DK166455B1 - ANALOGY PROCEDURE FOR THE PREPARATION OF TRIGLYCERIDES - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF TRIGLYCERIDES Download PDFInfo
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Description
DK 166455 B1DK 166455 B1
Opfindelsen angår en analogifremgangsmåde til fremstilling af hidtil ukendte triglycerider med den i krav 1's indledning angivne almene formel I. De finder anvendelse som lægemidler ved lipidfordøjelsesforstyrrelser og hyperaggregation af blodplader.BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to an analogous process for the preparation of novel triglycerides of the general formula I as set forth in claim 1. They are used as drugs for lipid digestion and platelet hyperaggregation.
5 Triglyceriderne af fedtsyrer med middellang kæde med 2-12 carbonatomer er nævnt i fransk medicinalpatentskrift nr. 3598 som stoffer, som tillader en forbedring af absorptionen af fedtstoffer. Desuden er triglycerider af polyumættede fedtsyrer beskrevet i andre patentskrifter. Specielt angives i FR-A-2.426.461 triglyceridet af 5,8,11,14-17-eicosapentaensyre til behandling af thrombo-emboliske forstyrrelser. Men triglyceridet af en polyumættet fedtsyre udgør ikke en 10 form, som tillader en god absorption i organismen af den polyumættede fedtsyre.5 The medium chain triglycerides of fatty acids of 2-12 carbon atoms are mentioned in French Patent Specification No. 3598 as substances which allow an improvement in the absorption of fats. In addition, triglycerides of polyunsaturated fatty acids are described in other patents. Specifically, FR-A-2,426,461 discloses the triglyceride of 5,8,11,14-17-eicosapentaenoic acid for the treatment of thrombo-embolic disorders. However, the triglyceride of a polyunsaturated fatty acid does not constitute a form which permits good absorption in the organism of the polyunsaturated fatty acid.
Navnlig da triglyceriderne af eicosapentaensyre i 1-stillingen hydrolyseres dårligt af pancreasli-paserne, gør syntesetriglyceriderne af eicosapentaensyre eller af docosahexansyre det ikke nødvendigvis muligt at opnå et monoglycerid i 2-stillingen (Nestor R. Bottino, Lipids 1967, 2 15 (6)). Imidlertid er det velkendt, at monoglyceriderne i 2-stillingen udgør den form, som absorbe res bedst af den menneskelige organisme.In particular, since the triglycerides of eicosapentaenoic acid at the 1-position are poorly hydrolyzed by the pancreatic lipids, the synthetic triglycerides of eicosapentaenoic acid or of docosahexanoic acid do not necessarily make it possible to obtain a monoglyceride at the 2-position (Nestor R. Bottino, Lipids 1967, 2) (6) . However, it is well known that the monoglycerides in the 2-position constitute the form that is best absorbed by the human organism.
, Det er således interessant at disponere over stoffer, som er i stand til at tilføre organismen sådanne monoglycerider. Det har vist sig, at visse triglycerider med bestemt struktur, navnlig 20 sådanne, som let hydrolyseres i 1 - og 3-stillingen af enzymer i fordøjelseskanalen, opfylder dette formål. Opfindelsen angår derfor en fremgangsmåde til fremstilling af triglycerider med formlen I, som har den egenskab let at frigøre monoglyceridet i 2-stillingen ved indvirkning af pancreaslipase.Thus, it is interesting to dispose of substances capable of supplying such monoglycerides to the organism. It has been found that certain triglycerides of particular structure, in particular 20, which are readily hydrolyzed in the 1- and 3-position by enzymes in the digestive tract, fulfill this purpose. The invention therefore relates to a process for the preparation of triglycerides of formula I which has the property of easily releasing the monoglyceride at the 2-position by the action of pancreatic lipase.
25 I virkeligheden hydrolyserer dette enzym fedtsyrerne med middellang kæde, som esterificerer 1- og 3-stillingen i glycerol, og de frigør således 2-monoglyceridet. Da mennesket ikke har nogen intestinal monoglyceridlipase, som er aktiv over for 2-stillingen, er den polyumættede fedtsyre, som er fikseret i 2-stillingen i glycerol, således meget bedre beskyttet i tarmen og frigøres aldrig på dette stadium. Således sikrer triglyceriderne defineret som i formel I en meget god 30 absorption af 2-monoglycerid, og de gør det således muligt for organismen at udnytte den polyumættede fedtsyre, som bæres af monoglyceridet, under de bedste betingelser.In fact, this enzyme hydrolyses the medium chain fatty acids which esterify the 1- and 3-position in glycerol, thus releasing the 2-monoglyceride. Thus, since man has no intestinal monoglyceride lipase active against the 2-position, the polyunsaturated fatty acid, which is fixed at the 2-position in glycerol, is thus much better protected in the gut and is never released at this stage. Thus, the triglycerides defined as in Formula I ensure a very good absorption of 2-monoglyceride, and thus enable the organism to utilize the polyunsaturated fatty acid carried by the monoglyceride under the best conditions.
På grund af den gode absorption af det 2-monoglycerid, som de frigør, kan de ved fremgangsmåden ifølge opfindelsen fremstillede triglycerider desuden benyttes i svagere terapeutiske 35 doser end banale syntesetriglycerider. Desuden har triglyceriderne med formlen I på galenisk plan en anden fordel. I virkeligheden nedbrydes de polyumættede fedtsyrer let, og de bliver derfor ildelugtende og vanskelige at anvende. De triglycerider, som fås ved fremgangsmåden 2 DK 166455 B1 ffølge opfindelsen, frembyder en stabilitet, som gør det muligt at afhjælpe denne ulempe, og de udgør derfor en meget velegnet form til indgift af en poiyumættet fedtsyre.Furthermore, due to the good absorption of the 2-monoglyceride which they release, the triglycerides prepared by the process of the invention can be used in weaker therapeutic doses than banal synthetic triglycerides. In addition, the galenic triglycerides of formula I have another advantage. In fact, the polyunsaturated fatty acids break down easily and therefore become smelly and difficult to use. The triglycerides obtained by the process according to the invention offer a stability which allows this disadvantage to be remedied and therefore constitute a very suitable form for administration of a polyunsaturated fatty acid.
Blandt de triglycerider, som fås ved fremgangsmåden ifølge opfindelsen, skal især nævnes 5 forbindelserne med formlen I: alpha-linolensyre C-j g'· 3,ω3 gamma-linolensyre C-|g: 3,ω6 stearidonsyre C-| g: 4,ω3 10 - dihomo-gamma-linolensyre C2o: 3,co6 dihomo-alpha-linolensyre C2o:3,ω3 eicosatetraensyre Q>2q'.4,ω3 arachidonsyre C20:4,ω6 eicosapentaensyre C20:5,ω3 15 - docosatetraensyre C22- 4,ω6 docosapentaensyre C22:5,co6 docosahexaensyre C22'· 6,ω3 docosapentaensyre C22:5,co3 20 og navnlig kan man nævne følgende triglycerid: 1,3-dioctanoyleicosapentaenoylglycerol med formlen 1 CH2-0-CO-(CH2)6-CH3 2 HCO-CO-(CH2)3-(CH=CH-CH2)5-CH3 25 | 3 CH2-0-CO-(CH2)6-CH3In particular, among the triglycerides obtained by the process of the invention are mentioned the compounds of formula I: alpha-linolenic acid C-gg '· 3, ω3 gamma-linolenic acid C- | g: 3, ω6 stearidonic acid C- | g: 4, ω3 10 - dihomo-gamma-linolenic acid C20: 3, co6 dihomo-alpha-linolenic acid C2o: 3, ω3 eicosatetraenoic acid Q> 2q'.4, ω3 arachidonic acid C20: 4, ω6 eicosapentaenoic acid C20: 5, ω3 15 - docosatetraenoic acid C22-4, ω6 docosapentaenoic acid C22: 5, co6 docosahexaenoic acid C22 '6, ω3 docosapentaenoic acid C22: 5, co3 20 and in particular, the following triglyceride is mentioned: 1,3-dioctanoyleicosapentaenoylglycerol of formula 1 CH2-0-CO ) 6-CH3 2 HCO-CO- (CH2) 3- (CH = CH-CH2) 5-CH3 | 3 CH2-O-CO- (CH2) 6-CH3
Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav 1's kendetegnende del anførte.The process according to the invention is characterized by the characterizing part of claim 1.
3030
Under foretrukne betingelser for iværksættelsen af fremgangsmåden ifølge opfindelsen går man frem som følger:Under preferred conditions for the implementation of the process of the invention, the procedure is as follows:
Det funktionelle derivat af syren med formlen II er fortrinsvis syrechloridet. Man kan lige-35 ledes benytte anhydridet, et blandet anhydrid eller en aktiv ester.The functional derivative of the acid of formula II is preferably the acid chloride. The anhydride, a mixed anhydride or an active ester can also be used.
Esterrficeringen udføres bekvemt i nærværelse af en tertiær base såsom pyridin eller triethylamin. Reaktionen udføres i et chioreret opløsningsmiddel såsom dichiormethan, dichlorethan, chloroform eller carbontetrachlorid. Man kan også benytte sådanne opløsningsmidler som dimethylformamid eller dimethylacetamid.The esterification is conveniently carried out in the presence of a tertiary base such as pyridine or triethylamine. The reaction is carried out in a chlorinated solvent such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride. Solvents such as dimethylformamide or dimethylacetamide may also be used.
3 DK 166455 B13 DK 166455 B1
Reduktionen af ketongruppen i 2-stillingen i forbindelse med formlen III kan være ejendommelig ved, at det reduktionsmiddel, som ikke frembringer nogen hydrolyse af estergrupperne, er et alkalimetalborhydrid såsom natriumborhydrid eller kaliumborhydrid i alkoholisk miljø, idet alkoholen er methanol, ethanol eller propanol.The reduction of the ketone group at the 2-position of Formula III may be characterized in that the reducing agent which does not produce any hydrolysis of the ester groups is an alkali metal borohydride such as sodium borohydride or potassium borohydride in an alcoholic environment, the alcohol being methanol, ethanol or propanol.
5 - Reduktionen udføres ved en kontrolleret pH-værdi, især 6,5-7,5.5 - The reduction is carried out at a controlled pH, especially 6.5-7.5.
Det funktionelle derivat af den polyumættede fedtsyre med formlen R-OH er fortrinsvis syrechloridet, anhydridet, et blandet anhydrid eller en aktiv ester.The functional derivative of the polyunsaturated fatty acid of formula R-OH is preferably the acid chloride, anhydride, mixed anhydride or active ester.
Esterificeringen af forbindelsen med formlen IV sker under betingelser, som fortrinsvis er identiske med dem, som er nævnt ovenfor i forbindelse med esterificeringen af dihydrox-10 yacetone.The esterification of the compound of formula IV takes place under conditions which are preferably identical to those mentioned above in connection with the esterification of dihydroxy-10acetone.
De funktionelle derivater af syrerne med formlen II og af polyumættede fedtsyrer med formlen R-OH fremstilles efter kendte metoder.The functional derivatives of the acids of formula II and of polyunsaturated fatty acids of formula R-OH are prepared by known methods.
15 De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser har interessante farmako logiske egenskaber. Navnlig har de den aktivitet, som er særegen for den polyumættede fedtsyre i 2-stillingen. Således har de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser følgende egenskaber: 20 - Aktivitet som prækursor for derivater af prostaglandintypen, aktivitet som prækursor for hydroxylerede fedtsyrer og aktivitet som prækursor for stoffer af leucotrientypen.The compounds of the process according to the invention have interesting pharmacological properties. In particular, they have the activity that is peculiar to the polyunsaturated fatty acid in the 2-position. Thus, the compounds prepared by the process of the invention have the following properties: 20 - Activity as a precursor for prostaglandin-type derivatives, activity as a precursor for hydroxylated fatty acids, and activity as a precursor for leucotri-type substances.
Disse egenskaber er mere eller mindre udtalte alt efter den pågældende polyumættede fedt-25 syre.These properties are more or less pronounced according to the polyunsaturated fatty acid in question.
I forhold til den polyumættede fedtsyre selv har de ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser de væsentlige fordele, som består i bedre stabilitet og en udmærket absorption i fordøjelseskanalen.Compared to the polyunsaturated fatty acid itself, the compounds prepared by the process of the invention have the substantial advantages which consist in better stability and excellent absorption in the digestive tract.
3030
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser finder anvendelse overalt, hvor man ønsker at tilføre organismen en polyumættet fedtsyre i situationer, hvor organismen mangler polyumættede fedtsyrer, fx i tilfælde af forstyrrelser ved fordøjelsen af lipider, metaboliske sygdomme eller ved alderdomstilstande. I denne type af situationer iagttager man meget 35 ofte et voksende behov hos organismen for en specifik polyumættet fedtsyre, og indgiften af forbindelserne fremstillet ved fremgangsmåden ifølge opfindelsen opfylder dette behov.The compounds of the process according to the invention are applicable wherever it is desired to add a polyunsaturated fatty acid to the organism in situations where the organism lacks polyunsaturated fatty acids, for example in the case of disturbances in the digestion of lipids, metabolic diseases or in old age conditions. In this type of situation, a growing need is often observed for the organism for a specific polyunsaturated fatty acid, and the administration of the compounds prepared by the process of the invention meets this need.
4 DK 166455 B14 DK 166455 B1
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser og specielt 1,3-dioctanoyl-2-eicosapentaenoylglycerol kan yderligere bruges som lægemidler.The compounds prepared by the process of the invention and especially 1,3-dioctanoyl-2-eicosapentaenoylglycerol can be further used as drugs.
De omhandlede forbindelser udgør meget nyttige lægemidler i den humane terapi, især i be-5 handlingen af lipidfordøjelsesforstyrrelser, metaboliske sygdomme, tilfælde af underernæring i forbindelse med alkoholisme og cirrose, artherosclerose, hypertension, hyperaggregation af blodplader, cerebral alderdomssvækkelse samt tilstande, hvor der ønskes en immmunomodu-lation. I dette sidste tilfælde benyttes de omhandlede forbindelser fx i behandlingen af autoim-munosygdomme såsom reumatoid polyarthritis, erythematøs lupus, pemphigus eller hemolytisk 10 anæmi eller til forebyggelse af transplanterede organers uforligeligheds reaktioner eller i behandlingen af visse reaktioner af hyperinflammatorisk eller allergisk type eller inflammatoriske bronchie-syndromer eller konstriktorisk bronchopati såsom astma.The compounds of the present invention are very useful drugs in human therapy, especially in the treatment of lipid digestive disorders, metabolic diseases, cases of alcoholism and cirrhosis malnutrition, arthrosclerosis, hypertension, platelet hyperaggregation, cerebral impairment, and conditions desired. an immunomodulation. In this latter case, the compounds of the present invention are used, for example, in the treatment of autoimmune diseases such as rheumatoid polyarthritis, erythematous lupus, pemphigus or hemolytic anemia or in preventing the incompatibility of transplanted organs or in the treatment of certain reactions of hyperinflammatory or allergic type syndromes or constrictive bronchopathy such as asthma.
Den sædvanlige dosis, som varierer efter den benyttede forbindelse og den pågældende li-15 delse, kan fx ligge mellem 50 mg og 6 g pr. dag hos voksne ad oral vej og fortrinsvis i tilfælde af 1,3-dioctanoyleicosapentaenoylglycerol mellem 140 mg og 300 mg pr. dag.The usual dose, which varies according to the compound used and the particular condition, may be, for example, between 50 mg and 6 g per day. daily in adults by oral route and preferably in the case of 1,3-dioctanoyleicosapentaenoylglycerol between 140 mg and 300 mg per day. day.
De ved fremgangsmåden ifølge opfindelsen fremstillede forbindelser kan således benyttes til fremstilling af farmaceutiske præparater, der som aktiv bestanddel indeholder et af de omhand-20 lede stoffer. Disse præparater fremstilles, så at de kan indgives ad fordøjelsesvejen eller pa-renteralt.Thus, the compounds of the process according to the invention can be used for the preparation of pharmaceutical compositions containing as active ingredient one of the present compounds. These preparations are prepared so that they can be administered by the digestive or parenteral route.
De kan være faste eller flydende og foreligge i de i den humane medicin normalt benyttede farmaceutiske former såsom fx uoversukrede eller oversukrede tabletter, gelatinekapsler, gra-25 nulater, stikpiller og injektionspræparater. De fremstilles efter gængse metoder.They may be solid or liquid and may be present in the pharmaceutical forms normally used in human medicine such as, for example, unsupervised or unsuccessful tablets, gelatine capsules, granules, suppositories, and injection preparations. They are manufactured by conventional methods.
Den eller de aktive bestanddele kan inkorporeres deri sammen med i disse farmaceutiske præparater normalt benyttede tilsætningsstoffer såsom talkum, gummiarabicum, lactose, stivelse, magnesiumstearat, kakaosmør, vandige eller ikke-vandige bærestoffer, fedtstoffer af animalsk 30 eller vegetabilsk oprindelse, paraffinderivater, glycoler og diverse fugte-, dispergerings- eller emulgeringsmidler samt konserveringsmidler.The active ingredient (s) may be incorporated therein together with additives commonly used in these pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, fats of animal or vegetable origin, paraffin derivatives, glycols and various wetting, dispersing or emulsifying agents and preservatives.
Nedenstående eksempler illustrerer fremgangsmåden ifølge opfindelsen.The following examples illustrate the method of the invention.
35 5 DK 166455 B135 5 DK 166455 B1
Eksempel 1 1.3-dioctanolveicosapentaenovlalvcerol Trin A: 1.3-dioctanovldihvdroxvacetoneExample 1 1.3-Dioctanolveicosapentaenoylalcerol Step A: 1,3-Dioctanoyl dihydroxacetone
Man blander under omrøring 22,125 g dihydroxyacetone og 187,5 ml dichlorethan og opvarmer 5 til tilbagesvaling i 10 minutter. Man tilsætter 60,5 ml pyridin og derpå dråbevis 119,75 g octanoylchlorid og 187,5 ml dichlorethan og lader genantage stuetemperatur under omrøring i løbet af 2 timer. Man frafiltrerer det dannede pyridinhydrochlorid, vasker filtratet med destilleret vand og derefter med en vandig 5%'s bicarbonatopløsing og atter med destilleret vand indtil en endelig pH-værdi på 5,2, hvorefter man tørrer den organiske opløsning. Man eliminerer opløs-10 ningsmidlet under formindsket tryk og får en viskos rest, som man omkrystalliserer af ethylce-tat, hvorved man får 60,16 g af den forventede forbindelse. Smp. 60°C.With stirring, 22.125 g of dihydroxyacetone and 187.5 ml of dichloroethane are mixed and heated to reflux for 10 minutes. 60.5 ml of pyridine and 119.75 g of octanoyl chloride and 187.5 ml of dichloroethane are added dropwise and the room temperature is allowed to stir with stirring over 2 hours. The pyridine hydrochloride formed is filtered off, the filtrate is washed with distilled water and then with an aqueous 5% bicarbonate solution and again with distilled water until a final pH of 5.2 is dried, and the organic solution is dried. The solvent is eliminated under reduced pressure to give a viscous residue which is recrystallized from ethyl acetate to give 60.16 g of the expected compound. Mp. 60 ° C.
Analyse: C-| 9H34O5 beregnet: C% 66,63 H% 10,01 15 fundet: 66,9 10,1Analysis: C- 9H34O5 calculated: C% 66.63 H% 10.01 Found: 66.9 10.1
Trin B: 1.3-dioctanovlalvcerolStep B: 1,3-dioctanovlalcerol
Man opløser under omrøring ved 25°C 30 g af det i forrige trin opnåede stof i 1500 ml ethanol.30 g of the substance obtained in the previous step is dissolved in 1500 ml of ethanol with stirring at 25 ° C.
Man indstiller opløsningens pH-værdi på 5,4 ved tilsætning af 0,6 ml halvkoncentreret eddike-20 syre. Derpå tilsætter man i løbet af 15 minutter 8,55 g natriumborhydrid, idet pH-værdien holdes under eller på 7,5 ved tilsætning af halvkoncentreret eddikesyre. Man eliminerer opløsningsmidlet under formindsket tryk, optager resten i dichlorethan og destilleret vand, fraskiller den organiske fase ved dekantering, vasker den med destilleret vand, tørrer den og eliminerer opløsningsmidlet under formindsket tryk. Man får 30,19 g af ff, tørrer den og eliminerer opløs-25 ningsmidlet under formindsket tryk. Man får 30,19 g af den forventede forbindelse. Smp. 26°C.The pH of the solution is adjusted to 5.4 by the addition of 0.6 ml of semi-concentrated acetic acid. Then, 8.55 g of sodium borohydride are added over 15 minutes, keeping the pH below or at 7.5 by the addition of semi-concentrated acetic acid. The solvent is eliminated under reduced pressure, the residue is taken up in dichloroethane and distilled water, the organic phase is separated by decantation, washed with distilled water, dried and eliminated under reduced pressure. 30.19 g of FF are obtained, dried and eliminated under reduced pressure. 30.19 g of the expected compound are obtained. Mp. 26 ° C.
Analyse: CigH3605 beregnet: C% 66,24 H% 10,53 fundet: 66,2 10,6 30Analysis: CigH3605 calcd: C% 66.24 H% 10.53 found: 66.2 10.6 30
Trin C: 1.3-dioctanovl-2-(5'.8',11'. 14', 17')-eicosapentaenovlalvcerolStep C: 1,3-dioctanovl-2- (5'8 ', 11'. 14 ', 17') - eicosapentaenovlalvcerol
Man opløser 1,35 g af den i forrige trin fremstillede forbindelse i 1,8 ml dichlorethan og 0,256 ml pyridin, og derpå tilsætter man dråbevis ved stuetemperatur 1 g eicosapentaenoylchlorid og 1,8 ml dichlorethan. Man omrører 20 minutter ved stuetemperatur, opbevarer natten over ved 5°C, 35 eliminerer det dannede pyridinhydrochlorid ved filtrering og inddamper filtratet under formindsket tryk. Man optager resten i 14,9 ml cyclohexan, vasker med 2,98 ml blanding af 0,1 N natriumhydroxidopløsning og ethanoi (1:1), fraskiller den organiske fase, vasker den indtil en pH-værdi på 7,3 med 2,98 ml af en blanding af 0,1 N natriumhydroxidopløsning, ethanol og vand DK 166455 B1 6 (1:5:5) og derefter med 2,98 ml af en blanding af vand og ethanol (1:1) indtil en pH-værdi på 5,4, hvorpå man afdamper opløsningsmidlet fra den organiske fase under formindsket tryk og får 2,07 g forbindelse, som man chromatograferer på silicagel, hvorved man får 669 mg af den forventede forbindelse.1.35 g of the compound prepared in the previous step are dissolved in 1.8 ml of dichloroethane and 0.256 ml of pyridine, then 1 g of eicosapentaenoyl chloride and 1.8 ml of dichloroethane are added dropwise at room temperature. Stir for 20 minutes at room temperature, store overnight at 5 ° C, eliminate the pyridine hydrochloride formed by filtration and evaporate the filtrate under reduced pressure. The residue is taken up in 14.9 ml of cyclohexane, washed with 2.98 ml of a mixture of 0.1 N sodium hydroxide solution and ethanol (1: 1), separated off the organic phase, washed to a pH of 7.3 with 2, 98 ml of a mixture of 0.1 N sodium hydroxide solution, ethanol and water (1: 5: 5) and then with 2.98 ml of a mixture of water and ethanol (1: 1) to a pH of 5.4, evaporating the solvent from the organic phase under reduced pressure to give 2.07 g of compound which is chromatographed on silica gel to give 669 mg of the expected compound.
55
Analyse: C39H6406 beregnet: C% 74,48 H% 10,26 fundet: 73,0 10,0 10 N.M.R. spektrum: N.M.R. spektret foretages i deuterochloroform og bekræfter forbindelsens struktur.Analysis: C39H6406 Calcd: C% 74.48 H% 10.16 Found: 73.0 10.0 10 N.M.R. spectrum: N.M.R. the spectrum is made in deuterochloroform and confirms the structure of the compound.
Eksempel 2Example 2
Man fremstiller gelatinekapsler efter recepten: 15 - 1,3-dioctanoyleicosapentaenoylglycerol......................................................... 100 mg tilsætningsstof...............................................................................................ad 300 mg (enkeltheder vedrørende tilsætningsstof: kaolin, majsstivelse, avicel, magnesiumstearat, talkum, aerosil).Gelatin capsules are prepared according to the recipe: 15 - 1,3-dioctanoyleicosapentaenoylglycerol ..................................... .................... 100 mg of additive ........................... .................................................. .................. at 300 mg (details regarding additive: kaolin, corn starch, avicel, magnesium stearate, talc, aerosil).
20 Eksempel 3Example 3
Man fremstiller bløde kapsler efter recepten: 1.3- dioctanoyleicosapentaenoylglycerol......................................................... 200 mg tilsætningsstof til dannelse af en kapsel.Soft capsules are prepared following the prescription: 1.3- dioctanoyleicosapentaenoylglycerol ........................................ ................. 200 mg of additive to form a capsule.
25 Eksempel 4Example 4
Man fremstiller en emulsion til intravenøs brug efter recepten: 1.3- dioctanoyleicosapentaenoylglyceroi......................................................... 10 g D,L-a-tocopherolacetat......................... 0,3 g sojalecithin.................................................................................................... 1,2 g 30 - glycerin N...................................................................................................... 1,8 g destilleret vand..............................................................................................ad 100 mlAn emulsion for intravenous use is prepared following the prescription: 1.3- dioctanoyleicosapentaenoylglycerol ..................................... .................... 10 g of D, La-tocopherol acetate ........................ .. 0.3 g soy lecithin ........................................... .................................................. ....... 1.2 g of 30 - glycerine N ................................... .................................................. ................. 1.8 g of distilled water ........................... .................................................. ................. for 100 ml
Klinisk undersøgelse 11 personer, hvoraf 6 udviser hyperaggregation af blodplader, medens 5 er normale, modtager 35 daglig ad oral vej 160 mg 1,3-dioctanoyl-2-eicosapentaenoylglycerol i 1 måned.Clinical study 11 people, 6 of whom show platelet hyperaggregation while 5 are normal, receive 160 mg of 1,3-dioctanoyl-2-eicosapentaenoylglycerol daily for 1 month.
Koefficienterne for aggregation af blodplader er beregnet i forvejen og efter behandlingen efter teknikken ifølge Ph. Darcet i Ann. Nutr. Alim. 1980, 34,277-290.The coefficients for platelet aggregation have been calculated in advance and after treatment according to the technique of Ph. Darcet in Ann. Nutr. Alim. 1980, 34, 277-290.
DK 166455 B1 7DK 166455 B1 7
Efter 1 måneds behandling viser det sig, at modifikationerne i aggregationen af blodpladerne hos de normale personer er meget lille, medens variationsamplituden er meget stor hos personerne med hyperaggregation. Efter behandlingen konstaterer man, at 4 af disse 6 personer har normale koefficienter for aggregation, 1 person har en næsten normal koefficient, 5 medens kun 1 person har en utilfredsstillende koefficient.After 1 month of treatment, it appears that the modifications in platelet aggregation in normal individuals are very small, whereas the variation amplitude is very large in hyperaggregation subjects. After treatment, it is found that 4 of these 6 people have normal coefficients for aggregation, 1 person has an almost normal coefficient, 5 while only 1 person has an unsatisfactory coefficient.
Claims (3)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8119945A FR2515174A1 (en) | 1981-10-23 | 1981-10-23 | NOVEL TRIGLYCERIDES, PROCESS FOR THE PREPARATION AND APPLICATIONS IN DIETETICS AND THERAPEUTICS |
| FR8119945 | 1981-10-23 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK108783D0 DK108783D0 (en) | 1983-03-04 |
| DK108783A DK108783A (en) | 1984-09-05 |
| DK166455B1 true DK166455B1 (en) | 1993-05-24 |
Family
ID=9263336
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK108783A DK166455B1 (en) | 1981-10-23 | 1983-03-04 | ANALOGY PROCEDURE FOR THE PREPARATION OF TRIGLYCERIDES |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0120169B1 (en) |
| DK (1) | DK166455B1 (en) |
| FR (1) | FR2515174A1 (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4701468A (en) * | 1983-04-15 | 1987-10-20 | Roussel-Uclaf | Oxidized triglycerides having therapeutic utility |
| US4871768A (en) * | 1984-07-12 | 1989-10-03 | New England Deaconess Hospital Corporation | Dietary supplement utilizing ω-3/medium chain trigylceride mixtures |
| US4753963A (en) * | 1985-09-26 | 1988-06-28 | The Procter & Gamble Company | Nutritional fat suitable for enteral and parenteral products |
| JPH0832628B2 (en) * | 1986-12-17 | 1996-03-29 | 株式会社ミドリ十字 | Triglyceride composition |
| FR2617161B1 (en) * | 1987-06-29 | 1989-10-27 | Azar Robert | NOVEL UNSATURATED FATTY ACID GLYCERIDES AND PROCESS FOR OBTAINING SAME |
| DE3734147C2 (en) * | 1987-10-09 | 1998-10-29 | Braun Melsungen Ag | Isotonic omega-3 fatty acid-containing fat emulsion and its use |
| DK565288D0 (en) | 1988-10-11 | 1988-10-11 | Novo Industri As | PROCEDURE FOR THE PREPARATION OF TRIGLYCERIDES, APPLICATION OF SUCH TRIGLYCERIDES, AND AN EMULSION CONTAINING SUCH TRIGLYCERIDES |
| DE3903057A1 (en) * | 1989-02-02 | 1990-08-09 | Braun Melsungen Ag | FAT EMULSION FOR ENDOTRACHEAL APPLICATION, ITS PRODUCTION AND APPLICATION |
| DE3903056A1 (en) * | 1989-02-02 | 1990-08-09 | Braun Melsungen Ag | FAT EMULSION FOR INTRAPERITONEAL APPLICATION, ITS PRODUCTION AND APPLICATION |
| JP4175698B2 (en) | 1998-06-19 | 2008-11-05 | サントリー株式会社 | Novel triglyceride and composition containing the same |
| IL142537A0 (en) | 2001-04-11 | 2002-03-10 | Yeda Res & Dev | Pharmaceutical compositions for the treatment of autoimmune diseases |
| DE102008057867A1 (en) | 2008-11-18 | 2010-05-20 | B. Braun Melsungen Ag | Fat emulsion for the artificial nutrition of severely ill intensive care patients |
-
1981
- 1981-10-23 FR FR8119945A patent/FR2515174A1/en active Granted
-
1983
- 1983-03-04 DK DK108783A patent/DK166455B1/en not_active IP Right Cessation
- 1983-03-23 EP EP83400601A patent/EP0120169B1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DK108783A (en) | 1984-09-05 |
| FR2515174B1 (en) | 1984-01-13 |
| DK108783D0 (en) | 1983-03-04 |
| EP0120169B1 (en) | 1986-11-20 |
| FR2515174A1 (en) | 1983-04-29 |
| EP0120169A1 (en) | 1984-10-03 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PBP | Patent lapsed |