Transmucosal drug delivery system

Abstract

Disclosed are preparations and formulations of high thermodynamic activity lipophilic associations (LA), in which there is pairing between an ionizable pharmaceutical agent and a lipophilic species having ionic characteristics opposite to that of the pharmaceutical agent. Such lipophilic associations manifest high thermodynamic activity, as evidenced by their being predominantly in a liquid phase at room temperature or solvated in a lower-than-water dielectric solvent. Further the pharmaceutical agent being solubilized means that dissolution is not rate limiting to transmucosal absorption. This LA or LA-solvate is formulated into a low dielectric dosage form, from whence, upon the dosage form's hydration, the pharmaceutical agent is driven through the mucosal tissue and into systemic circulation. The invention therefore provides an enhanced transmucosal drug delivery system for ionizable pharmaceutical agents at or near physiological pH.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising:
 (a) an ionizable pharmaceutical agent hydrogen bonded or ion paired to one or more complementary lipophilic species, thereby forming a lipophilic association (LA), wherein the ionizable pharmaceutical agent possesses a basic functional group and the lipohilic species is oleic acid;   (b) a carrier wherein the carrier is a silica or a silicified microcrystalline cellulose and wherein the LA is adsorbed or absorbed to the carrier; and   (c) a water-soluble excipient;   wherein the pharmaceutical composition is formulated in a transmucosal dosage form and wherein said dosage form is a buccal tablet or sublingual tablet.   
     
     
         2 . A composition according to  claim 1  further comprising a solvent having a dielectric constant less than that of water, wherein the LA is solvated in the solvent to form a solubilized LA and wherein the solubilized LA is adsorbed or absorbed to the carrier. 
     
     
         3 . The composition according to  claim 2 , wherein the solvent is ethanol, ethyl acetate, isopropyl alcohol, triacetin, triethyl citrate, tributyl citrate, a polyethylene glycol, propylene glycol, bisabolol, glycerin, mineral oil, ethyl oleate, a fatty acid ester, squalane, an animal oil, a vegetable oil, a hydrogenated vegetable oil, isopropyl myristate, isopropyl palmitate, glycofurol, a terpene, an essential oil, an alcohol, a polyol, or a silicone fluid. 
     
     
         4 . The composition according to  claim 1 , wherein the water-soluble excipient is a sugar, polyol, alcohol, saccharide, polysaccharide, glycerin, propylene glycol, ethanol, isopropyl alcohol, ethyl acetate, triacetin, triethyl citrate, tributyl citrate, a dextrate, dextrin, dextrose, fructose, lactitol, lactose, erythritol, maltose, maltitol, maltodextrin, polydextrose, trehalose, mannitol, polyethylene glycol, sorbitol, sucrose or xylitol. 
     
     
         5 . The composition according to  claim 1 , wherein the molar ratio of lipophilic species to ionizable pharmaceutical agent is at least about 1:1. 
     
     
         6 . The composition according to  claim 1 , wherein the pharmaceutical agent is an antihypertensive agent, analgesic, antidepressant, opioid agonist, anesthetic, antiarrhythmic, antiarthritic, antispasmodic, ACE inhibitor, decongestant, antibiotic, antihistamine, anti-anginal, diuretic, anti-hypotensive agent, anti-Parkinson agent, bronchodilator, oxytocic agent, anti-diuretic, anti-hyperglycemic, antineoplastic and/or immunosuppresent agent, antiemetic, antiinfective, antifungal, antiviral, antimuscarinic, antidiabetic agent, antiallergy agent, anxiolytic, sedative, antipsychotic, bone modulating agent, cardiovascular agent, cholesterol lowering drug, antimalarial, antiepileptic, antihelminthic, agent for smoking cessation, cough suppressant, expectorant, mucolytic, nasal decongestant, dopaminergic, gastrointestinal agent, muscle relaxant, neuromuscular blocker, parasympathomimetic, prostaglandin, stimulant, anorectic, thyroid or antithyroid agent, hormone, antimigrane agent, antiobesity, and/or non-steroidal anti-inflammatory agent. 
     
     
         7 . The composition according to  claim 1 , wherein the pharmaceutical agent is dihydroergotamine, fentanyl, sufentanil, lidocaine, alfentanil, lofentanil, carfentanil, pentobarbital, buspirone, ergotamine, bisphosphonate, alendronic acid, nalbuphine, bupropion, metformin, diethylcarbamazine, tramadol, heparin or a heparin derivative, amoxicillin, gabapentin, econazole, aspirin, prostaglandin, methylsergide, ergonovine, endorphins, enkephalins, oxytocin, opiates, heparin and its derivatives, clorazepic acid, barbiturate, albuterol, atropine, scopolamine, selegiline, timolol, nicotine, cocaine, novocaine, amphetamines, caffeine, methylphenidate, chlorpromazine, ketamine, epinephrine, estropipate, naloxone, naltrexone, furosemide, labetalol, metoprolol, nadolol, isoproterenol, terbutaline, sumatriptan, bupivacaine, prilocaine, Joratadine, chloropheniramine, clonidine, or tetracaine. 
     
     
         8 . The composition according to  claim 1 , wherein the pharmaceutical agent is nicotine. 
     
     
         9 . The composition according to  claim 1 , further comprising a buffering agent, colorant, flavoring, solvent, co-solvent, coating agent, binder, diluent, carrier, disintegrant, glident, lubricant, opacifying agent, humectant, granulating agent, gelling agent, polishing agent, suspending agent, sweetening agent, anti-adherent, preservative, emulsifying agent, antioxidant, levigating agent, plasticizer, surfactant, tonicity agent, viscosity agent, enteric agent, enteric coating, controlled-release agent or coating, wax, wetting agent, thickening agent, suppository base, stiffing agent, stabilizing agent, solubilizing agent, sequestering agent, ointment base, oleaginous vehicle, film-forming agent, essential oil, emollient, dissolution enhancer, dispersing agent, or cryoprotectant or combination thereof. 
     
     
         10 . A method of manufacturing the transmucosal pharmaceutical dosage form of  claim 1  comprising:
 admixing an ionizable pharmaceutical agent with one or more complementary lipophilic species to form a lipophilic association (LA); and 
 formulating the LA into a transmucosal dosage form; 
 wherein the admixing is performed under conditions such that the ionizable pharmaceutical agent hydrogen-bonds or ion pairs with the complementary lipophilic species, and further comprising admixing a carrier with the LA, wherein the LA is adsorbed or absorbed to the carrier. 
 
     
     
         11 . A transmucosal pharmaceutical dosage form, wherein said dosage form is a buccal tablet or sublingual tablet, manufactured by admixing an ionizable pharmaceutical agent with a one or more complementary lipophilic species to form a lipophilic association (LA), wherein the ionizable pharmaceutical agent possesses a basic functional group and the lipophilic species is oleic acid, wherein the admixing is performed under conditions such that the ionizable pharmaceutical agent hydrogen-bonds or ion pairs with the complementary lipophilic species, and further comprising admixing a carrier with the LA, wherein the LA is adsorbed or absorbed to the carrier and wherein the carrier is a silica or a silicified microcrystalline cellulose.