EP0075594A1 - Polymeres de glucose et leur procede de production - Google Patents

Polymeres de glucose et leur procede de production

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Publication number
EP0075594A1
EP0075594A1 EP19820901339 EP82901339A EP0075594A1 EP 0075594 A1 EP0075594 A1 EP 0075594A1 EP 19820901339 EP19820901339 EP 19820901339 EP 82901339 A EP82901339 A EP 82901339A EP 0075594 A1 EP0075594 A1 EP 0075594A1
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EP
European Patent Office
Prior art keywords
glucose
polymers
alpha
fraction
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP19820901339
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German (de)
English (en)
Inventor
David B. A. Silk
Myron A. Beigler
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Individual
Original Assignee
Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of EP0075594A1 publication Critical patent/EP0075594A1/fr
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof

Definitions

  • This invention relates to glucose polymers which are useful for the nourishment via the gastrointestinal tract of patients, who, on account of a variety of coexist ⁇ ing medical and/or surgical disorders are not able to eat sufficient food to maintain their nutritional state..
  • the invention relates to a new process and product wherein long chain glucose polymers have been produced by the fractionation of a hydrolysate of corn starch.
  • the said material consists of glucose polymers composed of 10-40 glucose units linked by 1-4 alpha and 1-6 alpha-D-glycosidic chemical bonds.
  • the in ⁇ vention also contemplates treating such glucose polymers, or selecting the source material, to provide glucose polymers of the stated degree of polymerization which have enhanced 1-4 alpha linkages and diminished 1-6 alpha linkages.
  • a glucose polymer mixture having at least 99% of its molecules less than 26 glucose units, at least 85% of its molecules less than 11 glucose units and at least 20% of its molecules less than 4 glucose units can be utilized by a human patient when intravenously administered by a peripheral vein of the patient.”
  • Milner, U.S. Patent 3,928,135, relates primarily to preparations of glucose polymers intended for intra ⁇ venous injection and is limited to starch sources contain ⁇ ing not more than 20% amylopectin because of the lack of enzymes in the blood which are capable of breaking down amylopectins.
  • the glucose polymers of the Milner patent when used for intravenous injection, are said to contain not more than 10 glucose units. The mixture does, however, contain substantial proportions of glucose and maltose. As stated in this patent at column 4, lines 22-30,
  • the invention also includes the novel glucose polymers that are suitable for intravenous use which comprise a mixture of polymers each of which is substantially no more than 10 glucose units long.
  • the difference between this intravenous product and the oral product is that the oral product also contains a propor ⁇ tion, e.g., 10% by weight of polymers more than 10 glucose units long, and may have present an unspecified number of 1-6 linked units.
  • McKay U.S. Patent No. 4,021,543 relates to the utilization of glucose polymers having an average short chain length of about 3 to 8 units in an oral electrolyte solution wherein the unpleasant taste of saline is sub ⁇ stantially reduced and simultaneously affording an increase caloric intake.
  • Formulated hospital diets indicated specifically for patients who have difficulty in eating or digesting normal foods have been developed to provide high biological value proteins, carbohydrates, fats, minerals, and vitamins. These complete foods have formulas of widely variable values with respect to ingredients which affect viscosity, osmolar- ity, and taste, to mention a few.
  • Osmolarity is a function of the number of individual ions per unit of solution. Osmotic pressure gradients are established across the membranes of cells lining the intestinal lumen. If the tonicity of the fed solution is high, water will cross from inside the cell and between cells to dilute the hypertonic solution. Thus, the lumen becomes filled with water, and this net efflux of water alone will result in filling the lumen and causing diarrhea.
  • the long chain length glucose polymers have unexpect ⁇ edly favorable digestion and absorption properties, thereby improving the kinetics of the resulting glucose adsorption in the human intestine. These characteristics of the product provide efficient adsorption of fluid and electrolytes. On account of these properties the product can be administered to patients with abnormalities of digestive and adsorptive functions as well as those with normal gastrointestinal function.
  • a further advantage is that the long chain length glucose polymers have favorable taste and processing prop ⁇ erties. In spite of their long chain length these polymers do not appreciably increase the viscosity of products to which they are added.
  • DP 10-40 mixture has a considerably lower reducing sugar content than glucose and short chain glucose polymers whereby the phenomenon of browning or the Maillard reaction does not occur or occurs in much diminished degree during the customary heat treatment of canning and sterilizing opera ⁇ tions.
  • This property renders fluid products using whole proteins or protein hydrolysate whiter (which therefore simulates whole milk) when processed through a high temper ⁇ ature sterilizer.
  • OMPI Difficulties with preparations intended for intravenous use are apparent.
  • the product must be sterile, it must be free of particulate matter, it must be free of pyrogens, and it must be substantially free of glucose polymers which cannot be depolymerized by enzymes in the blood.
  • the preparation of such a material is laborious and time-consuming and its administration requires medical skill and is hazardous unless employed with care and the proper equipment.
  • carbohydrates taken enterally ⁇ either by mouth, by nasogastric feeding techniques or if needed, by an abdominal ostomy) need not be sterile but only sanitary within the general requirements of food.
  • These carbohydrates need not be free of pyrogens, and they need not be free of amylopectin.
  • the fraction con ⁇ sists predominantly of glucose polymers having glucose chain lengths of 10 to 40 glucose units with negligible amounts of glucose, maltose and glucose polymers having a chain length of less than 10 units.
  • the fraction is satisfactorily digested and absorbed in the absence of luminal alpha-amylase activity and is therefore advantageous in cases of pancreatic malfunction where suf ⁇ ficient amounts of the enzyme amylase is lacking.
  • the fraction exhibits advantageous absorptive properties since glucose derived from the fraction's digestion is absorbed faster than when free glucose is presented for absorption to the cells lining the gut.
  • the long chain length glucose polymers are particularly advantageous for those persons having normal pancreatic function.
  • the long chain length glucose polymers have a further unexpected and substantial stimulating effect on water and electrolyte absorption making them particularly advantageous for those patients who suffer from diarrhea that results from exces ⁇ sive water and electrolyte secretion, however induced.
  • the ratio of 1-6 alpha:1-4 alpha-D-glycosidic bonds can be decreased by selection of the type of corn starch or by incubating the native corn starch with bacterial iso-maltose enzymes which cleave the branched 1-6 alpha- D-glycosidic linkages leaving predominantly 1-4 alpha-D- glycosidically linked long chain length glucose polymers.
  • corn starch is subjected to hydrolysis by acid or a suitable enzyme to the point of liquefying the starch and to provide an aqueous dispersion which is substantially free of residual starch granules and which has a dextrose equivalent value not substantially above three.
  • This intermediate product is then subjected to a second step in which a dextrinizing enzyme is used to produce a hydrolysate having a dextrose equivalent (D.E.) value not substantially above 18.
  • the hydrolysate of the Morehouse patent contains a nore or less continuous profile or spectrum of glucose polymers ranging from polymers having a DP of about 40 down to glucose.
  • this hydrolysate is a useful starting material and it may be treated, as illustrated in Example 1., to separate the desired fraction of glucose polymers.
  • a starch hydrolysate prepared in accordance with the Morehouse patent was used as the starting material. It contained a small quantity of glucose and maltose (e.g., less than 2%) . This starch hydrolysate was placed in aqueous solution in a concentration of between 10% and 30%, e.g. 20%, and the solution was pumped into a chamber con ⁇ taining a filter whose passage pore size was such that materials greater than a 2000 molecular weight cannot pass through the membrane. This provided a cut-off sieving of glucose polymers which are approximately 10 glucose units in length.
  • Fraction I was mainly 3 to 10 glucose units long, and Fraction II was greater than 10 but with most polymer under 30 glucose units long.
  • the first method filters the solution containing the original mixture of solubilized starch past the filter so that the filtrate contains less than 10 glucose unit polymers and the retentate contains the glucose polymers with glucose units greater than 10.
  • the diafiltration method of ultrafiltration an amount of water is added to the original solution equivalent to that which passes through the filter. This also dilutes the retentate and prevents pile up on the filter and permits larger amounts of lower than G10 material to pass through the filter.
  • the type of ultrafiltration equipment, the amount of dilution (diafiltr tion) , and the time the material circulates in front of the filter determines the complete ⁇ ness of fractionation of the two groups of polymers.
  • the low molecular weight Fraction I short chain polymers under GlO
  • the solution was concentrated to 10% solids.
  • the product was concentrated further by evaporation under vacuum until it was 30% solids.
  • This low molecular weight fraction was then spray dried to a white, fine, highly soluble powder of glucose polymers from 3 to 10 with a dextrose equivalent (D.E.) of about 14 to 15.
  • the high molecular weight Fraction II was back- flushed off of the filter and placed in a vacuum evaporator, taken to a 40% solids solution and spray dried.
  • the final product contained less than 5 per cent low molecular weight (DP ⁇ 10) fractions and had a dextrose equivalent of approximately 4.
  • Fraction II of Example 1 contains long chain glucose polymers that have ratios of 1-6 to 1-4 alpha-D- glycosidic linkages according to the starch used as starting material and according to the effect of acid and enzymatic hydrolysis on these linkages. Desired ratios of these linkages can be provided by selection of the starch or by treating the starch before or after fractionation with bacterial isomaitase enzyme, which selectivity cleaves the 1-6 linkage.
  • Example 1 After backflushing the high molecular weight Fraction II of Example 1 off.of the filter and concentrat ⁇ ing to 30% solids, the pH is adjusted to 7 and the bacterial enzyme isomaitase is added to the solution at a temperature range of 50°C to 95°C.
  • the length of time of the hydrolytic action of the enzyme determines the ratio of 1-6 to 1-4 alpha-D-glycosidically linked long chain length glucose polymers. No simple test is known to measure the exact amounts of 1-6 to 1-4 linkages. However, empirical tests indicative of digestion can be used, such as osmolality.
  • the hydroly ⁇ sis may be stopped by adjusting the pH to below 4.0 or by heating the mixture above 110°C until the enzyme is inacti ⁇ vated.
  • This enzymatically altered product has a greater 1-4 to 1-6 ratio than Fraction II.
  • it may be subjected to filtration as in Example 1 to separate a Fraction IIA which is substantially free.of ⁇ glucose and glucose polymers having a DP less than 10 which were produced by the enzymatic treatment.
  • An alternative process avoids having the elevated osmolality in the final product and the need for a second filtration.
  • Example 1 the hydrolysate that constituted the starting material of Example 1 is treated with isomaitase to cleave 1-6 linkages and the material is then subjected to filtration as in Example 1.
  • Fraction IIB resulting from this procedure consists predominantly of glucose polymers of DP 10 or more but with a greater ratio of 1-4 to 1-6 linkages than Fraction II.
  • corn starch hydrolysates in common use that have a D.E. below 5 are reported to be "cloudy in solution” and add viscosity to products in which they are incorporated.
  • the products of this invention are useful in making clear solutions and does not add appreciable viscosity to products.
  • the composition of average long chain length glu ⁇ cose polymers presently utilized in hospital diets as determined by high pressure liquid chromatography is shown in Table I. Approximately 51% of the total glucose content is contained in the G10-G40 fraction with 34% in the G4-G10 fraction and 14% contained as maltrotriose (G3) , maltose (G2) and free glucose (Gl) . (The letter “G” signifies a single glucose unit.) Table I
  • a typical composition of the liquid of the present invention as determined by high pressure liquid chromatog- raphy is in Table II.
  • the osmolality of the product shown in Table II, determined by the freezing point depression method, is shown below in Table III and is compared with glucose, maltose, Caloreen (trademark of a product of Roussel Laboratories, Ltd., Wembley, London, U.K.), and a maltodextrin contained in and sold as Vivonex by Morton-Norwich.
  • the Caloreen is said to contain an average glucose chain length of 5 units.
  • the Vivonex is said to contain an average glucose chain length of 5 units based upon a dextrose equivalent of 20.
  • Glucose Polymer Source Osmolality milliosmols/kg (100 g/kg water) (Freezing Point Depression)
  • Glucose 569 (derived from Geigy
  • Table III shows that the long chain polymers of this inventio exert a substantially lower osmotic pressure than any of the other sources of glucose polymers, including the average short chain length glucose polymers of the type used as the carbohydrate energy source of present low residue liquid nutritional diets.
  • a second critical factor which determines the value of formulated enteral feeding solutions is the kinetics of digestion and transport across the intestinal mucosa which result from the chemical form of the nutrients.
  • the absorptive properties of the long chain glucose polymer of this invention were investigated in the jejunum of normal human subjects using an in vivo steady state segmental perfusion technique as described in the journal GUT, Volume 11, page 947, 1970. Luminal alpha-amylase was therefore excluded from the 25 cm segment of jejunum studied by means of an occlusive balloon described in the cited reference.
  • pancreatic amylase activity Since the perfusion technique that was employed occuled pancreatic amylase activity from the segment of intestine studied, it is apparent that only digestive enzymes normally in the brush border sufficed for the very satisfactory breakdown of the long glucose chains, i.e., pancreatic alpha amylase activity was unnecessary. At the same time the osmolality of the fluids in the test section of the intestine was much lower; see Table III. The higher rate of absorption of the maltodextrin product and of Frac ⁇ tion I was to be expected because of the much lower average molecular weight of the glucose polymers. Any advantage of this high rate of absorption is more than offset by the greatly diminished osmolality of the product of the. invention.
  • the specially formulated long chain length glucose polymers of the present invention when hydrolyzed with pancreatic alpha-amylase compare favorably with glucose as to the transport kinetics across the intestinal mucosa.
  • the product of the invention under circumstances of normal gastrointestinal function, actually exerts a kinetic absorption equal to or perhaps slightly greater than glucose absorption, further illustrating the advantages of using such products as this is accomplished with greatly diminished osmolality.
  • a whole protein, lactose-free, complete dietary food with a low osmolarity in a rotary-retort sterilized can is provided as follows. This product is intended pri ⁇ marily as a tube diet fed.via the nasogastric route.
  • Osmolarity was 348 mOsm/L.
  • the protein source of this (a dry mix to be reconstituted with water) is a lactalbumin hydrolysate consisting primarily of di- and tri-peptides with 20% free a ino acids.
  • the glucose polymer is sprayed with a mixture/emulsion containing the oil, emulsifiers, and fat-soluble vitamins. The dry and coated powders are then blended.
  • This product reconstitutes to a clear solution with a stable emulsion and had a 480 mOsra/L. osmolarity.
  • glucose polymers are known to have higher 1-6 to 1-4 alpha-D-glycosidic bonds than others. They are digested more slowly when presented to the brush border of the normal human gut while occluding pancreatic enzymes. Isomaitase enzymes, whose function it is to cleave 1-6 bonds, are secreted at the brush border of the cells lining the mammalian gut. Heretofore, it was not observed that this enzyme is either limited in its rate of reaction or that the quantity secreted is limited when compared with substrate 1-6 linkages.
  • glucose polymers of G10 or greater with all of their advantages of digestibility and enhanced transport of electrolytes and water as shown above can be selected to have a relatively high 1-6 to 1-4 linkage ratio and, thereby, their digestion and resulting glucose transport can be significantly slowed.
  • This property of selective digestion rate is of value, for example, in feed ⁇ ing patients who are in need of tube feedings from gastroin ⁇ testinal disease, such as described above, but who are also diabetic, for example. In these cases, it is of considerable value to be able to feed a carbohydrate that is .”programmed" to transport glucose slowly from the lumen, through the intestinal wall, to the. serosal side and thereby not present a plasma glucose peak but provide a low but steady rate of infusion of glucose thereby diminishing glucose's insulin- stimulating effect.
  • This example further illustrates the value and medical properties of the greater than 10 glucose unit polymer of this invention.
  • High 1-6 to 1-4 ratio polymers as in Example 9 (a) can be provided by selection of a starch having such pro ⁇ portions and proceeding as in Example 1.
  • High 1-4 to 1-6 ratio polymers as in Example 9 (b) can be provided as in Example 2.
  • the high 1-6 to 1-4 ratio polymers of Example 9 (a) and the high 1-4 to 1-6 ratio polymers of Example 9 (b) may be formulated as in appropriate examples above.
  • Polymer of present invention contain ⁇ ing predominantly glucose polymers having a degree of polymerization of 10 to 40 59 21 205 10 600
  • OMPI prepared identically except that formulation I contained polymer (a) , Formulation II contained polymer (b) and Formulation IH contained polymer (c) as the carbohydrate component.
  • the other components of each formulation were standard ingredients (protein, lipid, vitamins and minerals) used in a complete dietary formula.
  • Polymer (a) was prepared as in Example 1, which was Fraction II (predominantly glucose polymers of 10 to 40 degrees of polymerization) and had been produced as retentate in ultrafiltration. The low content of calcium, magnesium, sodium and phosphorus was due to the fact that the corresponding salts diffused through the filter medium into the filtrate. Polymer (b) contained the mineral content of the 2-10 DP component. Polymer (c) was prepared as in Morehouse U.S. Patent No. 3,663,369, first stage; i.e., by treatment of starch with acid or enzyme to provide a liquid product free from residual starch but having a low dextrose equivalent. This polymer as produced for purposes of the present invention, consisted primarily of glucose polymers having a degree of polymerization of 10 to 40, but it also contained the mineral content of the starch and resulted, when formulated as Formulation III, in an unstable product.
  • Formulations I, II and III may be typically as described in Examples 7 and 8.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Materials Engineering (AREA)
  • Biochemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Polymers & Plastics (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Fraction de polymeres de glucose a poids moleculaire eleve d'un hydrolysat d'amidon possedant un degre de polymerisation de 10 a 40, obtenue en separant cette fraction d'un tel hydrolysat. Cette fraction presente une faible osmolarite, est rapidement absorbee par les intestins et presente d'autres avantages nutritifs. La fraction peut etre produite a partir de l'amidon de cereales selectionnees ou l'hydrolysat peut etre produit a partir de l'amidon de cereales selectionnees ou encore l'hydrolysat peut etre traite pour favoriser les polymeres de glucose avec liaisons 1-4(Alpha) ou 1-6(Alpha). On peut ainsi obtenir des produits dietetiques complets possedant une teneur calorique elevee et ne provoquant de diarrhee. Ces produits peuvent etre sous forme solide ou liquide, ils peuvent etre ingeres oralement ou administres au moyen d'une osteotomie naso-gastrique ou abdominale, et les preparations contenant cette fraction en combinaison avec des proteines et/ou des hydrolysats de proteines peuvent etre chauffees pour la sterilisation et presentent un brunissement indesirable reduit provoque par la reaction de Maillard.
EP19820901339 1981-03-31 1982-03-29 Polymeres de glucose et leur procede de production Withdrawn EP0075594A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US24964781A 1981-03-31 1981-03-31
US249647 1981-03-31

Publications (1)

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EP0075594A1 true EP0075594A1 (fr) 1983-04-06

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EP19820901339 Withdrawn EP0075594A1 (fr) 1981-03-31 1982-03-29 Polymeres de glucose et leur procede de production

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EP (1) EP0075594A1 (fr)
BE (1) BE892701A (fr)
WO (1) WO1982003329A1 (fr)

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US4886789A (en) * 1983-01-12 1989-12-12 M. L. Laboratories Plc Peritoneal dialysis and compositions for use therein
US6077836A (en) * 1983-01-12 2000-06-20 Ml Laboratotries, Plc Peritoneal dialysis and compositions for use therein
GB8300718D0 (en) * 1983-01-12 1983-02-16 Milner Research Ireland Ltd Glucose polymer solutions
GB8404299D0 (en) * 1984-02-18 1984-03-21 Milner Research Ireland Ltd Peritoneal dialysis
ATE106410T1 (de) * 1985-06-22 1994-06-15 Ml Lab Plc In kontinuierlicher peritonealdialyse verwendete polymere.
US6248726B1 (en) 1985-06-22 2001-06-19 M L Laboratories Plc Method of peritoneal dialysis using glucose polymer solutions
SE8602971D0 (sv) * 1986-07-03 1986-07-03 Novo Industri As Low calorie bulking agent, method for production thereof, and use thereof
US4871571A (en) * 1987-06-30 1989-10-03 Novo Industri A/S Dietetic foodstuff containing low calorie bulking agent
US4956458A (en) * 1988-05-13 1990-09-11 Warner-Lambert Company Purification of polydextrose by reverse osmosis
US5091015A (en) * 1990-05-22 1992-02-25 Warner-Lambert Company Polydextrose compositions
DK1194554T3 (da) * 1999-07-05 2007-01-29 Vlaams Interuniv Inst Biotech Administration af treklöverpeptider
FR2840612B1 (fr) * 2002-06-06 2005-05-06 Roquette Freres Polymeres solubles de glucose hautement branches et leur procede d'obtention
DK1545562T3 (da) * 2002-09-09 2006-08-21 Tno Forgrenede alfa-glucaner til vægtregulering
WO2012129017A1 (fr) 2011-03-18 2012-09-27 Baxter International Inc. Solutions de dialyse péritonéale comprenant des polymères de glucose
EP2983514A4 (fr) 2013-03-15 2017-03-15 Cargill, Incorporated Compositions d'hydrate de carbone
CN103404764B (zh) * 2013-08-23 2015-06-17 内蒙古伊利实业集团股份有限公司 一种抗性麦芽糊精及其制备方法

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US3663369A (en) * 1968-02-23 1972-05-16 Grain Processing Corp Hydrolysis of starch
GB1444901A (en) * 1972-05-02 1976-08-04 Milner Scient Medical Research Glucose polymers
US4021543A (en) * 1975-03-28 1977-05-03 Abbott Laboratories Process for disguising saline taste of pharmaceuticals and product thereof
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US4182756A (en) * 1977-11-21 1980-01-08 Abbott Laboratories High calorie solutions of low molecular weight glucose polymer mixtures useful for intravenous administration

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Title
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WO1982003329A1 (fr) 1982-10-14
BE892701A (fr) 1982-07-16

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