Compositions and methods for enhanced drug delivery

• US 5,607,691 A
• Filed: 05/24/1995
• Issued: 03/04/1997
• Est. Priority Date: 06/12/1992
• Status: Expired due to Fees

• Current Assignee: Affymax Incorporated
• Original Assignee: Affymax Incorporated
• Inventors: Lu, Amy, Solas, Dennis, Hale, Ron L., Zaffaroni, Alejandro C., Selick, Harold E., Oldenburg, Kevin R.
• Primary Examiner(s): Levy, Neil S.
• Application Number:
  US08/449,188
• Time in Patent Office: 650 Days
• Field of Search: 424/22, 424/448, 424/449, 424/485, 424/486, 604/20, 514/1, 514/2, 514/26, 514/169, 514/183, 514/553, 514/556
• US Class Current: 424/449
• 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 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 47/541 Organic ions forming an ion pair complex with the pharmacologically or therapeutically active agent
• CPC Class Codes: A61K 47/6957 the form being a device or a kit, e.g. stents or microdevices
• 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 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543

Abstract

The present invention relates to methods of delivering pharmaceutical agents across membranes, including the skin layer or mucosal membranes of a patient. A pharmaceutical agent is covalently bonded to a chemical modifier, via a physiologically cleavable bond, such that the membrane transport and delivery of the agent is enhanced.

Claims

1. An iontophoretic drug delivery system for administering a pharmaceutical agent to a patient comprising:

(a) a pharmaceutical agent-chemical modifier complex comprising;

a pharmaceutical agent, suitable for transdermal transport at therapeutically effective doses of less than 50 milligrams per day, having a derivatizable chemical functionality; and

a charged, naturally-occurring chemical modifier, conjugated to the agent'"'"'s derivatizable chemical functionality by a covalent, physiologically cleavable bond, wherein said chemical modifier is selected from the group consisting of taurine, betaine, L carnitine, choline, norcholine, lysine, N-methylated amino acids, trigonelline, stachydrine, betonicine, cytochrome c, squalamine, chonemorphine, and conessine;

where said pharmaceutical agent-chemical modifier complex has a charge-to-mass ratio of at least one charge per 1000 daltons, and

wherein upon iontophoretic delivery of said composition and cleavage of said covalent bond, said chemical modifier is present at a non-toxic level and said pharmaceutical agent is delivered to said subject at said therapeutically effective dose; and

(b) a means for iontophoretically delivering said composition at a selected skin site whereby said chemical modifier is cleaved from the complex by a physiological process and said pharmaceutical agent is released within the patient.

2. The device of claim 1 wherein the complex is selected from the group consisting of O-(indomethacinyl)norcholine;

(indomethacinyl)choline iodide;

3,17β

-estradiol-3-choline carbonate, iodide salt;

piroxicam-N,O-bis(choline chloride) carbonate ester;

digitoxin-4"'"'"'-(choline chloride) carbonate ester;

3,17β

-estradiol-17β

-betaine ester, chloride salt; and

indomethacin hydroxymethyl ketone choline iodide carbonate.

3. The device of claim 1 wherein the transdermal delivery of the complex is enhanced over the transdermal delivery of the agent alone.

4. The device of claim 1 wherein one or more chemical modifiers are covalently bonded to the pharmaceutical agent.

5. The device of claim 1 wherein the pharmaceutical is selected from the group consisting of digitalis drugs, steroidal compounds, non-steroidal anti-inflammatories, protein and peptide drugs, and nitrogen heterocycles.