Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, Alzheimer'S disease, sleep disorders, Parkinson'S disease, AIDS, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like

• US 8,741,336 B2
• Filed: 06/04/2012
• Issued: 06/03/2014
• Est. Priority Date: 09/13/2004
• Status: Active Grant

• Current Assignee: Morningside Venture Investments Ltd. (Morningside Group Ltd.)
• Original Assignee: Chrono Therapeutics Inc.
• Inventors: DiPierro, Guy, Giannos, Steven A.
• Primary Examiner(s): GULLEDGE, BRIAN M
• Application Number:
  US13/488,195
• Publication Number:
  US 20120302942A1
• Time in Patent Office: 729 Days
• Field of Search: None
• US Class Current: 424/449
• CPC Class Codes: A61K 31/04 Nitro compounds
• CPC Class Codes: A61K 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/155 Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
• CPC Class Codes: A61K 31/165 having aromatic rings, e.g. colchicine, atenolol, progabide
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/18 Sulfonamides compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63
• 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 31/195 having an amino group
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/216 of acids having aromatic rings, e.g. benactizyne, clofibrate
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4168 having a nitrogen attached in position 2, e.g. clonidine
• CPC Class Codes: A61K 31/42 Oxazoles
• CPC Class Codes: A61K 31/421 1,3-Oxazoles, e.g. pemoline, trimethadione
• CPC Class Codes: A61K 31/428 : condensed with carbocyclic rings
• CPC Class Codes: A61K 31/435 : having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/4436 : containing a heterocyclic ring having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/4439 : containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/445 : Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4453 : only substituted in position 1, e.g. propipocaine, diperodon
• CPC Class Codes: A61K 31/4458 : only substituted in position 2, e.g. methylphenidate
• 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 31/47 : Quinolines; Isoquinolines
• CPC Class Codes: A61K 31/473 : ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/485 : Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/4965 : Non-condensed pyrazines
• CPC Class Codes: A61K 31/498 : Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/4985 : Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/505 : Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 31/55 : having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/704 : attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7072 : having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/708 : having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• 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 9/7023 : Transdermal patches and similar drug-containing composite devices, e.g. cataplasms galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006
• CPC Class Codes: A61K 9/7084 : Transdermal patches having a drug layer or reservoir, and one or more separate drug-free skin-adhesive layers, e.g. between drug reservoir and skin, or surrounding the drug reservoir; Liquid-filled reservoir patches
• CPC Class Codes: A61M 2005/14268 : with a reusable and a disposable component
• CPC Class Codes: A61M 2037/0007 : having means for enhancing the permeation of substances through the epidermis, e.g. using suction or depression, electric or magnetic fields, sound waves or chemical agents
• CPC Class Codes: A61M 2037/0023 : Drug applicators using microneedles
• CPC Class Codes: A61M 2205/3337 : Controlling, regulating pressure or flow by means of a valve by-passing a pump
• CPC Class Codes: A61M 2205/3368 : Temperature
• CPC Class Codes: A61M 2205/50 : with microprocessors or computers
• CPC Class Codes: A61M 2205/502 : User interfaces, e.g. screens or keyboards
• CPC Class Codes: A61M 2205/8206 : battery-operated
• CPC Class Codes: A61M 37/00 : Other apparatus for introducing media into the body for reproduction or fertilisation A61B17/425; apparatus for iontophoresis or cataphoresis A61N1/30; Percutany, i.e. introducing medicines into the body by diffusion through the skin salt baths A61H33/04
• CPC Class Codes: A61M 37/0015 : by using microneedles
• CPC Class Codes: A61M 37/0092 : using ultrasonic, sonic or infrasonic vibrations, e.g. phonophoresis
• CPC Class Codes: A61M 39/22 : Valves or arrangement of valves A61M39/02, A61M39/0247, A61M39/16 take precedence; regulating valves in infusion systems A61M5/16881; in devices worn by the patient for the reception of urine, faeces, catamenial or other discharge, or in colostomy devices A61F5/4405
• CPC Class Codes: A61M 5/14248 : of the skin patch type
• CPC Class Codes: A61N 1/30 : Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system

Abstract

Systems and methods for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and treating hyperglycemia, Alzheimer'"'"'s disease, sleep disorders, Parkinson'"'"'s disease, Attention Deficit Disorder and nicotine addiction involve synchronizing and tailoring the administration of nutraceuticals, medications and other substances (for example, stimulants) in accordance with the body'"'"'s natural circadian rhythms, meal times and other factors. Improved control of blood glucose levels, extended alertness, and weight control, and counteracting of disease symptoms when they are at their worst are possible. An automated, pre-programmable transdermal administration system is used to provide pulsed doses of medications, pharmaceuticals, hormones, neuropeptides, anorexigens, pro-drugs, stimulants, plant extracts, botanicals, nutraceuticals, cosmeceuticals, phytochemicals, phytonutrients, enzymes, antioxidants, essential oils, fatty acids, minerals, vitamins, amino acids, coenzymes, or other physiological active ingredient or precursor. The system can utilize a pump, pressurized reservoir, a system for removing depleted carrier solution, or other modulated dispensing actuator, in conjunction with porous membranes or micro-fabricated structures.

Claims

1. A programmable transdermal drug delivery device comprising:

(a) an interface for coupling to the skin of a subject;

(b) a reservoir storing a quantity of an active substance, carrier materials, or a combination thereof;

(c) a delivery mechanism for modulating the quantity of the active substance supplied from the reservoir to the interface in response to a control signal;

(d) an electronic programmable timing mechanism coupled to the delivery mechanism and configured to generate the control signal according to a programmed administration schedule;

(e) a mechanism for removing the active substance and/or carrier materials from the interface, which functions to stop permeation or dosing of the active substance, while the device is maintained in contact with the skin of the subject; and

(f) a permeation enhancer selected from the group consisting of ethanol, isopropanol, propylene glycol, polyethylene glycol, amino acids, oleic acid, oleyl alcohol, long chain fatty acids, ethoxydiglycol, sodium xylene sulfonate, N-methylpyrrolidone, laurocapram, alkanecarboxylic acids, dimethylsulfoxide, polar lipids, and N-methyl-2-pyrrolidone.

2. The device of claim 1, wherein the delivery mechanism utilizes a motive force selected from the group consisting of a micro-pump, pressurized drug reservoir, a valve, an actuator, and any combination thereof to release active substance and/or carrier materials from the reservoir which controls a rate at which the active substance is supplied in response to the control signal.

3. The device of claim 1, further comprising a heating element.

4. The device of claim 3, wherein the heating element:

(a) can increase the temperature of an administration area for increased permeation;

(b) can increase the temperature of the active substance and/or carrier materials in the reservoir;

(c) can increase the temperature of the drug delivery device, or

(d) any combination thereof;

wherein heating (i) increases permeation of the active substance through the skin and/or (ii) increases removal of the carrier materials which in turn stops dosing of the active substance.

5. The device of claim 1, wherein the mechanism for removing the active substance and/or carrier materials from the interface is in response to a control signal.

6. The device of claim 5, wherein the mechanism for removing active substance and/or carrier materials from the interface comprises:

(a) stoppage of active substance permeation or dosing by a motive force, which can move gas, air, active substance, carrier materials, or any combination thereof;

(b) stoppage of active substance permeation or dosing by actuator, which can move gas, air, active substance, carrier materials, or any combination thereof;

(c) a second motive force, micropump or actuator, which can move gas, air, active substance, carrier materials, or any combination thereof;

(d) a heating element which may aid in evaporation;

(e) a gas cartridge, air cartridge, gas blowing apparatus, air blowing apparatus, or any combination thereof;

or

(f) any of (a) through (e) which respond to a control signal.

7. The device of claim 1, further comprising a waste reservoir for controlled stopping of the delivery of the active substance.

8. The device of claim 1, further comprising evaporative means for evaporation of the active substance and/or carrier materials to provide for controlled stopping of the delivery of the active substance.

9. The device of claim 8, wherein the evaporative means responds to a control signal.

10. The device of claim 1, further comprising a desiccant to provide for controlled stopping of the delivery of the active substance.

11. The device of claim 1, further comprising a vapor removal element to provide for controlled stopping of the delivery of the active substance.

12. The device of claim 11, wherein the vapor removal element responds to a control signal.

13. The device of claim 1, further comprising a hydrophilic substance to provide for controlled stopping of the delivery of the active substance.

14. The device of claim 1, further comprising a micropump to provide for controlled stopping of the delivery of the active substance.

15. The device of claim 1, wherein the active substance reservoir is pressurized to provide for controlled stopping of the delivery of the active substance.

16. The device of claim 1, wherein:

(a) the reservoir storing a quantity of an active substance is an active substance reservoir;

(b) the device further comprises an administration reservoir; and

(c) the active substance reservoir is separated from the administration reservoir.

17. The device of claim 1, further comprising a mechanism for causing the active substance to be delivered transdermally in response to the timing mechanism by passive absorption.

18. The device of claim 1, further comprising a porous membrane.

19. The device of claim 1, further comprising timing routines implemented by the timing mechanism, wherein the timing routines are selected to deliver the active substance by passive absorption at a time, rate, sequence and/or cycle that is synchronized with a biological rhythm of the human or animal.

20. The device of claim 19, wherein the timing routine is selected from the group consisting of:

(a) a timing routine to deliver the active substance at a time when the subject is asleep or is expected to be asleep;

(b) a timing routine to deliver the active substance at a time when the subject is awake or is expected to be awake;

(c) a timing routine to deliver the active substance at a time when the subject is waking up or is expected to be waking up;

(d) a timing routine to deliver the active substance in during or near mealtime;

(e) a timing routine to increase a dosage of the active substance at a preprogrammed time;

(f) a timing routine to decrease a dosage of the active substance at a preprogrammed time;

(g) a timing routine to terminate delivery of the active substance at a preprogrammed time;

(h) a timing routine to increase delivery of the active substance in response to a signal representative of a change in a physiological condition;

(i) a timing routine to deliver the active substance in response to a signal indicative of a demand by the subject; and

(j) a timing routine to deliver the active substance at regular intervals.

21. The device of claim 1, further comprising memory storing a dosing profile.

22. The device of claim 1, wherein the active substance is selected from the group consisting of active agents, stimulants, pharmaceutical agents, herbal supplements, Minerals, Vitamins, amino acids, Natural Hormones, antihistamines, and weight-loss compounds.

23. The device of claim 1, wherein the active substance is selected from the group consisting of:

(a) an active agent selected from the group consisting of glibenclamide, glipizide, rosiglitazone, metformin, dextroamphetamine, ephedrine, adrifina, ampakine, tacrine, donepezil, rivastigmine, galantamine, memantine, selegiline, ropinirole, apomorphine, pramipexole, biperiden, bromocriptine, levodopa, methylphenidate, dextro-amphetamine, bupropion, nitroglycerin, indomethacin, valdecoxib, tulobuterol, clonidine, oxybutynin, zolmitriptan, miglitol, entanyl, 5-fluorouracil, doxorubicin, cisplatin, zidovudine, gabapentin, triprolidine, fentanyl, diclofenac, theophylline, carbidopa, entacapone, metoprolol and caffeine;

(b) a stimulant selected from the group consisting of adrenaline, ephedrine, ephedrine derivatives, dopamine, caffeine, theobromine, theophylline, CX-516, CX546, CX614, CX717;

(c) pharmaceutical agents selected from the group consisting of rimonabant, leptin, ghrelin, nesfatin-1, and peptide YY 3-36;

(d) a mineral selected from the group consisting of boron, calcium, magnesium, chromium, selenium, and zinc;

(e) a vitamin selected from the group consisting of retinoids, retinol, retinal, retinoic acid, 3-dehydroretinol, Thiamine, Riboflavin, Niacin, Pantothenic acid, Pyridoxine, Biotin, Folic acid, Cyanocobalamin, Ascorbic acid, Lumisterol, Ergocalciferol, Cholecalciferol, Dihydrotachysterol, 7-Dehydrocholesterol, Tocopherol, Tocotrienol, Naphthoquinone;

(f) an amino acid selected from the group consisting of isoleucine, Alanine, Leucine, Asparagine, Lysine, Aspartate, Methionine, Cysteine, Phenylalanine, Glutamate, Threonine, Glutamine, Tryptophan, Glycine, Valine, Proline, Arginine, Serine, Histidine, Tyrosine, selenocysteine, pyrrolysine, taurine, n-acetylcysteine, GABA, dopamine, Carnosine, lanthionine, 2-Aminoisobutyric acid, dehydroalanine, ornithine, and citrulline;

(g) a coenzyme selected from the group consisting of Coenzyme A, Coenzyme B12, Coenzyme Q, NAD, FAD, ATP, and molybdopterin;

(h) an antioxidant selected from the group consisting of Glutathione, Lutein, alpha-lipoic acid, polyphenols, Pycnogenol, Grape seed extract, superoxide dismutase, epicatechin, proanthocyanidins, and sulfoxides;

(i) a compound selected from the group consisting of Guarana, Brown Seaweed, Fucus Vesiculosis, 5 HTP, yerba mate, flaxseed oil, L-caritine, Synephrine, oxedrine, Sympatol, Coleus forskohlii, forskohlin, diiodotyrosine, chromium poly-nicotinate, garlic extract, yeast extract, fatty acids, omega-3 fish oil, kava, kavalactones, Aniracetam, Bromocriptine, Carnosine, Centrophenoxine, Deprenyl, Gerovital-H3, Hydergine, Idebenone, Melatonin, Piracetam, Pramiracetam, Pyritinol, Resveratrol, Vinpocetine, Vitamin C, thymus, yohimbine, Morinda citrifolia, Proxeronine, Proxeronase, Xeronine, Damnacanthal, and Scopoletin;

(j) a steroid or steroid precursor selected from the group consisting of Anabolic steroids, Corticosteroids, glucocorticoids, mineralocorticoids, Sex steroids, androgens, estrogens, progestagens, Phytosterols, Ergosterols, progestational agents, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, dexamethasone, betamethasone, triamcinolone, methyltestosterone, 17-beta-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone, 17-beta-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel, norethindrone, norethisterone, norethiederone, progesterone, norgesterone, norethynodrel, and dehydroepiandrosterone (DHEA);

(k) a nutritional supplements selected from the group consisting of Resveratrol, Dimethlyglycine (DMG), 5 Hydroxy L-tryptophan (5-HTP), Inositol hexaphosphate (IP6), S-adenosylmethionine (SAMe), Glucosamine sulfate, N. Acetyl glucosamine, Choline, inositol and melatonin, creatine, pyruvate, beta-hydroxy beta-methylbutyrate (HMB), and ginseng;

(l) a natural hormone selected from the group consisting of black cohosh (Cimicifuga racemosa) root, rhizome extract, soy bean extracts, and wild Mexican yam extracts;

(m) an Ayuervedic herb extract selected from the group consisting of Adhatoda;

A. vasica, Arjun;

Terminalia arjuna, Asafoetida;

Ferula asafetida, Ashwaganda;

Withania sominifera, Asparagus;

A. racemosa, Bacopa;

B. monerii, Crataeva;

C. nurvala, Emblica;

F. ribes, Momordica;

M. charantia, Myrrh;

Commiphora mukul and C. myrrha. Saraca;

S. asoka, Tinospora; and

T. cordifolia; and

(o) and any combination thereof.

24. The device of claim 1, wherein the active substance is to treat or manage a condition or disease selected from the group consisting of fatigue, obesity, weight loss, weight management, hyperglycemia, Alzheimer'"'"'s disease, a sleep disorder, Parkinson'"'"'s disease, attention deficit disorder, nicotine addiction, cancer, headache, migraine, pain management, asthma, angina, hypertension, depression, epilepsy, AIDS, a cold and a flu.

25. The device of claim 1, wherein the active substance comprises nicotine and:

(a) the timing routines are selected to deliver the nicotine at times that are associated with nicotine cravings;

(b) and the timing routines are selected to deliver the nicotine immediately before the subject wakes up;

or

(c) any combination thereof.

26. The device of claim 1, wherein the active substance comprises an antihistamine and the timing routines are selected to deliver the antihistamine while the subject sleeps.

27. The device of claim 1, wherein the device utilizes iontophoresis to aid in delivery of the active substance.

28. A programmable transdermal drug delivery device comprising:

(a) an interface for coupling to the skin of a subject;

(b) a reservoir storing a quantity of an active substance, carrier materials, or a combination thereof;

(c) a delivery mechanism for modulating the quantity of the active substance supplied from the reservoir to the interface in response to a control signal;

(d) an electronic programmable timing mechanism coupled to the delivery mechanism and configured to generate the control signal according to a programmed administration schedule;

(e) a mechanism for removing the active substance and/or carrier materials from the interface, which functions to stop permeation or dosing of the active substance, while the device is maintained in contact with the skin of the subject; and

(f) an actuator to provide for controlled stopping of the delivery of the active substance.

29. The device of claim 28, wherein the delivery mechanism utilizes a motive force selected from the group consisting of a micro-pump, pressurized drug reservoir, a valve, an actuator, and any combination thereof to release active substance and/or carrier materials from the reservoir which controls a rate at which the active substance is supplied in response to the control signal.

30. The device of claim 28, further comprising a heating element.

31. The device of claim 30, wherein the heating element:

(a) can increase the temperature of an administration area for increased permeation;

(b) can increase the temperature of the active substance and/or carrier materials in the reservoir;

(c) can increase the temperature of the drug delivery device, or

(d) any combination thereof;

wherein heating (i) increases permeation of the active substance through the skin and/or (ii) increases removal of the carrier materials which in turn stops dosing of the active substance.

32. The device of claim 28, wherein the mechanism for removing the active substance and/or carrier materials from the interface is in response to a control signal.

33. The device of claim 32, wherein the mechanism for removing active substance and/or carrier materials from the interface comprises:

(a) stoppage of active substance permeation or dosing by a motive force, which can move gas, air, active substance, carrier materials, or any combination thereof;

(b) stoppage of active substance permeation or dosing by actuator, which can move gas, air, active substance, carrier materials, or any combination thereof;

(c) a second motive force, micropump or actuator, which can move gas, air, active substance, carrier materials, or any combination thereof;

(d) a heating element which may aid in evaporation;

(e) a gas cartridge, air cartridge, gas blowing apparatus, air blowing apparatus, or any combination thereof;

or

(f) any of (a) through (e) which respond to a control signal.

34. The device of claim 28, further comprising a waste reservoir for controlled stopping of the delivery of the active substance.

35. The device of claim 28, further comprising evaporative means for evaporation of the active substance and/or carrier materials to provide for controlled stopping of the delivery of the active substance.

36. The device of claim 35, wherein the evaporative means responds to a control signal.

37. The device of claim 28, further comprising a desiccant to provide for controlled stopping of the delivery of the active substance.

38. The device of claim 28, further comprising a vapor removal element to provide for controlled stopping of the delivery of the active substance.

39. The device of claim 38, wherein the vapor removal element responds to a control signal.

40. The device of claim 28, further comprising a hydrophilic substance to provide for controlled stopping of the delivery of the active substance.

41. The device of claim 28, further comprising a micropump to provide for controlled stopping of the delivery of the active substance.

42. The device of claim 28, wherein the active substance reservoir is pressurized to provide for controlled stopping of the delivery of the active substance.

43. The device of claim 28, wherein:

(a) the reservoir storing a quantity of an active substance is an active substance reservoir;

(b) the device further comprises an administration reservoir; and

(c) the active substance reservoir is separated from the administration reservoir.

44. The device of claim 28, further comprising a mechanism for causing the active substance to be delivered transdermally in response to the timing mechanism by passive absorption.

45. The device of claim 28, further comprising a porous membrane.

46. The device of claim 28, further comprising timing routines implemented by the timing mechanism, wherein the timing routines are selected to deliver the active substance by passive absorption at a time, rate, sequence and/or cycle that is synchronized with a biological rhythm of the human or animal.

47. The device of claim 46, wherein the timing routine is selected from the group consisting of:

(a) a timing routine to deliver the active substance at a time when the subject is asleep or is expected to be asleep;

(b) a timing routine to deliver the active substance at a time when the subject is awake or is expected to be awake;

(c) a timing routine to deliver the active substance at a time when the subject is waking up or is expected to be waking up;

(d) a timing routine to deliver the active substance in during or near mealtime;

(e) a timing routine to increase a dosage of the active substance at a preprogrammed time;

(f) a timing routine to decrease a dosage of the active substance at a preprogrammed time;

(g) a timing routine to terminate delivery of the active substance at a preprogrammed time;

(h) a timing routine to increase delivery of the active substance in response to a signal representative of a change in a physiological condition;

(i) a timing routine to deliver the active substance in response to a signal indicative of a demand by the subject; and

(j) a timing routine to deliver the active substance at regular intervals.

48. The device of claim 28, further comprising memory storing a dosing profile.

49. The device of claim 28, wherein the active substance is selected from the group consisting of active agents, stimulants, pharmaceutical agents, herbal supplements, Minerals, Vitamins, amino acids, Natural Hormones, antihistamines, and weight-loss compounds.

50. The device of claim 28, wherein the active substance is selected from the group consisting of:

(a) an active agent selected from the group consisting of glibenclamide, glipizide, rosiglitazone, metformin, dextroamphetamine, ephedrine, adrifina, ampakine, tacrine, donepezil, rivastigmine, galantamine, memantine, selegiline, ropinirole, apomorphine, pramipexole, biperiden, bromocriptine, levodopa, methylphenidate, dextro-amphetamine, bupropion, nitroglycerin, indomethacin, valdecoxib, tulobuterol, clonidine, oxybutynin, zolmitriptan, miglitol, entanyl, 5-fluorouracil, doxorubicin, cisplatin, zidovudine, gabapentin, triprolidine, fentanyl, diclofenac, theophylline, carbidopa, entacapone, metoprolol and caffeine;

(b) a stimulant selected from the group consisting of adrenaline, ephedrine, ephedrine derivatives, dopamine, caffeine, theobromine, theophylline, CX-516, CX546, CX614, CX717;

(c) pharmaceutical agents selected from the group consisting of rimonabant, leptin, ghrelin, nesfatin-1, and peptide YY 3-36;

(d) a mineral selected from the group consisting of boron, calcium, magnesium, chromium, selenium, and zinc;

(e) a vitamin selected from the group consisting of retinoids, retinol, retinal, retinoic acid, 3-dehydroretinol, Thiamine, Riboflavin, Niacin, Pantothenic acid, Pyridoxine, Biotin, Folic acid, Cyanocobalamin, Ascorbic acid, Lumisterol, Ergocalciferol, Cholecalciferol, Dihydrotachysterol, 7-Dehydrocholesterol, Tocopherol, Tocotrienol, Naphthoquinone;

(f) an amino acid selected from the group consisting of Isoleucine, Alanine, Leucine, Asparagine, Lysine, Aspartate, Methionine, Cysteine, Phenylalanine, Glutamate, Threonine, Glutamine, Tryptophan, Glycine, Valine, Proline, Arginine, Serine, Histidine, Tyrosine, selenocysteine, pyrrolysine, taurine, n-acetylcysteine, GABA, dopamine, Carnosine, lanthionine, 2-Aminoisobutyric acid, dehydroalanine, ornithine, and citrulline;

(g) a coenzyme selected from the group consisting of Coenzyme A, Coenzyme B12, Coenzyme Q, NAD, FAD, ATP, and molybdopterin;

(h) an antioxidant selected from the group consisting of Glutathione, Lutein, alpha-lipoic acid, polyphenols, Pycnogenol, Grape seed extract, superoxide dismutase, epicatechin, proanthocyanidins, and sulfoxides;

(i) a compound selected from the group consisting of Guarana, Brown Seaweed, Fucus Vesiculosis, 5 HTP, yerba mate, flaxseed oil, L-caritine, Synephrine, oxedrine, Sympatol, Coleus forskohlii, forskohlin, diiodotyrosine, chromium poly-nicotinate, garlic extract, yeast extract, fatty acids, omega-3 fish oil, kava, kavalactones, Aniracetam, Bromocriptine, Carnosine, Centrophenoxine, Deprenyl, Gerovital-H3, Hydergine, Idebenone, Melatonin, Piracetam, Pramiracetam, Pyritinol, Resveratrol, Vinpocetine, Vitamin C, thymus, yohimbine, Morinda citrifolia, Proxeronine, Proxeronase, Xeronine, Damnacanthal, and Scopoletin;

(j) a steroid or steroid precursor selected from the group consisting of Anabolic steroids, Corticosteroids, glucocorticoids, mineralocorticoids, Sex steroids, androgens, estrogens, progestagens, Phytosterols, Ergosterols, progestational agents, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, dexamethasone, betamethasone, triamcinolone, methyltestosterone, 17-beta-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone, 17-beta-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel, norethindrone, norethisterone, norethiederone, progesterone, norgesterone, norethynodrel, and dehydroepiandrosterone (DHEA);

(k) a nutritional supplements selected from the group consisting of Resveratrol, Dimethlyglycine (DMG), 5 Hydroxy L-tryptophan (5-HTP), Inositol hexaphosphate (IP6), 5-adenosylmethionine (SAMe), Glucosamine sulfate, N. Acetyl glucosamine, Choline, inositol and melatonin, creatine, pyruvate, beta-hydroxy beta-methylbutyrate (HMB), and ginseng;

(l) a natural hormone selected from the group consisting of black cohosh (Cimicifuga racemosa) root, rhizome extract, soy bean extracts, and wild Mexican yam extracts;

(m) an Ayuervedic herb extract selected from the group consisting of Adhatoda;

A. vasica, Arjun;

Teminalia arjuna, Asafoetida;

Ferula asafetida, Ashwaganda;

Withania sominifera, Asparagus;

A. racemosa, Bacopa;

B. monerii, Crataeva;

C. nurvala, Emblica;

E. ribes, Momordica;

M. charantia, Myrrh;

Commiphora mukul and C. myrrha, Saraca;

S. asoka, Tinospora; and

T. cordifolia; and

(o) and any combination thereof.

51. The device of claim 28, wherein the active substance is to treat or manage a condition or disease selected from the group consisting of fatigue, obesity, weight loss, weight management, hyperglycemia, Alzheimer'"'"'s disease, a sleep disorder, Parkinson'"'"'s disease, attention deficit disorder, nicotine addiction, cancer, headache, migraine, pain management, asthma, angina, hypertension, depression, epilepsy, AIDS, a cold and a flu.

52. The device of claim 28, wherein the active substance comprises nicotine and:

(a) the timing routines are selected to deliver the nicotine at times that are associated with nicotine cravings;

(b) and the timing routines are selected to deliver the nicotine immediately before the subject wakes up;

or

(c) any combination thereof.

53. The device of claim 28, wherein the active substance comprises an antihistamine and the timing routines are selected to deliver the antihistamine while the subject sleeps.

54. The device of claim 28, wherein the device utilizes iontophoresis to aid in delivery of the active substance.

55. A programmable transdermal drug delivery device comprising:

(a) an interface for coupling to the skin of a subject;

(b) a reservoir storing a quantity of an active substance, carrier materials, or a combination thereof;

(c) a delivery mechanism for modulating the quantity of the active substance supplied from the reservoir to the interface in response to a control signal;

(d) an electronic programmable timing mechanism coupled to the delivery mechanism and configured to generate the control signal according to a programmed administration schedule;

(e) a mechanism for removing the active substance and/or carrier materials from the interface, which functions to stop permeation or dosing of the active substance, while the device is maintained in contact with the skin of the subject; and

(f) one or more micro-fabricated structures, wherein the micro-fabricated structure is micro-needles.

56. The device of claim 55, wherein the delivery mechanism utilizes a motive force selected from the group consisting of a micro-pump, pressurized drug reservoir, a valve, an actuator, and any combination thereof to release active substance and/or carrier materials from the reservoir which controls a rate at which the active substance is supplied in response to the control signal.

57. The device of claim 55, further comprising a heating element.

58. The device of claim 57, wherein the heating element:

(a) can increase the temperature of an administration area for increased permeation;

(b) can increase the temperature of the active substance and/or carrier materials in the reservoir;

(c) can increase the temperature of the drug delivery device, or

(d) any combination thereof;

wherein heating (i) increases permeation of the active substance through the skin and/or (ii) increases removal of the carrier materials which in turn stops dosing of the active substance.

59. The device of claim 55, wherein the mechanism for removing the active substance and/or carrier materials from the interface is in response to a control signal.

60. The device of claim 59, wherein the mechanism for removing active substance and/or carrier materials from the interface comprises:

(a) stoppage of active substance permeation or dosing by a motive force, which can move gas, air, active substance, carrier materials, or any combination thereof;

(b) stoppage of active substance permeation or dosing by actuator, which can move gas, air, active substance, carrier materials, or any combination thereof;

(c) a second motive force, micropump or actuator, which can move gas, air, active substance, carrier materials, or any combination thereof;

(d) a heating element which may aid in evaporation;

(e) a gas cartridge, air cartridge, gas blowing apparatus, air blowing apparatus, or any combination thereof;

or

(f) any of (a) through (e) which respond to a control signal.

61. The device of claim 55, further comprising a waste reservoir for controlled stopping of the delivery of the active substance.

62. The device of claim 55, further comprising evaporative means for evaporation of the active substance and/or carrier materials to provide for controlled stopping of the delivery of the active substance.

63. The device of claim 62, wherein the evaporative means responds to a control signal.

64. The device of claim 55, further comprising a desiccant to provide for controlled stopping of the delivery of the active substance.

65. The device of claim 55, further comprising a vapor removal element to provide for controlled stopping of the delivery of the active substance.

66. The device of claim 65, wherein the vapor removal element responds to a control signal.

67. The device of claim 55, further comprising a hydrophilic substance to provide for controlled stopping of the delivery of the active substance.

68. The device of claim 55, further comprising a micropump to provide for controlled stopping of the delivery of the active substance.

69. The device of claim 55, wherein the active substance reservoir is pressurized to provide for controlled stopping of the delivery of the active substance.

70. The device of claim 55, wherein:

(a) the reservoir storing a quantity of an active substance is an active substance reservoir;

(b) the device further comprises an administration reservoir; and

(c) the active substance reservoir is separated from the administration reservoir.

71. The device of claim 55, further comprising a mechanism for causing the active substance to be delivered transdermally in response to the timing mechanism by passive absorption.

72. The device of claim 55, further comprising a porous membrane.

73. The device of claim 55, further comprising timing routines implemented by the timing mechanism, wherein the timing routines are selected to deliver the active substance by passive absorption at a time, rate, sequence and/or cycle that is synchronized with a biological rhythm of the human or animal.

74. The device of claim 73, wherein the timing routine is selected from the group consisting of:

(a) a timing routine to deliver the active substance at a time when the subject is asleep or is expected to be asleep;

(b) a timing routine to deliver the active substance at a time when the subject is awake or is expected to be awake;

(c) a timing routine to deliver the active substance at a time when the subject is waking up or is expected to be waking up;

(d) a timing routine to deliver the active substance in during or near mealtime;

(e) a timing routine to increase a dosage of the active substance at a preprogrammed time;

(f) a timing routine to decrease a dosage of the active substance at a preprogrammed time;

(g) a timing routine to terminate delivery of the active substance at a preprogrammed time;

(h) a timing routine to increase delivery of the active substance in response to a signal representative of a change in a physiological condition;

(i) a timing routine to deliver the active substance in response to a signal indicative of a demand by the subject; and

(j) a timing routine to deliver the active substance at regular intervals.

75. The device of claim 55, further comprising memory storing a dosing profile.

76. The device of claim 55, wherein the active substance is selected from the group consisting of active agents, stimulants, pharmaceutical agents, herbal supplements, Minerals, Vitamins, amino acids, Natural Hormones, antihistamines, and weight-loss compounds.

77. The device of claim 55, wherein the active substance is selected from the group consisting of:

(a) an active agent selected from the group consisting of glibenclamide, glipizide, rosiglitazone, metformin, dextroamphetamine, ephedrine, adrifina, ampakine, tacrine, donepezil, rivastigmine, galantamine, memantine, selegiline, ropinirole, apomorphine, pramipexole, biperiden, bromocriptine, levodopa, methylphenidate, dextro-amphetamine, bupropion, nitroglycerin, indomethacin, valdecoxib, tulobuterol, clonidine, oxybutynin, zolmitriptan, miglitol, entanyl, 5-fluorouracil, doxorubicin, cisplatin, zidovudine, gabapentin, triprolidine, fentanyl, diclofenac, theophylline, carbidopa, entacapone, metoprolol and caffeine;

(b) a stimulant selected from the group consisting of adrenaline, ephedrine, ephedrine derivatives, dopamine, caffeine, theobromine, theophylline, CX-516, CX546, CX614, CX717;

(c) pharmaceutical agents selected from the group consisting of rimonabant, leptin, ghrelin, nesfatin-1, and peptide YY 3-36;

(d) a mineral selected from the group consisting of boron, calcium, magnesium, chromium, selenium, and zinc;

(e) a vitamin selected from the group consisting of retinoids, retinol, retinal, retinoic acid, 3-dehydroretinol, Thiamine, Riboflavin, Niacin, Pantothenic acid, Pyridoxine, Biotin, Folic acid, Cyanocobalamin, Ascorbic acid, Lumisterol, Ergocalciferol, Cholecalciferol, Dihydrotachysterol, 7-Dehydrocholesterol, Tocopherol, Tocotrienol, Naphthoquinone;

(f) an amino acid selected from the group consisting of Isoleucine, Alanine, Leucine, Asparagine, Lysine, Aspartate, Methionine, Cysteine, Phenylalanine, Glutamate, Threonine, Glutamine, Tryptophan, Glycine, Valine, Proline, Arginine, Serine, Histidine, Tyrosine, selenocysteine, pyrrolysine, taurine, n-acetylcysteine, GABA, dopamine, Carnosine, lanthionine, 2-Aminoisobutyric acid, dehydroalanine, ornithine, and citrulline;

(g) a coenzyme selected from the group consisting of Coenzyme A, Coenzyme B12, Coenzyme Q, NAD, FAD, ATP, and molybdopterin;

(h) an antioxidant selected from the group consisting of Glutathione, Lutein, alpha-lipoic acid, polyphenols, Pycnogenol, Grape seed extract, superoxide dismutase, epicatechin, proanthocyanidins, and sulfoxides;

(i) a compound selected from the group consisting of Guarana, Brown Seaweed, Fucus Vesiculosis, 5 HTP, yerba mate, flaxseed oil, L-caritine, Synephrine, oxedrine, Sympatol, Coleus forskohlii, forskohlin, diiodotyrosine, chromium poly-nicotinate, garlic extract, yeast extract, fatty acids, omega-3 fish oil, kava, kavalactones, Aniracetam, Bromocriptine, Carnosine, Centrophenoxine, Deprenyl, Gerovital-H3, Hydergine, Idebenone, Melatonin, Piracetam, Pramiracetam, Pyritinol, Resveratrol, Vinpocetine, Vitamin C, thymus, yohimbine, Morinda citrifolia, Proxeronine, Proxeronase, Xeronine, Damnacanthal, and Scopoletin;

(j) a steroid or steroid precursor selected from the group consisting of Anabolic steroids, Corticosteroids, glucocorticoids, mineralocorticoids, Sex steroids, androgens, estrogens, progestagens, Phytosterols, Ergosterols, progestational agents, hydrocortisone, hydrocorticosterone acetate, cortisone acetate, dexamethasone, betamethasone, triamcinolone, methyltestosterone, 17-beta-estradiol, ethinyl estradiol, ethinyl estradiol 3-methyl ether, prednisolone, 17-beta-hydroxyprogesterone acetate, 19-nor-progesterone, norgestrel, norethindrone, norethisterone, norethiederone, progesterone, norgesterone, norethynodrel, and dehydroepiandrosterone (DHEA);

(k) a nutritional supplements selected from the group consisting of Resveratrol, Dimethlyglycine (DMG), 5 Hydroxy L-tryptophan (5-HTP), Inositol hexaphosphate (IP6), S-adenosylmethionine (SAMe), Glucosamine sulfate, N. Acetyl glucosamine, Choline, inositol and melatonin, creatine, pyruvate, beta-hydroxy beta-methylbutyrate (HMB), and ginseng;

(l) a natural hormone selected from the group consisting of black cohosh (Cimicifuga racemosa) root, rhizome extract, soy bean extracts, and wild Mexican yam extracts;

(m) an Ayuervedic herb extract selected from the group consisting of Adhatoda;

A. vasica, Arjun;

Teminalia arjuna, Asafoetida;

Ferula asafetida, Ashwaganda;

Withania sominifera, Asparagus;

A. racemosa, Bacopa;

B. monerii, Crataeva;

C. nurvala, Emblica;

E. ribes, Momordica;

M. charantia, Myrrh;

Commiphora mukul and C. myrrha, Saraca;

S. asoka, Tinospora; and

T. cordifolia; and

(o) and any combination thereof.

78. The device of claim 55, wherein the active substance is to treat or manage a condition or disease selected from the group consisting of fatigue, obesity, weight loss, weight management, hyperglycemia, Alzheimer'"'"'s disease, a sleep disorder, Parkinson'"'"'s disease, attention deficit disorder, nicotine addiction, cancer, headache, migraine, pain management, asthma, angina, hypertension, depression, epilepsy, AIDS, a cold and a flu.

79. The device of claim 55, wherein the active substance comprises nicotine and:

(a) the timing routines are selected to deliver the nicotine at times that are associated with nicotine cravings;

(b) and the timing routines are selected to deliver the nicotine immediately before the subject wakes up;

or

(c) any combination thereof.

80. The device of claim 55, wherein the active substance comprises an antihistamine and the timing routines are selected to deliver the antihistamine while the subject sleeps.

81. The device of claim 55, wherein the device utilizes iontophoresis to aid in delivery of the active substance.

82. The device of claim 55, wherein the micro-fabricated structures utilize iontophoresis to aid in delivery of the active substance.