Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2000-05-22
2001-05-08
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S548000
Reexamination Certificate
active
06228886
ABSTRACT:
The present application is related to “Water-Miscible Of Mono- And Diglycerides Having Antimicrobial Activity And Their Use In Inhibiting Infection,” “Nutritional Formulations Containing Water-Miscible Lipid Derivatives As Antimicrobial Agents,” “Water-Miscible Esters Of Monoglycerides Having Antimicrobial Activity,” and “Water-Miscible Esters Of Mono-And Diglycerides Having Antibacterial Activity And Their Use In Inhibiting Infection,” all of which are filed concurrently herewith, and the text of all of which are herein incorporated by reference.
TECHNICAL FIELD OF THE INVENTION
The present invention relates generally to the composition of nutritional products containing water-miscible lipid derivatives of mono- and diglycerides and fatty acids as antibacterial agents, and to the process of formulating these antibacterial agents in various nutritional matrices.
BACKGROUND OF THE INVENTION
It has been previously reported (Kabara,
The Pharmacological Effects of Lipids
, ed. 1987, and
Nutritional Biochemistry
, Vol. 6, July, 1995) that certain lipids have antimicrobial effects. Those lipids reported to have antiviral and antibacterial activity are highly lipophilic, have HLB values of 2 to 4 and likely act by affecting the infectious organism's lipid envelope or membrane leading to changes in the organism's permeability resulting in loss of infectivity.
The high lipophilicity of those lipids, however, makes it difficult to carry out prophylactic studies because the lipids are insoluble in aqueous solutions. The solubility problems can be overcome to some extent through the use of non-aqueous solvents such as ethanol or dimethylsulfoxide (DMSO) (Isaacs, Litov, and Thormar,
Nutritional Biochemistry,
1995). Such solvents, in many instances, are inappropriate for use in humans or animals. By way of example, ethanol and DMSO are contraindicated for use in infants.
Still another problem associated with the use of existing antimicrobial lipids is that the antimicrobial action is inhibited or greatly reduced in the presence of proteins (Kabara,
The Pharmacological Effects of Lipids
, ed. 1987; and U.S. Pat. No. 4,002,775,
Fatty Acids and Derivatives as Antimicrobial Agents,
1977). Thus, such lipids cannot be administered together with proteins such as are present in enteral nutritional formulations. There continues to be a need in the art therefore for antibacterial lipids that are soluble in aqueous formulations and those whose antibacterial activity is not adversely affected by the presence of intact protein.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a nutritional formulation that contains a bactericidal amount of water-miscible lipid derivatives. Preferred water-miscible lipid derivatives are diacetyltartaric acid esters of mono- and diglycerides. The diacetyltartaric acid esters of mono- and diglycerides can be those used as GRAS emulsifiers and known as DATEMs or can be novel such esters wherein 90% or more of the fatty acid content is accounted for by a single fatty acid. Where the latter form of diacetyltartaric acid esters of mono- and diglycerides are used, the fatty acid component preferably contains from 8 to 24 and, more preferably from about 10 to about 20 carbon atoms. The fatty acid can be saturated, unsaturated or hydroxylated.
The present invention further provides a process of inhibiting a bacterial infection in a subject in need of such treatment. In accordance with that process the subject is fed an effective antibacterial amount of a nutritional formulation containing diacetyltartaric acid esters of mono- and diglycerides.
DETAILED DESCRIPTION OF THE INVENTION
I. Nutritional Formulation
The present invention provides a nutritional formulation that contains effective antibacterial amounts of water-miscible lipid derivatives. The water-miscible lipid derivative comprises a lipophilic moiety linked via an ester or ether linkage to a hydrophilic moiety. The lipophilic moiety comprises a fatty acid, a monoacylglycerol (monoglyceride), a diacylglycerol (diglyceride) derivative, a monoetherglycerol derivative, or a dietherglycerol derivative. The hydrophilic moiety comprises an organic acid, an organic alcohol or a salt thereof.
In one embodiment, the water-miscible lipid derivative is a mono-/diglyceride wherein one or two of the glycerol carbon atoms are linked to an alkyl or acyl group and at least one of the remaining glycerol carbon atoms is linked via an ester linkage to an organic acid. In a preferred embodiment, the organic acid is tartaric acid that has been derivatized with acetyl groups. In accordance with this embodiment, the water-miscible lipid derivatives are diacetyltartaric acid esters of mono- and diglycerides.
Certain of such diacetyltartaric acid esters of mono- and diglycerides are known in the art as DATEMs and are GRAS emulsifiers for foodstuffs. DATEMs are formed by reacting diacetyltartaric anhydride with partial glycerides of edible oils, fats or fat-forming fatty acids. Sources of glycerides for the production of DATEMs include soy oil, palm oil, sunflower oil, beef tallow and monoglycerides. DATEMs can also be obtained from commercial sources. For example, DATEM SOY, Panodan FDP Kosher (derived from fully hydrogenated soybean oil) DATEM SUNF, SDK (derived from unhydrogenated sunflower oil), DATEM-C12 (derived from 90% C
12
monoglyceride) and DATEM-C08 (derived from 90% C
8
monoglyceride), are commercially available from Danisco Ingredients, Grinsted Division.
In another embodiment, the water-miscible lipid derivative corresponds to Formula I, below.
In formula I, each of R
A
and R
B
can independently be hydrogen, an acyl group having from 6 to 26 carbon atoms (C
6
-C
26
acyl), an alkyl group having from 6 to 26 carbon atoms (C
6
-C
26
alkyl), or an inorganic anion. Exemplary such anions are halides, nitrates, sulfates and phosphates. The acyl and alkyl groups can be saturated, unsaturated or hydroxylated. Preferably, the acyl and alkyl groups have from 8 to 24 carbon atoms and, more preferably from 10 to 20 carbon atoms. R
A
and R
B
can link to any of the C
A
, C
B
or C
C
carbons of the glycerol backbone. Similarly, the organic acid moiety (shown as tartaric acid in Formula I) can link to any of the C
A
, C
B
or C
C
carbons not linked to an acyl or alkyl group. One of ordinary skill in the art will recognize that other organic acids can be used in place of tartaric acid Each of R
C
and R
D
can independently be an acyl or an alkyl group containing from 2 to 6 carbon atoms, which groups can be saturated, unsaturated or hydroxylated. Exemplary R
C
and R
D
groups are acetyl and succinyl esters. In a compound of Formula I, 90% or more of the total fatty acid content is in the form a single fatty acid.
Where only one of R
A
or R
B
is an acyl group, the molecule is a monoacylglycerol (or monoglyceride) derivative. Where both of R
A
and R
B
are acyl groups, the molecule is a diacylglycerol (or diglyceride) derivative. Where only one of R
A
or R
B
is an alkyl group, it is a monoetherglycerol derivative, and if both R
A
and R
B
are alkyl groups, it is a dietherglycerol derivative. It is possible that the R
A
and R
B
can be one acyl group and one alkyl group. The linkage for the acyl group to the glycerol backbone is an ester lage, and the lage for the alkyl group to the glycerol backbone is an ether linkage.
In a preferred embodiment of Formula I, R
A
is a C
8
-C
24
acyl, R
B
is hydrogen, R
C
and R
D
are both acetyl and the lipids are diacetyltartaric acid esters of monoglycerides.
As used herein, the term “DATEM” will be used to mean those lipids known in the art as GRAS emulsifiers and which lipids have been approved as emulsifiers by the FDA and the EEC. These DATEMs are characterized by containing a mixture of fatty acids. As used herein, the phrase “diacetyltartaric acid esters of mono- and diglycerides” means DATEMs as well as novel lipids as defined above by Formula I.
Diacetyltartaric acid esters of mono- and diglycerides are made using standard techniques well known in the art
Anderson Steven N.
Guzman-Harty Melinda
Hilty Milo Duane
Lee Theresa Siu-Ling Wai
Liu Jin-Zhou
Abbott Laboratories
Dixon J. Michael
Fay Zohreh
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