Pharmaceutical compositions and methods for anesthesiological applications

Abstract

Pharmaceutical compositions and methods for inducing conscious sedation using such compositions are described, the compositions including a benzodiazepine-based compound, an NMDA antagonist, and optionally a β-blocker, antiemetic, an NSAID, and/or an antihistamine medication. Compositions may be incorporated into vehicles for extended release. Methods for fabricating the compositions and using them for anesthesiological applications are also described.

1 . A pharmaceutical composition, comprising a therapeutically effective quantity of a pharmaceutical formulation incorporated into a vehicle, wherein the pharmaceutical composition comprises:
 (a) a therapeutically effective quantity of at least one pharmaceutically active compound of a first class or at least one pharmaceutically active compound of a second class;   (b) a therapeutically effective quantity of a pharmaceutically active compound of a third class selected from the group consisting of β-blockers, antiemetic medicaments, NSAIDs, antihistamines, α-2-adrenergic agonists, pain relievers and combinations thereof, or pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof; and   (c) optionally, a pharmaceutically acceptable excipient,   wherein:
 (i) the pharmaceutically active compound of the first class is selected from the group consisting of midazolam, diazepam, lorazepam, flunitrazepam, alprazolam, chlordiazepoxide, clonazepam and clorazepate, and pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof, optionally in combination with a non-benzodiazepine compound selected from the group consisting of eszopiclone, ramelteon, zolpidem, and zaleplon; and 
 (ii) the pharmaceutically active compound of the second class is selected from the group consisting of ketamine, dextrorphan, etomidate, methadone, memantine, amantadine, dextromethorphan, and pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof; 
 with the proviso that the vehicle is optionally configured to provide extended release of the pharmaceutical formulation and is selected from the group consisting of extended release capsules ensconcing the pharmaceutical formulation and a matrix polymer structure holding the pharmaceutical formulation that is embedded into the matrix; and 
 with the further proviso that when the pharmaceutical composition includes the pharmaceutically active compounds of the first class, any pharmaceutically active compounds of the second class are absent from the composition, or when the pharmaceutical composition includes the pharmaceutically active compounds of the second class, any pharmaceutically active compounds of the first class are absent from the composition. 
   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the antiemetic medicament is selected from the group consisting of ondansetron, dolasetron, granisetron, palonosetron, promethazine, imenhydrinate, and meclizine. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the β-blocker, the α-2-adrenergic agonist or the pain reliever is selected from the group consisting of metoprolol, propranolol, acebutolol, nadolol, atenolol, betaxolol, esmolol, bisoprolol fumarate, carvedilol, nebivolol, penbutolol, timolol, sotalol, dexmedetomidine hydrochloride, and acetaminophen. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the NSAID is selected from the group consisting of bromfenac, ketorolac, etodolac, sulindac, diclofenac, aceclofenac, nepafenac, tolmetin, indomethacin, nabumetone, ketoprofen, dexketoprofen, ibuprofen, flurbiprofen, dexibuprofen, fenoprofen, loxoprofen, oxaprozin, naproxen, aspirin, salicylic acid, diflunisal, salsalate, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, meloxicam, piroxicam, ternoxicam, droxicam, lornoxicam, isoxicam, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib, nimesulide, clonixin, and licofelone. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the antihistamine is selected from the group consisting of hydroxyzine pamoate, hydroxyzine hydrochloride, diphenhydramine hydrochloride, meclizine, chlorpheniramine, clemastine, promethazine, and prochlorperazine. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutical formulation further comprises a therapeutically effective quantity of a receptor antagonist to benzodiazepines. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the receptor antagonist is flumazenil. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically active compound of the first class is midazolam, the pharmaceutically active compound of the second class is ketamine and the pharmaceutically active compound of the third class is metoprolol. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the pharmaceutically active compound of the first class is midazolam, the pharmaceutically active compound of the second class is ketamine and the pharmaceutically active compound of the third class is ondansetron. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the vehicle is adapted to allow the release of the pharmaceutical formulation in a period of time between about 12 hours and about 20 hours. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the vehicle comprises a polymer selected from the group consisting of esters of cellulose, poly(lactic-co-glycolic acid), polylactic acid, polyglycolide, dextrin, polyacetals, poly(N-(2-hydroxypropyl)methacrylamide), polycaprolactone, and poly-3-hydroxybutyrate. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the esters of cellulose are selected from the group consisting of methyl cellulose and hydroxypropyl methyl cellulose. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein the excipient is selected from the group consisting of gelatin, sodium saccharin, stevioside, peppermint oil, cherry flavor, lemon oil, raspberry flavor and combinations thereof. 
     
     
         14 . A method for providing an extended release pharmaceutical formulation to a patient in need thereof, the method comprising:
 (a) preparing the pharmaceutical formulation of  claim 1 ;   (b) incorporating the prepared pharmaceutical formulation into an extended release vehicle to form an extended release formulation; and   (c) orally administering the extended release formulation to a patient in need thereof,   
       thereby providing the extended release pharmaceutical formulation to the patient.