Tansmucosal drug delivery system

• US 20070071806A1
• Filed: 02/24/2004
• Published: 03/29/2007
• Est. Priority Date: 02/24/2003
• Status: Active Grant

• Current Assignee: Pharmaceutical Productions, Inc.
• Original Assignee: Pharmaceutical Productions, Inc.
• Inventors: McCarty, John
• Granted Patent: US 8,992,974 B2
• Time in Patent Office: Days
• US Class Current: 424/451
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/465 Nicotine; Derivatives thereof
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 31/663 Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
• CPC Class Codes: A61K 47/543 Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/006 Oral mucosa, e.g. mucoadhesive forms, sublingual droplets; Buccal patches or films; Buccal sprays
• CPC Class Codes: A61K 9/143 with inorganic compounds
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14

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.

Claims

1-96. -96. (canceled)

97. A pharmaceutical composition comprising an ionizable pharmaceutical agent and one or more complementary lipophilic species, wherein the ionizable pharmaceutical agent is associated with the complementary lipophilic species to form a lipophilic association (LA), wherein the LA is formulated in a transmucosal dosage form.

98. The composition of claim 97, wherein the LA has been solubilized with one or more solvents having a dielectric constant less than that of water to form a solubilized LA.

99. The composition of claim 97, which further comprises one or more carriers, wherein the LA is adsorbed or absorbed to the one or more carriers.

100. The composition of claim 97, wherein the pharmaceutical composition contains a silica and/or a silicified microcrystalline cellulose as a carrier.

101. The composition of claim 97, wherein the lipophilic species is

(a) a fatty acid, wherein the fatty acid is a caproic, caprylic, capric, lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic, linolenic, licanic, arachidonic or clupanadonic acid;

(b) a long-chain alkyl sulfonic acid, wherein the long-chain alkyl sulfonic acid is a caproic, caprylic, capric, lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic, linolenic, licanic, arachidonic or clupanadonic acid;

(c) a long-chain alkyl sulfuric acid, wherein the long-chain alkyl sulfuric acid is a caproic, caprylic, capric, lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic, linolenic, licanic, arachidonic or clupanadonic acid; and

/or

(d) a cetrimide, oleamidopropyl dimethylamine, didecyldimethyl ammonium chloride, a quaternary surfactant, cetylpyridinium chloride, hexetidine, benzalkonium chloride or an amine or amide of caproic, caprylic, capric, lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic, linolenic, licanic, arachidonic or clupanadonic acid.

102. The composition of claim 97, 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, endorphin, enkephalin, oxytocin, opiate, heparin and its derivatives, clorazepic acid, barbiturate, albuterol, atropine, scopolamine, selegiline, timolol, nicotine, cocaine, novocaine, amphetamine, caffeine, methylphenidate, chlorpromazine, ketamine, epinephrine, estropipate, naloxone, naltrexone, furosemide, labetalol, metoprolol, nadolol, isoproterenol, terbutaline, sumatriptan, bupivacaine, prilocalne, loratadine, chloropheniramine, clonidine, or tetracaine.

103. The composition of claim 97, wherein the pharmaceutical agent is nicotine.

104. The composition of claim 97, wherein the molar ratio of the lipophilic species to the pharmaceutical agent is at least about 1:

1.

105. The composition of claim 97, wherein the pharmaceutical composition, when dissolved in water, has a pH of about physiological pH of a target mucosal membrane.

106. The composition of claim 97, wherein at least about 90% of the pharmaceutical agent is released within about ten minutes when dissolution of the dosage form is conducted in 900 ml of deionized water at 50 RPM using USP Apparatus 2.

116. A method of treating a patient in need thereof by administering a pharmaceutical composition of claim 97.

117. The method of claim 116, wherein the transmucosal dosage form further comprises one or more solvents having a dielectric constant less than that of water, thereby forming a solubilized LA.

118. The method of claim 116, wherein the transmucosal dosage form further comprises one or more carriers, wherein the LA is adsorbed or absorbed to the one or more carriers.

119. The method of claim 116, wherein the pharmaceutical composition contains a silica and/or a silicified microcrystalline cellulose as a carrier.

120. The method of claim 116, wherein the lipophilic species is

(a) a fatty acid, wherein the fatty acid is a caproic, caprylic, capric, lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic, linolenic, licanic, arachidonic or clupanadonic acid;

(b) a long-chain alkyl sulfonic acid, wherein the long-chain alkyl sulfonic acid is a caproic, caprylic, capric, lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic, linolenic, licanic, arachidonic or clupanadonic acid;

(c) a long-chain alkyl sulfuric acid, wherein the long-chain alkyl sulfuric acid is a caproic, caprylic, capric, lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic, linolenic, licanic, arachidonic or clupanadonic acid; and

/or

(d) a cetrimide, oleamidopropyl dimethylamine, didecyldimethyl ammonium chloride, a quaternary surfactant, cetylpyridinium chloride, hexetidine, benzalkonium chloride or an amine or amide of caproic, caprylic, capric, lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic, linolenic, licanic, arachidonic or clupanadonic acid.

121. The method of claim 116, 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, endorphin, enkephalin, oxytocin, opiate, heparin and its derivatives, clorazepic acid, barbiturate, albuterol, atropine, scopolamine, selegiline, timolol, nicotine, cocaine, novocaine, amphetamine, caffeine, methylphenidate, chlorpromazine, ketamine, epinephrine, estropipate, naloxone, naltrexone, furosemide, labetalol, metoprolol, nadolol, isoproterenol, terbutaline, sumatriptan, bupivacaine, prilocalne, loratadine, chloropheniramine, clonidine, or tetracaine.

122. The method of claim 116, wherein the ionizable pharmaceutical agent is nicotine.

123. The method of claim 116, wherein the molar ratio of the lipophilic species to the pharmaceutical agent is at least about 1:

1.

124. The method of claim 116, wherein the pharmaceutical composition, when dissolved in water, has a pH of about physiological pH of a target mucosal membrane.

125. The method of claim 116, wherein at least about 90% of the pharmaceutical agent is released within about ten minutes when dissolution of the dosage form is conducted in 900 ml of deionized water at 50 RPM using USP Apparatus 2.

126. The method of claim 116, wherein nicotine is transmucosally delivered sublingually or buccally.

127. The method of claim 116, wherein the ionizable pharmaceutical agent is nicotine, and wherein the dosage form is useful for nicotine replacement therapy.

107. A method of manufacturing a transmucosal pharmaceutical dosage form comprising an ionizable pharmaceutical agent and one or more complementary lipophilic species, the method comprising:

(a) admixing the ionizable pharmaceutical agent with the one or more complementary lipophilic species to form a lipophilic association (LA);

(b) optionally solubilizing the LA with one or more solvents having a dielectric constant less than that of water to form a solubilized LA;

(c) optionally admixing the LA or solubilized LA with one or more carriers such that the LA or solubilized LA is adsorbed or absorbed to the one or more carriers to form a sorbed material; and

(d) formulating the LA, the solubilized LA, or the sorbed material into a transmucosal dosage form, wherein the transmucosal dosage form contains, optionally, one or more water-soluble excipients;

optionally, one or more disintegrants;

optionally, one or more lubricants.

108. The method according to claim 107, wherein the one or more solvents, if present in step (b), are 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, a silicone fluid, or a glyceride, and wherein the one or more water-soluble excipients, if present in step (d), are a sugar, a polyol, an alcohol, a saccharide, a polysaccharide, glycerin, propylene glycol, ethanol, isopropyl alcohol, ethyl acetate, triacetin, triethyl citrate, tributyl citrate, dextrate, a dextrin, dextrose, fructose, lactitol, lactose, erythritol, maltose, maltitol, a maltodextrin, a polydextrose, trehalose, mannitol, a polyethylene glycol, sorbitol, sucrose or xylitol.

109. The method of claim 107, wherein the one or more carriers are a silica or a silicified microcrystalline cellulose.

110. The method of claim 107, wherein the lipophilic species is

(a) a fatty acid, wherein the fatty acid is a caproic, caprylic, capric, lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic, linolenic, licanic, arachidonic or clupanadonic acid;

(b) a long-chain alkyl sulfonic acid, wherein the long-chain alkyl sulfonic acid is a caproic, caprylic, capric, lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic, linolenic, licanic, arachidonic or clupanadonic acid;

(c) a long-chain alkyl sulfuric acid, wherein the long-chain alkyl sulfuric acid is a caproic, caprylic, capric, lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic, linolenic, licanic, arachidonic or clupanadonic acid; and

/or

(d) a cetrimide, oleamidopropyl dimethylamine, didecyldimethyl ammonium chloride, a quaternary surfactant, cetylpyridinium chloride, hexetidine, benzalkonium chloride or an amine or amide of caproic, caprylic, capric, lauric, myristic, palmitic, stearic, arachidic, behenic, lignoceric, myristoleic, palmitoleic, oleic, gadoleic, erucic, ricinoleic, linoleic, linolenic, licanic, arachidonic or clupanadonic acid.

111. The method of claim 107, 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, endorphin, enkephalin, oxytocin, opiates, barbiturate, albuterol, atropine, scopolamine, selegiline, timolol, nicotine, cocaine, novocaine, amphetamine, caffeine, heparin and its derivatives, clorazepic acid, methylphenidate, chlorpromazine, ketamine, epinephrine, estropipate, naloxone, naltrexone, furosemide, labetalol, metoprolol, nadolol, isoproterenol, terbutaline, sumatriptan, bupivacaine, prilocalne, loratadine, chloropheniramine, clonidine, or tetracaine.

112. The method of claim 107, wherein the pharmaceutical agent is nicotine.

113. The method of claim 107, wherein the molar ratio of the lipophilic species to the pharmaceutical agent is at least about 1:

1.

114. The method of claim 107, wherein the pharmaceutical composition, when dissolved in water, has a pH of about physiological pH of a target mucosal membrane.

115. A pharmaceutical product prepared by the method of manufacture according to claim 107, wherein at least about 90% of the pharmaceutical agent is released within about ten minutes when dissolution of the dosage form is conducted in 900 ml of deionized water at 50 RPM using USP Apparatus 2.

128. A pharmaceutical composition comprising nicotine, oleic acid and silica, wherein the molar ratio of the oleic acid to the nicotine is at least about 1:

1 and the nicotine is associated with the oleic acid in the absence of a solvent to form a lipophilic association (LA), wherein the LA is adsorbed or absorbed to the silica and formulated into a sublingual or buccal tablet dosage form, wherein at least about 90% of the nicotine is released within about ten minutes when dissolution of the dosage form is conducted in 900 ml of deionized water at 50 RPM using USP Apparatus 2.

129. A method for transmucosal delivery of an ionizable pharmaceutical agent comprising:

admixing an ionizable pharmaceutical agent with one or more complementary lipophilic species to form a lipophilic association (LA) that consists essentially of the ionizable pharmaceutical agent and the one or more complementary lipophilic species and that contains, optionally, one or more solvents having a dielectric constant less than that of water;

optionally, one or more carriers; and

/or, optionally, one or more water-soluble excipients;

formulating the LA in a transmucosal dosage form; and

administering the transmucosal dosage form to a target mucosal membrane in order to deliver the pharmaceutical agent through the mucosal membrane and into systemic circulation.