Mixture for Transdermal Delivery of Low and High Molecular Weight Compounds

• US 20080154210A1
• Filed: 05/25/2005
• Published: 06/26/2008
• Est. Priority Date: 05/28/2004
• Status: Abandoned Application

• Current Assignee: Oryxe
• Original Assignee: Oryxe
• Inventors: Dolbear, Geoff E., Jordan, Frederick
• Application Number:
  US11/597,700
• Publication Number:
  US 20080154210A1
• Time in Patent Office: Days
• US Class Current: 604/210
• CPC Class Codes: A61F 2013/00906 for transcutaneous or transdermal drugs application
• CPC Class Codes: A61K 2800/782 Enzyme inhibitors; Enzyme antagonists
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/385 having two or more sulfur atoms in the same ring
• CPC Class Codes: A61K 31/423 condensed with carbocyclic rings
• CPC Class Codes: A61K 31/568 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
• CPC Class Codes: A61K 31/616 by carboxylic acids, e.g. acetylsalicylic acid
• CPC Class Codes: A61K 31/7008 Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61K 36/88 Liliopsida (monocotyledons)
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/095 Oxytocins; Vasopressins; Related peptides
• CPC Class Codes: A61K 38/39 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• CPC Class Codes: A61K 38/465 acting on ester bonds (3.1), e.g. lipases, ribonucleases
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/44 Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14
• CPC Class Codes: A61K 8/14 Liposomes; Vesicles
• CPC Class Codes: A61K 8/498 having 6-membered rings or their condensed derivatives, e.g. coumarin
• CPC Class Codes: A61K 8/65 : Collagen; Gelatin; Keratin; Derivatives or degradation products thereof
• CPC Class Codes: A61K 8/86 : Polyethers
• CPC Class Codes: A61K 8/922 : of vegetable origin
• CPC Class Codes: A61K 8/9789 : Magnoliopsida [dicotyledons]
• CPC Class Codes: A61K 8/9794 : Liliopsida [monocotyledons]
• 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 9/107 : Emulsions ; Emulsion preconcentrates; Micelles composition of emulsions A61K47/00
• CPC Class Codes: A61K 9/127 : Liposomes
• CPC Class Codes: A61K 9/1273 : Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances polymers grafted or coated on phosphatidyl liposomes A61K9/1271, on non-phosphatidyl liposomes A61K9/1272
• CPC Class Codes: A61K 9/1277 : Processes for preparing; Proliposomes
• CPC Class Codes: A61M 35/003 : Portable hand-held applicators having means for dispensing or spreading integral media hand-held massage devices with liquid delivery A61H7/003
• CPC Class Codes: A61Q 19/02 : for chemically bleaching or whitening the skin
• CPC Class Codes: A61Q 19/06 : for countering cellulitis
• CPC Class Codes: A61Q 19/08 : Anti-ageing preparations

Abstract

Aspects of the present invention concern the discovery of a transdermal delivery composition that can deliver low, medium and high molecular weight pharmaceuticals and cosmetic agents. Embodiments include transdermal delivery compositions with therapeutic and cosmetic application, transdermal delivery devices for providing said transdermal delivery compositions to subjects in need thereof, and methods of making and using of the foregoing.

Claims

1. A transdermal delivery composition comprising an ethoxylated fatty moiety or lipid moiety and a delivered agent, wherein the amount of ethoxylation of said fatty moiety or lipid moiety is 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 ethoxylations per molecule, and wherein said fatty moiety or lipid moiety comprises 10 carbon residues.

2. The transdermal delivery composition of claim 1 further comprising water.

3. The transdermal delivery composition of claim 1 further comprising alcohol.

4. The transdermal delivery composition of claim 1, wherein said fatty moiety or lipid moiety comprises at least 10 carbon residues but less than or equal to 30 carbon residues.

5. The transdermal delivery composition of claim 1, wherein the amount of ethoxylation is the same as the number of carbons residues in the fatty moiety or lipid moeity.

6. The transdermal delivery composition of claim 1, wherein the fatty moiety or lipid moiety chain length is 10 carbon residues in length.

7. The transdermal delivery composition of claim 1, wherein the fatty moiety chain length is 12 carbon residues in length.

8. The transdermal delivery composition of claim 1, wherein the fatty moiety chain length is 14 carbon residues in length.

9. The transdermal delivery composition of claim 1, wherein the fatty moiety chain length is 16 carbon residues in length.

10. The transdermal delivery composition of claim 1, wherein the fatty moiety chain length is 18 carbon residues in length.

11. The transdermal delivery composition of claim 1, wherein the fatty moiety chain length is 20 carbon residues in length.

12. The transdermal delivery composition of claim 1, wherein the fatty moiety chain length is 22 carbon residues in length.

13. The transdermal delivery composition of claim 1, wherein the fatty moiety chain length is 24 carbon residues in length.

14. The transdermal delivery composition of claim 1, wherein the fatty moiety is a fatty acid.

15. The transdermal delivery composition of claim 14, wherein the fatty acid is unsaturated.

16. The transdermal delivery composition of claim 14, wherein the fatty acid is polyunsaturated.

17. The transdermal delivery composition of claim 14, wherein the fatty acid is palmitoleic acid (C16:

1, delta

     9).

18. The transdermal delivery composition of claim 14, wherein the fatty acid is selected from the group consisting of C16:

1, delta 1;

C16;

1, delta 2;

C16;

1, delta 3;

C16;

1, delta 4;

C16;

1, delta 5;

C16;

1, delta 6;

C16;

1, delta 7;

C16;

1, delta 8;

C16;

1, delta 9;

C16;

1, delta 10;

C16;

1, delta 11;

C16;

1, delta 12;

C16;

1, delta 13; and

C16;

1, delta 14.

19. The transdermal delivery composition of claim 1, wherein said fatty moiety is a fatty amine.

20. The transdermal delivery composition of claim 1, wherein said lipid moiety is a sphingolipid.

21. The transdermal delivery composition of claim 1, wherein said lipid moiety is a glycolipid.

22. The transdermal delivery composition of claim 1, wherein said lipid moiety is a glycosphingolipid.

23. The transdermal delivery composition of claim 1, wherein said transdermal delivery system comprises a homogeneous mixture of an ethoxylated fatty moiety.

24. The transdermal delivery composition of claim 1, wherein said transdermal delivery system comprises a heterogeneous mixture of ethoxylated fatty acids.

25. The transdermal delivery composition of claim 1, wherein the delivered agent is a hormone.

26. The transdermal delivery composition of claim 25, wherein said hormone is a polypeptide.

27. The transdermal delivery composition of claim 26, wherein the polypeptide is selected from the group consisting of oxytocin, vasopressin, melanocyte-stimulating hormone, corticortropin, lipotropin, thyrotropin, growth hormone, prolactin, luteinizing hormone, human chorionic gonadotropin, follicle stimulating hormone, corticotropin-releasing factor, gonadotropin-releasing factor, prolactin-releasing factor, prolactin-inhibiting factor, growth-hormone releasing factor, somatostatin, thyrotropin-releasing factor, calcitonin, calcitonin gene-related peptide, parathyroid hormone, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, gastrin, secretin, cholecystokinin, motilin, vasoactive intestinal peptide, substance P, pancreatic polypeptide, peptide tyrosine tyrosine, neuropeptide tyrosine, amphiregulin, insulin, glucagon, placental lactogen, relaxin, angiotensin II, atrial natriuretic peptide, and melatonin.

28. The transdermal delivery composition of claim 25, wherein the hormone is a non-peptide hormone.

29. The transdermal delivery composition of claim 25, wherein the hormone is selected from the group consisting of thyroxine, triiodothyronine, estradiol, estrone, progesterone, testosterone, cortisol, corticosterone, aldosterone, epinephrine, norepinepherine, and calctriol.

30. The transdermal delivery composition of claim 1, wherein said delivered agent is collagen.

31. The transdermal delivery composition of claim 1, wherein said delivered agent is an anesthetic.

32. The transdermal delivery composition of claim 31, wherein said anesthetic is selected from the group consisting of articaine, procaine, tetracaine, chloroprocaine and benzocaine, novocain, mepivicaine, bupivicaine, benzocaine, and lidocaine.

33. The transdermal delivery composition of claim 1, wherein said delivered agent is an analgesic.

34. The transdermal delivery composition of claim 33, wherein said delivered agent is selected from the group consisting of tramadol hydrochloride, fentanyl, metamizole, morphine sulphate, ketorolac tromethamine, hydrocodone, oxycodone, morprhine, loxoprofen, Capsaicin, and Boswellin.

35. The transdermal delivery composition of claim 1, wherein said delivered agent is an NSAID.

36. The transdermal delivery composition of claim 35, wherein said non-steroidal anti inflammatory drug (NSAID) is selected from the group consisting of ibuprofen (2-(isobutylphenyl)-propionic acid);

methotrexate (N-[4-(2, 4 diamino 6-pteridinyl-methyl]methylamino]benzoyl)-L-glutamic acid);

aspirin (acetylsalicylic acid);

salicylic acid;

diphenhydramine (2-(diphenylmethoxy)-N,N-dimethylethylamine hydrochloride);

naproxen (2-naphthaleneacetic acid, 6-methoxy-9-methyl-, sodium salt, (−

));

phenylbutazone (4-butyl-1,2-diphenyl-3,5-pyrazolidinedione);

sulindac-(2)-5-fluoro-2-methyl-1-[[p-(methylsulfinyl)phenyl]methylene-]-1H-indene-3-acetic acid;

diflunisal (2′

,4′

,-difluoro-4-hydroxy-3-biphenylcarboxylic acid;

piroxicam (4-hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-2-carboxamide 1,1-dioxide, an oxicam;

indomethacin (1-(4-chlorobenzoyl)-5-methoxy-2-methyl-H-indole-3-acetic acid);

meclofenamate sodium (N-(2,6-dichloro-m-tolyl) anthranilic acid, sodium salt, monohydrate);

ketoprofen (2-(3-benzoylphenyl)-propionic acid;

tolmetin sodium (sodium 1-methyl-5-(4-methylbenzoyl-1H-pyrrole-2-acetate dihydrate);

diclofenac sodium (2-[(2,6-dichlorophenyl)amino]benzeneatic acid, monosodium salt);

hydroxychloroquine sulphate (2-{[4-[(7-chloro-4-quinolyl)amino]pentyl]ethylamino}ethanol sulfate (1;

1);

penicillamine (3-mercapto-D-valine);

flurbiprofen ([1,1-biphenyl]-4-acetic acid, 2-fluoro-alphamethyl-, (+−

));

cetodolac (1-8-diethyl-13,4,9, tetrahydropyrano-[3-4-13]indole-1-acetic acid;

mefenamic acid (N-(2,3-xylyl)anthranilic acid; and

diphenhydramine hydrochloride (2-diphenyl methoxy-N,N-di-methylethamine hydrochloride).

37. The transdermal delivery composition of claim 1, wherein the delivered agent is an anti-inflammatory compound selected from the group consisting of hydrocortisone, prednisolone, triamcinolone, cortisone and piroxicam.

38. The transdermal delivery composition of claim 1, wherein the delivered agent is an anti-infective compound selected from the group consisting of amoxicillin, clavulanate potassium, itraconazole, acyclovir, fluconazole, terbinafine hydrochloride, erythromycin ethylsuccinate, acetyl sulfisoxazole, penicillin V, cephalexin, erythromycin, azithromycin, tetracycline, ciproflaxin, gentamycin, sulfathiazole, nitrofurantoin, norfloxacin, flumequine, and ibafloxacin, metronidazole, nystatin, lamivudine, indinavir sulfate, and stavudine.

39. The transdermal delivery composition of claim 1, wherein the delivered agent is metformin hydrochloride or acarbose.

40. The transdermal delivery composition of claim 1, wherein the delivered agent is an immunogen.

41. The transdermal delivery composition of claim 40, wherein the immunogen comprises a polynucleotide.

42. The transdermal delivery composition of claim 1 wherein the delivered agent is an immune response modifier.

43. The transdermal delivery composition of claim 42, wherein the immune response modifier is selected from the group consisting of purine derivatives, adenine derivatives, cyclosporine, and CpGs.

44. The transdermal delivery composition of claim 1, wherein the delivered agent is an enzyme inhibitor selected from the group consisting of zileuton, captopril, and lisinopril.

45. The transdermal delivery composition of claim 1, wherein the delivered agent is selected from the group consisting of ergotamine, melatonin, sumatriptan, zolmitriptan, and rizatriptan.

46. The transdermal delivery composition of claim 1, wherein the delivered agent is selected from the group consisting of zolpidem, zolpidem tartrate, triazolam, and hycosine butylbromide.

47. The transdermal delivery composition of claim 1, wherein the delivered agent is selected from the group consisting of iohexol, technetium, TC99M, sestamibi, iomeprol, gadodiamide, ioversol, and iopromide.

48. The transdermal delivery composition of claim 1, wherein the delivered agent is selected from the group consisting of alsactide, americium, betazole, histamine, mannitol, metyrapone, petagastrin, phentolamine, radioactive B₁₂, gadodiamide, gadopentetic acid, gadoteridol, perflubron, cyclosporine, sildenafil citrate, paclitaxel, ritonavir, and saquinavir.

93. A transdermal delivery device comprising the transdermal delivery composition of claim 1, wherein said device comprises:

a removable cartridge, wherein said removable cartridge is configured to contain said transdermal delivery composition, and wherein said removable cartridge comprises a movable wall and a one-way valve;

a body portion, said body portion being adaptable to receive the removable cartridge, wherein the body portion comprises an internal wall having an aperture configured to communicate with the one-way valve;

a movable member, wherein said movable member partially defines a dosing chamber along with the internal wall, and wherein movement of said movable member alters the volume of said dosing chamber;

a plunger, said plunger being actuatable between a first position wherein said plunger interacts with the movable wall of said removable cartridge, and a second position, wherein said plunger is biased to be in said second position;

a non-invasive applicator; and

a slidable member attached to said plunger, said slidable member being actuatable between a first position and a second position corresponding to the first and second positions of said plunger, wherein when said slidable member is in said first position, fluid communication between the one-way valve and the dosing chamber is permitted, and wherein when said slidable member is in said second position, fluid communication between said dosing chamber and the non-invasive applicator is permitted.

94. The transdermal delivery device of claim 93, further comprising a rotatable shaft, wherein said rotatable shaft has a threaded portion extending through a threaded aperture in the moveable member, whereby rotation of the rotatable shaft results translation of the movable member in the direction of the axis of the shaft.

95. The transdermal delivery device of claim 94, wherein the dosing chamber has a non-circular cross-section, and wherein the movable member comprises a layer of deformable material along the edges in contact with the walls of the dosing chamber.

96. The transdermal delivery device of claim 94, wherein the rotatable shaft extends through a portion of the moveable member away from the center of the upper surface of the movable member.

97. The transdermal delivery device of claim 93, wherein the non-invasive applicator comprises a roll-on applicator.

98. The transdermal delivery device of claim 93, wherein the slidable member is operably connected to the plunger via a spring.

99. The transdermal delivery device of claim 93, wherein the plunger is biased to be in said second position via a spring connected to said body portion.

100. The transdermal delivery device of claim 93, wherein the plunger comprises a toothed surface, said toothed surface configured to interact with a locking member to prevent return of said plunger to the second position.

101. The transdermal delivery device of claim 100, wherein the locking member is operably connected to a release button, whereby pressing the release button moves the locking member so as to permit return of the plunger to the second position.

102. A transdermal delivery device for dispensing a measured quantity of the transdermal delivery composition of claim 1, the device comprising:

a reservoir, said reservoir comprising a movable wall and a one-way valve, wherein said movable wall can be actuated to result in fluid flow through the one-way valve;

a plunger, said plunger being actuatable between a first position, wherein said plunger is not in contact with the movable wall of said reservoir, and a second position, wherein said plunger interacts with the movable wall of the reservoir and further translation of the plunger in the direction of the movable wall results in fluid flow through the one-way valve of the reservoir; and

a dosing member, said dosing member being movable between a plurality of positions, wherein each of said plurality of positions corresponds to a given quantity of transdermal delivery composition to be dispensed.

111. A method of providing a delivered agent to a mammal in need thereof, comprising:

providing the transdermal delivery device of claim 93;

obtaining an amount of transdermal delivery system comprising said delivered agent from said transdermal delivery device; and

contacting said mammal with said transdermal delivery system.

112. A method of providing a delivered agent to a mammal in need thereof, comprising:

obtaining an amount of transdermal delivery system of claim 1 comprising said delivered agent from said transdermal delivery device;

contacting said mammal with said transdermal delivery system; and

monitoring said mammal for the effect of said delivered agent.

49. A transdermal delivery composition comprising

a transdermal delivery enhancer comprising a multifunctional backbone, wherein said multifunctional backbone comprises at least two reactive groups (R), wherein at least one reactive group is substituted with a fatty moiety, wherein at least one reactive group is substituted with a polyethoxy moiety, wherein R is selected from the group consisting of —

OH, COOH, SH, and NH₂, wherein said fatty moiety is selected from the group consisting of a fatty acid, a fatty alcohol, a fatty amine, and a modified fatty acid; and

a delivered agent.

50. The transdermal delivery composition of claim 49, wherein said (R) groups on said multifunctional backbone are homogeneous.

51. The transdermal delivery composition of claim 49, wherein said (R) groups on said multifunctional backbone are heterogeneous.

52. The transdermal delivery composition of claim 49, wherein said penetration enhancer comprises at least 10 ethoxylations per molecule but less than or equal to 19 ethoxylations per molecule.

53. The transdermal delivery composition of claim 49, wherein said multifunctional backbone is a tri-alcohol.

54. The transdermal delivery composition of claim 53, wherein said fatty moiety is a fatty acid, and wherein said fatty acid comprises at least 10 carbon residues.

55. The transdermal delivery composition of claim 49, wherein said multifunctional backbone is a triacid.

56. The transdermal delivery composition of claim 55, wherein at least one of said (R) groups on said triacid is substituted with a fatty alcohol.

57. The transdermal delivery composition of claim 55, wherein said triacid has a benzene ring.

58. The transdermal delivery composition of claim 57, wherein said triacid is selected from the group consisting of hemi-mellitic acid, trimellitic acid, trimesic acid, and nitrilotriacetic acid.

59. The transdermal delivery composition of claim 57, wherein said triacid comprises a toluene group.

60. The transdermal delivery composition of claim 57, wherein said triacid comprises a naphthalene group.

61. The transdermal delivery composition of claim 49, wherein said multifunctional backbone is an amino acid.

62. The transdermal delivery composition of claim 61, wherein said amino acid is selected from the group consisting of glutamic acid, aspartic acid, cysteine, glutamine, serine, threonine, tyrosine, lysine and aminomalonic acid.

63. The transdermal delivery composition of claim 49, wherein said multifunctional backbone is triethanolamine.

64. The transdermal delivery composition of claim 49, wherein said multifunctional backbone is diethanolamine.

65. The transdermal delivery composition of claim 49, wherein said multifunctional backbone is dimethylolurea.

66. The transdermal delivery composition of claim 49, wherein said multifunctional backbone is glucosamine.

67. The transdermal delivery composition of claim 49, wherein said multifunctional backbone is a sugar.

68. The transdermal delivery composition of claim 67, wherein said sugar comprises between 4 and 6 R groups, wherein said R groups are —

OH.

69. The transdermal delivery composition of claim 49, wherein the delivered agent is a hormone.

70. The transdermal delivery composition of claim 69, wherein said hormone is a polypeptide.

71. The transdermal delivery composition of claim 69, wherein the polypeptide is selected from the group consisting of oxytocin, vasopressin, melanocyte-stimulating hormone, corticortropin, lipotropin, thyrotropin, growth hormone, prolactin, luteinizing hormone, human chorionic gonadotropin, follicle stimulating hormone, corticotropin-releasing factor, gonadotropin-releasing factor, prolactin-releasing factor, prolactin-inhibiting factor, growth-hormone releasing factor, somatostatin, thyrotropin-releasing factor, calcitonin, calcitonin gene-related peptide, parathyroid hormone, glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, gastrin, secretin, cholecystokinin, motilin, vasoactive intestinal peptide, substance P, pancreatic polypeptide, peptide tyrosine tyrosine, neuropeptide tyrosine, amphiregulin, insulin, glucagon, placental lactogen, relaxin, angiotensin II, atrial natriuretic peptide, and melatonin.

72. The transdermal delivery composition of claim 69, wherein the hormone is a non-peptide hormone.

73. The transdermal delivery composition of claim 72, wherein the hormone is selected from the group consisting of thyroxine, triiodothyronine, estradiol, estrone, progesterone, testosterone, cortisol, corticosterone, aldosterone, epinephrine, norepinepherine, and calctriol.

74. The transdermal delivery composition of claim 49, wherein said delivered agent is collagen.

75. The transdermal delivery composition of claim 49, wherein said delivered agent is an anesthetic.

76. The transdermal delivery composition of claim 75, wherein said anesthetic is selected from the group consisting of articaine, procaine, tetracaine, chloroprocaine and benzocaine, novocain, mepivicaine, bupivicaine, benzocaine, and lidocaine.

77. The transdermal delivery composition of claim 49, wherein said delivered agent is an analgesic.

78. The transdermal delivery composition of claim 77, wherein said delivered agent is selected from the group consisting of tramadol hydrochloride, fentanyl, metamizole, morphine sulphate, ketorolac tromethamine, hydrocodone, oxycodone, morprhine, loxoprofen, Capsaicin, and Boswellin.

79. The transdermal delivery composition of claim 49, wherein said delivered agent is an NSAID.

80. The transdermal delivery composition of claim 79, wherein said non-steroidal anti inflammatory drug (NSAID) is selected from the group consisting of ibuprofen (2-(isobutylphenyl)-propionic acid);

methotrexate (N-[4-(2, 4 diamino 6-pteridinyl-methyl]methylamino]benzoyl)-L-glutamic acid);

aspirin (acetylsalicylic acid);

salicylic acid;

diphenhydramine (2-(diphenylmethoxy)-NN-dimethylethylamine hydrochloride);

naproxen (2-naphthaleneacetic acid, 6-methoxy-9-methyl-, sodium salt, (−

));

phenylbutazone (4-butyl-1,2-diphenyl-3,5-pyrazolidinedione);

sulindac-(2)-5-fluoro-2-methyl-1-[[p-(methylsulfinyl)phenyl]methylene-]-1H-indene-3-acetic acid;

diflunisal (2′

,4′

,-difluoro-4-hydroxy-3-biphenylcarboxylic acid;

piroxicam (4-hydroxy-2-methyl-N-2-pyridinyl-2H-1,2-benzothiazine-2-carboxamide 1,1-dioxide, an oxicam;

indomethacin (1-(4-chlorobenzoyl)-5-methoxy-2-methyl-H-indole-3-acetic acid);

meclofenamate sodium (N-(2,6-dichloro-m-tolyl) anthranilic acid, sodium salt, monohydrate);

ketoprofen (2-(3-benzoylphenyl)-propionic acid;

tolmetin sodium (sodium 1-methyl-5-(4-methylbenzoyl-1H-pyrrole-2-acetate dihydrate);

diclofenac sodium (2-[(2,6-dichlorophenyl)amino]benzeneatic acid, monosodium salt);

hydroxychloroquine sulphate (2-{[4-[(7-chloro-4-quinolyl)amino]pentyl]ethylamino}ethanol sulfate (1;

1);

penicillamine (3-mercapto-D-valine);

flurbiprofen ([1,1-b]phenyl]-4-acetic acid, 2-fluoro-alphamethyl-, (+−

));

cetodolac (1-8-diethyl-13,4,9, tetrahydropyrano-[3-4-13]indole-1-acetic acid;

mefenamic acid (N-(2,3-xylyl)anthranilic acid; and

diphenhydramine hydrochloride (2-diphenyl methoxy-N,N-di-methylethamine hydrochloride).

81. The transdermal delivery composition of claim 49, wherein the delivered agent is an anti-inflammatory compound selected from the group consisting of hydrocortisone, prednisolone, triamcinolone, cortisone and piroxicam.

82. The transdermal delivery composition of claim 49, wherein the delivered agent is an anti-infective compound selected from the group consisting of amoxicillin, clavulanate potassium, itraconazole, acyclovir, fluconazole, terbinafine hydrochloride, erythromycin ethylsuccinate, acetyl sulfisoxazole, penicillin V, cephalexin, erythromycin, azithromycin, tetracycline, ciproflaxin, gentamycin, sulfathiazole, nitrofurantoin, norfloxacin, flumequine, and ibafloxacin, metronidazole, nystatin, lamivudine, indinavir sulfate, and stavudine.

83. The transdermal delivery composition of claim 49, wherein the delivered agent is metformin, metformin hydrochloride or acarbose.

84. The transdermal delivery composition of claim 49, wherein the delivered agent is an immunogen.

85. The transdermal delivery composition of claim 49, wherein the immunogen comprises a polynucleotide.

86. The transdermal delivery composition of claim 49 wherein the delivered agent is an immune response modifier.

87. The transdermal delivery composition of claim 86, wherein the immune response modifier is selected from the group consisting of purine derivatives, adenine derivatives, cyclosporine, and CpGs.

88. The transdermal delivery composition of claim 49, wherein the delivered agent is selected from the group consisting of zileuton, captopril, and lisinopril.

89. The transdermal delivery composition of claim 49, wherein the delivered agent is selected from the group consisting of ergotamine, melatonin, sumatriptan, zolmitriptan, and rizatriptan.

90. The transdermal delivery composition of claim 49, wherein the delivered agent is selected from the group consisting of zolpidem, zolpidem tartrate, triazolam, and hycosine butylbromide.

91. The transdermal delivery composition of claim 49, wherein the delivered agent is selected from the group consisting of iohexyl, technetium, TC99M, sestamibi, iomeprol, gadodiamide, ioversol, and iopromide.

92. The transdermal delivery composition of claim 49, wherein the delivered agent is selected from the group consisting of alsactide, americium, betazole, histamine, mannitol, metyrapone, petagastrin, phentolamine, radioactive B₁₂, gadodiamide, gadopentetic acid, gadoteridol, perflubron, cyclosporine, sildenafil citrate, paclitaxel, ritonavir, and saquinavir.

113. A method of providing a delivered agent to a mammal in need thereof, comprising:

obtaining an amount of transdermal delivery system of claim 49 comprising said delivered agent from said transdermal delivery device;

contacting said mammal with said transdermal delivery system; and

monitoring said mammal for the effect of said delivered agent.

114. A transdermal delivery device comprising the transdermal delivery composition of claim 49, wherein said device comprises:

a removable cartridge, wherein said removable cartridge is configured to contain said transdermal delivery composition, and wherein said removable cartridge comprises a movable wall and a one-way valve;

a body portion, said body portion being adaptable to receive the removable cartridge, wherein the body portion comprises an internal wall having an aperture configured to communicate with the one-way valve;

a movable member, wherein said movable member partially defines a dosing chamber along with the internal wall, and wherein movement of said movable member alters the volume of said dosing chamber;

a plunger, said plunger being actuatable between a first position wherein said plunger interacts with the movable wall of said removable cartridge, and a second position, wherein said plunger is biased to be in said second position;

a non-invasive applicator; and

a slidable member attached to said plunger, said slidable member being actuatable between a first position and a second position corresponding to the first and second positions of said plunger, wherein when said slidable member is in said first position, fluid communication between the one-way valve and the dosing chamber is permitted, and wherein when said slidable member is in said second position, fluid communication between said dosing chamber and the non-invasive applicator is permitted.

115. The transdermal delivery device of claim 114, further comprising a rotatable shaft, wherein said rotatable shaft has a threaded portion extending through a threaded aperture in the moveable member, whereby rotation of the rotatable shaft results translation of the movable member in the direction of the axis of the shaft.

116. The transdermal delivery device of claim 114, wherein the dosing chamber has a non-circular cross-section, and wherein the movable member comprises a layer of deformable material along the edges in contact with the walls of the dosing chamber.

117. The transdermal delivery device of claim 115, wherein the rotatable shaft extends through a portion of the moveable member away from the center of the upper surface of the movable member.

118. The transdermal delivery device of claim 114, wherein the non-invasive applicator comprises a roll-on applicator.

119. The transdermal delivery device of claim 114, wherein the slidable member is operably connected to the plunger via a spring.

120. The transdermal delivery device of claim 114, wherein the plunger is biased to be in said second position via a spring connected to said body portion.

121. The transdermal delivery device of claim 114, wherein the plunger comprises a toothed surface, said toothed surface configured to interact with a locking member to prevent return of said plunger to the second position.

122. The transdermal delivery device of claim 121, wherein the locking member is operably connected to a release button, whereby pressing the release button moves the locking member so as to permit return of the plunger to the second position.

123. A transdermal delivery device for dispensing a measured quantity of the transdermal delivery composition of claim 49, the device comprising:

a reservoir, said reservoir comprising a movable wall and a one-way valve, wherein said movable wall can be actuated to result in fluid flow through the one-way valve;

a plunger, said plunger being actuatable between a first position, wherein said plunger is not in contact with the movable wall of said reservoir, and a second position, wherein said plunger interacts with the movable wall of the reservoir and further translation of the plunger in the direction of the movable wall results in fluid flow through the one-way valve of the reservoir; and

a dosing member, said dosing member being movable between a plurality of positions, wherein each of said plurality of positions corresponds to a given quantity of transdermal delivery composition to be dispensed.

103-110. -110. (canceled)