Compositions and method comprising heterocyclic compounds containing two heteroatoms as membrane penetration enhancers

• US 5,030,629 A
• Filed: 08/11/1989
• Issued: 07/09/1991
• Est. Priority Date: 01/12/1987
• Status: Expired due to Term

• Current Assignee: Therapeutic Patch Research NV
• Original Assignee: Vithal J. Rajadhyaksha
• Inventors: Rajadhyaksha, Vithal J.
• Primary Examiner(s): Shah: Mukund J.
• Assistant Examiner(s): Datlow, Philip I.
• Application Number:
  US07/393,584
• Time in Patent Office: 697 Days
• Field of Search: 514/772, 514/788, 514/946, 514/947, 514/228.8, 514/256, 514/274, 514/275, 514/211, 514/356, 514/392, 514/423, 514/470, 514/652, 514/385, 514/374, 514/376, 514/377
• US Class Current: 514/211.07
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• 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

Abstract

A method and compositions for enhancing absorption of topically administered physiologically active agents through the skin and mucous membranes of humans and animals in a transdermal device or formulation for local or systemic use, comprising a therapeutically effective amount of a pharmaceutically active agent and a non-toxic, effective amount of penetration enhancing agent of the formula I: ##STR1## wherein R is a saturated or unsaturated, straight or branched, cyclic or acyclic hydrocarbon group with from 1 to 19 carbon atoms, alkoxyalkyl, haloalkyl, specifically trifluoromethyl, alkoxy, amino, alkylamino and acylamino; R'"'"' and R" are hydrogen, alkyl, trifluoromethyl, alkoxyalkyl, aminoalkyl, alkyl- and acylaminoalkyl, carboxy, carbalkoxy, hydroxyalkyl or lower alkyl ester thereof; X is O or NR₁ wherein R₁ is hydrogen, alkyl, alkenyl, alkoxyalkyl, carbalkoxyalkyl, aminoalkyl, alkyl- and acylaminoalkyl, hydroxyalkyl or hydroxyalkyloxyalkyl and lower alkyl ester thereof; and n is 2 or 3 are disclosed.

Claims

1. A pharmaceutical composition for enhancing absorption of a topically administered formulation through dermal or mucosal membrane, for local or systemic application, comprising a therapeutically effective amount of a pharmaceutically active cardiovascular agent and a non-toxic, effective amount of a membrane penetration enhancing agent of formula I:

##STR9## wherein R is a saturated or unsaturated, straight or branched, cyclic or acyclic hydrocarbon group with from 1 to 19 carbon atoms, alkoxyalkyl, haloalkyl, specifically trifluoromethyl, alkoxy, amino, alkylamino and acylamino;

R'"'"' and R" are hydrogen, alkyl, trifluoromethyl, alkoxyalkyl, aminoalky, alkyl- and acylaminoalkyl, carboxy, carbalkoxy, hydroxyalkyl or lower alkyl ester thereof;

X is O or NR₁ wherein R₁ is hydrogen, alkyl, alkenyl, alkoxyalkyl, carbalkoxyalkyl, aminoalkyl, alkyl- and acylaminoalkyl, hydroxyalkyl or hydroxyalkyloxyalkyl and lower alkyl ester thereof; and

n is 2 or 3.

2. The composition of claim 1 wherein the membrane penetration enhancing agent is represented by formula I wherein R is alkyl, alkoxy, haloalkyl or alkoxyalkyl, R'"'"' and R" are H, alkyl or alkoxyalkyl;

X is O or NR₁, wherein R₁ is hydrogen, carbalkoxyalkyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkyloxyalkyl and lower alkyl esters thereof and n is 2 or 3.

3. The composition of claim 2 wherein said pharmaceutically active agent is a cardiovascular agent selected from the group consisting of isosorbide dinitrate, clonidine, propranolol, nifedipine, nicardipine, diltiazem, and lisinopril.

4. The composition of claim 1 further comprising pharmaceutically acceptable excipients.

5. A method of enhancing the rate of dermal or mucosal membrane absorption of a topically administered composition for local or systemic application, comprising applying to the skin of a human or an another animal a therapeutically effective dosage amount of a pharmaceutically active cardiovascular agent and a non-toxic, effective amount of a membrane penetration enhancing agent of formula I:

##STR10## wherein R is a saturated or unsaturated, straight or branched, cyclic or acyclic hydrocarbon group with from 1 to 19 carbon atoms, alkoxyalkyl, haloalkyl, specifically trifluoromethyl, alkoxy, amino, alkylamino and acylamino;

R'"'"' and R" are hydrogen, alkyl, trifluoromethyl, alkoxyalkyl, aminoalkyl, alkyl- and acylaminoalkyl, carboxy, carbalkoxy, hydroxyalkyl or lower alkyl ester thereof;

X is O or NR₁ wherein R₁ is hydrogen, alkyl, alkenyl, alkoxyalkyl, carbalkoxyalkyl, aminoalkyl, alkyl- and acylaminoalkyl, hydroxyalkyl or hydroxyalkyloxyalkyl and lower alkyl ester thereof; and

n is 2 or 3.

6. The method of claim 5 wherein the membrane penetration enhancing agent is represented by formula I wherein R is alkyl, alkoxy, haloalkyl or alkoxyalkyl, R'"'"' and R" are, H, alkyl or alkoxyalkyl;

X is O or NR₁ wherein R₁ is hydrogen, carbalkoxyalkyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkyloxyalkyl and lower alkyl esters thereof and n is 2 or 3.

7. The method of claim 6 wherein said pharmaceutically active agent is a cardiovascular agent selected from the group consisting of isosorbide dinitrate, clonidine, propranolol, nifedipine, nicardipine, diltiazem, and lisinopril.