417 Specialty Lipids and Their Biofunctionality Symposium held at the 76th AOCS Annual Meeting in Philadelphia, Pennsylvania, May 1985 III I| Medium Chain Triglycerides and Structured Lipids Vigen K. Babayan New England Deaconess Hospital, Harvard Medical School, Boston, MA 02215 Lipids are an essential component of our body composi- tion and necessary in our daily food intake. Conventional fats and oils are composed of glycerides of long chain fatty acids and are designated as long chain triglycerides (LCT). Body fat as well as the fats and oils in our daily intake fall into this category. In enteral and parenteral hyperalimentation, we can identify such LCT fats and oils. Soy, corn, safflower and sunflowerseed oils are typical of the LCT oils. In the search for alternative noncarbohydrate fuels, medium chain triglycerides (MCT) are unique and have established themselves in the areas of malabsorption syn- drome cases and infant care and as a high energy, rapidly available fuel. Structure lipids with a MCT backbone and linoleic acid built into the triglyceride molecule have been developed to optimize the triglyceride structure that is best for patients, particularly the critically ill. Structured lipids with built-in essential fatty acid components or other polyunsaturated fatty acids promise greater flexi- bility in patient care and nitrogen support. Lipids 22, 417-420 (1987).
`
`Recent years have brought a renewed interest in lipids
`and their role in the metabolic and dietetic applications
`in health care of hospitalized patients as well as the public
`at large (1-33; Shah, N.M., and Iber, F.L., private com-
`munication}.
`This symposium focuses on a specific, unique segment
`of the lipid picture: the medium chain triglycerides (MCT)
`and structure lipids prepared from them.
`A review and summary is presented here to lay the
`groundwork for the papers that follow. Each presenta-
`tion supplements the broad picture that is evolving from
`the animal and human research that is progressing at
`various universities and laboratories.
`
`Fats and oils of animal, vegetable and marine origin have
`a fatty acid spectrum that ranges from C2-C24, with varia-
`tions in not only physical and chemical characteristics but
`also in isomers and positional structure in the triglyceride
`molecule. Most fats and oils are composed of long chain
`fatty acids and are termed long chain triglycerides (LCT). Caproic
`Caprylic
`Dairy fat, meat fat and vegetable oils fall into this Capric
`Undecanoic
`category (Table 1).
`The lauric fats, however, are composed primarily of Lauric
`fatty acids of C14 chain length and shorter. Coconut and Myristic
`palm kernel oils are typical of this class of lauric fats.
`Palmitic
`Stearic
`They represent the main source of the C8-Clo acids re- Oleic
`Linoleic
`quired for synthesis of MCT (Table 2).
`MCT are different from all of the fats and oils we con- Arachidic
`ventionally use. Where conventional fats and oils are
`
`Type of oil
`Fatty acid Babassu Coconut Cohune Palm kernel Tacum
`
`0.4
`5.3
`5.9
`
`44.2
`15.8
`8.6
`2.9
`15.1
`1.7
`0.1
`
`0.5
`8.0
`6.4
`48.5
`17.6
`8.4
`2.5
`6.5
`1.5
`0.1
`
`0.3
`8.7
`7.2
`0.1
`47.3
`16.2
`7.7
`3.2
`8.3
`1.0
`
`0.3
`3.9
`4.0
`49.6
`16.0
`8.0
`2.4
`13.7
`2.0
`0.1
`
`0.2
`2.9
`2.3
`51.8
`22.0
`6.8
`2.3
`9.3
`2.4
`
`absorbed via the lymphatic system and are carnitine-
`dependent for chylomicron formation and transport, MCT
`are absorbed via the portal system, are not carnitine-
`dependent and do not require chylomicron formation. The
`metabolic pathways of the MCT and LCT distinguish the
`unique aspects of the MCT (Tables 3 and 4; Fig. 1).
`Aside from the transport difference, MCT demonstrate
`certain additional characteristics of considerable advan-
`tage. Whereas lipids generally are slowly absorbed and
`metabolized and energy is expended to oxidize and utilize
`them as fuel or building blocks, MCT are absorbed and
`
`1
`
`Oils
`
`Type of oil
`Corn Peanut Safflower Soybean Sunflowerseed
`
`0.1
`6.5
`
`2.4
`13.1
`77.7
`
`0.2
`
`0.1
`12.2 11.6
`0.2
`0.1
`0.1
`2.2
`3.1
`27.5 46.5
`57.0 31.4
`0.9
`0.1
`
`1.5
`1.4
`0.1
`3.0
`1.0
`
`0.1
`11.0
`0.1
`4.0
`23.4
`53.2
`7.8
`0.3
`
`0.1
`
`0.5
`0.2
`6.8
`0.1
`4.7
`18.6
`68.2
`0.5
`0.4
`
`Fatty acid
`
`Lauric
`Myristic
`Palmitic
`Palmitoleic
`Margaric
`Stearic
`Oleic
`Linoleic
`Linolenic
`Arachidic
`Gadoleic
`Eicosadienoic
`Behenic
`Lignoceric
`
`TABLE 2
`
`HYDRITE EXHIBIT 1019
`(1 OF 4)
`
`TABLE
`Typical Long Chain Triglyceride
`REVIEW AND DISCUSSION
`Typical Lauric Fats and Oils
`LIPIDS, Vol. 22, No. 6 (1987)
`

`
`~8
`
`3
`
`Medium Chain Triglyceride Oil Specifications
`
`Free fatty acids (as oleic)
`Saponification value
`Iodine value (Wijs}
`Acetyl value
`Setting point
`Color (Lovibond}
`Unsaponifiables
`
`Fatty acid composition
`C6
`1-2%
`Cs
`65-75%
`Clo
`25-35%
`C12
`2% max
`
`V.K. BABAYAN
`
`0.05% max
`345-355
`1.0 max
`5.0 max
`- 5 C
`10 yellow/1.0 red
`0.5 max
`
`In the area of parenteral nutrition, we have been limited
`for many years to lipid emulsions based on soybean oil
`and now safflower oil (Table 5). Both are LCT types of
`lipid and pose a number of problems.
`The current practice of using lipid emulsion in a total
`parenteral nutrition (TPN) regimen has been based on the
`need for a noncarbohydrate source for fuel and energy and
`the need to satisfy essential fatty acid requirements
`and/or deficiencies. LCT supply caloric needs and alleviate
`essential fatty acid deficiency. They have, however,
`shown a tendency to deposit as fat (a large proportion
`of the infused lipid) rather than to satisfy immediate fuel
`requirements. LCT lipid emulsions also are too slow in
`clearing from the blood and oxidize too slowly to supply
`fuel and energy.
`At present, there is controversy over the optimum
`feeding regimen for the critically ill patient. An all-
`carbohydrate TPN system may promote visceral protein
`attraction and obligatory hepatic lipogenesis. There is no
`consensus, however, that lipid emulsions composed of
`LCT are optimal. There is concern that these emulsions
`are less than ideal because of a relative carnitine deficien-
`cy that occurs in sepsis, which blocks their entry into the
`mitochondria
`for
`/~-oxidation. Numerous additional
`studies have shown reduced clearance of these emulsions
`in the critically ill patient and increased potential for
`elongation, desaturation and deposition in the liver and
`other organs.
`In contrast, MCT have been shown to have a carnitine-
`independent entry into the mitochondria, to have a
`more rapid/3-oxidation and to be less likely to undergo
`elongation and deposition (39-42). Emulsions composed
`
`metabolized as rapidly as glucose while having better
`than twice the caloric density of protein and carbo-
`hydrate. They are easily oxidized and utilized as fuel and
`energy, with little tendency to deposit as body fat. For
`a quick, high energy source, MCT are outstanding.
`These unique features of MCT have been recognized
`and utilized over the years. Oral supplementations and
`enteral feeding formulas of MCT products are available
`for use in a variety of areas, including care of infants,
`epileptic children and cystic fibrosis patients and for in-
`testinal resection (35-37). For such established areas of
`MCT use, the practice has been to physically mix 15-20%
`of a highly polyunsaturated vegetable oil (to insure essen-
`tial fatty acid requirements) with the MCT oil (38).
`
`TABLE 4
`
`Physicochemical characteristics
`
`Physiologic considerations
`
`Potential therapeutic applications
`
`MCT present more interfacial surface for
`enzyme action/unit time
`
`Intraluminal enzymatic hydrolysis of
`AMCT is more rapid and complete than
`LCT
`
`Greater water solubility of MCT
`hydrolysis products
`
`Bile salts are not required for dispersion
`in water
`
`Smaller molecular size of MCT vs LCT
`
`Shorter chain length of fatty acids derived
`from MCT
`Small molecular size and lower pK of fatty
`acids derived from MCT
`
`Greater water solubility of MCFA
`
`Small amounts of MCT may enter intestinal
`cell without prior hydrolysis
`More efficient penetration of diseased
`mucosal surface
`Intramucosal metabolism of MCFA
`different from LCFA:
`Decreased affinity for esterifying
`enzymes
`Decreased affinity for activating enzymes
`Minimal reesterification of MCFA to
`MCT
`No chylomicron formation
`Different routes of transport of MCT
`vs LCT:
`Portal transport of MCT (as MCFA)
`Lymphatic transport of LCT (as
`chylomicrons)
`
`Decreased intraluminal concentrations of
`pancreatic hpase {pancreatic insuffi-
`ciency, cystic fibrosis}
`Decreased small-bowel absorptive surface
`{intestinal resection}
`Decreased intraluminal concentrations of
`bile salts {intrahepatic and extra-
`hepatic biliary-tract obstruction, chronic
`parenchymal liver disease}
`Pancreatic insufficiency
`
`Nontropical sprue, tropical sprue
`
`Abeta-lipoproteinemia
`Hypobeta-lipoproteinemia
`
`Lymphatic obstruction (lymphomas}
`Intestinal lymphangiectasia
`
`HYDRITE EXHIBIT 1019
`(2 OF 4)
`
`TABLE
`Rationale for Use of Medium Chain Triglycerides (MCT)
`LIPIDS, Vol. 22, No. 6 (1987)
`

`
`MCT AND STRUCTURED LIPIDS
`
`419 ADIPOSE TI$SU! mcm. ran.,,. ~ ~T~r ,ao /
`
`l~'r (cid:12)9 tOlli i
`
`vnlli.v~(li01
`
`/
`
`l.Cl"-o(vl) ~
`
`Z
`
`~
`
`[
`
`TABLE 5
`C~ Fatty Acid Composition of Oils for Parenteral Emulsions Cs
`
`acid
`
`Soybean
`
`Type of oil
`Safflower
`
`i Jl',, "~, U:m (cid:12)9 Lore c~tm mTl'~r argo / -~,~ co, 4----~ f v \ / T-__I \ ! ~ I I ~"~. ~ I I ............. "- ...... II 6UT LUMEN INI~S'rlNAL EPITHELIAL CELL FIG. 1. Transport of medium and long chain triglycerides.
`+ C~s = C~ C,~ = C,8 C8 C,~ = Mixture (nonrandom distribution) C8 C8 C. C,. = Ec. Ec. Ec.= C~ C18 = C,~ = C,e = Rearranged mixture (random distribution) FIG. 2. Physical mix vs rearrangement.
`
`6:0
`8:0
`I0:0
`12:0
`14:0
`16:0
`18:0
`18:1
`18:2
`18:3
`20:0
`20:1
`
`--
`--
`--
`0.I
`10.5
`3.2
`22.3
`54.5
`8.5
`0.2
`0.9
`
`--
`--
`--
`0.I
`6.7
`2.7
`12.9
`77.5
`tr
`0.5
`0.5
`
`MCT
`
`<2
`70
`30
`<2
`--
`--
`--
`--
`--
`--
`--
`
`principally of MCT may offer a unique and readily
`available fuel for the injured and stressed patient (43).
`Also, since MCT readily undergo f~-oxidation, ketonemia
`is usually much more pronounced than with LCT emul-
`sions. Skeletal muscle can readily burn ketone bodies for
`fuel and may spare the oxidation of branched chain amino
`acids and reduce skeletal protein catabolism {44-52).
`In an effort to develop the optimum lipid structure for
`parenteral use, we considered structured lipids using
`MCT and LCT having linoleic and/or linolenic fatty acids.
`The resulting rearranged triglycerides have both medium
`chain fatty acids and a polyunsaturated fatty acid on the
`
`same glycerine molecule. Based upon the molar ratios of
`the MCT and the LCT with a high unsaturated fatty acid,
`one can obtain the structured lipid of the desired com-
`binations (Fig. 2). We have considered further the struc-
`tured lipids with an MCT backbone by adding the essen-
`tial fatty acid (linoleic acid} into the triglyceride molecule
`various levels (45,46).
`If LCT emulsions are too slow in clearing and suffer
`from other drawbacks, and MCT emulsions may be too
`rapid in clearing and suffer from the absence of essential
`fatty acids, then the structured lipid with sufficient
`linoleic acid to satisfy essential fatty acid needs will also
`serve to slow down the clearance of the MCT backbone
`to a more acceptable level (Table 6). A structured lipid
`
`HYDRITE EXHIBIT 1019
`(3 OF 4)
`
`Fatty
`-- --
`--
`at
`LIPIDS, Vol. 22, No. 6 (1987)
`

`
`V.K. BABAYAN
`
`6
`
`Captex 810 series
`structured lipids I%}
`
`A
`
`62
`32
`6
`<1
`
`B
`
`39
`43
`16
`2
`
`C
`
`15
`40
`27
`3
`
`D
`
`3
`20
`44
`34
`
`I MCT (3 short}
`II MCT (2 short, 1 long}
`III MCT (1 short, 2 long}
`IV LCT (3 long}
`
`having about 25% linoleic acid (Captex 810B} appears to
`be suitable for such parenteral lipid emulsion use. Pre-
`clinical and clinical testing remains to supply the needed
`data to validate this concept. The animal studies to date
`are encouraging and show certain additional benefits for
`the use of such structured lipids in hyperalimentation.
`Further investigation is warranted.
`The rationale for and concept of preparing structured
`lipids are gaining support of research laboratories. It ap-
`pears feasible that triglycerides where at least one fatty
`acid is a polyunsaturated fatty acid and at least one is
`a medium chain fatty acid can be obtained in glyceride
`otis. The actual format and combination of the fatty acids
`on the glycerine molecule will have to be investigated.
`Whether we shall require specific structures of high purity
`or can take advantage of molecular rearrangement
`to
`yield a mixture of structures will be determined by the
`functionality of such compositions. It appears highly
`probable, however, that lipid compositions of medium and
`long chain glycerides will advance our application of such
`lipids, both for the treatment of patients and the general
`welfare of the public.
`
`pp. 1-30,
`
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`University of Pennsylvania Press, Philadelphia.
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`Sonderdruck aus Supplementa 17 zur Zeitschrift fur
`Ernahrungswissenschaft {Steinkopff, D., ed.} pp. 1-8, Springer
`Verlag, Darmstadt, West Germany.
`150-158.
`3. Johnson, R.C., and Cotter, R. {1986} Nutr. Int. 2,
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`nual meeting, Philadelphia, October 1966.
`16. Schwabe, A.D., Bennett, L.R., and Bowman, L.P. (1964)J. AppL Physiol. 19,
`335-337.
`
`561.
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`19.
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`20.
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`21.
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`22.
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`23.
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`24.
`25.
`
`26.
`
`27.
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`17.
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`18.
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`Turkenkope, I.J., Maggio, C.A., and Greenwood, M.R.C. (1982}
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`Babayan, V.K. {1981} J. Am. Oil Chem. Soc. 58,
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`Capmul 8210 {MCM} Pharmaceutical Grade Bulletin, Capital
`City Products, Columbus, OH.
`Captex 300 Bulletin, Capital City Products, Columbus, OH.
`Thistle, J.L., Carlson, G.L., Hofmann, A.F., and Babayan, V.K.
`~1977} Gastroenterology 72,
`1141.
`Mack, E.A., Saite, C., Goldfarb, S., Crummy, A.B., Thistle, J.L.,
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`41. Sailer, D., and Muller, M. {1981} JPEN5,
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`
`[Received September 3, 1986]
`
`HYDRITE EXHIBIT 1019
`(4 OF 4)
`
`420
`TABLE
`Approximate Composition of Glycerides
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`LIPIDS, Voi, 22, No. 6 (1987)