Transdermal flux enhancers in combination with iontophoresis in topical administration of pharmaceuticals

• US 5,023,085 A
• Filed: 11/29/1989
• Issued: 06/11/1991
• Est. Priority Date: 11/29/1989
• Status: Expired due to Fees

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Potts, Russell O., Francoeur, Michael L.
• Primary Examiner(s): Page, Thurman
• Assistant Examiner(s): BROUILLETTE, D GABRIELLE
• Application Number:
  US07/443,699
• Time in Patent Office: 559 Days
• Field of Search: 424/449, 514/946, 514/947, 604/20
• US Class Current: 424/449
• CPC Class Codes: A61K 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 9/0009 involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis microelectromechanical systems A61K9/0097
• 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: 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 31/002 Devices for releasing a drug at a continuous and controlled rate for a prolonged period of time artificial gland structures or devices A61F2/022; intra-uterine contraceptive devices A61F6/14; tampons for introducing into the vagina A61F13/20, A61L15/00; suppositories or bougies for intra-vaginal or intra-uterine application A61K9/02; physical forms of medicinal preparations for sustained or differential drug release A61K9/20, A61K9/50
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders

Abstract

Transdermal flux enhancers such as oleic acid and 1-dodecylazacycloheptan-2-one are used in combination with iontophoresis in the topical administration of pharmaceutical agents.

Claims

1. A method of treating a disease in a human or lower animal which comprises iontophoretic administration of a pharmaceutical composition comprising:

(a) a pharmaceutically effective amount of an active agent;

(b) an aqueous solvent; and

(c) a transdermal flux enhancing amount of a dermal penetration enhancer which is selected from the group consisting of 1-alkylazacycloheptan-2-one, said alkyl having from 8 to 16 carbon atoms, and a cis-olefin of the formula

space="preserve" listing-type="equation">CH.sub.3 (CH.sub.2).sub.x CH═

CH(CH.sub.2).sub.y R.sup.3

where R³ is CH₂ OH, CH₂ NH₂ or COR⁴, and R⁴ is OH or (C₁ -C₄)alkoxy, x and y are each an integer from 3 to 13 and the sum of x and y is from 10 to 16.

2. A method according to claim 1 wherein the dermal penetration enhancer is selected from the group consisting of cis-9-tetradecenoic acid, cis-6-pentadecenoic acid, cis-6-hexadecenoic acid, cis-9-hexadecenoic acid, cis-9-octadecenoic acid (oleic acid), cis-6-octadecenoic acid, cis-11-octadecenoic acid, cis-12-octadecenoic acid, cis-5-eicosenoic acid, cis-9-eicosenoic acid, cis-11-eicosenoic acid, cis-14-eicosenoic acid, 1-decylazacycloheptan-2-one, 1-dodecylazacycloheptan-2-one and 1-tetradecylazacycloheptan-2-one.

3. A method according to claim 2 wherein the dermal penetration enhancer is cis-9-octadecenoic acid.

4. A method according to claim 1 wherein the aqueous solvent further comprises, in addition to water, methanol, ethanol, isopropyl alcohol, propylene glycol, polyethylene glycol or glycerin.

5. A method according to claim 1 wherein the active agent is an ionized or ionizable pharmaceutical agent.

6. A method of claim 5 wherein the pharmaceutical agent is an analgesic or antiinflammatory agent used in the treatment of pain or an inflammatory disease.

7. A method of claim 6 wherein the analgesic or antiinflammatory agent is selected from the group consisting of aspirin, acetaminophen, indomethacin, ibuprofen, naproxen, a compound of the formula ##STR6## piroxicam, and prodrugs of piroxicam of the formula ##STR7## wherein R is CH(R¹)OCOR² or CH(R¹)OCOOR², R¹ is hydrogen or methyl and R² is (C₁ -C₉)alkyl;

or a pharmaceutically acceptable salt of said analgesic or antiinflammatory agents.

8. A method according to claim 5 wherein the pharmaceutical agent is an antibacterial agent used in the treatment of a bacterial infection.

9. A method of claim 8 wherein the antibacterial agent is selected from the group consisting of erythromycin, azithromycin, oxytetracycline, tetracycline, doxycycline, penicillin G, penicillin V, ampicillin and amoxicillin;

or a pharmaceutically acceptable salt thereof.

10. A method according to claim 5 wherein the pharmaceutical agent is an antifungal agent used in the treatment of a fungal infection.

11. A method according to claim 10 wherein the antifungal agent is selected from the group consisting of fluconazole and tioconazole, or a pharmaceutically acceptable salt thereof.

12. A method of claim 5 wherein the pharmaceutical agent is used in the treatment of a cardiovascular disease.

13. A method of claim 12 wherein the pharmaceutical agent is selected from the group consisting of nifedipine, amlodipine, prazosin, doxazosin, a compound of the formula ##STR8## and a compound of the formula ##STR9## wherein X is O or C═

O;

or a pharmaceutically acceptable salt thereof.

14. A method of claim 5 wherein the pharmaceutical agent is selected from the group consisting of sertraline, insulin, glipizide, a compound of the formula ##STR10## and a compound of the formula ##STR11## or a pharmaceutically acceptable salt thereof.

15. A method according to any one of claims 5 to 14 wherein the dermal penetration enhancer is cis-9-octadecenoic acid.