Transdermal drug delivery systems containing quaternary ammonium salts and methods of using the same

• US 20030091620A1
• Filed: 03/21/2002
• Published: 05/15/2003
• Est. Priority Date: 09/08/1999
• Status: Abandoned Application

• Current Assignee: Charles D. Ebert, David Fikstad, Lawrence R. Nilssen, Srinivasan Venkateshwaran
• Original Assignee: Charles D. Ebert, David Fikstad, Lawrence R. Nilssen, Srinivasan Venkateshwaran
• Inventors: Venkateshwaran, Srinivasan, Ebert, Charles D., Nilssen, Lawrence R., Fikstad, David
• Application Number:
  US10/105,032
• Publication Number:
  US 20030091620A1
• Time in Patent Office: Days
• US Class Current: 424/449
• CPC Class Codes: A61K 47/186 Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/7053 obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
• CPC Class Codes: A61K 9/7061 Polyacrylates
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 23/02 Local anaesthetics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• 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 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/14 : for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system

Abstract

A transdermal drug delivery system is disclosed, which includes a polymer, a drug and an amount of a quaternary ammonium salt that is sufficient to act as a penetration enhancer. The quaternary ammonium salt may also be present in an amount sufficient to act as an irritation reducer. Further, the transdermal drug delivery system may also contain a co-enhancer, which provides a synergistic skin permeation enhancing effect when combined with the quaternary ammonium salt. A method for enhancing the transdermal delivery of a drug is also disclosed.

Claims

1. A transdermal composition comprising a pharmaceutically acceptable carrier, a drug, and a quaternary ammonium salt constituting from about 0.1% to about 4.5% by weight of the carrier.

2. The transdermal composition of claim 1, wherein said quaternary ammonium salt is a compound having the formula:

3. The transdermal composition of claim 1, wherein said quaternary ammonium salt is benzalkonium chloride;

benzalkonium saccharinate;

behenalkonium chloride;

cetalkonium chloride;

erucalkonium chloride;

lauralkonium chloride;

myristalkonium chloride;

myristalkonium saccharinate (Quaternium-3);

stearalkonium chloride;

olealkonium chloride;

tallowalkonium chloride;

dodecylbenzyltrimethylammonium chloride (Quaternium-28);

dodecylbenzyl trimethyl ammonium 2-ethylhexanoate;

ethylbenzyl alkyldimethylammonium cyclohexylsulfanamate (Quaternium-8);

ethylbenzyl dimethyl dodecyl ammonium chloride (Quaternium-14);

dodecylbenzyl dimethyl octadecyl ammonium chloride;

dodecylbenzyl triethanol ammonium chloride (Quaternium-30);

benzoxonium chloride;

benzylbis(2-hydroxyethyl)(2-dodecyloxyethyl)ammonium bromide;

benzylbis(2-hydroxyethyl)(2-dodecyloxyethyl)ammonium chloride;

benzethonium chloride;

methylbenzethonium chloride;

N,N-(diethyl-N-[2-[4-(1,1,3,3-tetramethylbutyl)phenoxy]ethyl] benzenemethanaminium chloride (phenoctide);

dodecarbonium chloride;

babassuamidopropalkonium chloride;

wheatgermamidopropalkonium chloride, or a mixture thereof.

4. The transdermal composition of claim 1, wherein said quaternary ammonium salt is benzalkonium chloride, stearalkonium, behenalkonium chloride, olealkonium chloride, erucalkonium chloride, benzethonium chloride, methylbenzethonium chloride, phenoctide, wheatgermamidopropalkonium chloride, babassuamidopropalkonium chloride or a mixture thereof.

5. The transdermal composition of claim 1, wherein the quaternary ammonium salt is benzethonium chloride.

6. The transdermal composition of claim 1, wherein the quaternary ammonium salt is methylbenzethonium chloride.

7. The transdermal composition of claim 1, wherein the quaternary ammonium salt is benzalkonium chloride.

8. The transdermal composition of claim 1, wherein the quaternary ammonium salt is olealkonium chloride.

9. The transdermal composition of claim 1, wherein the quaternary ammonium salt is phenoctide.

10. The transdermal composition of claim 2, wherein the quaternary ammonium salt is present in an amount sufficient to act as an anti-irritant.

11. The transdermal composition of claim 10, wherein said quaternary ammonium salt is a member selected from the group consisting of alkyl-, dimethyl benzenemethanaminium salts;

acyl-, dimethyl benzenemethanaminium salts;

mixed acyl-/alkyl-, dimethyl benzenemethanaminium salts;

ethylbenzyl dodecyl dimethylammonium chloride, dodecylbenzyltrimethylammonium chloride, dodecylbenzyl triethanolammonium chloride, benzoxonium chloride, benzethonium chloride;

methylbenzethonium chloride;

phenoctide;

dodecarbonium chloride; and

mixed alkyl-/acyl-, amidopropalkonium salts.

12. The transdermal composition of claim 1, wherein said quaternary ammonium salt constitutes about 1% by weight of the pharmaceutically acceptable carrier.

13. The transdermal composition of claim 1, wherein said quaternary ammonium salt constitutes about 2% by weight of the pharmaceutically acceptable carrier.

14. The transdermal composition of claim 1, wherein said pharmaceutically acceptable carrier is a biocompatible polymer.

15. The transdermal composition of claim 1, wherein said pharmaceutically acceptable carrier is an adhesive.

16. The transdermal composition of claim 15, wherein said adhesive is a member selected from the group consisting of acrylics, vinyl acetates, natural and synthetic rubbers, ethylene-vinyl acetate copolymers, polysiloxanes, polyacrylates, polyurethanes, plasticized polyether block amide copolymers, plasticized styrene-rubber block copolymers, and mixtures thereof.

17. The transdermal composition of claim 1, wherein said pharmaceutically acceptable carrier comprises a viscous material suitable for inclusion in a liquid reservoir.

18. The transdermal composition of claim 17, wherein said viscous material forms a gel.

19. The transdermal composition of claim 2, wherein the counter-ion is selected from the group consisting of chloride, bromide, iodide, acetate, 2-ethylhexanoate, sulfate, phosphate. arylsulfonates, cyclohexylsulfamate, benzoate, saccharinate, and a mixture thereof.

20. The transdermal composition of claim 1, further comprising a diluent, excipient, emollient, plasticizer, skin irritation reducing agent, or a mixture thereof.

21. The transdermal composition of claim 1, further comprising a co-enhancer that acts synergistically with the quaternary ammonium salt to enhance the penetration of the drug.

22. The transdermal composition of claim 21, wherein said co-enhancer comprises a compound represented by the formula:

R-Y

wherein R is a straight chain alkyl of about 7 to 17 carbon atoms, a non-terminal alkenyl of about 7 to 22 carbon atoms, or a branched-chain alkyl from about 12 to 22 carbons; and

Y is —

OH, —

COOH, —

OCOCH₃, —

SOCH₃, —

P(CH₃)₂O, —

COO(C₂H₄O)_mH, —

(OC₂H₄)_mOH, —

COOCH₂CH(OH)CH₃, —

COOCH₂CH(OH)CH₂OH, —

COOCH₂CHXCH₂X, —

CO(OCH₂CO)_nOM, —

CO[OCH(CH₃)CO]_nOM —

COOCH[CH(OH)]₄CH₂OH, —

CO[C₆H₁₂O₆, sucrose], —

CONR¹R², —

COO(CH₂)₂NR¹R², —

COO[CH(CH₃)CH₃]NR¹R ², —

COOR³, or N-pyrrolidone;

where X is H or RCOO—

;

M is H or a pharmaceutically acceptable counter ion;

R¹ and R² are independently H, CH₃, C₂H₅, C₃H₇, C₂H₄OH, or C₃H₇OH;

R³ is CH₃, C₂H₅, or C₃H₇;

m is an integer of 2 to 6; and

n is an integer of 1 to 4.

23. The transdermal composition of claim 21, wherein said co-enhancer is a member selected from the group consisting of fatty acids and their salts, fatty alcohols, branched aliphatic alcohols, fatty acid alkyl esters, fatty acid monoesters of sorbitol and glycerol, fatty acid esters with glycolic acid and lactylic acid and their salts, fatty acid amides, alkylpyrrolidones and mixtures thereof.

24. The transdermal composition of claim 21, wherein said co-enhancer is a member selected from the group consisting of oleic acid;

lauric acid;

oleyl alcohol;

lauryl alcohol;

2-butyl-octanol;

2-hexyl decanol;

2-octyl-decanol;

2-hexyldodecanol;

2-octyl-dodecanol;

2-decyl-tetradecanol;

2-tetradecyl-octadecanol;

methyl and ethyl laurate;

sorbitan monooleate and monolaurate;

glycerol monooleate and monolaurate;

lauric, myristic, capric, stearic, and oleic diethanolamide;

lauric, myristic, capric, stearic, and oleic monoethanolamide;

lauric, myristic, capric, stearic, and oleic monoisopropanolamide;

caproyl, lauroyl and stearoyl lactylic acid and their salts;

caproyl, lauroyl and stearoyl glycolic acid and their salts;

N-n-octyl and N-n-dodecyl pyrrolidone.

25. The transdermal composition of claim 21, wherein said co-enhancer is oleic acid;

lauric acid;

oleyl alcohol;

lauryl alcohol;

2-butyl-octanol;

sorbitan monooleate;

glycerol monooleate;

lauric, stearic, and oleic diethanolamide;

lauric monoisopropanolamide;

caproyl lactylic acid;

N-n-octyl pyrrolidone, or a mixture thereof.

26. The transdermal composition of claim 1, wherein said drug is a member selected from the group consisting of:

antibiotics, neoplastic agents, agents affecting the immune response, blood calcium regulators, peptide and protein hormones, agents useful in glucose regulation, antithrombotics and hemostatics, antihyperlipidemic agents, thyromimetic and antithyroid drugs, anti-ulcer agents, histamine H2-receptor agonists and antagonists, inhibitors of allergic response, local anesthetics, analgesics and analgesic combinations, antipsychotics, anti-anxiety agents, antidepressants agents, anorexigenics, bone-active agents, diagnostic agents, antidiarrheals, antimigraine agents, antimotion sickness agents, antinauseants, antiparkinsonism agents, antipruritics, antipyretics, antispasmodics, anticholinergics, sympathomimetics, xanthine derivatives, cardiovascular agents, central nervous system stimulants, decongestants, diagnostics, hormones, immunosuppressives, parasympatholytics, parasympathomimetics, sedatives, tranquilizers and mixtures thereof.

65. The transdermal composition of claim 1, wherein the drug is oxybutynin, buspirone, fentanyl, testosterone, progesterone, estradiol, propentofylline, or a mixture thereof, or a salt, isomer, or analog thereof.

75. A method of enhancing transdermal delivery of a drug and reducing skin irritation associated with the transdermal delivery comprising the step of:

applying a transdermal drug delivery system as recited in claim 1 to a selected skin surface.

27. A transdermal composition comprising a pharmaceutically acceptable carrier, a drug, and a quaternary ammonium salt, wherein the quaternary ammonium salt constitutes an amount sufficient to enhance penetration of the drug with reduced skin irritation.

28. The transdermal composition of claim 27, wherein the quaternary ammonium salt is present in low concentration.

29. The transdermal composition of claim 28, wherein the low concentration represents no greater than 4.5% by weight of the carrier.

30. The transdermal composition of claim 28, wherein the low concentration represents no greater than 4.0% by weight of the carrier.

31. The transdermal composition of claim 28, wherein the low concentration represents no greater than 3.0% by weight of the carrier.

32. The transdermal composition of claim 28, wherein the low concentration represents no greater than 2.0% by weight of the carrier.

33. The transdermal composition of claim 28, wherein the low concentration represents no greater than 1.0% by weight of the carrier.

34. The transdermal composition of claim 28, wherein said quaternary ammonium salt is a compound having the formula:

35. The transdermal composition of claim 28, wherein said quaternary ammonium salt is benzalkonium chloride;

benzalkonium saccharinate;

behenalkonium chloride;

cetalkonium chloride;

erucalkonium chloride;

lauralkonium chloride;

myristalkonium chloride;

myristalkonium saccharinate (Quaternium-3);

stearalkonium chloride;

olealkonium chloride;

tallowalkonium chloride;

dodecylbenzyltrimethylammonium chloride (Quaternium-28);

dodecylbenzyl trimethyl ammonium 2-ethylhexanoate;

ethylbenzyl alkyldimethylammonium cyclohexylsulfanamate (Quaternium-8);

ethylbenzyl dimethyl dodecyl ammonium chloride (Quaternium-14);

dodecylbenzyl dimethyl octadecyl ammonium chloride;

dodecylbenzyl triethanol ammonium chloride (Quaternium-30);

benzoxonium chloride;

benzylbis(2-hydroxyethyl)(2-dodecyloxyethyl)ammonium bromide;

benzylbis(2-hydroxyethyl)(2-dodecyloxyethyl)ammonium chloride;

benzethonium chloride;

methylbenzethonium chloride;

N,N-(diethyl-N-[2-[4-( 1,1,3,3-tetramethylbutyl)phenoxy]ethyl] benzenemethanaminium chloride (phenoctide);

dodecarbonium chloride;

babassuamidopropalkonium chloride;

wheatgermamidopropalkonium chloride, or a mixture thereof.

36. The transdermal composition of claim 28, wherein said quaternary ammonium salt is benzalkonium chloride, stearalkonium, behenalkonium chloride, olealkonium chloride, erucalkonium chloride, benzethonium chloride, methylbenzethonium chloride, phenoctide, wheatgermamidopropalkonium chloride, babassuamidopropalkonium chloride or a mixture thereof.

37. The transdermal composition of claim 28, wherein the quaternary ammonium salt is benzethonium chloride.

38. The transdermal composition of claim 28, wherein the counter-ion is selected from the group consisting of chloride, bromide, iodide , acetate, 2-ethylhexanoate, sulfate, phosphate, arylsulfonates, cyclohexylsulfamate, benzoate, saccharinate and a mixture thereof.

66. The transdermal composition of claim 27, wherein the drug is oxybutynin, buspirone, fentanyl, testosterone, progesterone, estradiol, propentofylline, or a mixture thereof, or a salt, isomer, or analog thereof.

39. A method of reducing skin irritation of a transdermal composition comprising a pharmaceutically acceptable carrier,

comprising the step of incorporating a low concentration of a quaternary ammonium salt.

40. The method of claim 39, wherein the low concentration represents no greater than 4% by weight of the carrier.

41. The method of claim 39, wherein the low concentration represents no greater than 3% by weight of the carrier.

42. The method of claim 39, wherein the low concentration represents no greater than 2% by weight of the carrier.

43. The method of claim 39, wherein the low concentration represents no greater than 1% by weight of the carrier.

44. The method of claim 39, wherein the low concentration represents no greater than 0.8% by weight of the polymeric carrier.

45. The transdermal composition of claim 39, wherein said quaternary ammonium salt is a compound having the formula:

46. The transdermal composition of claim 39, wherein said quaternary ammonium salt is benzalkonium chloride;

benzalkonium saccharinate;

behenalkonium chloride;

cetalkonium chloride;

erucalkonium chloride;

lauralkonium chloride;

myristalkonium chloride;

myristalkonium saccharinate (Quaternium-3);

stearalkonium chloride;

olealkonium chloride;

tallowalkonium chloride;

dodecylbenzyltrimethylammonium chloride (Quaternium-28);

dodecylbenzyl trimethyl ammonium 2-ethylhexanoate;

ethylbenzyl alkyldimethylammonium cyclohexylsulfanamate (Quaternium-8);

ethylbenzyl dimethyl dodecyl ammonium chloride (Quaternium-14);

dodecylbenzyl dimethyl octadecyl ammonium chloride;

dodecylbenzyl triethanol ammonium chloride (Quaternium-30);

benzoxonium chloride;

benzylbis(2-hydroxyethyl)(2-dodecyloxyethyl)ammonium bromide;

benzylbis(2-hydroxyethyl)(2-dodecyloxyethyl)ammonium chloride;

benzethonium chloride;

methylbenzethonium chloride;

N,N-(diethyl-N-[2-[4-(1,1,3,3-tetramethylbutyl)phenoxy]ethyl] benzenemethanaminium chloride (phenoctide);

dodecarbonium chloride;

babassuamidopropalkonium chloride;

wheatgermamidopropalkonium chloride, or a mixture thereof.

47. The transdermal composition of claim 39, wherein said quaternary ammonium salt is benzalkonium chloride, stearalkonium, behenalkonium chloride, olealkonium chloride, erucalkonium chloride, benzethonium chloride, methylbenzethonium chloride, phenoctide, wheatgermamidopropalkonium chloride, babassuamidopropalkonium chloride or a mixture thereof.

48. The transdermal composition of claim 39, wherein the quaternary ammonium salt is benzethonium chloride.

49. The transdermal composition of claim 39, wherein the counter-ion is selected from the group consisting of chloride, bromide, iodide, acetate, 2-ethylhexanoate, sulfate, phosphate, arylsulfonates, cyclohexylsulfamate, benzoate, saccharinate and a mixture thereof.

67. The transdermal composition of claim 39, wherein the drug is oxybutynin, buspirone, fentanyl, testosterone, progesterone, estradiol, propentofylline, or a mixture thereof, or a salt, isomer, or analog thereof.

69. The method of claim 39, wherein the skin irritation manifests as erythema, papule, vesicle, or a combination thereof.

70. The method of claim 39, wherein the skin irritation is caused by microbial growth.

71. The method of claim 70, wherein the microbial comprises gram-positive bacteria.

50. A method of synergistically enhancing transdermal penetration of a drug in a transdermal composition comprising a carrier, a penetration enhancer, and a drug, comprising the step of incorporating a low concentration of a quaternary ammonium salt.

51. The method of claim 50, wherein the low concentration represents no greater than 4% by weight of the carrier.

52. The method of claim 50, wherein the low concentration represents no greater than 3% by weight of the carrier.

53. The method of claim 50, wherein the low concentration represents no greater than 2% by weight of the carrier.

54. The method of claim 50, wherein the low concentration represents no greater than 1% by weight of the carrier.

55. The method of claim 50, wherein the low concentration represents no greater than 0.8% by weight of the carrier.

56. The transdermal composition of claim 50, wherein said quaternary ammonium salt is a compound having the formula:

57. The transdermal composition of claim 50, wherein said quaternary ammonium salt is benzalkonium chloride;

benzalkonium saccharinate;

behenalkonium chloride;

cetalkonium chloride;

erucalkonium chloride;

lauralkonium chloride;

myristalkonium chloride;

myristalkonium saccharinate (Quaternium-3);

stearalkonium chloride;

olealkonium chloride;

tallowalkonium chloride;

dodecylbenzyltrimethylammonium chloride (Quaternium-28);

dodecylbenzyl trimethyl ammonium 2-ethylhexanoate;

ethylbenzyl alkyldimethylammonium cyclohexylsulfanamate (Quaternium-8);

ethylbenzyl dimethyl dodecyl ammonium chloride (Quaternium-14);

dodecylbenzyl dimethyl octadecyl ammonium chloride;

dodecylbenzyl triethanol ammonium chloride (Quaternium-30);

benzoxonium chloride;

benzylbis(2-hydroxyethyl)(2-dodecyloxyethyl)ammonium bromide;

benzylbis(2-hydroxyethyl)(2-dodecyloxyethyl)ammonium chloride;

benzethonium chloride;

methylbenzethonium chloride;

N,N-(diethyl-N-[2-[4-(1,1,3,3-tetramethylbutyl)phenoxy]ethyl] benzenemethanaminium chloride (phenoctide);

dodecarbonium chloride;

babassuamidopropalkonium chloride;

wheatgermamidopropalkonium chloride, or a mixture thereof.

58. The transdermal composition of claim 50, wherein said quaternary ammonium salt is benzalkonium chloride, stearalkonium, behenalkonium chloride, olealkonium chloride, erucalkonium chloride, benzethonium chloride, methylbenzethonium chloride, phenoctide, wheatgermamidopropalkonium chloride, babassuamidopropalkonium chloride or a mixture thereof.

59. The transdermal composition of claim 50, wherein the quaternary ammonium salt is benzethonium chloride.

60. The transdermal composition of claim 50, wherein the penetration enhancer comprises a compound represented by the formula:

R-Y

wherein R is a straight chain alkyl of about 7 to 17 carbon atoms, a non-terminal alkenyl of about 7 to 22 carbon atoms, or a branched-chain alkyl from about 12 to 22 carbons; and

Y is —

OH, —

COOH, —

OCOCH₃, —

SOCH₃, —

P(CH₃)₂O, —

COO(C₂H₄O)_mH, —

(OC₂H₄)_mOH, —

COOCH₂CH(OH)CH₃, —

COOCH₂CH(OH)CH₂OH, —

COOCH₂CHXCH₂X, —

CO(OCH₂CO)_nOM, —

CO[OCH(CH₂)CO]_nOM —

COOCH[CH(OH)]₄CH₂OH, —

CO[C₆H₁₂O₆, sucrose], —

CONR¹R², —

COO(CH₂)₂NR¹R², —

COO[CH(CH₃)CH₃]NR¹R², —

COOR³, or N-pyrrolidone;

where X is H or RCOO—

;

M is H or a pharmaceutically acceptable counter ion;

R¹ and R² are independently H, CH₃, C₂H₅, C₃H₇, C₂H₄OH, or C₃H₇OH;

R³ is CH₃, C₂H₅, or C₃H₇;

m is an integer of 2 to 6; and

n is an integer of 1 to 4.

61. The transdermal composition of claim 50, wherein said enhancer is a member selected from the group consisting of fatty acids and their salts, fatty alcohols, branched aliphatic alcohols, fatty acid alkyl esters, fatty acid monoesters of sorbitol and glycerol, fatty acid esters with glycolic acid and lactylic acid and their salts, fatty acid amides. alkylpyrrolidones and mixtures thereof.

62. The transdermal composition of claim 50, wherein said enhancer is a member selected from the group consisting of oleic acid;

lauric acid;

oleyl alcohol;

lauryl alcohol;

2-butyl-octanol;

2-hexyl decanol;

2-octyl-decanol;

2-hexyldodecanol;

2-octyl-dodecanol;

2-decyl-tetradecanol;

2-tetradecyl-octadecanol;

methyl and ethyl laurate;

sorbitan monooleate and monolaurate;

glycerol monooleate and monolaurate;

lauric, myristic, capric, stearic, and oleic diethanolamide;

lauric, myristic, capric, stearic, and oleic monoethanolamide;

lauric, myristic, capric, stearic, and oleic monoisopropanolamide;

caproyl, lauroyl and stearoyl lactylic acid and their salts;

caproyl, lauroyl and stearoyl glycolic acid and their salts;

N-n-octyl and N-n-dodecyl pyrrolidone.

63. The transdermal composition of claim 50, wherein said enhancer is oleic acid;

lauric acid;

oleyl alcohol;

lauryl alcohol;

2-butyl-octanol;

sorbitan monooleate;

glycerol monooleate;

lauric, stearic, and oleic diethanolamide;

lauric monoisopropanolamide;

caproyl lactylic acid ;

N-n-octyl pyrrolidone, or a mixture thereof.

64. The transdermal composition of claim 50, wherein the counter-ion is selected from the group consisting of chloride, bromide, iodide, acetate, 2-ethylhexanoate, sulfate, phosphate, arylsulfonates, cyclohexylsulfamate, benzoate, saccharinate and a mixture thereof.

68. The transdermal composition of claim 50, wherein the drug is oxybutynin, buspirone, fentanyl, testosterone, progesterone, estradiol, propentofylline, or a mixture thereof, or a salt, isomer, or analog thereof.

72. The method of claim 50, wherein the penetration enhancement is from about 10-100% greater than would be expected of an additive effect from using the quaternary ammonium salt and a penetration enhancer.

73. The method of claim 50, wherein the penetration enhancement is from about 20-100% greater than would be expected of an additive effect from using the quaternary ammonium salt and a penetration enhancer.

74. The method of claim 50, wherein the penetration enhancement is from about 10-50% greater than would be expected of an additive effect from using the quaternary ammonium salt and a penetration enhancer.

76. A transdermal composition for reducing skin irritation, comprising a low concentration of a quaternary ammonium salt, wherein the composition results in no greater than mild skin irritation when applied to the skin.