CA1173692A - Nutrient compositions and method of administering the same - Google Patents

Abstract

ABSTRACT
Compositions of dipeptides and/or tripeptides are disclosed for dietary purposes, orally, intragastro-intestinally and intravenously. The tripeptides and dipeptides contain one glycine residue as the N-terminal amino acid grouping. Other amino acid residues contained in the tripeptide or dipeptide can include leucine, isoleucine, valine, threonine, methionine, phenylalanine, iysine, tryptophan, arginine, histidine, alanine, proline and glutamic acid.

Description

~3~2 This inven~ion relates ~o nutrlent compositi~ns ~or mammals and mor~ partlcularly to nutrien~ compositions con~aining ol~gopep~ides and methods o~ administering ~hem to mammalsD

Desc~ption of the Prior Art:
M~n and o-~her mamm~ls require proteîn daily ~o satisfy vital ~unctionsO Proteins are converted to ami~o acids in the di~es~ive system and the resulting amino acids are employed by the body for growth, developrnent, multi-plication and metabolic functionsO The human body requi~es a daily supply o~ the essent~al amino acids which ar~ lysine, leucine, isoleucîne, tryptophan, methionine, vali~e, phenyl-alanine~ and ~hreo~ineO There are o~her amino acidsg called "non-essential," which the body employs as a source o nitrogenO The non-essentLal amino acids are alanine, glycine, serlne, proline, histidine, tyrosine and cysteineD
In t~e absence o t~le essen~ial amino acids, there is a r~pid deteriora~ion o~ ~he nu~xi~lonal state which results in dysfunc~ion of prac~ically every orgall in ~he body with consequen~ heal-~h problems such as liver ailure~
anemia, in~ec~long diarrhea and re~ard~d growth~
In ~he absence of protein or in circumstances where a medical patient is unable to ~ssimllate proteln~ i~ i9 possible ~o supply free amino acids in~ravenously and in~ra-gastrointestinally a~ a solutionO Elemental diets ~hich were popular ln the practice o: mecllcine in l:he 1970 ~ s ~l36 employed such solutions o~ ~ree amino aclds, r~lese ~olu~
-~ions are hyper~onic. Hypertonic solu~iorls, wh~ er in the intestines or in the blovd vessels ar~ not well tolerated and may cause undes~ra~le e~fects such as diarrhea and de-hydratîon. ~l~s~ problems may '~e critiral in sick patients.
Wn~ile ~he body can me~abol-Lze amlno ac~ds, the body~s transport system can more ef~ectively utilize peptides which can be absorbed and thereafter hydroly~.ed withill the body~s cells ~o amino acidsO
More r~cent discoveries have indicated that the hurllan digestive system incLudes separate sltes or absorp-~ion of dipep~ides and absorp-~ion of ~ripep~ides in ~he intestinal ~ucosaO When absorbed, the dipeptldes and tri- -pep~ides are hydrolyzed into consti~uent 3mino acids. The hydrolysis ~hus occurs a~ter the peptides are wi~hln a body cellO S~e Acllbi and Soleirnanpour~ JO cl-lnD InvestO 53:
136~-137~ 7~).
~he pept-lde transport system has the following featuresO
(a) It does not ~ake up amino acids~ but Lns~ ad transports dipeptides and ~ripepti~esO
~b~ I~ has lit~le or no af~inlty for pep~ides with more than three amino acids r sidues~
(c) It has higher maximum rate of uptake ~an an amino ar;cl carrier systemO
(d~ It pre:~ers peptides with lipophili~ amino acids in the N - ~erminal pos L~ion O

- 2 ~

~ ~36~2 ~ e~ Its greatest actlvlty ls in the jeju~um and its least activity is in the duodenum with the ileum being between these extremesO
The elemental diets employing free amino acids are usually hypertonicO The hypertonicity cre~tes secondary problems in medlcal patients with gastrointeskinal flisordex50 There are repor~s o~ the administra~ion o~ a single dipeptide or a single trlpeptide for academic cllnical evalua~ionO
1~ Howe~er today there remains a problem o supplying adequate amino acid nutrients ~o a ~ammal such as a human medical patient, in a ~orm where the amino acid co~tent can be assimila~ed by the transport sys~em withou~ ~he ad-verse e~ects of hypertonicityO
According ~o the presen~ lnvention, a nutrient com-positîon is provided wh:ich is an aqueous solu~ion o:f oli.go-peptides ~dipeptides and/or tripeptid~s) wherein each o~ ~he oligopeptldes has a glyc-Lne resldue a8 ~he M-terminal amino acid grouping~ The aqueous solution o oligopeptides can be supplied a~ twice (in ~he case of dipeptides) or three times (in the case o~ tripeptides) the concentration o~
amino acids a~ ~he same osmolali~y as a corresponding solution o~ ~ree amino acidsO Moreover the oligopeptides are readily assimilated by the txansport system an~ readily converted to amino acid residuesv Wl~hin ~he body cells~
the oligopeptides o~ this invention have a glycine groupi.ng as the N--~erminal grouping o ~he oligopep~idesv The glyclne

3 fi 9 ~
termina~ed oligopep~ides achieve a desirable in~ac~ tran~-port o~ ~he oligope~p~ide lnto a cell. The glycine group-ing protects ~he oligopeptl~e from hy~rolysis into amino acids by the pep~idases on a cell membrane~ Premature hy-drolysis of the oligopeptide into amino acids would upset the osmolality of the system~ The glyc-lne grouping is also lipophilic and ~he oligopeptide has an enhanced transport through the cell membraneO The ol~gopeptide can be cleaved into its componen~ amîno acids inside the body cell.
The glycine-~erminated oligopeptide~ are particular-ly water-sol~ble which permi~s the use of such oligopeptides in high concentra~ionsO This feature is o special imp~tance in treating patients having a restric~ed-watex diet; eOgO, certain heart patients and kidney patient~O The glyci~e-term~nated oligopeptides have good therl~al s~abilîty which permi~s the autoclavin$ o~ such ma~erials ~r sterilizationO
The glycine-termlna~ed oligopeptides in solution also have good shelf-life stability~
The oligopep tides may be adminis tered intraven.ously 3 ?O along with other nutrient compositions such as fa~s, glucose, saccharides, minerals, trace elements and vitaminsO ~he oLigopeptide solution may be introdueed orally or by other intragastrointestinal ~ministration techniques, eOgO, stomach ~ub~s and inser~ion ~ubes el~ewhere in ~he intesti nal ~ractO
The oligopeptide solution contains rom a~out one to twent~ percent by weig~t of t~le oligopeptides, pre~erably ~ 1736~2 about one to five percen~ by weigh~O The aqueous solu~lon may be an electrolyte soLution suitable :or intrav~nou~
feeding or ~or in~ragas~rointestinal administration. The aqueous solution itself may contain the other nutrient additives ~uch as fats~ polyols7 glucose, mono- or oligo sac~harides, minerals~ trace elements and vitaminsO
Aqueous dietary compositions are prepared which include at leas~ two tripeptides or a~ leas~ two dipeptides or mix~ures containing at least one dipeptide and at least one tripeptideO The ~erm oligopeptide~ as used herein, includes dipeptides and tripeptides. The oligopeptides include a glycine residue and one or two other essential amino acid residues such ~s lysine, leucine, isoleueine~
tryp~ophan, methionine~ vaLine, ph~nylalanine, ~hreonine;
or non-essen~ial amino acids such as arginine, histidine, alanine, proline and glutamic. acidO ~he glycine residue is the N-terminaL residue in the oligopeptideO
The concentration o~ the oligopeptide in the aqueous solution is from 1 ~o 20 percent by weight, pre~er~'l-Jly from 1 to 5 pe~cen~ by weightO Aqueous solu~ions contalning about 2.5 weigh~ percen~ of the ollgopeptides have useful biological absorption character~sticsO The selec~ion of the oligopeptides in the composition depends upon the re~u-lre-ments ~or essential and non-essential amino acidsJ
A typical mi~ure of ~ripepticles is set for~h in Table . l o ~1736~2 The rni~ure o~ Table 1 is lntended to approgima~e one 850-mg. portion of a prote-ln Oæ high biological value. Tlle mixture o Ta~le 1, in one liter o~ water~ -comprises a useful nutrient composîtîonO
TabLe 1 On~ 850-m~. Portion T~pep~ldes Amount (m~) glyclne-leucine-leucine 77 glycine-isoleucine-isoleucin~ 59 glycine-val:ine-valine 70 glycine-threonine-threoniIIe 53 glycine-me~hionine-methionine 71 glycine-phenylalanine-phenylalanine75 glycine-lysine-lysine 57 glycine-~ryptophan ~ryp~ophan 21 gl~cine-alanlne-alanine 367 The ~irst eight trlpeptides o~ Table 1 provlde all of the essential amino acidsO The glycine-aLanine-alanine tripeptide æa~is~les a need ~or non-essen~:lal amino acidsO
~ne s truc tura 1 ~oxmula -~or glyc ine-Leuc~ne~leucine is as foll~ws:

The gl~cine unit H3~-CH2C- supplies the N-terminal grouping in ~he tripeptid~- or dipep~ide~

~ ~ompos-i~iQn o:E dipeptldes ~ provided in T~ble 2 or pre~aring a one~ er aqueous solu~ion o~ dipeptides which supplie~ -~he human daily amino acid recluiremen~O I~
wiLl be ob~exved ~ha~ ~le dîpeptides include a glycine residue whîc'n is the N-~erminal residue.
T~ble 2 - One L-i~er Solution Dipep~id~ grams glycine-isoLeucine 205 glycine-leucine 305 glycine~lysine 301 glycine-metllionlne 302 glycine-phenylalanine 3.3 glycine-~hreonine 1.6 glycine- tryptopharl O 0 63 glycine-valine 2 . 5 gly~ine argi~ine 509 glycine~histid~ne 105 glyclne~ala~ine 5u4 glycine-glutamic acid So9 glycine-prolinP 5 kæl~IOD OF ADMINISTRATION
The aqueous oligopeptide solu~ion may be ingested orally along wi~h other nu~rien~s such as conventionaL
~oods of prepared vitamins, fats~ polyols, glucose~ oligo saccharides, rninerals and ~race elementsO For paren-teral adrninistration~ a supply o.~ ~he oligopeptlde soLution ~ :L73692 may be merged through a Y ~onnectlon with a suppl.~ o~
glucose solu~îon or o~her paren~eral sol~tions~ In appro-priate 3.nstances, the oligopeptide solution m~ be mi~ed with polyol solu-~ionsg gl.ucose solutions and/or other parenteral solutlons to create a mix~ure which may be administered pare~erally.
Solu~ions containing ~he ol-lgopeptides and polyoLs are especi~lly help~ulO Preferred polyols are caxbohydra-te alcohols such as sorbitol and ~litolO Solutions o~ oligo-p~ptides and polyols can b~ heated without undesirable reaction between the polyols and oligopeptides~ This is distinguishable from solutions of glucose and oligopep-tides which may react upon heating.
~le same oligopep~ide.mix~ure for oral use can also be used ~or parenteral nutritlonO Frequentl~, in the prac--tice of medicine, situations are encountered in whlch pa-tients are unable to receiv2 their dally nutrie~lt require ments orallyO The development of total paren-teral nutri-tion by Du~rick and colleagues ~Dudriclc et al, Surgery 64:134-1~23 19683 has made posslble the întravetlous in:Eu-sion o~ su~icient energy and essen~ial nu~rient require- :
mentsO The intra~enous solutions currently used ~re m~de Up 0~ free amino acids which made these solutions ~yper-tonicO There~ore, the solutions must be given through catheters placed ln large central veins, frequentLy con~
sidered ~o be a surgical procedureO Serious complica~ions, ~ ~ .

~ ~73Çi92 such as infection, have b~en reported to accompan.~ this central vein me~hod o~ parent~ral nutri~ionO In addi~-.Lon, there could be sexious complications as khe result o infusion o~ hypertonic 801u~ions, such as thrombosis o t~e vein~ dehydration, and even comaO The aclminis~ration o~
oligopeptides rather ~han free am!ino acids ~llows admlnistra ion o~ thP same amount of amino acid residue ln solutions which are no~ hyper~onic and therefore can be introduced into peripheral veins~ which procedure is not conside~ed to be a surgical procedureO
The conc~ntration of the oligopeptides in an intra-venous solution should be such that ~he amino acid compo-sition oE th~ solution is similar to ~he amino acid com-posi~ion of ~he currently-used free amino acid solutton which has shown to be satlsfac~ory Eor main~aining pro~ein nutri-tionO
The oligopeptides of the pres~n~ compos ltions are water-soluble~ e compositlon preferably contains some oligopeptides o-f non-essential amino acids to supply nl~ro-genO The compositlon permits intact transportation o the oligopeptide into the cells ~ollowed by intra-cellular hydrolysis.
In~ravenous injec~ion of the oligopeptides results in an increase in the insulin output when compared wi~h the output resulting ~om intravenous injection o~ corres-ponding ~ree amino ~cids~ The oligopeptides rapidly dis-appear ollowing intravenous inje~tion, ind.icating that they ar~ rapidly utili.zedO The speed o~ utilization .is ~ 9 _ ~ . 173~2, par~icularly rapid wi.th kidIIey tissue; less rapid with muscle tissue.
Although the lns7ention has been shown in connec~
tion with certain specific embodiments, it will be readlly apparent ~o those skilled in ~che art that vaxious changes in form and arxangemellt of steps can be mad~ to 5ui1: r2-quiremen~s wi~hou~ depar~ing from.~e sp:iri~ and scope o:E the in~ention.

Claims (10)

The embodiments of the invention in which an exclu-sion property or privilege is claimed are defined as follows:

1. A nutrient composition comprising an aqueous solution containing at least two oligopeptides selected from the class consisting of dipeptides and tripeptides, wherein the said oligopeptides include a single glycine unit which is the N-terminal amino acid residue of the oligopeptide.

2. A nutrient composition of Claim 1 wherein the said oligopeptide comprises from 1 to 20 weight percent of the said aqueous solution.

3. A nutrient composition of Claim 1 wherein the said aqueous solution is an electrolyte solution.

4. A nutrient composition of Claim 1 wherein the said tripeptides are selected from the class consisting of:
Glycine-leucine-leucine, glycine-isoleucine-isoleucine, glycine-valine-valine, glycine-threonine-threonine, glycine-methionine-methionine, glycine-phenylalanine-phenylalanine, glycine-lysine-lysine and glycine-tryptophan-tryptophan.

5. A nutrient composition of Claim 1 including other nutrients selected from the class consisting of fats, polyols, glucose, oligosaccharides, minerals, trace elements and vitamins.

6. A nutrient composition of Claim 1 including oligopeptides having amino acid residues of all the essen-tial amino acids.

7. A nutrient composition including the composition of Claim 6 and at least one oligopeptide of non-essential amino acids.

8. A nutrient composition of Claim 1 wherein the said dipeptides are selected from the class consisting of: glycine-isoleucine, glycine-leucine, glycine-lysine, glycine-methionine, glycine-phenylalanine, glycine-threonine, glycine-tryptophan and glycine-valine.

9. A nutrient composition of Claim 5 wherein the said other nutrients includes one or more carbohydrate alcohols.

10. A nutrient composition of Claim 9 wherein the said carbohydrate alcohols are sorbitol or xylitol.