a patient-acceptable transnasal anticonvulsive delivery system, which may be useful for the emergency management of status epilepticus and fever seizures in a prompt and convenient manner of administration.

BACKGROUND OF THE INVENTION

Status epilepticus is a neurological emergency in which mortality ranges from 3 35%. The major goal of treatment is rapid management of pathological seizure activity; the longer that the episode of status epilepticus is untreated, the more difficult it is to control and the greater the risk of permanent brain damage. Thus, critical to the management of the patient is a clear plan, involving prompt treatment with effective drugs in adequate doses having a proper pharmaceutical formulation as well as attention to hypoventilation and hypotension.

Currently several drug regimens have been proven to be applicable in treating status epilepticus. Diazepam and lorazepam are the most widely used benzodiazepines for this purpose. Intravenous administration of anticonvulsants is the most rapid way to suppress epileptic convulsions. However, other routes of administration may be highly desirable when intravenous administration is inconvenient and delaying, for instance, because of technical difficulties such as requirements for sterile equipment and skilled personnel, and because of the possible development of thrombophlebitis. In addition, intravenous medication is often associated with hypotension, cardiac dysrhythmia or central nervous system depression. In this regard Moolenaar [Moolenaar et al., Int. J. Pharm., 5: 127 137 (1986)] attempted to administer diazepam in humans via several other routes such as intramuscular injection, oral tablet and rectal solution. Only the rectal administration was found to provide a fairly rapid absorption and thus, it might be looked upon as an alternative route to IV injection. However, the rectal route is a very inconvenient way of drug administration particularly in emergency treatment. In U.S. Pat. No. 4,863,720 of Burghardt, a sublingual sprayable pharmaceutical preparation is disclosed, in which the active drug can be a benzodiazepine, optimally comprising polyethylene glycol (PEG) and requiring ethanol, di- and/or triglyceride of fatty acids and a pharmaceutically acceptable propellant gas.

More recently, it appears that the mucosal membrane of the nose offers a practical route of administration for therapeutic effect of many medicinal substances. Intranasal administration has the advantages that drugs may be administered readily and simply to achieve a systemic or localized effect, as required. However, the major problem associated with intranasal drug administration is the fact that most drug molecules diffuse poorly and slowly through the nasal mucosal membrane and thus the desired levels of the therapeutic agent cannot be achieved by means of simple transnasal administration. An additional constraint concerning nasal administration is that a small administration volume is needed; it is not generally possible to administer more than approximately 150 .mu.l per nostril; above this, the formulation will be drained out into the pharynx and swallowed. Therefore, a great need exists for solvent vehicles, in which the solubility of the drug is high and which, on the other hand, are non-irritating to the nasal mucosa. The intranasal absorption of drugs can be increased by coadministering a chemical adjuvant or permeation enhancers. For example, Lau and Slattery [Lau et al., Int. J. Pharm., 54: 171 174 (1989)] attempted to administer a benzodiazepine such as diazepam and lorazepam by dissolving these medicaments in a variety of solvents; triacetin, dimethylsulfoxide, PEG 400, Cremophor EL, Lipal-9-LA, isopropyl adipate and Azone. While many of the solvents dissolved diazepam and lorazepam in the desired concentrations, they were too irritatable to be used, when administered to the nose. Cremophor EL was found to be the least irritating for nasal mucosal tissue, but the nasal absorption in the use of this vehicle in humans was rather slow (T.sub.max.ident.1.4 hours) and the peak concentration was low relative to that observed after IV administration. In U.S. Pat. No. 4,950,664 of Rugby described the nasal administration of a benzodiazepine hypnotic in a pharmaceutically acceptable nasal carrier. The carrier may be an aqueous saline solution, an alcohol, a glycol, a glycol ether or mixtures thereof. The results of pharmacokinetic studies in dogs showed that the time to maximum plasma concentration for triazolam was achieved at 18 minutes after the nasal administration, while an effective treatment within 5 minutes is considered to be an attractive goal. Bechgaard and Hjortkjer [Bechgaard et al., J. Pharm. Pharmacol., 49: 747 750 (1997)] described the use of pure organic solvents such as glycofurol and tetraethyleneglycol, and their combinations as carriers for nasal delivery of diazepam. The absolute bioavailability, measured during the first 30 minutes, after the nasal administration, was 49 62% for the most promising carrier systems examined. In PCT WO 95/31217, Dumex described the use of a pharmaceutical emulsion preparation based on tocopherol and its derivatives for intranasal administration of biologically active compounds including benzodiazepines.

SUMMARY OF THE INVENTION

The present invention is a novel method of vehicle modulated administration of an anticonvulsive agent to the mucous membranes of humans and animals. The vehicle system is an aqueous pharmaceutical carrier comprising an aliphatic alcohol or a glycol and their combinations with a biological surfactant such as a bile salt or a lecithin.

An objective of the present invention is to provide a pharmaceutically acceptable carrier system which is capable of enhancing the transmucosal permeation and absorption of an anticonvulsive agent. The ingredients used in the pharmaceutical composition are preferably those of GRAS materials (generally recognized as safe), so there are no major toxicity issues of concern. Another objective of the present invention is to provide a method of controlling the transmucosal delivery of an anticonvulsant at an appropriately adjusted rate so as to achieve an optimum therapeutic effect, while avoiding or reducing adverse side effects. Such compositions are particularly suitable for intranasal administration of the medicaments in the acute treatment of status epilepticus and fever seizures.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, a certain aqueous co-solvent system comprising one aliphatic alcohol, one glycol and a biological surfactant provides a rate-controlled and enhanced transnasal delivery of an anticonvulsive agent. The alcohol of the present invention is selected from C.sub.1 to C.sub.5 aliphatic alcohols; a glycol is selected from propylene glycol, polyethylene glycol (PEG) 200, PEG 300 and PEG 400, and PEG 600; and a biological surfactant is selected from bile salts such as sodium cholate, sodium deoxycholate, sodium taurocholate, sodium glycocholate, and sodium ursodeoxycholate or a lecithin such as lysophosphotidylcholine, dipalmitoylphosphotidylcholin, distearoylphosphotidylcholin, dipalmitoylphosphotidyl-ethanolamine, and dipalmitoylphosphotidylglycerol. The above-described compositions can be used for medicinal preparations comprising anticonvulsive agents applicable to the mucosal membranes of humans and animals. More specifically, these compositions are ones, which comprise a benzodiazepine such as diazepam, clonazepam, and lorazepam, and a mono-carbamate based new anticonvulsive compound, (S)-2-carbamoyloxyl-1-o-chlorophenylethanol represented by the following formula:

##STR00001## adapted for intranasal administration in a solution, suspension, gel or other useful nasal formulation. These nasal compositions may be employed for any of the known therapeutic purposes for which such anticonvulsants are known including phenytoins (phenytoin, mephenytoin and ethotoin), barbiturates (phenobarbital, mephobarbital, and primidone), iminostilbenes (carbamazepine), succinimides (ethosuximide), valproic acid, oxazolidinediones (trimethadione) and other antiseizure agents (gabapentin, lamotrigine, acetazolamide, felbamate, and .gamma.-vinyl GABA). The utilization of an intranasal formulation of the anticonvulsant greatly facilitates administration. As compared with parenteral administration, for example, a simple sprayer, dropper or nebulizer will suffice for prompt and convenient delivery of the medicaments, in particular, for the emergency treatment of acute convulsive attack phenomena of epilepsy. From a clinical point of view, intranasal administration often provides an improved duration of anticonvulsive effect. By the present invention, the therapeutic effect, in terms of onset, intensity, and duration, can be more efficiently and accurately controlled by varying the proportion of aliphatic alcohol and glycol in the vehicle and by a single-dose and/or multiple-dose administration of the preparation of the invention. Although this invention has been described with respect to an anticonvulsant as a model compound, it is understood that this invention is also applicable to the other biologically active agents that are applicable to the mucosal membranes of humans and animals.
 

Claim 1 of 3 Claims

1. A pharmaceutical composition for the administration of diazepam to the nasal mucosal membranes of a mammal in a rate-controlled manner of absorption comprising diazepam and an aqueous vehicle comprising: about 60% by volume of an aliphatic alcohol having from 1 to 5 carbon atoms; about 30% by volume of a glycol selected from the group consisting of propylene glycol, polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and polyethylene glycol 600; about 1% by weight of a biological surfactant selected from the group consisting of a bile salt selected from the group consisting of sodium cholate, sodium deoxycholate, sodium glycocholate, sodium taurocholate, and sodium ursodeoxycholate and a lecithin selected from the group consisting of lysophosphotidylcholine, dipalmitoylphosphotidylcholin, distearoylphosphotidylcholin, dipalmitoylphosphotidylethanolamine, and dipalmitoylphosphotidylglycerol; and about 10% by volume of water.
 

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