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WO1998003184A9 - Derives de levane, leur preparation, leur composition et leurs applications, y compris d'ordre medical et alimentaire - Google Patents

Derives de levane, leur preparation, leur composition et leurs applications, y compris d'ordre medical et alimentaire

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Publication number
WO1998003184A9
WO1998003184A9 PCT/US1997/013782 US9713782W WO9803184A9 WO 1998003184 A9 WO1998003184 A9 WO 1998003184A9 US 9713782 W US9713782 W US 9713782W WO 9803184 A9 WO9803184 A9 WO 9803184A9
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levan
derivative
molecular weight
daltons
amount
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WO1998003184A1 (fr
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Definitions

  • This invention relates to derivatives of levans, which are polysaccharides, and for their methods of making and novel uses.
  • Levan is a polymer of fructose, C 6 H 12 0r , and this polymer is a polysaccharide with ⁇ -(2->6) linkages between the fructose rings where the numbers describe the carbon atoms in the fructose ring which are linked and the ⁇ describes the stereochemical relationship.
  • Levans have also been described as fructans in which the predominant glycosidic linkage between the D-fructofuranoside monomeric units is ⁇ -(2->6).
  • the levans are generally made by microorganisms and do not occur as high molecular weight compounds in plants. Some low molecular weight levans having a molecular weight of less than 100,000 Daltons can occur in grasses.
  • Bacillus megatherium Bacillus mesentericus Bacillus mesentericus
  • Bacillus vulgatus and other Bacillus spp are Bacillus vulgatus and other Bacillus spp .
  • Jerusalem artichokes and in onions It is now available as a commercial product in food processing. Inulins are naturally occurring in plants.
  • PCT Publication No. WO 86/04091 to IGI Biotechnology discloses the microbial production of polyfructose where a water soluble levan is made having a weight average molecular weight of 10,000 to 40 million. There is no sulfate or other derivative mentioned in this publication.
  • the material is used as a colloidal stabilizer agent for foods, beverages, pharmaceuticals, dentifrices and cosmetics.
  • German Patent No. 3,725,554 and its corresponding U.S. Patent No. 5,055,457 to Schrinner et al. at Hoechst discloses a combination of a polysaccharide sulfate and a xanthine derivative in tablets which shows an anti-AIDS activity by inhibiting reverse transcriptase.
  • the examples given for formulations use a sodium salt of pentosan polysulfate.
  • the formula of the pentosan polysulfate shows two sulfates per sugar unit, which are on a chain of xylose molecules (a pentosan) at the C-2 and C-3 carbons.
  • the pentosan in this patent is a (l->4) linked polymer.
  • Pentosan is a polysaccharide of five-carbon sugar (xylose) , not a six-carbon sugar (fructose) .
  • the sulfated polysaccharides are defined as having a molecular weight of 1,000 to 20,000 Daltons, with particularly preferred weight of about 5,000 to 12,000 Daltons and especially of about 6,000 Daltons.
  • levan sulfate is used either alone or mixed with pentoxifyllin according to their invention.
  • the levan sulfate in Table 1 has a specific molecular weight of 8,000 Daltons and is 100% sulfated.
  • the levan sulfate shows no activity at 10 ⁇ g/ml or 20 ⁇ g/ml toward the inhibition of syncytium (HIV) formation, whereas the product of the present invention shows 50% inhibition at 0.5 ⁇ g/ml and fully inhibits at 1.0 ⁇ g/ml.
  • the sulfated polysaccharides are prepared by a different procedure than the product of the present invention. This patent provides no structural details and thus comparison as to any similarity to the present product is not possible.
  • the levan sulfate of the present invention has a higher molecular weight of about 500,000 Daltons and is preferably not 100% sulfated.
  • Formula 1 infra and in the description of the nmr results in Table 2 there is one sulfate on the C-l of each sugar unit, and about half that number of sulfates distributed between the C-3 and C-4 carbons based on the stoichiometric data from the elemental analysis combined with the nmr spectral information on the position of the sulfates on the ring carbons.
  • U.S. Patent No. 5,273,892 to Okutani discloses a hetropolysaccharide which contains a mixture of sugars and include components such as galactose, galaturonic acid, N- acetyl fucosamine and pyruvic acid in a ratio of 2:3:1:1.
  • High molecular weight heteropolysaccharides are quite common in bacterial cell walls and in gum arabic. See D. L. Cook et al, "Comparative Pharmacology and Chemistry of
  • Vogler 's starting materials were partially hydrolyzed polysaccharides with a low molecular weight, whereas the levan starting material here was not hydrolyzed and is of high molecular weight.
  • the optical rotation of Vogler' s polysulfate of hydrolyzed levan is -4.7° whereas the rotation of the levan sulfate here is -17.3°. This is a substantially significant difference in this physical property and demonstrates the difference in these two materials.
  • levan which is the ⁇ -(2- >6) polymer of fructose have been made with unique properties.
  • the levan which is preferably used as the starting material has a much higher molecular weight than ordinary levan. It has a molecular weight of at least 1 x 10 6 Daltons and preferable an average molecular weight of about 2 x 10 6 Daltons, in a narrow distribution range in the natural state and it is produced in high yield from any available inexpensive sucrose.
  • These novel levan derivatives, which are made from levan have high molecular weights, are on the order of about 500,000 Daltons.
  • the derivatives are characterized as levan derivatives having predominant ⁇ -(2->6) glycosidic linkages between the D- fructofuranoside monomeric units.
  • the preferred derivatives are sulfates, phosphates and acetates which can be present in an amount of from 0.2 to 3 sulfates, phosphates or acetates per fructose ring.
  • levan derivatives have many novel uses. Among them are as an inhibitor of smooth muscle cell proliferation, an anti-AIDS agent, as an excipient for use in making tablets, and as an agent to transform water and certain organic solvents into a gel.
  • Other uses include wound healing for medical use, for dermatological use, for subcutaneous packing for medical or dental use, and for veterinary use in treatment of inflamed udders and mastitis in cattle. These uses are especially relevant if there are bleeding complications.
  • the subcutaneous packing can be used, for example, for burns, surface wounds or skin infections.
  • levan derivatives and levan cross-linked products are described below.
  • the especially preferred levan sulfate begins the description.
  • the higher molecular weight levan sulfate of the present invention is a white granular solid which is very soluble in water and it is non-hygroscopic. In some reactions the color can be from cream to pale yellow. It stores well.
  • the generic formula for levan sulfate can be written as:
  • the value of x varies from 0 to 2 and wherein the sulfate is present in an amount of 0.2 to 3 sulfates per fructose ring.
  • the value of n ranges from about 1250 to 1550.
  • the levan polymer has about 8% branching and it is expected that the sulfated polymer has the same.
  • the sulfated levan compound has a molecular weight of about 500,000 Daltons as determined by gel permeation chromatography (GPC) . This large size is unique and believed to be much larger than any other levan compound reported in the literature.
  • Shifts upfield for C-1 and downfield for C-3 and C-4 indicate addition of a sulfate (replacement of an OH with a charged group) .
  • the C-1 is preferentially sulfated with subsequent sulfate substitution occurring on C-3 and C-4 without preference.
  • C-1 is fully sulfated, and C-3 and C-4 partially sulfated.
  • Lack of splitting on C-1 indicates that the position is fully sulfated.
  • Triplet splitting on C-3 and C-4 indicates that each position is partially sulfated (some sulfated, some not) .
  • the C-5 signal is split into a triplet by the three possible sulfated environments.
  • the linkage carbons they are shifted upfield and downfield, respectively, as expected when the molecule is substituted with a large negative group.
  • compositions for sulfated levans are preferably:
  • Example 1 a preferred composition has C: 15%, S: 18.4%, O: 48.2%, H: 2.1% and Na: 14.18%.
  • a second preferred levan derivative is the phosphated levan which has a similar structure to levan sulfate with the phosphate groups substituted for the sulfate groups.
  • the generic formula for levan phosphate can be written as:
  • the value of x varies from 0 to 2 and wherein the phosphate is present in an amount of 0.2 to 3 phosphates per fructose ring.
  • the value of n ranges from about 1250 to 1550.
  • the molecular formula for levan phosphate shows a minimum of one phosphate group per five fructose residues, as the sodium salt, with the phosphate groups acting to cross link chains of levan, with a range up to one phosphate group per fructose residue. Over the range of compounds the C-1 is preferentially phosphated with subsequent phosphate substitution occurring on C-3 and C-4 without preference.
  • C-1 is fully phosphated, and C-3 and C-4 partially phosphated.
  • the phosphate can be present in an amount of 0.2 to 3 phosphates per fructose ring.
  • the weight range of compositions for phosphated levans are preferably:
  • An aqueous solution or gel of levan phosphate also maintains its gel integrity when frozen and thawed, and when heated to 100°C where it is still a gel and then cools back to room temperature. The gel retains it structure up to 100°C
  • the levan phosphate also gels certain organic solvents, including methanol, ethanol, 50% ethanol/water, n-propanol, iso-propanol, n-butanol, iso-butanol, tert- butanol, methyl ethyl ketone, dimethylformamide (DMF) , dioxan, and dimethyl sulfoxide. This is very unusual since a polysaccharide does not normally gel organic solvents.
  • the phosphated levans can be used to cause water to gel or become a solid phase. Applications of this gel include use as topical applications of pharmaceuticals and for cosmetic applications.
  • the gels can be used to extinguish fires, by holding water in place at the site of the fire. They can also be used to hold water in place either in or on soil and earth.
  • the phosphated levans can be used as a food ingredient, including foods to be frozen or heated, as a thickening agent or a fat substitute.
  • a third preferred derivative is levan acetate which is insoluble in water, methanol and ethanol. It is partly soluble in chloroform, and acetonitrile, and very soluble in dimethylsulfoxide.
  • the nuclear magnetic resonance (nmr) shows the structure with the acetate preferentially fully substituted on C-1 and subsequently partially substituted on C-3 and
  • the weight range of components for levan acetates are preferably: C from 43% to 47%
  • Levan acetate has an insolubility in water and a chiral nature.
  • One potential use for levan acetate is as a chromatographic support for chiral separations.
  • Levan acetate can also be used to make thin films with potential use in foods and packaging.
  • levan acetate (2 g) is dissolved in one of several organic solvents (20 to 30 ml) and the solution is spread on a surface. As the solvent is evaporated (mild heat and forced air) a transparent or semitransparent film forms.
  • levan is crosslinked with epichlorohydrin. This material can be used to separate racemic mixtures of chiral compounds including sugars and amino acids. The compound exhibits a very low pressure drop across a column.
  • the compound can also be used as a substrate for capillary electrophoresis .
  • the preparation of the levan derivatives begins with an original fructose polymer which has an average molecular weight of about 2 million Daltons where the molecular weight is a distribution around this average value.
  • One such levan, made by B . polymyxa can be made from sucrose cheaply and in large quantities. See U.S. Patent No. 5,547,863 (U.S. Patent Application Serial No. 07/393,604, filed August 14, 1989, issuing August 20, 1996) by Han and Clarke.
  • a further description of this higher molecular weight levan is also given in "Production and Characterization of Microbial Levan," by Y. W. Han and M. A. Clarke, J.
  • Examples 1-5 In these examples, a series of runs were conducted to make the sulfated levan.
  • the procedure involves starting with a high molecular weight form of levan produced by the procedure described by Y. W. Han and M. A. Clarke in "Production and Characterization of Microbial Levan,” J. Agriculture and Food Chemistry, 1990, 3_8_, 393.
  • the levan was sulfated by the procedure generally described in Biochem. J. 58, 532- 536 (1954) using 5.8 ml of chlorosulfonic acid in 36 ml of pyridine and 2.65 g of levan.
  • Example 1 has the best yield and exemplifies preferred conditions.
  • Example 2 , 3 and 4 when the amount of chlorosulfonic acid is reduced, the yield also is reduced.
  • Example 3 the amount of pyridine dilutes further and results in low yields.
  • Example 5 there is sufficient chlorosulfonic acid, but with the low amount of pyridine, the yield is not as large as in Example 1.
  • Example 5 The data from Table 5 can be used to derive molar formulas for the products.
  • Example 1 After obtaining the elemental weight from the two runs, the number of moles of each element is calculated. Since a fructose ring has 6 carbon atoms, the ratio of molar amounts are normalized to C equal 6. The factor used was 4.8. The average molar amounts for the two runs are determined and the results are set forth in Table 6 below.
  • the sodium is slightly higher than the sulfur, indicating 3 positive charges/monomer, rather than the 2.75 positive charges from the varied substitution.
  • the higher sodium could be from an incompletely dialyzed salt.
  • the proposed formula is
  • a 5 fructose chain can be considered where four fructose chains have 2 sulfates and one fructose chain has 3 sulfates.
  • the O balance is given in Table 9.
  • a 10 g sample of levan of high molecular weight of at least 1 x 10 6 Daltons was dissolved in 200 ml pyridine, cooled to 0°C, and treated with 10 ml PC1 3 , added dropwise.
  • the mixture was stirred until it reached room temperature.
  • Example 6 of the levan used was finely ground to pass a 24 mesh screen and, therefore, had a much larger surface area for reaction than did the levan in Example 8. It is believed that this is the reason why Example 6 has a higher yield of product with a lower phosphorous content per weight.
  • Example 10 This example illustrates another method to produce levan phosphate by Method 2.
  • a 10 g sample of levan obtained by the procedure as used in Example 1 was dissolved in 200 ml pyridine and the solution was cooled to 0°C. Then, 10 g of P0C1 3 was added slowly. A condenser was then connected to the flask and the solution was heated to 80°C for four hours. The solution was cooled and 200 ml of saturated sodium carbonate was added. The aqueous layer was separated and dialyzed for 100 hours. Some of the material remaining in the bag was suspended in water and freeze dried. The effluent from the centrifuge was concentrated and freeze- dried, yielding 6.0 g of white powder.
  • Example 11 This example illustrates a method to produce levan acetate.
  • a 10 g sample of levan obtained by the procedure as used in Example 1 was- suspended in 150 ml of dry pyridine and 25 ml of acetic anhydride was added. The mixture was heated to 100°C and held at 100°C for two hours. The mixture was poured into 700 ml of absolute ethanol with stirring. The solid precipitate that formed was filtered off, washed with ethanol and air dried. The yield was 13 g and the determination of the degree of acetylation showed 28.17 % acetyl groups.
  • Example 12 This example illustrates the production of levan crosslinked with epichlorohydrin.
  • the composition data for the levan cross-linked with epichlorohydrin are set forth in Table 11. TABLE 11
  • This crosslinked product can be used to form thin plastic films as well as being used as a support medium for separation of chiral compounds.
  • a column of cross-linked epichlorohydrin was found to separate a mixture of D(+) and L(-) fucose.
  • the epichlorohydrin cross-linked levan may serve as a substrate to separate racemic mixtures of stereoisomers.
  • the cross-linked material may serve as a substrate for gel permeation chromatography because of its swelling characteristics.
  • levan derivatives such as levan sulfates, phosphates, and acetates
  • the higher molecular weight levan derivatives have many unique properties. The following are some of the applications for which they can be used.
  • the levan derivatives can be used for the inhibition of the proliferation of smooth muscle cells (smc) .
  • the materials have an anti-clotting factor activity or smooth muscle cell inhibition. They can be used for heart patients and in all surgery and for treatment to reduce, delay or prevent restenosis after angioplasty.
  • Compounds which inhibit the proliferation of smooth muscle cells are a goal for many drug companies and the compound tested below exhibited better activity than heparin at low doses in the range of less than 1.0 ⁇ g/ml and at medium doses in the range of between 1 and 10 ⁇ g/ml.
  • the activity of this material is given in Example 13.
  • Example 13 This example illustrates the property of the inhibition of the proliferation of smooth muscle cells by levan sulfate.
  • Example 1 A sample of levan sulfate as made by the procedure in Example 1 was tested for antiproliferative activity against smooth muscle cells in culture by using the standard assay for smc proliferation in which cell count is assayed.
  • the comparison material was commercial heparin.
  • the results of the test are set forth in the Figure.
  • the activity of the levan sulfate, code named Spriex-1 was approximately one log greater than the commercial heparin when expressed in % inhibition in heparin equivalents for smc growth inhibition.
  • the levan derivatives can be used for their anti-AIDS activity.
  • the compounds have a positive effect against
  • Example 14 The evaluation of the material for its anti-AIDS activity is set forth in Example 14.
  • Example 14 This example illustrates the anti-AIDS activity of levan sulfate.
  • Levan sulfate made according to Example 1 from a levan with a high molecular weight was tested for inhibition of HIV replication in a human T-cell line (MT4) .
  • Effective dose giving 50% reduction of virus growth (ED 50 ) was 0.5 ⁇ g/ml.
  • the levan sulfate shows 50% inhibition of syncytium formation at 0.5 ⁇ g/ml and fully inhibits at 1.0 ⁇ g/ml which results are totally unexpected.
  • the levan derivatives can be used as a carrier compound or excipient when making drug formulations with other drugs.
  • Formulas for tableting are known and there are standard recipes. These levan derivatives serve this function because the original polyfructose also serves this function.
  • the levan derivatives can be used as a gel former to transform water into * a gel and certain organic solvents into gel form. An example is described in Example 15.
  • Example 15 This example illustrates the use of levan phosphate as a gel former.
  • levan phosphate as made in Examples 6 to 9 When levan phosphate as made in Examples 6 to 9 is added to water in an amount of from about 0.1-10%, or when it is added to a dilute salt solution, the water becomes a gel.
  • the gel has a viscosity in the ranges set forth in Table 3 which depend on the temperature.
  • gels are in applications where water can be used to exclude air such as in fire extinguishing. Additional medical applications include using the gel as a vehicle to apply medicine to body skin such as in the treatment of burns and wound healing. Additional uses in food manufacture and processing are as fat substitutes, to add stability, texture and mouthfeel to reduced fat foods.
  • Example 16 This example illustrates the use of levan phosphate as a gel former with certain organic solvents.
  • levan phosphate as made in Examples 6-9, is added to any of, by not only, ethanol, methanol, propanol, butanol and their mixtures with water, or to dimethyl sulfoxide, or to formamide, or other polar organic solvents, the liquid becomes a gel.
  • Levan phosphate is added in an amount of 0.5% to 10%.
  • Ethanol/water mixtures include potable ethanol liquors, liquerers, cordials and distilled liquors.
  • Example 17 This example illustrates the use of levan acetate in film formation.
  • a sample of levan acetate as made by the procedure in Example 11 in a white powder form is dissolved in an organic solvent such as dimethyl sulfoxide and the solution is applied to a surface. When the solvent has evaporated with heat the levan acetate remains as a thin transparent film. It is anticipated that this film is edible.
  • Example 17 illustrates the separation possible with D(+) and L(-) fucose.
  • This example illustrate the use of cross-linked levan as a separation agent.
  • a separatory column was filled with the granular, pale yellow cross-linked levan as prepared in Example 7, which was crossed-linked by epichlorohydrin and which was insoluble in water, but which swells in water, holding water within the granules.
  • An aqueous solution of a chiral mixture of D(+) and L(-) fucose was passed over the column and the components were separated on the column into their optically active components.

Abstract

Nouveaux dérivés de la lévane, qui est le β-(2-⊃6)polymère du fructose, dotés de caractéristiques uniques. La matière de départ à base de lévane présente une masse moléculaire bien plus élevée que la lévane ordinaire, de l'ordre d'au moins 1 x 106 Daltons, et de préférence d'environ 2 x 106 Daltons, dans une plage de distribution étroite. Les nouveaux dérivés de lévane sont caractérisés en ce qu'ils comprennent des liaisons glycosidiques β-(2-⊃6) prédominantes entre les motifs monomères de D-fructofuranoside. En ce qui concerne les dérivés hydrosolubles, ils présentent une masse moléculaire élevée de l'ordre d'environ 500,000 Daltons. Parmi les dérivés préférés on compte les sulfates, les phosphates et les acétates qui peuvent être présents en une teneur comprise entre 0,2 et 3 par noyau de fructose. Ces dérivés de lévane se prêtent à de nombreuses utilisations nouvelles. Ils peuvent ainsi être utilisés comme inhibiteurs de la prolifération des cellules des muscles lisses, comme agents anti-SIDA, comme excipients dans la fabrication de pilules et comme agents de gélification de l'eau. Ils peuvent également être utilisés pour la cicatrisation à des fins médicales et à des fins dermatologiques, comme matériaux de bourrage sous-cutanés à des fins médicales ou dentaires et dans le traitement des pis enflammés et des mammites chez le bétail, en médecine vétérinaire. Lorsque la lévane est elle-même réticulée par l'épichlorhydrine, elle agit comme agent filmogène pour produire des films minces en matière plastique.
PCT/US1997/013782 1996-07-19 1997-07-18 Derives de levane, leur preparation, leur composition et leurs applications, y compris d'ordre medical et alimentaire Ceased WO1998003184A1 (fr)

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US8946153B2 (en) 2010-03-29 2015-02-03 Ferring B.V. Fast dissolving pharmaceutical composition
US9731018B2 (en) 2011-09-16 2017-08-15 Ferring B.V. Fast dissolving pharmaceutical composition
TW201422254A (zh) 2012-11-21 2014-06-16 Ferring Bv 用於速釋及延釋的組成物
EP3472117A4 (fr) * 2016-06-20 2020-07-29 Integrity Bio-Chemicals, LLC Liants améliorés pour la granulation de minerai de fer et matériaux adhésifs à base de ciment
MX2019005902A (es) * 2016-11-23 2019-10-02 Integrity Bio Chemicals Llc Composiciones entrecruzadas de polisacaridos y mezclas de concreto que contienen lo mismo.

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US5547863A (en) * 1989-08-14 1996-08-20 The United States Of America As Represented By The Secretary Of The Agriculture Production of fructan (levan) polyfructose polymers using bacillus polymyxa

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