N-.omega.,(.omega.-1)-dialkyloxy)- and N-(.omega.,(.omega.-1)-dialkenyloxy)Alk-1-YL-N,N,N-tetrasubstituted ammonium lipids and uses therefor

• US 5,049,386 A
• Filed: 05/15/1990
• Issued: 09/17/1991
• Est. Priority Date: 01/07/1985
• Status: Expired due to Term

• Current Assignee: Syntec Incorporated (Atos SE)
• Original Assignee: Syntec Incorporated (Atos SE)
• Inventors: Felgner, Philip L., Gadek, Thomas R., Roman, Richard B., Jones, Gordon H., Eppstein, Deborah A.
• Primary Examiner(s): Cashion, Jr., Merrell C.
• Assistant Examiner(s): HORNE, LEON
• Application Number:
  US07/524,257
• Time in Patent Office: 490 Days
• Field of Search: 424/427
• US Class Current: 424/427
• 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 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• 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
• CPC Class Codes: C07D 453/02 containing not further condensed quinuclidine ring systems
• CPC Class Codes: C12N 15/88 using microencapsulation, e.g. using amphiphile liposome vesicle

Abstract

This invention relates to compounds of the formula ##STR1## or an optical isomer thereof wherein R¹ and R² are the same or different and are an alkyl or alkenyl group of 6 to 24 carbon atoms; R³, R⁴ and R⁵ are the same or different and are alkyl of 1 to 8 carbon atoms, aryl, aralkyl of 7 to 11 carbon atoms, or when two or three of R³, R⁴, and R⁵ are taken together to form quinuclidino, piperidino, pyrrolidino, or morpholino; n is 1 to 8; and X is a pharmaceutically acceptable anion.

Claims

1. A method for the transdermal, topical or ocular delivery of a drug to the skin or to a mucous membrane of a human or animal subject, comprising the steps of:

(1) forming a liposome comprising a therapeutically effective amount of a drug and a compound of Formula I;

##STR8## or an optical isomer thereof, wherein R¹ and R² are the same or different and are an alkyl or alkenyl group of 6 to 24 carbon atoms;

R³, R⁴ and R⁵ are such that;

(i) they are the same or different and are each alkyl of 1 to 8 carbon atoms, aryl, or aralkyl of 7 to 11 carbon atoms, or

(ii) two taken together form pyrrolidino, piperidino, or morpholino, and the third is alkyl of 1 to 8 carbon atoms, aryl, or aralkyl of 7 to 11 carbon atoms, or

(iii) all three together form quinuclidino;

n is 1 to 8; and

X is a pharmaceutically acceptable anion; and

(2) applying the liposome to the skin or a mucous membrane of said subject.

3. The method of claim 1 wherein R¹ and R² are the same and are alkyl of 10 to 20 carbon atoms, R³, R⁴ and R⁵ are methyl or ethyl, n is 1 to 4 and X is a halide ion.

4. The method of claim 3 wherein n is 1.

5. The method of claim 4 wherein the lipid of Formula I is (±

) N-(2,3-di-(9-(Z)-octadecenyloxy))-prop-1-yl,N,N,N-trimethylammonium chloride or an optical isomer thereof.

2. A method for the transdermal, topical or ocular delivery of a polyanion, comprising the steps of:

(1) forming a polyanion-liposome complex comprising a polyanion and a compound of Formula I ##STR9## or an optical isomer thereof, wherein R¹ and R² are the same or different and are an alkyl or alkenyl group of 6 to 24 carbon atoms;

R³, R⁴ and R⁵ are such that;

(i) they are the same or different and are each alkyl of 1 to 8 carbon atoms, aryl, aralkyl of 7 to 11 carbon atoms, or

(ii) two taken together form pyrrolidino, piperidino, or morpholino, and the third is alkyl of 1 to 8 carbon atoms, aryl, or aralkyl of 7 to 11 carbon atoms, or (iii) all three together from quinuclidino;

n is 1 to 8; and

X is a pharmaceutically acceptable anion; and

(2) applying the complex to the skin or mucous membrane of a subject in need thereof.

6. The method of claim 2 wherein R¹ and R² are the same and are alkyl of 10 to 20 carbon atoms, R³, R⁴ and R⁵ are methyl or ethyl, n is 1 to 4 and X is a halide ion.

7. The method of claim 6 wherein n is 1.

8. The method of claim 7 wherein the lipid of Formula I is (±

) N-(2,3-di-(9-(Z)-octadecenyloxy))-prop-1-yl,N,N,N-trimethylammonium chloride or an optical isomer thereof.