Synthetic monesters are employed as calorie sources for parenteral or enteral nutrition. The monoesters are hydrolyzed and respired by the body and offer the advantage of high calorie density when compared to conventional or other synthetic calorie sources.

BACKGROUND OF THE INVENTION 
This invention relates to the field of nutrition, and more particularly to 
parenteral nutrition via peripheral veins. 
Total parenteral nutrition (TPN) is a recent advance in the maintenance of 
patients having an impaired gastrointestinal capacity. Such patients may 
have lost the use of a large portion of their intestinal tract, either 
permanently due to surgical intervention as may be required in cancer or 
Crohn's disease, or temporarily as a result of chemotherapeutic drugs or 
in the treatment of diverticulitis. Objectives of TPN include 
administering all of the patient's requirements of calories and essential 
nutrients directly into the circulatory system, bypassing the digestive 
tract entirely, or administering nutrients to the remnant digestive tract 
in a form that will provide as much nutrition as possible without injuring 
either the circulatory system or the intestines. 
A major difficulty in TPN has been the sensitivity of the intestines or 
vasculature to contact with nutrient solutions having high osmolarity. To 
date, it has been necessary to use such highly concentrated solutions 
because at lower concentrations the nutrient solutions supply insufficient 
calories before exceeding the patient's ability to deal with excess 
diluent. Generally, a patient must receive at least 2500 ml daily of a 20% 
glucose solution to reach the 2000 minimum calories required, and caloric 
requirements can be greater in many stressed patients. 
Attempts to deal with this problem have included infusing the solution via 
a central venous catheter. A catheter is threaded from a peripheral vein 
in an arm or a leg, for example, into the vena cava. Highly concentrated 
nutrient solutions can be passed through the catheter into the large 
volume of central venous blood, where rapid dilution of the solution 
obviates vascular injury and reduces local hemolysis. Central venous 
catheters, however, among other disadvantages require a special procedure 
to insert. It would be safer and considerably more convenient if 
parenteral nutrition could be administered via a peripheral vein. 
Calorie sources for infusion which are alternate or supplemental to 
glucose, amino acids or lipid emulsions have been previously suggested or 
disclosed. See Birkhahn, R. et al., "J. Par. Ent. Nutr." 5(1):24-31 
(1981); Birkhahn, R. et al., "Am. J. Clin. Nutr.", 30: 2078-2082 (1977); 
Birkhahn, R. et al., "Am. J. Clin. Nutr." 31:436-441 (1978); Birkhahn, R. 
et al., "J. Nutr." 109:1168-1174 (1979); Birkhahn, R. et al., "J. Par. 
Ent. Nutr." 3(5):346-349 (1979); LeVeen, H., "Am. J. Dig. Dis." 17:20 
(1950); LeVeen, H., "Am. J. Clin. Nutr." 5:251 (1957) and Milner, U.S. 
Pat. No. 3,928,135. None of the compounds have proven entirely 
satisfactory, especially for peripheral vein infusion. The principal 
difficulties have included insufficient calorie density for peripheral 
infusion, incomplete metabolism of the compounds, toxic metabolites, side 
effects, and insufficient water solubility. 
Accordingly, the objectives of this invention include: 
(a) providing compounds for parenteral or enteral nutrition which are 
biologically available; 
(b) providing compounds having a biologically available caloric content in 
considerable excess of glucose; 
(c) providing compounds which are nontoxic to the vasculature, the 
intestines and the cellular elements of the blood, in particular compounds 
which exhibit insufficient surfactant properties to hemolyze or otherwise 
damage erythrocytes; 
(d) providing compounds which can be dissolved in solutions to yield 
infusates having improved calorie density; 
(e) providing and administering to patients the above compounds in 
conventional parenteral solution containers along with other nutrients 
such as vitamins, electrolytes, trace metals and amino acids; and 
(f) providing compounds which are hydrolyzed by the tissues or intestinal 
flora to substrates of oxidative metabolism. 
These and other objects will be apparent from consideration of this 
specification as a whole. 
SUMMARY OF THE INVENTION 
The foregoing objects are achieved by enteral or parenteral administration 
of novel compounds having the formula 
EQU AOOCR 
wherein 
A is the residue of a nontoxic, biologically available normal or branched 
chain aliphatic group containing at least one hydroxyl substituent and one 
or more oxy or additional hydroxyl substituents; and 
--OOCR is the residue of a fatty acid having less than 7 carbon atoms, an 
alpha-keto carboxylic acid, or a fatty acid having an even number of 
carbon atoms and being substituted with oxy or hydroxyl at the 2 carbon 
position, with hydroxyl at the 3 carbon position, and/or with oxy or 
hydroxyl at any odd numbered carbon thereafter, provided that no more than 
6 consecutive carbon atoms remain unsubstituted with oxy or hydroxyl; 
provided that when --OOCR is the residue of a fatty acid having less than 7 
carbon atoms, then A is not a residue of glycerol. 
The resulting monoesters are highly water soluble and contain improved 
calorie density. They are nontoxic upon parenteral administration in 
nutritional doses and are hydrolyzed in the body. 
DETAILED DESCRIPTION OF THE INVENTION 
The fundamental reasoning underlying this invention is that medium or long 
chain fatty acids, when hydroxylated in the fashion provided herein and 
esterified to nutrient polyols, provide a high calorie compound that is 
readily hydrolyzed in the body to low molecular weight oxidative 
intermediates or to low molecular weight substances which are readily 
converted to such intermediates. 
"Biologically available" as that term is used herein means that the 
monoester and its ester hydrolysis products are substantially oxidized in 
the body to CO.sub.2, H.sub.2 O or other low molecular weight products 
excreted as ordinary byproducts of tissue respiration. 
Certain normal or branched chain aliphatic groups containing at least two 
hydroxyl substituents are widely recognized as toxic, e.g. ethylene 
glycol, propylene glycol, 1,2-butanediol, 1,4-butanediol. These substances 
will be apparent to those skilled in the art, and are not to be employed 
as components in assembling the monoesters herein. "Nontoxic" monoesters 
or hydrolysis products are those which exhibit an LD.sub.50 in mice at 
greater than 1 g/kg body weight upon continuous administration by the 
route contemplated for the monoester, e.g. oral or parenteral. 
The "A" radical generally falls into several representative classes. The 
first class is the residues of saccharides, including the monosaccharide 
pentoses or hexoses and their corresponding ketoses. Monosaccharides are 
preferred as they are most readily hydrolyzed by the body upon parenteral 
administration. Suitable monosaccharides may be reducing sugars such as 
glucose or fructose or nonreducing sugars such a sorbose or mannose. The 
corresponding sugar alcohols such as sorbitol or mannitol also may be 
employed, although these are not preferred because their rate of 
biological utilization is not as high as monosaccharides. The 
monosaccharide or sugar alcohol is esterified at any of the hydroxyl 
groups of the monosaccharide or sugar alcohol, but generally the 1, 5 or 6 
positions are preferred. 
Group "A" also may be the residue of a nontoxic, short chain biologically 
available normal aliphatic diol or triol. Exemplary "A" groups of this 
class are (CH.sub.2 OH).sub.2 CH--, CH.sub.2 (OH)CH(OH)CH.sub.2 -- and 
CH.sub.3 CH(OH)CH.sub.2 CH.sub.2 --, with the 1-or 3-glyceryl ester being 
most preferred. 
The group --OOCR will contain about from 4 to 10 carbon atoms, ordinarily 4 
to 6, and is preferably normal. The number of hydrophilic substitutents 
should be directly proportional to the number of carbon atoms, with a 
greater proportion in the case of a branched chain carbon skeleton. --OOCR 
groups include, hexanoic acid, alpha keto acids and hydroxylated fatty 
acids , the latter most being preferred. Representative --OOCR groups 
include 
##STR1## 
Preferably, --OOCR is 5, 7-dihydroxyoctanoic acid or hexanoic acid. 
Hexanoic acid is preferably esterified with monosaccharides. 
Selection of groups A and R will have the objective of optimizing several 
characteristics of the resulting monoester. First, the monoester must be 
soluble at room temperature in substantially neutral aqueous solutions, 
e.g. those having a pH of about from 5.5 to 7.5. Thus, radicals having 
alkylene residues of greater than C.sub.4 will need to be used sparingly 
to improve the water solubility of the monoesters. However, even poorly 
soluble monoesters can be employed as supplements to other nutrients or 
other more soluble polyesters, or their solubility may be increased by the 
use of a cosolvent such as ethanol. Generally, the monoesters and their 
hydrolysis products should have a solubility of greater than about 3 mole 
percent in water at room temperature. 
The second characteristic to be optimized is biological availability, as 
defined briefly above. The monoesters must be hydrolyzed in the body after 
infusion or ingestion, although the manner in which this occurs is not as 
important as the fact that it does. Monoesters should be selected which 
are susceptible to solvolysis or hydrolysis upon contact of the monoester 
with components such as hydrogen ions present in the blood. Esters 
selected for susceptibility to solvolysis will have --OOCR groups with 
polar functionalities at the 3 or 5 positions. 
Most likely, hydrolysis is the primary result of enzymatic action in blood 
cells, plasma and body tissues and organs. Also, enzymatic hydrolysis by 
intestinal flora will occur after enteral administration. Hydrolysis will 
be dependent upon many factors. For example, some monoesters may be 
optimal in the TPN of patients with gastrointestinal disease while the 
same monoesters might not be optimal for a patient with liver disease if 
the monoester is principally hydrolyzed by liver enzymes. Thus, the 
clinician must use some discretion in selecting monoesters for optimal 
biological availability. The experimental method for the selection will be 
relatively straightforward, however. The ultimate criterion is 
stabilization of weight loss, or a gain in weight, in the patient being 
treated. A more immediate assay for availability would be to determine 
plasma increases in representative monoester hydrolysis products, e.g. 
glycerol. In such a case a monoester is biologically available if it is 
hydrolyzed in the body at a rate sufficient to supply nutrition. This rate 
may be quite low, however, if the monoester is to serve as a supplementary 
nutrient. 
The monoester must be nontoxic as defined above. However, it may be of 
value to select monoesters on the basis of more specific data than lethal 
dose in mice. For example, the influence of the monoesters on lipases and 
esterases in blood and tissues can be readily determined by assaying the 
particular enzyme activity on a given, usually normal physiological, 
substrate for the enzyme in the presence or absence of the monoester or 
its hydrolysis products. It should be noted that competitive, reversible 
inhibition of existing enzyme systems by the monoesters or their 
hydrolysis products is not disadvantageous. In fact, one feature of this 
invention is that hydrolysis of the monoesters is in part dependent upon 
the unexpectedly fortuitous existence of unfastidious esterases which 
ordinarily hydrolyze other substrates in the body. The administration of 
the monoesters may result in some transient inhibition of these normal 
hydrolytic activities, but induction of greater amounts of the enzymes in 
question soon will overcome any such inhibition. The impact of the 
monoesters on existing in vivo hydrolyzing systems is lessened by the use 
of a multiplicity of monoesters in the infusate, e.g. a mixture of 
monosaccharide and glycerol esters of fatty acids and their oxy or 
hydroxyl derivatives. 
Monoesters should be chosen which can be autoclaved with minimal thermal 
hydrolysis and without other rearrangements such as polymerization. This 
will be an objective if the monoesters are to be infused parenterally, but 
will not be of concern where the monoesters are to be administered 
enterally and sterile administration is not required. If the monoesters 
are thermally unstable they may be sterilized by other known methods, for 
example, sterile filtration. The monoesters of this invention may be 
autoclaved in solution with amino acids. 
Representative monoesters which are contemplated in the practice of this 
invention are described in Table I. 
TABLE I 
______________________________________ 
1. CH.sub.2 (OH)CH(OH)CH.sub.2 OOC(CH.sub.2).sub.3 CH(OH)CH.sub.2 
CH(OH)CH.sub.3 
2. CH.sub.2 (OH)CH(OH)CH.sub.2 OOCCH.sub.2 CH(OH)CH.sub.3 
3. CH.sub.3 CH(OH)CH.sub.2 CH.sub.2 OOCCH.sub.2 CH(OH)CH.sub.3 
##STR2## 
5. CH(CH.sub.2 OH).sub.2 OOC(CH.sub.2).sub.3 CH(OH)CH.sub.2 CH(OH)CH.sub. 
3 
6. CH.sub.3 CH(OH)CH.sub.2 CH.sub.2 OOC(CH.sub.2).sub.3 CH(OH)CH.sub.2 
CH(OH)CH.sub.3 
7. CH.sub.3 CH[OOCCH.sub.2 CH(OH)CH.sub.3 ]CH.sub.2 CH.sub.2 OH 
##STR3## 
##STR4## 
10. 
##STR5## 
##STR6## 
12. CH.sub.2 (OH)CH(OH)CH.sub.2 OOCCH(OH)CH(CH.sub.3).sub.2 
##STR7## 
______________________________________ 
The monoesters have the principal advantage over glucose in having an 
extremely high available calorie density. The following Table 2 
demonstrates the high energy density of the monoesters in comparison with 
other calorie sources. 
TABLE 2 
______________________________________ 
Parenteral 
Solution 
Mole for TPN+ 
Compound Weight ATP* Kcal/Mol 
mM 
______________________________________ 
glycerol 92 19 228 2193 
glucose 180 38 456 1096 
1,3-butanediol 
90 31 372 1344 
monobutyrin# 162 48 923 856 
glyceryl 5,7-dihydrox- 
250 78 936 534 
yoctanoate 
glucose 278 84 1008 496 
monohexanoate 
glucose 5,7-dihydroxy- 
338 97 1164 429 
octanoate 
______________________________________ 
#Birkhahn et al. "J. Par. Ent. Nutr." 5(1):24 (1981). 
*calculated adenosine triphosphate generated upon complete respiration of 
the compound. 
+0.5 Kcal/ml solution 
The monoesters described herein are useful in stabilizing or increasing 
patient weight, reducing nitrogen loss (particularly the alpha-keto 
carboxylic acid esters) and effecting other metabolic and physiological 
improvement in the clinical state of the patient. 
For parenteral administration, the selected monoester or mixture of 
monoesters is dissolved in an aqueous solution at the desired 
concentration. This concentration may be that which is intended for use, 
e.g. about from 5 to 20 mole percent, or may be more concentrated, e.g. 
about from 10 up to 50 mole percent or the saturation solubility limit of 
the monoester. Concentrated solutions are maintained at the greater 
concentration to enhance the monoester stability during autoclaving or 
storage. Such solutions then are diluted to the desired administration 
concentration at some convenient point before use. If necessary, the 
monoester need not be dissolved in an aqueous solution at all until 
reconstitution before administration. This, however, is not as 
commercially desirable as supplying a ready-to-use solution. 
The monoester solution frequently will be mixed with other nutrients or 
with drugs. Such other nutrients may include nitrogen sources such as 
amino acids, essential fatty acids such as linoleic or linolenic acid, 
vitamins, minerals, and electrolytes including trace elements. Other 
calorie sources such as carbohydrates or lipids will not ordinarily be 
needed. The amino acids are mixed with the monoester prior to or after 
sterilization. A mixture of essential amino acids nutritionally balanced 
according to the Rose proportions will ordinarily be sufficient, although 
nonessential amino acids may be included. The proportions may be adjusted 
for special disease states, e.g., inborn errors of metabolism, in accord 
with known practice. Supplemental nutrients also will be selected to avoid 
adverse effects on the monoesters during sterilization and/or storage, 
e.g. accelerated hydrolysis. The pH may range about from 5.5 to 7.5. Other 
conventional additives such as antioxidants, buffers and the like may be 
included as well. 
The solutions are packaged in conventional parenteral solution containers, 
either glass or thermoplastic flexible bags. Such containers are sterile 
sealed and will contain means for communicating with the patient's 
circulation, either alone or in concert with other devices. Typically, the 
means for communicating with the patient's circulation will be a frangible 
member associated with the container which is adapted to enter into fluid 
communication with an administration set. Such sets also are well known. 
The solutions usually are parenterally administered by infusion into a 
peripheral vein. The monoester concentration is not critical. It should 
not be so low as to introduce undue amounts of water into the patient, nor 
so high as to cause peripheral vascular irritation. Generally an 
osmolarity below about 600 mOsm. is satisfactory for peripheral parenteral 
infusion. Less advantageously, the solution may be infused through a 
central venous catheter. The solutions are infused at a rate sufficient to 
maintain the nutritional status of the patient in concert with the intake 
of other nutrients. Infusion will be ordinarily about from 25 to 40 
Kcal/Kg patient weight/day, but the amount administered parenterally will 
depend upon the patient's oral intake of monoester or other nutrients. 
The monoesters herein can be taken orally, and they have the advantage of a 
higher energy content than glucose so are less likely to cause diarrhea or 
other intestinal distress at a given Kcal dose when compared to glucose. 
The monoesters, alone or in combination with other nutrients as described 
above or with drugs, can be taken by gastric tube or as a component of 
ordinary meals. Since the monoesters are to function as nutrients they are 
supplied in quantities sufficiently high to provide greater than 20%, 
preferably greater than 50% of the calories required by the patient. 
The monoesters may be made by modifications of known synthetic methods.

The invention will be more fully understood from a study of the following 
examples. 
EXAMPLE 1 
Preparation of Glyceryl 5,7-Dihydroxyoctanoate 
5,7-dihydroxyoctanoic acid delta-lactone was prepared in several steps from 
cyclopentanone and 2-benzyloxy-1-chloropropane. Thus, alkylation of 
cyclopentanone was effected by treatment with sodium hydride in 
tetrahydrofuran (THF) solution to generate the alpha-anion, followed by 
the dropwise addition of a THF solution of 2-benzyloxy-1-chloropropane. 
Reaction workup yielded 2-(2-benzyloxy-1-propyl) cyclopentanone. This 
ketone was treated with peroxy trifluoroacetic acid under Baeyer-Villiger 
conditions to give the 7-benzyl ether of 5,7-dihydroxyoctanoic acid 
gamma-lactone. The benzyl group was removed by catalytic hydrogenation, 
yielding 5,7-dihydroxyoctanoic acid delta-lactone. 
Esterification was accomplished as follows: A solution of 9.2 g of glycerol 
and 15.8 g of 5,7-dihydroxyoctanoic acid delta-lactone in 100 ml dioxane 
containing 0.1 g sodium hydride was heated at reflux for 18 hours. The 
solution was cooled to room temperature, 1 ml of H.sub.2 O was added, and 
volatile materials were removed in vacuo. The residual oil was taken up in 
chloroform, washed with a minimum volume of water and dried over anhydrous 
MgSO.sub.4. After filtration, the chloroform solution was concentrated to 
a colorless oil (23.8 g), which was identified as glyceryl 
5,7-dihydroxyoctanoate. 
EXAMPLE 2 
Preparation of Glucose Monohexanoate 
The method of Pfander and Laederach [H. Pfander and M. Laederach, Carbohyd. 
Res. 99(2), 175-79 (1982)] was used. 1-Hexanoylimidazole was prepared by 
stirring 2 equivalents of imidazole with 1 equivalent hexanoyl chloride in 
toluene solution. The mixture was filtered and concentrated to a 
low-melting solid. This product, 1-hexanoylimidazole, was further purified 
by distillation. 
The imidazole derivative (1 equivalent) was treated with 2 equivalents of 
B-D-glucose and a catalytic amount of sodium hydride in pyridine at room 
temperature. After stirring for 24 hours the solution was concentrated, 
chloroform was added, and the precipitate was removed by filtration. The 
filtrate was concentrated to a colorless solid, which was further purified 
by chromatography. Yields of product, 1-0-hexanoyl-B-D-glucopyranose, 
ranged from 20-60%, depending on the precautions taken to maintain 
anhydrous reaction conditions. 
EXAMPLE 3 
The compounds of Examples 1 and 2 were each dissolved in water to a 
concentration calculated to yield 0.5 Kcal/ml. 200 ml of each of the 
solutions were prepared by sterile filtration. The sterilized solutions 
were continuously infused into rats at a rate of 120 ml/Kg/day. The rats 
were able to metabolize the monoesters and to subsist on them in the 
absence of oral food intake.