Use of dibutyl adipate and isopropyl myristate in topical and transdermal products

• US 5,326,566 A
• Filed: 08/19/1993
• Issued: 07/05/1994
• Est. Priority Date: 05/17/1991
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Parab, Prakash V.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Bawa, Raj
• Application Number:
  US08/108,279
• Time in Patent Office: 320 Days
• Field of Search: 424/401, 424/484, 424/78.02, 514/946, 514/947, 514/938, 514/969
• US Class Current: 424/401
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 8/37 Esters of carboxylic acids
• 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: A61Q 19/00 Preparations for care of the skin

Abstract

The present invention relates to composition and methods for enhancing and/or controlling epidermal, dermal and transdermal penetration of topically applied pharmacologically active agents by use of dibutyl adipate, or a mixture of dibutyl adipate and isopropyl myristate.

Claims

1. A single or multiple phase topical composition for enhancing skin penetration of a pharmacologically active agent comprising:

a pharmacologically effective amount of a pharmacologically active agent, such agent being an oil-soluble steroid, retinoid or aretinoid or a water-soluble α

- or β

-hydroxycarboxylic acid, ketocarboxylic acid or ester, lactone or salt thereof; and

(1) when the active agent is oil-soluble, an oil phase containing as a first solvent system, dibutyl adipate or a mixture of dibutyl adipate and isopropyl myristate, the oil-soluble active agent being solutiblized in the first solvent system, the first solvent system being present in an amount such that the oil-phase has a degree of unsaturation of 1 to 1.5 with respect to the oil-soluble active agent, any excess oil-soluble active agent not solubilized in the oil-phase being suspended in the composition;

or

(2) when the active agent is water-soluble,

(i) a second oil phase containing as a second solvent system, dibutyl adipate or a mixture of dibutyl adipate and isopropyl myristate; and

(ii) a water phase, the water-soluble active agent being solubilized in the water phase, any excess water-solublle active agent not solubilized in the water phase being solubilized in the second oil phase and/or suspended in the composition.

2. The composition as claimed in claim 1, wherein the active agent is oil-soluble and the first solvent system is present in an amount such that the oil phase has a degree of unsaturation of 1 with respect to the oil-soluble active agent.

3. The composition as claimed in claim 1, wherein the active agent is oil-soluble and the first solvent system is present in an amount such that the oil phase has a degree of unsaturation of 1.5 with respect to the oil-soluble active agent.

4. The composition as claimed in claim 1, wherein the active agent is oil-soluble and excess active agent not solubilized in the oil phase is present and is in suspension in the composition.

5. The composition as claimed in claim 1, wherein the first solvent system is dibutyl adipate and the second solvent system is dibutyl adipate.

6. The composition as claimed in claim 1, wherein the first solvent system is a mixture of dibutyl adipate and isopropyl myristate and the second solvent system is a mixture of dibutyl adipate and isopropyl myristate.

7. The composition as claimed in claim 1, wherein the dibutyl adipate is present in an amount of from about 0.1 wt % to about 99 wt %, based on the weight of the composition;

and the isopropyl myristate is present in an amount 0 to about 99 wt %, based on the weight of the composition.

8. The composition as claimed in claim 7, wherein the dibutyl adipate is present in an amount of from about 0.1 wt % to about 50 wt %, based on the weight of the composition, and the isopropyl myristate is present in an amount of about 1 wt % to about 30 wt %, based on the weight of the composition.

9. The composition as claimed in claim 1, wherein the active agent is present in an amount from about 0.001 wt % to about 80 wt %, based on the weight of the composition.

10. The composition as claimed in claim 1, wherein the oil-soluble active agent is tretinoin, halobetasol propionate or 11-cis, 13-cis-12-hydroxymethyl retionic acid delta lactone and the water-soluble active agent is an α

-hydroxycarboxylic acid or a dermatologically acceptable salt thereof.

11. The composition as claimed in claim 10, wherein the α

-hydroxycarboxylic acid or dermatologically acceptable salt thereof is lactic acid, ammonium lactate or lysine lactate.

12. The composition as claimed in claim 1, wherein the active agent is water-soluble and excess active agent not solubilized in the water phase is present and is in suspension in the composition.

13. A method of obtaining in a warm blooded mammal an enhanced rate of skin penetration of a pharmacologically active agent selected from the group consisting of oil-soluble steroids, retinoids and aretinoids and water-soluble α

- or β

hydroxycarboxylic acid, ketocarboxylic acids, esters, lactones and salts thereof, comprising

(a) contacting the sin of said mammal with a single or multiple phase topical composition comprising;

a pharmacologically effective amount of said active agent; and

when the active agent is oil-soluble, an oil phase containing as a solvent system, dibutyl adipate or a mixture of dibutyl adipate and isopropyl myristate, the oil-soluble active agent being solubilized in the oil phase, any excess oil-soluble active agent not solubilized in the oil phase being suspended in the composition;

or

when the active agent is water-soluble,

(i) a second oil phase containing as a second solvent system, dibutyl adipate or a mixture of dibutyl adipate and isopropyl myristate; and

(ii) a water phase, the water-soluble active agent being solubilized in the water phase, any excess water-soluble active agent not solubilized in the water phase being solubilized in the second oil phase and/or suspended in the composition; and

(b) when the active agent is oil-soluble, adjusting the amount of the solvent system and/or the relative amounts of dibutyl adipate and isopropyl myristate, when the solvent system is said mixture of dibutyl adipate and isopropyl myristate, so that the oil phase has a degree of unsaturation of 1 to 1.5 with respect to the oil-soluble active agent and the composition provides during said contacting an enhanced rate of skin penetration of the oil-soluble active agent;

or

when the active agent is water-soluble, adjusting the amount of the second solvent system and/or the relative amount of dibutyl adipate and isopropyl myristate, when the second solvent system is said mixture of dibutyl adipate and isopropyl myristate, so that the composition provides during said contacting an enhanced rate of skin penetration of the water-soluble active agent.

14. The method as claimed in claim 13, wherein the oil-soluble active agent is halobetasol propionate, tretinoin or 11-cis, 13-cis-12-hydroxymethyl retionic acid delta lactone.

15. The method as claimed in claim 13, wherein the water-soluble active agent is an α

-hydroxycarboxylic acid or a salt thereof.

16. The method as claimed in claim 13, wherein the water-soluble active agent is lactic acid, ammonium lactate or lysine lactate.

17. A method for enhancing skin penetration of a pharmacologically active agent selected from the group consisting of water-soluble α

-hydroxycarboxylic acids and dermatologically acceptable salts thereof and oil-soluble, halobetasol propionate, tretinoin, and 11-cis, 13-cis- 12-hydroxymethyl retionic acid delta lactone, the active agent being present in a dermatologically acceptable topical composition which, when the active agent is oil-soluble, has an oil phase or a water phase and an oil phase, or when the active agent is water-soluble, has an oil phase and a water phase, the active agent being solubilized in the oil phase when the active agent is halobetasol propionate, tretinoin, or 11-cis, 13-cis-12-hydroxymethyl retionoic acid delta lactone or solubilized in the water phase when the active agent is an α

-hydroxycarboxylic acid or a dermatologically acceptable salt thereof;

which method comprises;

incorporating in said composition a skin penetration enhancing amount of dibutyl adipate or a mixture of isopropyl myristate and dibutyl adipate, provided that, when the active agent is halobetasol propionate, tretinoin, or 11-cis, 13-cis-12-hydroxymethyl retionic acid delta lactone, the amount of the dibutyl adiptate, or the mixture of isopropyl myristate and dibutyl adipate, employed results in the oil phase of the composition having an unsaturation of 1 to 1.5 with respect to the oil-soluble active agent and the composition having an enhanced rate of skin penetration of the oil-soluble active; and

when the active agent is an α

-hydroxycarboxylic acid or a dermatologically acceptable salt thereof, the amount of the dibutyl adipate, or the mixture of isopropyl myristate and dibutyl adipate, results in the composition having an enhanced rate of skin penetration of the water-soluble active agent.