Transdermal compositions
The present invention is directed to transdermal compositions and the uses thereof. These compositions include at least one of the following components: a C 1 -C 6 dialkyl, C 12 -C 30 dialkyl quaternary ammonium salt, a C 12 -C 30 fatty acid, a nitrogenous organic base, C 12-30 fatty alcohol, monoglyceride or the reaction products thereof.
1. A process for making a hydrate of a tertiary amide of the formula:
or pharmaceutically acceptable salts thereof, wherein:
R 4 is a fatty group of 11-29 carbon atoms;
R 5 and R 6 are independently lower alkyl, aryl, aryl lower alkyl, or fatty group containing 11-29 carbon atoms or R 7 ;
R 7 is R 1 —Ar—O—R 2 —O—R 3 —;
R 2 and R 3 are independently alkylene groups containing 1-6 carbon atoms;
R 1 is a lower alkyl; and
Ar is aryl;
said fatty group either being completely saturated or containing 1-8 carbon-carbon double bonds;
the process comprising:
(a) providing a mixture comprising (i) an aqueous medium, (ii) a quaternary ammonium salt, and (iii) a fatty acid or salt thereof, wherein
the quaternary ammonium salt is of the formula
wherein
R 9 and R 10 are independently lower alkyl; and
X is a counterion; and
the fatty acid contains 12-30 carbon atoms;
(b) maintaining the mixture for sufficient time under conditions effective to form the tertiary amide,
wherein said conditions effective to form the tertiary amide comprise
(i) pH of the mixture less than 4.5; and
(ii) temperature of the mixture above the melting point of the fatty acid and below the boiling point of the aqueous medium; and
(c) cooling the mixture to ambient temperature,
so that the hydrate is formed.
2. The process of claim 1 , wherein the molar ratio of the quaternary ammonium salt to the fatty acid is from about 10:1 to about 1:10.
3. The process of claim 2 , wherein the molar ratio of the quaternary ammonium salt to the fatty acid is from about 5:1 to about 1:5.
4. The process of claim 2 , wherein the molar ratio of the quaternary ammonium salt to the fatty acid is from about 2:1 to about 1:2.
5. The process of claim 2 , wherein the molar ratio of the quaternary ammonium salt to the fatty acid is about 1:1.
6. The process of claim 1 , wherein said conditions effective to form the tertiary amide comprise temperature of the mixture above 60° C.
7. The process of claim 1 , wherein the mixture further comprises (iv) a nitrogenous organic base.
8. The process of claim 7 , wherein the nitrogenous base is present in a molar amount from about 0.2 to about 1.0 per mole of quaternary ammonium salt.
9. The process of claim 7 , wherein the nitrogenous base is present in a molar amount from about 0.3 to about 0.6 per mole of quaternary ammonium salt.
10. The process of claim 7 , wherein the nitrogenous base is present in a molar amount from about 0.16 to about 0.50 per mole of quaternary ammonium salt.
11. The process of claim 7 , wherein the nitrogenous base is of the formula H 2 N(C 1-6 alkyl or C 1-6 alkanol), HN(C 1-6 alkyl or C 1-6 alkanol) 2 or N(C 1-6 alkyl or C 1-6 alkanol) 3 , wherein each instance of C 1-6 alkyl or C 1-6 alkanol is independently selected.
12. The process of claim 7 , wherein the nitrogenous base is of the formula N(C 1-6 alkanol) 3 .
13. The process of claim 7 , wherein the nitrogenous base is triethanolamine, trimethanolamine, trimethylamine, triethylamine or tromethamine.
14. The process of claim 7 , wherein the nitrogenous base is triethanolamine.
15. The process of claim 1 , wherein X is a halide.
16. The process of claim 1 , wherein X is a chloride.
17. The process of claim 1 , wherein:
R 5 and R 6 are independently a fatty group containing 11-29 carbon atoms; or
one of R 5 and R 6 is aryl or aryl lower alkyl, and the other is is R 7 .
18. The process of claim 1 , wherein the quaternary ammonium salt is distearyl dimethyl ammonium chloride or benzethonium chloride.
19. The process of claim 1 , wherein R 4 contains 15-21 carbon atoms.