US20130109753A1 - Sn-2-monoacylglycerols and lipid malabsorption - Google Patents

Sn-2-monoacylglycerols and lipid malabsorption Download PDF

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US20130109753A1
US20130109753A1 US13/808,779 US201113808779A US2013109753A1 US 20130109753 A1 US20130109753 A1 US 20130109753A1 US 201113808779 A US201113808779 A US 201113808779A US 2013109753 A1 US2013109753 A1 US 2013109753A1
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composition
acid
accordance
group
inflammation
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Bruce Bistrian
Frederic Destaillats
Cristina Cruz-Hernandez
Fabiola Dionisi
Isabelle Masserey-Elmelegy
Manuel Oliveira
Julie Celine Moulin
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Nestec SA
Beth Israel Deaconess Medical Center Inc
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Nestec SA
Beth Israel Deaconess Medical Center Inc
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Assigned to NESTEC S.A., BETH ISRAEL DEACONESS MEDICAL CENTER, INC. reassignment NESTEC S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CRUZ-HERNANDEZ, CRISTINA, DIONISI, FABIOLA, BISTRIAN, BRUCE, DESTAILLATS, FREDERIC, MASSEREY-ELMELEGY, ISABELLE, MOULIN, JULIE CELINE, OLIVEIRA, MANUEL
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Definitions

  • the present invention relates generally to the field of lipids and in particular aims at improving lipid absorption, for example under conditions of lipid malabsorption.
  • One embodiment of the present invention relates to a composition comprising an sn-2 monoacylglycerol derivative, wherein the sn-1 and sn-3 positions are blocked by protective groups.
  • the acyl group may be a fatty acid, for example one with anti-inflammatory properties.
  • bioactive fatty acids under conditions of malabsorption such as in pancreatic insufficiency, bile salt deficiency, short gut due to gut removal or mucosal disease is critical.
  • bioactive fatty acids having, e.g., anti-inflammatory properties is therefore critical in these conditions as this type of fatty acids could help to lower the inflammation response.
  • MAGs monoacylglycerols
  • a food composition prepared with only sn-2 MAGs to improve lipid absorption would, hence, lose its benefit with time.
  • the present invention is related to the use of sn-2 MAGs and MAG derivatives (see FIG. 1 ) to deliver bioactive fatty acids such as eicosapentaenoic acid (EPA), e.g., under lipid malabsorption conditions.
  • bioactive fatty acids such as eicosapentaenoic acid (EPA), e.g., under lipid malabsorption conditions.
  • EPA eicosapentaenoic acid
  • MAGs do not need to be digested prior to absorption and have intrinsic emulsifying properties allowing a good dispersion of oil droplets prior to absorption in the intestine. Further, MAGs are better absorbed than free fatty acids.
  • the lipid maldigestion/malabsorption conditions were obtained using Orlistat®, a well known pancreatic and gastric lipases inhibitor.
  • Animals were fed with long-chain polyunsaturated fatty acid (LC-PUFA) supplements containing mainly eicosapentaenoic (EPA) acid.
  • LC-PUFA long-chain polyunsaturated fatty acid
  • EPA eicosapentaenoic
  • Fish oil was used as a source of triacylglycerols and different EPA glycerides, for example those of FIG. 1 , were evaluated.
  • the fatty acid profile of red blood cells and plasma lipids was assessed.
  • fatty acid profiles of different tissues were determined.
  • one embodiment of the present invention is a composition comprising an sn-2 monoacylglycerol derivative, wherein the sn-1 and sn-3 positions are blocked by protective groups.
  • the acyl group may be any fatty acid, for example.
  • composition of the present invention may be used to provide at least one essential fatty acid in order to prevent essential fatty acid deficiency, or to provide at least one distal fatty acid, such as arachidonic, eicosapentaenoic, or docosahexaenoic acid in conditions where elongation and desaturation of linoleic or alpha linolenic acid are impaired.
  • essential fatty acid such as arachidonic, eicosapentaenoic, or docosahexaenoic acid in conditions where elongation and desaturation of linoleic or alpha linolenic acid are impaired.
  • the acyl group may be a fatty acid with anti-inflammatory properties. Which fatty acids have anti-inflammatory properties is known to those of skill in the art.
  • fatty acids having anti-inflammatory properties may be selected from the group consisting of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), ⁇ -linolenic acid (ALA), stearidonic acid (SA), ⁇ -linolenic acid (GLA), dihomo- ⁇ -linolenic acid (DGLA), n-3 docosapentanenoic acid (DPA), sciadonic acid and juniperonic acid.
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • ALA ⁇ -linolenic acid
  • SA stearidonic acid
  • GLA ⁇ -linolenic acid
  • DGLA dihomo- ⁇ -linolenic acid
  • DPA docosapentanenoic acid
  • composition may comprise a mixture of different MAGs with different fatty acids in sn-2 position and/or with different protective groups in sn-1 and/or sn-3 position.
  • the fatty acids may be mixed in a way, for example, that a particular ratio between n-3 and n-6 fatty acids is used.
  • n-3 Fatty acids include for example ⁇ -linolenic acid, stearidonic acid, n-3 eicosatrienoic acid, n-3 eicosatetraenoic acid, eicosapentaenoic acid, clupanodonic acid, docosahexaenoic acid, n-3 tetracosapentaenoic acid.
  • n-6 Fatty acids include for example linoleic acid, ⁇ -linolenic acid, n-6 eicosadienoic acid, dihomo- ⁇ -linolenic acid, arachidonic acid, n-6 docosadienoic acid, adrenic acid, n-6 docosapentaenoic acid (Osbond acid).
  • conjugated fatty acids such as rumenic or calendic, catalpic or eleostearic acids or nonmethylene-interrupted ⁇ 5-polyenoic (NMIP) fatty acids such as taxoleic, pinolenic, sciadonic or juniperonic acids can be mixed in a way to sn-2 MAG derivatives
  • the composition may contain a combination of different sn-2 MAG derivatives; for example with a ratio of n-3 to n-6 fatty acids of about 5:1 to about 15:1; for example about 8:1 to about 10:1.
  • such protective groups should be tasteless or have a taste that is generally perceived as pleasant.
  • the protective groups may be selected from the group consisting of acetyl groups, ethyl groups, propyl groups, vanillin, or other molecules able to form acetals.
  • a protective group is selected that is able to bridge the hydroxyl groups in sn-1 and sn-3 position.
  • fatty acids and protective groups may be selected based on the intended benefit to be delivered and the nature of the final composition. All these combinations are comprised by the present invention.
  • the sn-2 monoacylglycerol derivative may be selected from the group consisting of 1,3-diacetyl-2-eicosapentaenoylglycerol, 1,3-diethyl-2-eicosapentaenoylglycerol, 1,3-dipropyl-2-eicosapentaenoylglycerol, a vanillin derivative of sn-2 monoeicosapentaenoylglycerol, other acetal derivatives of monoeicosapentaenoylglycerol, or combinations thereof.
  • composition of the present invention may be any kind of edible composition.
  • a composition is considered “edible” if it is approved for human or animal consumption.
  • the composition is a composition to be administered orally or enterally.
  • the composition may be selected from the group consisting of a food product, an animal food product, a pharmaceutical composition, a nutritional composition, a nutraceutical, a drink, a food additive or a medicament.
  • the composition may be a liquid nutritional formula to be administered enterally, e.g., in hospitals.
  • the composition may also be a nutritional formulation to be administered to people above the age of 60.
  • the composition may also be a powdered composition to be reconstituted in milk or water.
  • the composition may be a shelf stable powder. Shelf stability can be obtained, for example by providing the composition with a water activity smaller than 0.2, for example in the range of 0.19-0.05, preferably smaller than 0.15.
  • Water activity or a w is a measurement of the energy status of the water in a system. It is defined as the vapor pressure of water divided by that of pure water at the same temperature; therefore, pure distilled water has a water activity of exactly one.
  • the caloric density of the composition of the present invention may be adjusted to the needs of the patient.
  • composition in accordance with the present invention may have a caloric density in the range of 0.5 kcal/ml to 15 kcal/ml.
  • caloric densities for patients suffering from malabsorption and/or low appetite rather high caloric densities may be preferred.
  • caloric densities in the range of 7-12 kcal/ml may be used.
  • the composition may also contain a protein source and/or a carbohydrate source. Easily digestible carbohydrates and/or proteins are preferred.
  • At least partially hydrolysed proteins are easier to digest and absorb. Hence, it may be desirable to supply at least partially hydrolysed proteins (degree of hydrolysis between 2 and 20%). If hydrolysed proteins are required, the hydrolysis process may be carried out as desired and as is known in the art. For example, a protein hydrolysate may be prepared by enzymatically hydrolysing a protein fraction in one or more steps. For an extensively hydrolysed protein, the proteins may be subjected to triple hydrolysis using Alcalase 2.4 L (EC 940459), then Neutrase 0.5 L (obtainable from Novo Nordisk Ferment AG) and then pancreatin at 55° C.
  • Alcalase 2.4 L EC 940459
  • Neutrase 0.5 L obtainable from Novo Nordisk Ferment AG
  • the amount of fatty acids in the composition of the present invention may be adjusted to the patients needs.
  • the MAG derivatives are administered in an amount sufficient to at least partially cure or arrest the symptoms of the disease and its complications.
  • An amount adequate to accomplish this is defined as “a therapeutically effective dose”. Amounts effective for this purpose will depend on a number of factors known to those of skill in the art such as the severity of the disease and the weight and general state of the patient.
  • MAG derivatives are administered to a patient susceptible to or otherwise at risk of a particular disease in an amount that is sufficient to at least partially reduce the risk of developing a disease.
  • a prophylactic effective dose Such an amount is defined to be “a prophylactic effective dose”.
  • the precise amounts depend on a number of patient specific factors such as the patient's state of health and weight.
  • compositions of the present invention are to be administered in an amount sufficient to provide the MAG derivatives in a therapeutically effective dose or a prophylactic effective dose.
  • the composition may comprise the sn-2 MAG derivatives in an amount corresponding to about 3% to 40% of the energy of the composition.
  • sn-2 MAG derivatives in an amount corresponding to about 3% to 40% of the energy of the composition.
  • arachidonic acid, eicosapentaenoic acid, and/or docosahexaenoic acid may meet essential fatty acid needs as well as provide effective anti-inflammatory effects.
  • the composition of the present invention may be for use in the delivery of functional fatty acids.
  • Functional fatty are for the purpose of the present invention fatty acids that deliver a health benefit.
  • composition of the present invention may be for use in the delivery of fatty acids having anti-inflammatory properties.
  • composition of the present invention is in particular useful under conditions of lipid maldigestion or malabsorption.
  • composition of the present invention may be to be administered to subjects suffering from a lipid maldigestion or malabsorption condition.
  • composition is useful for subject suffering from any kind of lipid maldigestion or malabsorption condition.
  • a malabsorption condition may be due to pancreatic insufficiency, bile salt deficiency, a mucosal disorder and/or a short gut.
  • the composition in accordance with the present invention may be for use in the treatment or prevention of inflammatory disorders.
  • the present invention also relates to the use of a sn-2 MAG derivative, wherein the sn-1 and sn-3 positions are blocked by protective groups and wherein the acyl group is a fatty acid having anti-inflammatory properties for the preparation of a composition to treat or prevent inflammatory disorders, in particular under lipid maldigestion and/or malabsorption conditions.
  • the inflammatory disorder may be selected from the group consisting of acute inflammations such as sepsis, and chronic inflammations such as inflammatory bowel disease, Crohn's disease, ulcerative colitis, necrotizing enterocolitis, skin inflammation, such as UV or chemical-induced skin inflammation, eczema, reactive skin, psoriasis, vitiligo, acne, inflammatory bowel syndrome, liver inflammation, alcoholic cirrhosis, allergy, atopy, bone inflammation, rheumatoid arthritis, systemic lupus, dermato-myositis, thyroiditis, type I diabetes, celiac disease, Biermer's disease, multiple sclerosis, encephalomyelitis, eye inflammation, obesity-associated inflammation, age-related low-grade inflammation, Blau's syndrome, Alzheimer's disease, cardiovascular diseases, atherosclerosis, metabolic syndrome, or combinations thereof.
  • acute inflammations such as sepsis
  • chronic inflammations such as inflammatory bowel disease, Crohn's disease, ulcerative
  • FIG. 1 shows examples of EPA glycerides used in the present invention: (A) 1,3-diacetyl-2-eicosapentaenoylglycerol and [B] an acetal derivative of sn-2 monoeicosapentaenoylglycerol.
  • FIG. 2 shows the incorporation of EPA in red blood cells.
  • the concept was tested in a lipid maldigestion or malabsorption animal model.
  • the maldigestion or malabsorption condition was obtained using Orlistat, a well known pancreatic and gastric lipases inhibitor.
  • Animals were fed during 21 days with long-chain polyunsaturated fatty acid (LC-PUFAs) supplements containing mainly eicosapentaenoic (EPA) acid.
  • LC-PUFAs long-chain polyunsaturated fatty acid
  • EPA eicosapentaenoic
  • Fish oil was used as a source of triacylglycerols and the different EPA glycerides provided in FIG. 1 were evaluated.
  • Orlistat was given at a level sufficient to decrease lipid absorption by 40%.
  • a group receiving fish oil without Orlistat was used as a positive control.
  • D-3, D7, D14 and D21 fatty acid profile of red blood cells and plasma lipids were performed.
  • fatty acid profiles of different tissues were determined
  • the main objective was to follow the level of EPA in red blood cell and plasma lipids.
  • the main comparison evaluated was the difference in EPA level between groups receiving EPA derivatives ( FIG. 1 ) in combination with Orlistat and the positive control group (fish oil+Orlistat).

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US10961483B2 (en) * 2015-07-02 2021-03-30 Stepan Company Method for preparing 2-monoacylglycerides

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US9000039B2 (en) * 2011-04-04 2015-04-07 Nestec S.A. Sn-1(3) monoacylglycerides and lipid absorption
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