Vitaminized compositions for treating hypercholesterolemia

Anti-anal leakage agents are used in combination with vitamin-fortified liquid fatty acid polyester compositions to provide pharmaceutical and food compositions for treating and/or preventing hypercholesterolemia while avoiding undesired anal leakage of the polyesters.

BACKGROUND OF THE INVENTION 
The present invention relates to certain edible, but non-absorbable and 
non-digestible, liquid polyesters which can be used as low calorie fat 
substitutes in foods and as pharmaceutical compositions. The polyesters 
herein interfere with the body's absorption of cholesterol and thereby 
provide a means for treating hypercholesterolemia. The polyesters can 
undesirably interfere with the body's source of fat-soluble vitamins, but 
this problem is overcome by fortification with vitamins. It has now been 
determined that the liquid polyesters herein can also cause an undesired 
anal leakage effect. By the present invention, certain agents are added to 
the polyester/vitamin compositions to avoid this undesired effect. Highly 
preferred compositions for treating hypercholesterolemia and/or 
hyperlipidemia comprising the polyesters, an anti-anal leakage agent, and 
one or more fat-soluble vitamins are provided. 
High blood cholesterol (hypercholesterolemia) is recognized as being a risk 
factor in cardiovascular disease which comprises a major health care 
problem today. Epidemiological studies have demonstrated that, with few 
exceptions, populations consuming large quantities of saturated fat and 
cholesterol have a relatively high concentration of serum cholesterol and 
a high mortality rate from coronary heart disease. While it is recognized 
that other factors can also contribute to the development of 
cardiovascular disease, there appears to be a causal relationship between 
the concentration of serum cholesterol, in which hypercholesterolemia 
results in the accumulation of undesirable amounts of cholesterol in 
various parts of the circulatory system (atherosclerosis) or in soft 
tissues (xanthomatosis), and coronary disease and coronary mortality 
rates. 
A variety of dietary and drug regimens have been suggested for alleviating 
or preventing hypercholesterolemia. 
By providing a fat substitute which is non-absorbable and non-digestible, 
the total content of cholesterol in the body can be lowered. Mineral oil 
is a well-known laxative and has been suggested for use as a fat 
substitute and as a kind of "intestinal solvent" to dissolve cholesterol 
and cause its removal in body wastes. However, mineral oil has never been 
accepted for these uses. Moreover, mineral oil is partially absorbed by 
the body and undesirably deposits in the liver. 
In the present invention, liquid, non-absorbable, non-digestible polyesters 
of sugars (or sugar alcohols) are used as fat substitutes in foods and, 
conveniently, in unit dose forms as therapeutic compositions. The 
polyesters herein are fat-like in their physical properties and are 
excellent fat substitutes for use in low calorie foods and diets. 
Moreover, the polyesters herein efficiently inhibit absorption of 
cholesterol by the body and, in contrast with mineral oil, are not 
absorbed and/or deposited in the liver during usage in a 
treatment/prevention regimen with persons having or likely to develop 
hypercholesterolemia. 
The polyesters herein are used in combination with fat-soluble vitamins so 
as to supply the body's requirement therefor. 
The anal leakage effect of the liquid polyesters of the type disclosed 
herein can be overcome by adding an anti-anal leakage agent of the type 
disclosed hereinafter to the vitamin-fortified, liquid polyesters herein, 
or to foods containing same. 
The following references are relevant to the present invention. 
The copending application of Mattson, Ser. No. 628,265, filed Nov. 3, 1975, 
entitled COMPOSITIONS FOR INHIBITING ABSORPTION OF CHOLESTEROL, discloses 
vitamin-fortified liquid and solid polyesters of the general type employed 
herein, their use as anti-hypercholesterolemic and anti-hyperlipidemic 
agents, and their stool-softening laxative effect. 
The concurrently-filed application of Jandacek, Ser. No. 657,528, filed 
Feb. 12, 1976, P&G Attorney's Docket No. 2308, entitled COMPOSITIONS FOR 
TREATING HYPERCHOLESTEROLEMIA, discloses binary compositions comprising a 
source of fatty acids and a liquid polyester of the type employed herein. 
U.S. Pat. No. 3,600,186 (1971) to Mattson and Volpenhein discloses low 
calorie food compositions containing polyol polyesters of the general type 
employed herein, and their use in combination with hardstocks which are 
fatty acid sources. The anti-anal leakage effect of fatty acids is not 
noted. In a fat balance experiment, the diet fed to animals contained 
water-soluble vitamins, but there is no mention of fat-soluble vitamins in 
the polyester component of this diet. 
The copending application of Mattson and Volpenhein, entitled 
PHARMACEUTICAL COMPOSITIONS FOR INHIBITING ABSORPTION OF CHOLESTEROL, Ser. 
No. 425,010, filed Dec. 14, 1973, now U.S. Pat. No. 3,954,976 discloses 
and claims sugar polyesters of the general type employed herein for the 
treatment and/or prevention of hypercholesterolemia. A variety of optional 
carriers are mentioned, including the fatty acid, stearic acid. The 
anti-anal leakage effect of stearic acid is not mentioned. The use of the 
disclosed polyesters in combination both with fat-soluble vitamins and 
fatty acids is not disclosed. 
U.S. Pat. No. 1,656,474 (1928) to Dubin discloses edible fat compositions 
consisting of ethyl and glycerol esters of odd chain fatty acids in 
combination with fat-soluble vitamins. 
Mattson and Nolen, The Journal of Nutrition Vol. 102, No. 9, Sept. 1972, at 
pages 1171-1175, report on the lack of absorbability of sugar polyesters 
of the general type employed herein in rats. The rats were fed 
water-soluble vitamins in the diet and given one drop of fat-soluble 
vitamins per week. 
Fallet, Glueck, Mattson and Lutmer, Clinical Research XXIII No. 3 page 319A 
(1975) report the lowering of both serum cholesterol and vitamin A and E 
levels in subjects receiving sugar polyesters of the present type. 
U.S. Pat. No. 2,962,419 ( 1960) to Minich relates to neopentyl fatty 
esters, their use as fat substitutes, and their use with "vitamins", among 
other things. Fat-soluble vitamins do not appear to be specifically 
contemplated in the Minich disclosure. 
U.S. Pat. No. 3,160,565 (1964) to H. E. Duell relates to sugar mono-, di- 
and tri-esters and their use as carriers for various orally-administered 
medicinals, including the B vitamins. 
U.S. Pat. No. 3,849,554 (1974) to Winitz discloses means for reducing blood 
serum cholesterol by ingesting diets comprising a fatty acid source, said 
diets being low in sucrose. 
U.S. Pat. No. 2,893,990 (1959) to Hass, et al., discloses fatty acid mono- 
and di-esters of sucrose which aid in the absorption of fat from the 
digestive tract. 
U.S. Pat. No. 3,158,490 (1964) to Baur and Lutton discloses non-cloudy 
salad oils containing esters of disaccharides in which there are not more 
than five unesterified hydroxy groups. See also U.S. Pat. Nos. 3,059,009 
(1962) and 3,059,010 (1962) to Schmid and Baur. 
U.S. Pat. No. 2,997,492 (1961) to Martin is directed to a method of making 
partial fatty acid esters of hexitols. U.S. Pat. No. 2,997,491 (1961) to 
Huber is directed to the synthesis of partial fatty esters of inositol. 
The general methods of synthesis disclosed in these patents can be used to 
prepare the liquid polyesters herein. Preferred methods of synthesis are 
fully disclosed hereinafter. 
In addition to the foregoing, there are other patents directed to the use 
of fat-soluble vitamins in a variety of naturally-occurring oils not 
contemplated by the present invention. See, for example, U.S. Pat. No. 
2,685,517, issued Aug. 3, 1954, to Nutrition Products, Inc. 
SUMMARY OF THE INVENTION 
Administration of anti-hypercholesterolemic amounts of a composition 
comprising a liquid polyester of the type described herein and a 
fat-soluble vitamin to an animal (especially humans) afflicted with or 
susceptible to hypercholesterolemia is an effective means of controlling 
the body's cholesterol level without interfering with the body's levels of 
the fat-soluble vitamins A, D, E and K. However, administration of 
cholesterol-controlling amounts of the liquid polyesters can result in an 
undesired "laxative" effect, namely, leakage of the liquid polyester 
through the anal sphincter. By combining the liquid polyester/vitamin 
compositions with an anti-anal leakage agent, especially a C.sub.12, or 
higher, saturated fatty acid, or edible source which provides such fatty 
acids in the gut, this undesired anal leakage effect is prevented. (By 
"anti-anal leakage agent", or "AAL" agent, herein is meant those materials 
which prevent frank leakage of the liquid polyesters. The natural 
stool-softening effect of the polyesters is not substantially affected, 
nor is it a problem.) 
The present invention encompasses compositions of matter which comprise a 
liquid, non-absorbable, non-digestible polyol fatty acid polyester of the 
type described hereinafter, sufficient fat-soluble vitamins selected from 
the group consisting of vitamin A, vitamin D, vitamin E and vitamin K, or 
mixtures thereof, to prevent abnormally low tissue levels of any of said 
fat-soluble vitamins in animals ingesting said compositions, and an 
anti-anal leakage, or "stiffening", amount of an anti-anal leakage agent, 
especially sources of C.sub.12, or higher, saturated fatty acids. The 
compositions can be used as fat substitutes in foods or can be 
self-administered to reduce the body's cholesterol level. Such 
compositions also find use as diet aids for the hyperlipidemic individual. 
The present invention also encompasses non-anal leakage pharmaceutical 
compositions in effective unit dosage amounts for inhibiting the 
absorption of cholesterol without altering the body's level of fat-soluble 
vitamins, said compositions comprising from about 1 gram to about 5 grams 
of the liquid polyesters herein, the fat-soluble vitamins, and sufficient 
AAL agent, especially a C.sub.12, or higher, saturated fatty acid, or 
edible source thereof, to prevent anal leakage in humans ingesting said 
compositions. 
The polyester materials herein are non-absorbable and non-digestible 
fat-like materials and are suitable for use as fat substitutes in low 
calorie fat-containing food compositions. Accordingly, the present 
invention also encompasses low calorie fat-containing food compositions 
comprising non-fat ingredients and fat ingredients wherein from about 10% 
to about 100% of the total fat ingredients comprise the liquid, 
non-absorbable, non-digestible polyesters of the type disclosed 
hereinafter, said food compositions being fortified with sufficient 
fat-soluble vitamins, or mixtures thereof, over and above that naturally 
present in said food compositions, to prevent abnormally low levels of any 
of said fat-soluble vitamins in humans ingesting said compositions, said 
compositions also containing an effective amount of an AAL agent, 
especially a C.sub.12, or higher, saturated fatty acid, or an edible 
source of fatty acids, which prevent an undesired anal leakage effect. 
-behenoyl 
The present invention also encompasses methods for inhibiting the 
absorption of cholesterol without decreasing the tissues' supply of 
fat-soluble vitamins or causing an anal leakage effect comprising 
systemically (generally, orally) administering to animals susceptible to 
or afflicted with hypercholesterolemia successive therapeutically 
effective doses of the compositions of the foregoing type. 
It is to be understood that the edible, non-absorbable, non-digestible 
polyester materials herein are liquids at body temperature, i.e., have a 
melting point of ca. 37.degree. C, or below. (Edible, non-absorbable, 
non-digestible polyester materials that are solid at body temperature do 
not exhibit the undesirable anal leakage effects noted with the liquid 
polyesters. Indeed, such solid polyesters can be used as one type of AAL 
agent herein.) In general, the liquid polyesters are those which are made 
from unsaturated fatty acids, whereas the solid polyesters are 
substantially saturated.

DETAILED DESCRIPTION OF THE INVENTION 
The consumption of diets containing sucrose polyesters (SPE) has been shown 
to result in the desirable decrease in absorption of dietary cholesterol 
in animals; see Mattson, Jandacek and Glueck, Clinical Research 23 445A 
(1975). Similar results have been noted in humans. 
The following is a brief description of animal studies whereby the effect 
of the ingestion of the nonabsorbable, non-digestible sucrose polyesters 
herein on vitamin A (an oil-soluble vitamin) uptake in rats was first 
determined. 
In general terms, the animal studies involved feeding groups of rats a 
vitamin A-free diet for seven days. During this time, the animals were fed 
either cottonseed oil (CSO) or SPE, or mixtures of the two, as the sole 
source of fats in the diet. (The SPE is described in more detail 
hereinafter.) 
After the initial seven-day period, the diets of the animals were 
supplemented with vitamin A. Following the seven days on the diets 
containing vitamin A, the animals were sacrificed and their livers were 
removed and analyzed for vitamin A content by the Carr-Price method, using 
the procedure of Ames, Risley and Harris. 
In studies of the foregoing type the marked differences of the response of 
the animals to the type of dietary fat ingested was unequivocal. Thus, 
when the dietary fat was CSO, over 70% of the vitamin A that was consumed 
was stored in the liver. The complete replacement of the normal dietary 
fats with SPE resulted in the storage of less than 10% of the vitamin A 
that was consumed. 
In light of studies of the foregoing type, it is possible to provide a 
picture of the effect of SPE on fat-soluble vitamin (and cholesterol) 
uptake by the individual. Under usual dietary conditions (i.e., when 
ingesting ordinary absorbable, digestible oils or fats such as CSO), 
vitamin A, like cholesterol, initially is dissolved in an oil phase of 
triglycerides in the lumen of the intestinal tract. A portion of the 
triglycerides is hydrolyzed to monoglycerides and free fatty acids which, 
together with bile salts, form a micellar phase. Vitamin A is then 
distributed between the oil phase of unhydrolyzed triglyceride and the 
micellar phase. The proportion of vitamin A in each will be a function of 
the volume of each phase and the distribution coefficient of the vitamin. 
Eventually, almost all of the triglycerides are hydrolyzed and a major 
portion of the vitamin is absorbed. 
In contrast, SPE and triglycerides are miscible. When both are present, a 
single oil phase is formed. The digestion products of the triglycerides 
enter the micellar phase but SPE, because it is not hydrolyzed, remains as 
an oil phase. A significant portion of the ingested vitamin A (and 
cholesterol) remains in this SPE oil phase, the amount again depending on 
the volumes of the SPE oil and micellar phases and the distribution 
coefficient of the vitamin. When the SPE is discharged, unchanged, in the 
stools, the oil-soluble vitamin A dissolved in the SPE is also lost. A 
similar sequence of events presumably occurs also in the case of vitamin E 
and also with the other fat-soluble vitamins, D and K. 
As can be seen from the foregoing, the physicochemical properties which 
make the SPE so useful in preventing uptake of cholesterol by the body are 
the self-same properties which undesirably interfere with uptake of 
fat-soluble vitamins. 
This type of interference with the absorption of vitamins A and E has been 
demonstrated in human volunteers who consumed SPE. The consequence of SPE 
ingestion was a drop in the blood (plasma) levels of these vitamins. 
By the present invention SPE-type polyesters are fortified with fat-soluble 
vitamins, especially vitamin A, vitamin E and vitamin D, and mixtures 
thereof. (The polyesters can also be fortified with vitamin K. However, 
since the body can synthesize vitamin K, supplementation of the polyesters 
therewith is probably not critical to adequate nutrition in the normal 
subject.) The vitamin-fortified polyesters are used as fat substitutes in 
foods, in unit dose forms as pharmaceutical compositions, or are provided 
in bulk form for self-administration in a therapeutic or dietetic regimen. 
In studies of the foregoing type, rats which ingested about 300 mg. to 
about 3000 mg. total liquid polyester per day and human volunteers who 
ingested from about 10 grams to about 50 grams total liquid polyester per 
day exhibited undesired anal leakage of the polyesters. The studies 
indicated that this anal leakage effect was not caused by ingestion of the 
fat-soluble vitamins but, rather, was a direct result of passage of the 
polyesters through the anal sphincter. Briefly, this undesired effect is 
not unlike the laxative effect which can be caused by the ingestion of 
excessive amounts of mineral oil. 
The types of anti-anal leakage agents which can be used herein to overcome 
the above-described problem without interfering with the beneficial 
effects of the present compositions are disclosed immediately hereinafter. 
Anti-Anal Leakage Agents 
One class of materials which provide the anti-anal leakage effect herein 
includes fatty acids having a melting point of ca. 37.degree. C. or 
higher, and ingestible, digestible sources of such fatty acids. The fatty 
acid AAL agents include, for example, the C.sub.12 -C.sub.24 saturated 
fatty acids, and ingestible, digestible sources thereof. 
While not intending to be limited by theory, it appears that the foregoing 
type of AAL agent functions via the formation of calcium or magnesium 
fatty acid soaps in the gut. These soaps apparently interact with the 
liquid polyesters herein and impart at "stiffening" effect thereto. Once 
"stiffened", or partly solidified, in the gut, the polyesters do not leak 
through the anal sphincter. The antihypercholesterolemic effect of the 
liquid polyesters is not diminished. Non-limiting examples of saturated 
fatty acids and sources thereof which can be used as the AAL agent herein 
include the free saturated fatty acids per se, compounds such as esters 
(e.g., triglycerides) that yield such saturated fatty acids on hydrolysis 
in the gut, soaps of the fatty acids such as the sodium, potassium, etc., 
water-soluble soaps, as well as the calcium and magnesium water-insoluble 
soaps. Highly preferred herein for their anti-anal leakage effect are the 
C.sub.16 -C.sub.22, most preferably C.sub.16 -C.sub.18, saturated fatty 
acids, or edible sources thereof. 
Specific examples of materials useful as the foregoing type of AAL agent 
herein include natural or processed fats yielding C.sub.12 -C.sub.24 
saturated fatty acids in the gut, e.g., materials such as cocoa butter, 
palm oil, palm kernel oil, coconut oil, tallow, lard, enriched 
concentrates of triglycerides having high levels of saturated fatty acids 
obtainable from these sources and sources such as highly saturated 
cottonseed oil fractions obtained by processes such as crystallization or 
directed rearrangement which yield the desired higher concentrations of 
the more saturated fatty acids in the resulting "hardstock " fractions. 
Such materials are all available by well-known processes. 
Partially hydrogenated oils, including all of the above, as well as 
partially hydrogenated soybean oil, safflower seed oil, rapeseed oil, or 
such materials which are hydrogenated and concentrated, for example by 
crystallization, to provide fractions which are enriched in sources of the 
longer-chain, substantially saturated fatty acids, are all useful as the 
AAL agent herein. (By "substantially hydrogenated" herein is meant oils 
having an iodine value of ca. 50, or lower.) 
Of course, any of the foregoing unsaturated oils are useful herein after 
they have been substantially completely hydrogenated to convert the 
unsaturated fatty acid (ester) groups to the corresponding saturated fatty 
acids. 
Synthetic materials, especially fatty acid esters made from the C.sub.12 
-C.sub.24, more preferably C.sub.16 -C.sub.22, most preferably C.sub.16 
-C.sub.18, saturated fatty acids are useful herein. Such materials include 
the esters of tetrahydric alcohols such as erythritol, esters of 
pentahydric alcohols such as xylitol, and esters of hexahydric alcohols 
such as sorbitol, and the like. 
The C.sub.12 -C.sub.24 saturated fatty acid esters of monohydric alcohols 
such as methyl, ethyl, and propyl alcohols (preferably ethyl alcohol) are 
also useful herein. Esters of dihydric alcohols such as 1,2-propanediol, 
1,3-butanediol, and the like, can also be used. 
Highly preferred AAL agents herein which yield the foregoing fatty acids on 
hydrolysis in the gut are those which, in combination with the liquid 
polyesters herein, provide compositions having aesthetically pleasing 
organoleptic qualities, i.e., better "mouth feel". Such aesthetically 
pleasing materials include naturally occurring cocoa butter and various 
synthetic cocoa and confectioners' butters. These preferred AAL agents 
include, for example, the so-called "position-specific" triglycerides such 
as 1-stearoyl diolein (SOO); 2-oleoyl-1,3-distearin (SOS); or the 
corresponding compounds wherein the stearoyl group is replaced by 
palmitoyl, arachidoyl or behenoyl groups. Another class of aesthetically 
preferred anti-laxative agents herein are 1-oleoyl distearin (OSS), 
1-palmitoyl distearin (PSS), 1-arachidoyl distearin (ASS) and 1-behenoyl 
distearin (BSS). 
These highly preferred, position-specific triglycerides which can be used 
as a fatty acid source-type of AAL agent herein can be prepared according 
to the methods described in U.S. Pat. No. 3,809,711, Yetter, issued May 7, 
1974, the disclosures of which are incorporated herein by reference. 
As noted hereinabove, the foregoing types of AAL agents appear to function 
by providing a saturated fatty acid in the gut, said fatty acid thereafter 
presumably forming an insoluble calcium or magnesium soap in situ. This 
soap then appears to provide the "stiffening" effect on the liquid 
polyester, thereby preventing the undesirable anal leakage effect. As 
noted hereinabove, the solid polyester materials of the present type 
(i.e., solid, edible, but non-digestible, non-absorbable polyesters) do 
not cause the undesirable anal leakage effect. It has been determined that 
these solid polyester materials can also be used as an AAL agent and these 
represent a second class of AAL agents herein. Since these solid polyester 
materials do not hydrolyze in the gut to form free fatty acids, or calcium 
or magnesium fatty acid soaps, their anti-anal leakage effect must be the 
result of a different mechanism from that which operates with the 
hydrolyzable esters and fatty acid sources described immediately 
hereinabove. Presumably, the combination of the solid polyester with the 
liquid polyesters simply provides a stiffening effect due to some type of 
crystallization or phase change within the gut. 
It will be appreciated that by combining liquid and solid non-absorbable, 
non-digestible polyesters to provide the desired anti-anal leakage effect, 
wholly edible, but non-digestible, non-absorbable, non-caloric 
compositions are secured. These compositions are quite effective in the 
treatment of hypercholesterolemia and in low calorie diets. 
Typical examples of edible, solid, non-absorbable, non-digestible polyester 
AAL agents herein include sucrose octastearate, sucrose octapalmitate, 
sucrose heptastearate, xylitol pentastearate, galactose pentapalmitate, 
and like, saturated polyol polyesters having at least four --OH groups 
esterified with C.sub.10 -C.sub.22 saturated fatty acids. 
Another type of edible AAL agent herein comprises fatty acid esters which 
are non-digestible by virtue of branching on the .alpha.-carbon atom of 
the fatty acid moiety. Such materials, which are well known in the 
chemical arts, include, for example, .alpha.-methyl and 
.alpha.,.alpha.-dimethyl C.sub.10 -C.sub.18 fatty acid esters of lower 
alcohols such as ethanol and of polyols such as glycerol. 
Liquid Polyesters 
The liquid polyol polyesters (or, simply, polyesters) employed in this 
invention comprise certain polyols, especially sugars or sugar alcohols, 
esterified with at least four fatty acid groups. Accordingly, the polyol 
starting material must have at least four esterifiable hydroxyl groups. 
Examples of preferred polyols are sugars, including monosaccharides and 
disaccharides, and sugar alcohols. Examples of monosaccharides containing 
four hydroxyl groups are xylose and arabinose and the sugar alcohol 
derived from xylose, which has five hydroxyl groups, i.e., xylitol. (The 
monosaccharide, erythrose, is not suitable in the practice of this 
invention since it only contains three hydroxyl groups, but the sugar 
alcohol derived from erythrose, i.e., erythritol, contains four hydroxyl 
groups and accordingly can be used.) Suitable five hydroxyl 
group-containing monosaccharides are galactose, fructose, and sorbose. 
Sugar alcohols containing six -OH groups derived from the hydrolysis 
products of sucrose, as well as glucose and sorbose, e.g., sorbitol, are 
also suitable. Examples of disaccharide polyols which can be used include 
maltose, lactose, and sucrose, all of which contain eight hydroxyl groups. 
Preferred polyols for preparing the polyesters for use in the present 
invention are selected from the group consisting of erythritol, xylitol, 
sorbitol, glucose and sucrose. Sucrose is especially preferred. 
The polyol starting material having at least four hydroxyl groups must be 
esterified on at least four of the -OH groups with a fatty acid containing 
from about 8 to about 22 carbon atoms. Examples of such fatty acids 
include caprylic, capric, lauric, myristic, myristoleic, palmitic, 
palmitoleic, stearic, oleic, ricinoleic, linoleic, linolenic, eleostearic, 
arachidic, arachidonic, behenic, and erucic acid. The fatty acids can be 
derived from naturally occurring or synthetic fatty acids; they can be 
saturated or unsaturated, including positional and geometrical isomers. 
However, in order to provide liquid polyesters of the type used herein, at 
least about half of the fatty acid incorporated into the polyester 
molecule must be unsaturated. Oleic and linoleic acids, and mixtures 
thereof, are especially preferred. 
The liquid polyol fatty acid polyesters useful in this invention must 
contain at least four fatty acid ester groups. Polyol fatty acid polyester 
compounds that contain three or less fatty acid ester groups are digested 
in and the products of digestion are absorbed from the intestinal tract 
much in the manner of ordinary triglyceride fats, whereas the polyol fatty 
acid polyester compounds that contain four or more fatty acid ester groups 
are substantially non-digestible and consequently non-absorbable by the 
human body. It is not necessary that all of the hydroxyl groups of the 
polyol be esterified with fatty acid, but it is preferable that the 
polyester contain no more than two unesterified hydroxyl groups. Most 
preferably, substantially all of the hydroxyl groups of the polyol are 
esterified with fatty acid, i.e., the compound is substantially completely 
esterified. The fatty acids esterified to the polyol molecule can be the 
same or mixed (but, as noted above, a substantial amount of the 
unsaturated acid ester groups must be present to provide liquidity). 
To illustrate the above points, a sucrose fatty triester would not be 
suitable for use herein because it does not contain the required four 
fatty acid ester groups. A sucrose tetra-fatty acid ester would be 
suitable, but is not preferred because it has more than two unesterified 
hydroxyl groups. A sucrose hexa-fatty acid ester would be preferred 
because it has no more than two unesterified hydroxyl groups. Highly 
preferred compounds in which all the hydroxyl groups are esterified with 
fatty acid include the liquid sucrose octa-fatty acid esters. 
The following are non-limiting examples of specific liquid polyol fatty 
acid polyesters containing at least four fatty acid ester groups suitable 
for use in the present invention: glucose tetraoleate, the glucose 
tetraesters of soybean oil fatty acids (unsaturated), the mannose 
tetraesters of mixed soybean oil fatty acids, the galactose tetraesters of 
oleic acid, the arabinose tetraesters of linoleic acid, xylose 
tetralinoleate, galactose pentaoleate, sorbitol tetraoleate, the sorbitol 
hexaesters of unsaturated soybean oil fatty acids, xylitol pentaoleate, 
sucrose tetraoleate, sucrose pentaoleate, sucrose hexaoleate, sucrose 
heptaoleate, sucrose octaoleate, and mixtures thereof. 
As noted above, highly preferred polyol fatty acid esters are those wherein 
the fatty acids contain from about 14 to about 18 carbon atoms. 
The polyol fatty acid polyesters suitable for use herein can be prepared by 
a variety of methods well known to those skilled in the art. These methods 
include: transesterification of the polyol with methyl, ethyl or glycerol 
fatty acid esters using a variety of catalysts; acylation of the polyol 
with a fatty acid chloride; acylation of the polyol with a fatty acid 
anhydride; and acylation of the polyol with a fatty acid, per se. As an 
example, the preparation of polyol fatty acid esters is described in U.S. 
Pat. No. 2,831,854, incorporated herein by reference. 
Specific, but non-limiting, examples of the preparation of polyol fatty 
acid esters suitable for use in the practice of this invention are as 
follows. 
Erythritol tetraoleate -- Erythritol and a five-fold molar excess of methyl 
oleate are heated at 180.degree. C. under vacuum, with agitation, in the 
presence of sodium methoxide catalyst over two reaction periods of several 
hours each. The reaction product (predominately erythritol tetraoleate) is 
refined in petroleum ether and crystallized three times from several 
volumes of acetone at 1.degree. C. 
Xylitol pentaoleate -- Xylitol and a five-fold molar excess of methyl 
oleate in dimethylacetamide (DMAC) solution are heated at 180.degree. C 
for five hours in the presence of sodium methoxide catalyst, under vacuum. 
During this time the DMAC is removed by distillation. The product 
(predominately xylitol pentaoleate) is refined in petroleum ether solution 
and, after being freed of petroleum ether, is separated as a liquid layer 
four times from acetone at ca. 1.degree. C and twice from alcohol at ca. 
10.degree. C. 
Sorbitol hexaoleate is prepared by essentially the same procedure used to 
prepare xylitol pentaoleate except that sorbitol is substituted for 
xylitol. 
Sucrose octaoleate is prepared by substantially the same procedure as that 
used to prepare erythritol tetraoleate except that sucrose is substituted 
for erythritol. 
The SPE material used in the animal studies described hereinabove was a 
preferred, purified reaction product which primarily comprised a mixture 
of sucrose hexa-, hepta-, and octa-esters (avg. ca. 7.5 ester groups per 
molecule), prepared from mixed C.sub.14 -C.sub.18 fatty acids. 
Vitamins 
The vitamins used to fortify the foregoing polyesters are described in 
detail hereinafter. It will be appreciated that commercial preparations of 
the appropriate vitamins and/or appropriate vitamin mixtures which provide 
vitamins A, D, E and K can be used herein. 
In general terms, the vitamins are classified as either "fat-soluble" or 
"water-soluble". The fat-soluble vitamins are used to fortify the 
polyester materials herein. The fat-soluble vitamins include vitamin A, 
vitamin D, vitamin E, and vitamin K. 
Vitamin A (retinol) can be used to fortify the polyesters herein. Vitamin A 
is a fat-soluble alcohol of the formula C.sub.20 H.sub.29 OH. Natural 
vitamin A is usually found esterified with a fatty acid; metabolically 
active forms of vitamin A also include the corresponding aldehyde and 
acid. All such fat-soluble forms of vitamin A (including the carotenoids) 
are contemplated for use in the present invention and are considered to be 
encompassed by the term "vitamin A" as used herein. The role of vitamin A 
in normal human metabolism has not been established with certainty, but it 
is known that this vitamin is essential to proper vision. 
Vitamin D (calciferol) can be used to fortify the polyesters herein. 
Vitamin D is a fat-soluble vitamin well known for use in the treatment and 
prevention of rickets and other skeletal disorders. "Vitamin D" comprises 
sterols, and there are at least 11 sterols with vitamin D-type activity. 
Of these, only those known as D.sub.2 and D.sub.3 are of substantial 
practical importance. Ergosterol, a plant sterol closely related to 
cholesterol in structure, is known as "provitamin D.sub.2 " and 
7-dehydrocholesterol is known as "provitamin D.sub.3 ". Each of these 
provitamins is converted to the corresponding active form by irradiation 
with ultraviolet light. Ergocalciferol (D.sub.2) is prepared commercially 
for use as a vitamin supplement. Cholecalciferol (D.sub.3) is a form 
synthesized in animal tissues and is chiefly found in the natural fish 
oils. The present invention fully contemplates the use of any of the 
vitamins and provitamins having "vitamin D-type" activity and the term 
"vitamin D" as used herein is intended to encompass all such fat-soluble 
materials. 
Vitamin E (tocopherol) is a third fat-soluble vitamin which can be used in 
the present invention. Four different tocopherols have been identified 
(alpha, beta, gamma and delta), all of which are oily, yellow liquids, 
insoluble in water but soluble in fats and oils. Of the four tocopherols, 
alpha is the most active biologically, a factor which may be related to 
better absorption from the intestine. Delta tocopherol is the most potent 
anti-oxidant of the four. It has been suggested that vitamin E deficiency 
may cause a variety of symptoms such as fetal abnormalities and deaths, 
myocardial degeneration, and necrosis of the liver, but the role of this 
vitamin in human nutrition is not yet well established. The term "vitamin 
E" as employed herein is intended to encompass all the fat-soluble 
tocopherols having "vitamin E-type" activity. 
Vitamin K exists in at least three forms, all belonging to the group of 
chemical compounds known as quinones. The naturally-occurring fat-soluble 
vitamins are K.sub.1 (phylloquinone), K.sub.2 menaquinone, and K.sub.3 
(menadione). Vitamin K deficiency usually results in poor clotting of the 
blood, among other symptoms. The term "vitamin K" as employed herein is 
intended to include all the foregoing fat-soluble quinones having "vitamin 
K-type" activity. From the foregoing it is to be understood that vitamins 
A, D, E and K, the corresponding provitamins and derivatives thereof, such 
as esters, having vitamin A, D, E or K-type activity in animals, 
especially humans, are fully contemplated for use herein and are 
encompassed by the term "vitamin" as used herein. 
The amount of the individual fat-soluble vitamins used to fortify the 
present compositions can vary with the age of the age of the recipient, 
the dosage regimen used, and the amount of the vitamin ingested from other 
dietary sources. For example, in younger, growing children or in pregnant 
females it is recognized that larger amounts of any given vitamin should 
be ingested to supply optimal nutritional benefits than are needed with 
adult males. If the user of the present compositions happens to ingest 
foods which are extremely rich in a given fat-soluble vitamin, less of 
that vitamin need be used in the present compositions to insure adequate 
intestinal uptake for good nutrition. In any event, an attending physician 
can, if so desired, measure the amount of fat-soluble vitamins in the 
plasma. Based on these data, the appropriate type and amount of 
fat-soluble vitamin used to fortify the polyesters herein can then be 
determined on an individual basis. 
More simply, the formulator of the compositions herein can fortify the 
polyesters with a recommended daily allowance (RDA), or increment or 
multiple of an RDA, of any of the fat-soluble vitamins to insure that the 
user of the compositions will maintain a nutritionally adequate uptake of 
said vitamins. For example, with vitamin A a daily amount in the range of 
20 international units (I.U.) to about 57 I.U. per kilogram of body weight 
can be employed. With vitamin D, fortification of the compositions to 
provide about 400 I.U., total, per day is ample. When supplementing with 
vitamin E, the amount of the vitamin optimal for dietary intake ranges 
from 3-6 I.U. for infants to 25-30 I.U., total, per day, for adults. When 
supplementing with vitamin K, it is more difficult to estimate the amount 
to be ingested to provide adequate nutrition since the microorganisms 
living in the intestine can synthesize this vitamin. However, it is known 
that ingestion of from 0.5 mg.-1 mg. of vitamin K per day will prevent 
insufficiency. 
As can be seen from the foregoing, the amount of the fat-soluble vitamins 
employed herein to fortify the polyesters can vary. In general, the 
polyesters are fortified with sufficient fat-soluble vitamin to provide 
from about 0.08% to about 150% of the average RDA. 
In therapeutic regimens the dosage of the compositions herein can vary with 
the severity of the hypercholesterolemic condition and the duration of the 
treatment. Individual dosages can range from about 0.01 mg./kg. to about 
500 mg./kg., and greater (unless otherwise specified, the unit designated 
"mg./kg." as used herein refers to mg. of liquid polyester per kilogram of 
body weight), preferably from about 0.1 mg./kg. to about 125 mg./kg. per 
dosage, with up to six dosages, preferably three dosages, being given 
daily, most preferably at meal times. Because of the AAL agent, such high 
dosages can be administered without fear of producing anal leakage 
effects. Dosages of less than about 0.1 mg./kg. do not materially inhibit 
the absorption of cholesterol in most patients. The dosages can be 
administered orally in any suitable unit dosage form such as pills, 
tablets, and capsules. Preferred are capsules made from gelatin. The 
dosages can also be administered as part of a controlled dietary regimen, 
e.g., as a synthetic salad oil or cooking oil or fat. 
The pharmaceutical compositions herein can comprises the 
polyester/vitamin/AAL agent alone, or in combination with any desired, 
non-interferring pharmaceutical carrier. As used herein, the term 
"pharmaceutical carrier" means a solid or liquid filler, diluent or 
encapsulating substance. Some examples of the substances which can serve 
as pharmaceutical carriers are sugars such as lactose, glucose and 
sucrose; starches such as corn starch and potato starch; cellulose and its 
derivatives such as sodium carboxymethylcellulose, ethylcellulose, 
cellulose acetate; powdered tragacanth; malt; gelatin; talc; oils such as 
peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and soybean 
oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol, and 
polyethylene glycol; agar; alginic acid; pyrogen-free water; isotonic 
saline; ethyl alcohol and phosphate buffer solutions, as well as other 
non-toxic compatible substances used in pharmaceutical formulations. 
Wetting agents and lubricants such as sodium lauryl sulfate, as well as 
coloring agents, flavoring agents and preservatives can also be present in 
the compositions, according to the desires of the formulator. 
The pharmaceutical carriers of the foregoing type can optionally be 
employed in conjunction with the liquid polyesters herein to provide a 
practical size to dosage relationship, composition forms which can be 
easily ingested, and means for providing accurate unit dosages in a 
convenient form. The pharmaceutical carrier usually will comprise from 
about 5% to about 50% by weight of the total pharmaceutical composition. 
Since the liquid polyesters of the present compositions are not unlike 
cooking and salad oils and fats in their physical properties, the present 
compositions can be used as a partial or total replacement for normal 
triglyceride fats in any fat-containing food composition to provide 
anit-hypercholesterolemic and low calorie benefits. In order to achieve 
these benefits in a reasonable time, it is necessary that at least about 
10% of the fat in the food composition comprises the polyesters herein. 
Highly desirable food compositions are those wherein the fatty component 
comprises up to about 100% of the polyester/anti-anal leakage compositions 
herein. Accordingly, the compositions of this invention can be used as a 
partial or complete replacement for normal triglyceride fats in a salad or 
cooking oil, or in plastic shortenings for use in frying, cake making, 
bread making, and the like. The compositions can also be used as partial 
or complete replacements for normal triglyceride fats in fat-containing 
food products such as mayonnaise, margarine, and dairy products. 
Preferred fat-containing food compositions of the present type comprise 
non-fat ingredients and fat ingredients wherein from about 10% to about 
95% of the total fat consists essentially of a liquid sugar fatty acid 
polyester having at least four fatty acid ester groups, each fatty acid 
having from about 8 to about 22 carbon atoms, said sugar fatty acid 
polyester and/or food composition made therefrom also comprising an AAL 
agent of the type disclosed here and being fortified with the fat-soluble 
vitamins. Such food compositions will most often contain at least about 
10%, generally 15% to 25% (by weight liquid polyester) of a fatty acid 
source which provides the anti-anal leakage effect. Highly preferred are 
food compositions wherein the sugar fatty acid ester contains no more than 
two unesterified hydroxyl groups. Liquid sucrose polyesters, especially 
those wherein the ester groups are mainly of the unsaturated type and 
contain 14 to 18 carbon atoms, when used in the manner of this invention, 
are especially preferred for use in such anti-hypercholesterolemic and low 
calorie food compositions. 
The total AAL agent employed in any of the compositions and methods herein 
will depend somewhat on the total amount of liquid polyester being 
ingested per day. The anti-anal leakage should be present in an amount 
equaling at least about 10% by weight of the liquid polyester. It is more 
preferred that the AAL agent comprises at least about 20% by weight of the 
liquid polyester to ensure that anal leakage does not occur, even at high 
ingestion rates. Compositions wherein the weight of AAL agent comprises 
from about 20% to about 50% of the weight of liquid polyester provide 
excellent control of serum cholesterol without anal leakage of the 
polyester. 
Compositions comprising edible fatty acids, their edible salts or their 
edible, digestible esters as the AAL agent preferably comprise from about 
10% to about 50% of these materials by weight of polyester. Compositions 
using the palatable position-specific triglycerides as the AAL agent 
preferably comprise about 20% to about 40% (by weight of liquid polyester) 
of these AAL agents. When the edible, non-digestible solid polyesters are 
used as the AAL agent, they are preferably used at a rate of from about 
20% to about 50% by weight of the liquid polyester. 
The following, non-limiting examples illustrate the compositions and 
processes of this invention. It will be appreciated that sugars and sugar 
alcohols, appropriately esterified, are encompassed by the term "sugar" as 
used herein and such materials can be interchanged in the compositions. 
EXAMPLE I 
Gelatin capsules for use by the hypercholesterolemic patient are prepared 
by conventional methods, as follows: 
______________________________________ 
Ingredient Amount per Capsule 
______________________________________ 
Sucrose polyester* 
2000 mg. 
Retinol 0.3 RDA 
Stearic Acid 750 mg. 
______________________________________ 
*Liquid, mixed hexa-, hepta- and octa-sucrose esters, predominately the 
octa-ester, esterified with mixed soybean oil fatty acids, predominately 
in the C.sub.16 -C.sub.18 chain length. 
The capsules of the foregoing type are prepared by simply mixing the 
ingredients and filling the standard gelatin capsules. The capsules are 
administered orally three times daily (three with each meal). This 
treatment regimen inhibits cholesterol uptake significantly and decreases 
the serum cholesterol levels in the circulatory systems of humans with, or 
disposed towards, hypercholesterolemia. Vitamin A levels in the patients 
are not decreased significantly from the normal. The patients are not 
troubled by undesired anal leakage with this regimen. 
Similar results are obtained when the sucrose polyester in the capsules of 
Example I is replaced with an equivalent quantity of a fatty acid 
polyester selected from the group consisting of glucose tetraoleate; 
glucose tetrastearate; mixed glucose tetraesters of soybean oil fatty 
acids; mixed mannose tetraesters of tallow fatty acids; mixed galactose 
tetraesters of olive oil fatty acids; mixed arabinose tetraesters of 
cottonseed oil fatty acids; xylose tetralinoleate; galactose 
pentastearate; sorbitol tetraoleate; sucrose tetrastearate; sucrose 
pentastearate; sucrose hexaleate; sucrose heptaoleate; and sucrose 
octaoleate, respectively. 
In the composition of Example I the retinol is replaced by an equivalent 
dosage level of a commercial vitamin A ester concentrate and equivalent 
results are secured. 
In the composition of Example I, the stearic acid anti-anal leakage 
ingredient is replaced by an equivalent amount of methyl stearate, ethyl 
stearate, propyl stearate, methyl behenate, ethyl behenate, hydrogenated 
palm oil, hydrogenated rapeseed oil and mixed hydrogenated tallow 
triglycerides, respectively, and equivalent results are secured. 
Preferred compositions of the type of Example I for inhibiting the 
absorption of cholesterol, especially in the human body, preferably 
comprise from about 0.1 gram to about 5 grams of the liquid polyester, an 
effective amount (as disclosed hereinabove) of the AAL agent and at least 
about 0.1 RDA of one or more of the fat-soluble vitamins. 
EXAMPLE II 
Gelatin capsules comprising a unit dosage form of an AAL agent, a liquid 
polyester and vitamin E are prepared by conventional means, as follows: 
______________________________________ 
Ingredient Amount per Capsule 
______________________________________ 
Sucrose octaoleate 
3500 mg. 
Vitamin E* 0.2 RDA 
Hydrogenated palm oil 
750 mg. 
______________________________________ 
*Consists of mixed alpha, beta, gamma and delta tocopherols. 
The above capsules are administered orally three times daily (three per 
meal/70 kg. man) over a one-month period. This treatment regimen 
substantially inhibits cholesterol uptake in the patient and decreases the 
serum level of cholesterol. No vitamin E deficiency in the patient is 
noted. No anal leakage from use of the capsules is noted. 
The capsules of Example II are additionally supplemented with sufficient 
.beta.-carotene to provide a 0.25 RDA of vitamin A per capsule. 
The hydrogenated palm oil is replaced by an equivalent amount of tristearin 
and equivalent anti-anal leakage results are secured. 
When oleic acid is used to replace the hydrogenated palm oil, no 
substantial anti-anal leakage effect is noted. 
EXAMPLE III 
Gelatin capsule comprising an AAL agent, a liquid polyester and containing 
a mixture of the fat-soluble vitamins are as follows: 
______________________________________ 
Ingredient Mg. per Capsule 
______________________________________ 
Sucrose octaoleate 
2000 
Vitamin A 0.1 
Vitamin D 0.01 
Vitamin E 0.1 
Vitamin K 0.1 
Ethyl stearate 750 
______________________________________ 
The vitamin A employed in the capsules of Example III is retinol; the 
vitamin D is a 1:1 mixture of irradiated ergosterol and irradiated 
7-dehydrocholesterol; the vitamin E comprises a commercial mixture of 
alpha, beta, gamma and delta tocopherols; and the vitamin K comprises the 
fat-soluble phylloquinone. 
Three capsules of the type prepared in Example III are administered orally 
five times daily (three with each meal) to inhibit cholesterol uptake and 
decrease the level of cholesterol in the circulatory system of a 70 kg. 
patient afflicted with hypercholesterolemia. The body levels of 
fat-soluble vitamins A, D, E and K do not decrease below normal. No anal 
leakage is noted. Similar capsules in this dosage range without ethyl 
stearate cause an undesired laxative effect, i.e., leakage of polyester 
through the anal sphincter. 
EXAMPLE IV 
A highly palatable, low calorie composition suitable for use by patients on 
anti-hypercholesterolemic therapeutic regimens and/or as a cooking fat 
substitute by individuals on an anti-hyperlipidemic diet is as follows: 
______________________________________ 
Ingredient % by Weight 
______________________________________ 
Cocoa butter 50 
Vitaminized liquid sucrose 
50 
polyester* 
______________________________________ 
*Avg. 7.5 ester of sucrose and unsaturated, mixed soybean oil fatty acids 
fortified to provide 1000 I.U. of vitamin A per one ounce of composition. 
The composition of the foregoing type is suitable for use in standard 
fashion as a low calorie cooking fat. The continued use of the composition 
as a replacement for regular cooking fats lowers the body's cholesterol 
level but does not cause depletion of vitamin A in the tissues. No anal 
leakage of the liquid polyester is noted. 
In the composition of Example IV the natural cocoa butter is replaced by an 
equivalent amount of the position-specific trigylcerides SOO, SOS, OSS, 
PSS, ASS and BSS, respectively, and equivalent compositions are secured. 
EXAMPLE V 
A plastic shortening is prepared from the following ingredients. 
______________________________________ 
Ingredient % by Weight 
______________________________________ 
Cocoa butter 40 
Vitaminized xylitol pentaoleate* 
50 
OSS 10 
______________________________________ 
*Vitaminized with sufficient irradiated ergosterol to provide 40.0 I.U. o 
vitamin D per two ounce serving. 
The composition of Example V is prepared by thoroughly mixing the indicated 
ingredients. The composition is suitable for use in frying and other types 
of cooking where a plastic fat is employed. The fat composition of Example 
V can also be employed in the preparation of baking doughs suitable for 
use by the hypercholesterolemic patient. Continued ingestion of the 
plastic shortening of Example V, or foods made therefrom, reduces the 
body's serum cholesterol level and does not result in vitamin D 
deficiency. No anal leakage of the xylitol pentaoleate is noted. 
The shortening of Example V can be used by the normal or hyperlipidemic 
patient to control body weight. 
EXAMPLE VI 
A vitamin-fortified, non-anal leakage, low calorie, 
anti-hyperchlesterolemic composition prepared with an edible, but 
non-absorbable, non-digestible, solid polyester AAL agent is as follows. 
______________________________________ 
Ingredient % by Weight 
______________________________________ 
Vitaminized sucrose octaoleate* 
70 
Sucrose octastearate 30 
______________________________________ 
*Vitamin-fortified with a commercial mixture of vitamins A, D, E and K 
sufficient to provide an RDA of each of these vitamins per three ounce 
serving. 
The composition of Example VI is prepared by simply combining the 
ingredients. The composition is suitable for use as a cooking fat by the 
hypercholesterolemic patient to reduce serum cholesterol levels while 
maintaining normal levels of the fat-soluble vitamins. No anal leakage of 
the sucrose octaoleate is noted. 
The composition of Example VI can be used by the normal or hyperlipidemic 
patient to control serum cholesterol without increasing caloric intake. 
In the composition of Example VI the sucrose octastearate is replaced by an 
equivalent amount of sucrose heptastearate and sucrose octapalmitate, 
respectively, as the AAL agent, and equivalent results are secured.