`
`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,
`
`1. Senior, J.R., ed. {1968} inMedium Chain Triglycerides,
`University of Pennsylvania Press, Philadelphia.
`2. Babayan, V.K. {1974} in Early History and Preparation of MCT,
`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,
`23-25.
`4. Babayan, V.K. {1967} J. Am. Oil Chem. Soc. 45,
`5. Kaunitz, H., Slanetz, C.A., Johnson, R.E., Babayan, V.K., and
`Barsky, G. (1953} J. Am. Oil Chem. Soc. 35,
`10-14.
`6. Greenberger, N.J., and Skillman, T.G. (1969) N. Engl. J. Med" 230,
`1045-1058.
`7. Kalser, M.H. {1971} Adv. Int. Med. 17,
`301-322.
`8. Bach, A.C., and Babayan, V.K. {1982} Am. J. Clin. Nutr. 36,
`950-962.
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`613-620.
`10. Laveau, M.M., and Hashim, S.A. t1978} J. Nutr. 108,
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`621-629.
`12. Travis, D., Minenna, A., and Frier, H. {1957} Fed. Proc. 4,
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`14. Stewart, J.W., Wiggers, K.D., Jacobsen, N.L., and Berger, P.G.
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`15. Scheig, R., and Klatskin, G., Paper presented at the AOCS an-
`nual meeting, Philadelphia, October 1966.
`16. Schwabe, A.D., Bennett, L.R., and Bowman, L.P. (1964)J. AppL Physiol. 19,
`335-337.
`
`561.
`
`19.
`
`20.
`
`21.
`
`22.
`
`23.
`
`24.
`25.
`
`26.
`
`27.
`28.
`
`29.
`
`17.
`
`18.
`
`Tantibhedhyangkul, P., and Hashim, S.A. (1975} Pediatrics 55,
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`Tantibhedhyangkul, P., and Hashim, S.A. {1978} Pediatrics 61,
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`Tantibhedhyangkul, P., and Hashim, S.A. {1973} Am. J. Clin. Nutr. 64,
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`Tantibhedhyangkul, P., and Hashim, S.A. {1971} Bull. NYAcad" Med. 47,
`17-33.
`Roy, C.C., Ste-Marie, M., Chartrand, L., Weber, A., Bard, H.,
`and Doray, B. {1975} J. Pediatr. 86,
`446-950.
`Geliebter, A., Torbay, N., Filippo, E., Bracco, S., Hashim, A.,
`and Van Itallie, T.B. {1983} J. Am. Clin. Nutr. 37,
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`Turkenkope, I.J., Maggio, C.A., and Greenwood, M.R.C. (1982}
`1254-1263.
`49A-51A.
`Babayan, V.K. {1981} J. Am. Oil Chem. Soc. 58,
`Captex 810 Series Bulletin, Capital City Products, Columbus,
`OH.
`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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`438-439.
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`1097-1103.
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`presented at the meeting of the American Association of Enteral
`and Parent Nutrition, New Orleans, Jan. 1981.
`40. Eckart, J., Adolph, M., VanderMuhlen, N., and Naab, V. {1980}
`360-366.
`115-119.
`41. Sailer, D., and Muller, M. {1981} JPEN5,
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`N.R. 11983} Am. J. Clin. Nutr. 38,
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`43. Sobrado, J., Moldawer, L.L., Pomposelli, J., Babayan, V.K.,
`Bistrian, B.R., and Blackburn, G.L. 11985} Am. J. Clin. Nutr. 42,
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`44. Maiz, A., Yamazaki, K., Sobrado, J., Babayan, V.K., Moldawer,
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`910-915.
`46. Yamazaki, K., Maiz, A., Sobrado, J., Babayan, V.K., Moldawer,
`L.L., Bistrian, B.R., and Blackburn, G.L. (1984) JPEN 8,
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`47. Hamawy, K., Moldawer, L., Georgieff, M., Valicenti, A.,
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`
`K.E., Kolpek, J.H., and Rapp, R.P. {1986} Nutr. Clin. Prac. 1, 49. Record,
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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)