CN102834117A - Anionic polysaccharides functionalised by at least two hydrophobic groups supported by an at least trivalent spacer - Google Patents

Anionic polysaccharides functionalised by at least two hydrophobic groups supported by an at least trivalent spacer Download PDF

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CN102834117A
CN102834117A CN2011800119392A CN201180011939A CN102834117A CN 102834117 A CN102834117 A CN 102834117A CN 2011800119392 A CN2011800119392 A CN 2011800119392A CN 201180011939 A CN201180011939 A CN 201180011939A CN 102834117 A CN102834117 A CN 102834117A
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polysaccharide
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functional group
acid
amine
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CN102834117B (en
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R·沙尔韦
R·索拉
O·索拉
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Adocia SAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B11/00—Preparation of cellulose ethers
    • C08B11/02—Alkyl or cycloalkyl ethers
    • C08B11/04—Alkyl or cycloalkyl ethers with substituted hydrocarbon radicals
    • C08B11/10—Alkyl or cycloalkyl ethers with substituted hydrocarbon radicals substituted with acid radicals
    • C08B11/12—Alkyl or cycloalkyl ethers with substituted hydrocarbon radicals substituted with acid radicals substituted with carboxylic radicals, e.g. carboxymethylcellulose [CMC]
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B11/00—Preparation of cellulose ethers
    • C08B11/02—Alkyl or cycloalkyl ethers
    • C08B11/04—Alkyl or cycloalkyl ethers with substituted hydrocarbon radicals
    • C08B11/14—Alkyl or cycloalkyl ethers with substituted hydrocarbon radicals with nitrogen-containing groups
    • 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
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0018—Pullulan, i.e. (alpha-1,4)(alpha-1,6)-D-glucan; Derivatives thereof
    • 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
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0021—Dextran, i.e. (alpha-1,4)-D-glucan; Derivatives thereof, e.g. Sephadex, i.e. crosslinked dextran
    • 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
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0045—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Galacturonans, e.g. methyl ester of (alpha-1,4)-linked D-galacturonic acid units, i.e. pectin, or hydrolysis product of methyl ester of alpha-1,4-linked D-galacturonic acid units, i.e. pectinic acid; Derivatives thereof
    • 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
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
    • C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
    • 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
    • C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
    • C08B37/0084—Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates

Abstract

The present invention relates to novel anionic polysaccharide derivatives partially functionalised by at least two vicinal hydrophobic groups, said identical or different hydrophobic groups being supported by an at least trivalent radical or spacer. The invention also relates to methods for synthesising same. The invention further relates to the use of functionalised polysaccharides according to the invention for preparing pharmaceutical compositions including one of the polysaccharides according to the invention and at least one active principle.

Description

Carry out functionalized anion polysaccharide through at least two by the entrained hydrophobic group of tervalent at least sept
The present invention relates to novel biocompatible polymer based on anion polysaccharide; Said anion polysaccharide is undertaken functionalized through at least two by the entrained hydrophobic group of tervalent at least sept; Said novel biocompatible polymer can be useful, especially for using active component (AP) in order to treat and/or prevent purpose to the human or animal.
Because its structure and its biocompatibility, the hydrophobic group through at least two vicinities carries out functionalized anion polysaccharide, in pharmacopedics and more particularly has special benefit through forming in the field that complex makes the protein active ingredients stabilisation.
Especially in the natural constituent of cell membrane, the known molecular compound that carries (promptly by same group connected) hydrophobic chain of at least two vicinities, for example phospholipid and triglyceride.These chemical compounds are very important, especially for the stabilisation of transmembrane protein.Yet they are the molecules with low molar mass and strong-hydrophobicity, and such molecule only for example dissolves in the vesicle at labyrinth.
Applicant's contribution is that the group that has synthesized through carrying two biocompatible, contiguous hydrophobic chains carries out functionalized polysaccharide.Adjustable these polymerizable compounds of its hydrophobicity have major benefit in the preparation of pharmacy activity component.
The present invention relates to the novel anionic polysaccharide, its hydrophobic group through at least two vicinities carries out functionalized, and said identical or different hydrophobic group is entrained by tervalent at least group or sept.In one embodiment, the carboxyl of said polysaccharide is partly replaced by at least two hydrophobic group, and said identical or different hydrophobic group is entrained by tervalent at least group or sept.In one embodiment, the hydroxyl of said polysaccharide is partly replaced by at least two hydrophobic group, and said identical or different hydrophobic group is entrained by tervalent at least group or sept.These novel anionic polysaccharide that comprise hydrophobic group have excellent biological compatibility, and its hydrophobicity can easily regulate, and do not make biocompatibility and bad stability.
The invention still further relates to the synthetic method of said novel anionic polysaccharide.
In one embodiment; Said polysaccharide is selected from the polysaccharide that comprises carboxyl; Said polysaccharide or be selected from the polysaccharide that carries carboxyl natively, or be selected from from the polysaccharide that comprises carboxyl natively and obtain or be converted into the synthetic polysaccharide that the neutral polysaccharide of carboxyl obtains from its hydroxyl; Be selected from its carboxyl at least one or its hydroxyl at least one by at least two identical or different, be labeled as-the substituted polysaccharide of hydrophobic group of Hy:
● (Hy) the grafting or be connected to this anion polysaccharide of said hydrophobic group through linking arm R; Said linking arm R carries at least three reactive functional groups and is connected with this polysaccharide through key F; Said key F produces owing to the reactive functional groups of linking arm precursor R ' and the carboxyl of this anion polysaccharide or the coupling between the hydroxyl; And (Hy) be connected with linking arm R through at least one G of functional group, the said G of functional group is owing to the coupling between the reactive functional groups of the reactive functional groups of hydrophobic compound (Hy ') and linking arm precursor R ' produces for said hydrophobic group.
● the carboxyl of not functionalized anion polysaccharide exists with the form of cationic carboxylate, and said cation is preferably alkali metal cation, for example Na +Or K +,
● F is amide functional group, ester functional group or carbamate-functional,
● G is amide functional group, ester functional group or carbamate-functional,
● Hy is the group that produces owing to the coupling between the reactive functional groups of the reactive functional groups of hydrophobic compound (Hy ') and linking arm precursor R '; It is made up of the chain that comprises 4-50 carbon atom; Said chain randomly is branching and/or undersaturated, randomly comprises one or more hetero atoms, and for example O, N are or/and S; Randomly comprise one or more saturated, undersaturated or aromatic rings or heterocycle
● the R trivalent group that the chain that comprises 1-15 carbon atom constitutes of serving as reasons; Said chain randomly is branching and/or undersaturated; Randomly comprise one or more hetero atoms; For example O, N are or/and S; Randomly comprise one or more saturated, undersaturated or aromatic rings or heterocycle, and owing to the reaction of the precursor R ' with at least three identical or different reactive functional groups produces, said at least three identical or different reactive functional groups are selected from alcohol functional group, acid functional group and amine functional group.
Therefore; The present invention relates to anion polysaccharide; It is selected from the polysaccharide that comprises carboxyl, said polysaccharide or be selected from the polysaccharide that carries carboxyl natively, or be selected from from the polysaccharide that comprises carboxyl natively and obtain or be converted into the synthetic polysaccharide that the neutral polysaccharide of carboxyl obtains from its hydroxyl; With in its hydroxyl that is selected from formula I at least one by at least two identical or different, be labeled as-Hy hHydrophobic group replace or its carboxyl at least one by at least two identical or different, be labeled as-Hy cThe substituted polysaccharide of hydrophobic group:
Figure BDA00002089881000031
Formula I
Wherein, n cAnd n hThe sugar unit of representing this polysaccharide passes through-F c-R c-[G c-Hy c] RcAnd/or-F h-R h-[G h-Hy h] RhCarry out functionalized degree, and n h>=0 and n c>=0,0.01≤n wherein h+ n c≤0.5,
● F cBe amide functional group, or be ester functional group,
● F hBe carbamate-functional,
● the carboxyl of not functionalized anion polysaccharide exists with the form of cationic carboxylate, and said cation is preferably alkali metal cation, for example Na +Or K +,
● G hOr G cBe amide functional group, or be ester functional group, or be carbamate-functional that it is because hydrophobic compound (Hy h' or Hy c') reactive functional groups and linking arm precursor R h' or R c' reactive functional groups between coupling and produce,
● Hy hOr Hy cFor because hydrophobic compound (Hy h' or Hy c') reactive functional groups and linking arm precursor R h' or R c' reactive functional groups between coupling and the identical or different group that produces, Hy hOr Hy cChain by comprising 4-50 carbon constitutes, and said chain randomly is branching and/or undersaturated, randomly comprises one or more hetero atoms, and for example O, N be or/and S, randomly comprises one or more saturated, undersaturated or aromatic rings or heterocycle,
● R cThe trivalent group that the chain that comprises 1-15 carbon of serving as reasons constitutes; Said chain randomly is branching and/or undersaturated; Randomly comprise one or more hetero atoms; For example O, N be or/and S, randomly comprises one or more saturated, undersaturated or aromatic rings or heterocycle, and owing to have the precursor R of at least three identical or different reactive functional groups c' reaction and produce, said at least three identical or different reactive functional groups are selected from alcohol functional group, acid functional group and amine functional group,
● R hThe trivalent group that the chain that comprises 1-15 carbon of serving as reasons constitutes; Said chain randomly is branching and/or undersaturated; Randomly comprise one or more hetero atoms; For example O, N be or/and S, randomly comprises one or more saturated, undersaturated or aromatic rings or heterocycle, and owing to have the precursor R of at least three reactive functional groups h' reaction and produce, a reactive functional groups in said at least three reactive functional groups is that amine and other reactive functional groups are selected from alcohol functional group, acid functional group and amine functional group,
● r hBe integer, its expression grafting is at tervalent at least linking arm R hOn the number of hydrophobic group, and 2≤r h≤4,
● r cBe integer, its expression grafting is at tervalent at least linking arm R cOn the number of hydrophobic group, and 2≤r c≤4.
In one embodiment, n h+ n cBe 0.02-0.4.
In one embodiment, n h+ n cBe 0.03-0.3.
In one embodiment, polysaccharide according to the present invention is selected from the polysaccharide of formula II:
Figure BDA00002089881000041
Formula II
Wherein,
-n cThe carboxyl of representing this polysaccharide is through chain string-F c-R c-[G C-Hy c] RcCarry out functionalized degree, and be 0.01-0.5,
-F c, R c, G c, Hy cAnd r cThe definition that provides above meeting,
-when the carboxyl of this polysaccharide through-F c-R c-[G C-Hy c] RcCarry out when functionalized, the said carboxyl of this polysaccharide is cationic carboxylate so, and said cation is preferably alkali metal cation, for example Na +Or K +, and
-as not functionalized linking arm R cReactive functional groups when being acid functional group, it is also with salifiable form, exists with the form of cationic carboxylate, said cation is preferably alkali metal cation, for example Na +Or K +With linking arm R that ought be not functionalized cReactive functional groups when being amine functional group, it exists with the form of anionic salt, said anion is preferably negative halogen ion.
In one embodiment, polysaccharide according to the present invention is selected from the polysaccharide of formula III:
Figure BDA00002089881000051
Formula III
Wherein,
-n c, F cAnd R cThe definition that provides above meeting,
-identical or different G C1And G C2Meet G cDefinition,
-identical or different Hy C1And Hy C2Meet Hy CDefinition.
In one embodiment, polysaccharide according to the present invention is selected from the polysaccharide of formula IV:
Figure BDA00002089881000061
Formula IV
Wherein,
-n c, F cAnd R cThe definition that provides above meeting,
-identical or different G C1, G C2And G C3Meet G cDefinition,
-identical or different Hy C1, Hy C2And Hy C3Meet Hy CDefinition.
In one embodiment, polysaccharide according to the present invention is selected from the polysaccharide of formula V:
Figure BDA00002089881000062
Formula V
Wherein,
-n hThe hydroxyl of representing this polysaccharide is through chain string-F h-R h-[G h-Hy h] RhCarry out functionalized degree, and be 0.01-0.5,
-F h, R h, G h, Hy hAnd r hThe definition that provides above meeting,
The carboxyl of-this polysaccharide exists with the form of cationic carboxylate, and said cation is preferably alkali metal cation, for example Na +Or K +, and
-as not functionalized linking arm R hReactive functional groups when being acid functional group, it is also with salifiable form, exists with the form of cationic carboxylate, said cation is preferably alkali metal cation, for example Na +Or K +With linking arm R that ought be not functionalized hReactive functional groups when being amine functional group, it exists with the form of anionic salt, said anion is preferably negative halogen ion.
In one embodiment, polysaccharide according to the present invention is selected from the polysaccharide of formula VI:
Figure BDA00002089881000071
Formula VI
Wherein,
-n h, F hAnd R hThe definition that provides above meeting,
-identical or different G H1And G H2Meet G hDefinition,
-identical or different Hy H1And Hy H2Meet Hy hDefinition.
In one embodiment, polysaccharide according to the present invention is selected from the polysaccharide of formula VII:
Figure BDA00002089881000081
Formula VII
Wherein,
-n h, F hAnd R hThe definition that provides above meeting,
-identical or different G H1, G H2And G H3Meet G hDefinition,
-identical or different Hy H1, Hy H2And Hy H3Meet Hy hDefinition.
" group " or " derivant " or " atomic group ", especially Hy, R, Q are meant owing between the said precursor or the reaction between said precursor and the said polysaccharide unit price or the polyvalent chain string that produce.
Said precursor; For example Hy ', R ' and Q '; Be specific chemical compound; It can be for example hydrophobicity alcohol, hydrophobic amine, hydrophobicity acid or aminoacid, thereby said hydrophobicity alcohol, hydrophobic amine, hydrophobicity acid or aminoacid will react and provides like top defined unit price or polyvalent group or derivant or atomic group Hy, R and Q.
" anion () " be meant and comprise not functionalized and polysaccharide salifiable carboxyl.
" degree of functionalization (functionalized degree) " is meant group-F c-R c-[G c-Hy c] RcAnd/or-F h-R h-[G h-Hy h] RhNumber/sugar unit, perhaps in other words, the group-F for the total number of sugar unit c-R c-[G c-Hy c] RcAnd/or-F h-R h-[G h-Hy h] RhTotal number.This notion can also be expressed as through-F c-R c-[G c-Hy c] RcAnd/or-F h-R h-[G h-Hy h] RhCarry out the molfraction of the hydroxyl or the carboxyl of this functionalized polysaccharide.
" transforming degree (conversion degree) " is meant the number/sugar unit of the hydroxyl that is converted into carboxyl, perhaps in other words, and the total number of the hydroxyl that is converted into carboxyl for the total number of sugar unit.This notion can also be expressed as molfraction.For example, wherein " hydroxyl is converted into the degree/sugar unit of carboxyl " to be equal to or greater than 0.15 polysaccharide be the polysaccharide that wherein grafting has at least 15 carboxyls/100 sugar unit.
" degree of polymerization (extent of polymerization) m " is meant the average number/polymer chain of repetitive (monomer).It is through calculating mumber average molar mass divided by the average quality that repeats primitive.
" mumber average molar mass (M n) " be meant the arithmetic mean of instantaneous value of the quality of each polymer chain.Therefore, be n for number iHave a molal weight M iChain i, have M n=(Σ in iM i)/(Σ in i).
Weight-average molar mass (M w) pass through M w=(Σ in iM i 2)/(Σ in iM i) obtain n wherein iFor having molal weight M iThe number of polymer chain i.
Said polymer can also characterize through the distribution of chain length, and the distribution of said chain length is also referred to as polydispersity index (Ip), and equals M wDivided by M n
In one embodiment, the said polysaccharide that comprises carboxyl is to carry the polysaccharide of carboxyl natively, and is selected from alginate, hyaluronan, polygalacturonic acid.
In one embodiment; The said polysaccharide that comprises carboxyl is synthetic polysaccharide, and said synthetic polysaccharide perhaps is equal to or greater than 0.15 neutral polysaccharide acquisition from general formula VIII wherein " hydroxyl is converted into the degree/sugar unit of carboxyl " from the polysaccharide acquisition that comprises carboxyl natively:
Figure BDA00002089881000091
Formula VIII
Wherein,
-said natural polysaccharide is selected from the polysaccharide that the monomer that is connected by the glycosidic bond through (1,6) and/or (1,4) and/or (1,3) and/or (1,2) type constitutes with occupying the majority,
-L for owing to the precursor of linking arm Q and this polysaccharide-key that coupling between the OH functional group produces, and be ester functional group, carbamate-functional or ether functional group,
-i representes this polysaccharide " hydroxyl is converted into degree/sugar unit of chain string L-Q ",
-Q is selected from the group of general formula I X:
Figure BDA00002089881000101
Formula IX
Wherein:
1≤a+b+c≤6,0≤a≤3,0≤b≤3 and 0≤c≤3,
R 3And R 4Be identical or different, and be selected from-H, the C1-C3 alkyl of linearity or branching ,-group of COOH and general formula X:
Figure BDA00002089881000102
Formula X
Wherein:
1≤d≤3, and
R ' 3And R ' 4Be identical or different, and be selected from-the C1-C3 alkyl group of H and linearity or branching.
In one embodiment, a+b+c≤5.
In one embodiment, a+b+c≤4.
In one embodiment, i is 0.1-3.
In one embodiment, i is 0.2-2.5.
In one embodiment, i is 0.5-1.7.
In one embodiment, i is 0.8-1.2.
In one embodiment, the monomer that is connected by the glycosidic bond through (1,6) type of said polysaccharide constitutes with occupying the majority.
In one embodiment, the polysaccharide that constitutes of the said monomer that is connected by the glycosidic bond through (1,6) type is a dextran with occupying the majority.
In one embodiment, the monomer that is connected by the glycosidic bond through (1,4) type of said polysaccharide constitutes with occupying the majority.
In one embodiment, the polysaccharide that constitutes of the said monomer that is connected by the glycosidic bond through (1,4) type is selected from Aureobasidium pullulans polysaccharide, alginate, hyaluronan, xylan, polygalacturonic acid or water-soluble cellulose with occupying the majority.
In one embodiment, said polysaccharide is the Aureobasidium pullulans polysaccharide.
In one embodiment, said polysaccharide is alginate.
In one embodiment, said polysaccharide is a hyaluronan.
In one embodiment, said polysaccharide is an xylan.
In one embodiment, said polysaccharide is a polygalacturonic acid.
In one embodiment, said polysaccharide is a water-soluble cellulose.
In one embodiment, the monomer that is connected by the glycosidic bond through (1,3) type of said polysaccharide constitutes with occupying the majority.
In one embodiment, the polysaccharide that constitutes of the said monomer that is connected by the glycosidic bond through (1,3) type is the curdled milk polysaccharide with occupying the majority.
In one embodiment, the monomer that is connected by the glycosidic bond through (1,2) type of said polysaccharide constitutes with occupying the majority.
In one embodiment, the polysaccharide that constitutes of the said monomer that is connected by the glycosidic bond through (1,2) type is an inulin with occupying the majority.
In one embodiment, the monomer formation that is connected by the glycosidic bond through (1,4) and (1,3) type of said polysaccharide with occupying the majority.
In one embodiment, the polysaccharide of the said monomer formation that is connected by the glycosidic bond through (1,4) and (1,3) type is a glucosan with occupying the majority.
In one embodiment, the monomer formation that is connected by glycosidic bond of said polysaccharide through (1,4) and (1,3) and (1,2) type with occupying the majority.
In one embodiment, the polysaccharide of the said monomer formation that is connected by the glycosidic bond through (1,4) and (1,3) and (1,2) type is a mannan with occupying the majority.
In one embodiment, polysaccharide according to the present invention is characterised in that chain string L-Q is selected from following chain string, the implication that provides above wherein L has:
Figure BDA00002089881000121
In one embodiment, polysaccharide according to the present invention is characterised in that chain string L-Q is selected from following chain string, the implication that provides above wherein L has:
Figure BDA00002089881000122
In one embodiment, polysaccharide according to the present invention is characterised in that chain string L-Q is selected from following chain string, the implication that provides above wherein L has:
In one embodiment, polysaccharide according to the present invention is characterised in that chain string L-Q is following chain string, and wherein L has top implication:
Figure BDA00002089881000131
In one embodiment, polysaccharide according to the present invention is characterised in that chain string L-Q is following chain string, and wherein L has top implication:
Figure BDA00002089881000132
In one embodiment, said polysaccharide is selected from the polysaccharide of formula II, III or IV, wherein group-Hy cFor being derived from the group of hydrophobicity alcohol, itself since the hydroxy functional group of this hydrophobicity alcohol with at least one by tervalent at least radicals R cPrecursor R cCoupling between the ' entrained reactive functional groups and producing, and
-G cBe ester functional group, or be carbamate-functional,
-R cAnd F cThe definition that provides above having.
In one embodiment, said polysaccharide is selected from the polysaccharide of formula V, VI or VII, wherein group-Hy hFor being derived from the group of hydrophobicity alcohol, itself since the hydroxy functional group of this hydrophobicity alcohol with at least one by tervalent at least radicals R hPrecursor R hCoupling between the ' entrained reactive functional groups and producing, and
-G hBe ester functional group, or be carbamate-functional,
-R hAnd F hThe definition that provides above having.
In one embodiment, said hydrophobicity alcohol is selected from aliphatic alcohol.
In one embodiment, said hydrophobicity alcohol is selected from by comprising alcohol 4-18 carbon, that branching or alkyl chain non-branching, unsaturated or saturated constitute.
In one embodiment, said hydrophobicity alcohol is selected from by comprising more than alcohol 18 carbon, that branching or alkyl chain non-branching, unsaturated or saturated constitute.
In one embodiment, said hydrophobicity alcohol is capryl alcohol.
In one embodiment, said hydrophobicity alcohol is dodecanol.
In one embodiment, said hydrophobicity alcohol is 2-ethyl butanol.
In one embodiment, said hydrophobicity alcohol is selected from myristyl alcohol, spermol, stearyl alcohol, cetearyl alcohol, butanols, oleyl alcohol, lanoline.
In one embodiment, said hydrophobicity alcohol is selected from cholesterol derivative.
In one embodiment, said cholesterol derivative is a cholesterol.
In one embodiment, said hydrophobicity alcohol is selected from menthol derivative.
In one embodiment, said hydrophobicity alcohol is the menthol with racemic form.
In one embodiment, said hydrophobicity alcohol is the D isomer of menthol.
In one embodiment, said hydrophobicity alcohol is the L isomer of menthol.
In one embodiment, said hydrophobicity alcohol is selected from tocopherol.
In one embodiment, said tocopherol is an alpha-tocopherol.
In one embodiment, said alpha-tocopherol is the racemate of alpha-tocopherol.
In one embodiment, said tocopherol is the D isomer of alpha-tocopherol.
In one embodiment, said tocopherol is the L isomer of alpha-tocopherol.
In one embodiment, said hydrophobicity alcohol is selected from the alcohol that carries aryl.
In one embodiment, the said alcohol that carries aryl is selected from benzylalcohol, phenethanol.
In one embodiment, said hydrophobicity alcohol is selected from unsaturated fatty alcohol.
In one embodiment, said unsaturated fatty alcohol is selected from Mang geraniol, β-citronellol and farnesol.
In one embodiment, said hydrophobicity alcohol is 3,7-dimethyl-1-capryl alcohol.
In one embodiment, said polysaccharide is selected from the polysaccharide of formula II, III or IV, wherein group-Hy cFor being derived from the group of hydrophobicity acid, itself since the carboxyl functional group of this hydrophobicity acid with at least one by tervalent at least radicals R cPrecursor R cCoupling between the ' entrained reactive functional groups and producing, and
-G cBe ester functional group, or be amide functional group,
-R cAnd F cThe definition that provides above having.
In one embodiment, said polysaccharide is selected from the polysaccharide of formula V, VI or VII, wherein group-Hy hFor being derived from the group of hydrophobicity acid, itself since the carboxyl functional group of this hydrophobicity acid with at least one by tervalent at least radicals R hPrecursor R hCoupling between the ' entrained reactive functional groups and producing, and
-G hBe ester functional group, or be amide functional group,
-R hAnd F hThe definition that provides above having.
In one embodiment, said hydrophobicity acid is selected from fatty acid.
In one embodiment, said fatty acid is selected from by comprising acid 6-50 carbon, that branching or alkyl chain non-branching, unsaturated or saturated constitute.
In one embodiment, said fatty acid is selected from linear fatty acid.
In one embodiment, said linear fatty acid is selected from caproic acid, enanthic acid, sad, capric acid, n-nonanoic acid, capric acid, hendecanoic acid, dodecylic acid, Palmic acid, stearic acid, arachidic acid, behenic acid, tricosanic acid, lignoceric acid, carboceric acid, octocosoic acid and melissic acid.
In one embodiment, said fatty acid is selected from unsaturated fatty acid.
In one embodiment, said unsaturated fatty acid is selected from myristoleic acid, palmitoleic acid, oleic acid, elaidic acid, linoleic acid, α-linoleic acid, arachidonic acid, eicosapentaenoic acid, erucic acid and docosahexenoic acid.
In one embodiment, said fatty acid is selected from bile acid and derivant thereof.
In one embodiment, said bile acid and derivant thereof are selected from cholic acid, dehydrocholic acid, deoxycholic acid and chenodeoxy cholic acid.
In one embodiment, said fatty acid is selected from the acid of carrying aryl.
In one embodiment, said acid of carrying aryl is phenylacetic acid.
In one embodiment, said polysaccharide is selected from the polysaccharide of formula II, III or IV, wherein group-Hy cFor being derived from the group of hydrophobic amine, itself since the amine functional group of this hydrophobic amine with at least one by tervalent at least radicals R cPrecursor R cCoupling between the ' entrained reactive functional groups and producing, and
-G cBe amide functional group, or be carbamate-functional,
-R cAnd F cThe definition that provides above having.
In one embodiment, said polysaccharide is selected from the polysaccharide of formula V, VI or VII, wherein group-Hy hFor being derived from the group of hydrophobic amine, itself since the amine functional group of this hydrophobic amine with at least one by tervalent at least radicals R hPrecursor R hCoupling between the ' entrained reactive functional groups and producing, and
-G hBe amide functional group, or be carbamate-functional,
-R hAnd F hThe definition that provides above having.
In one embodiment, said hydrophobic amine is selected from fatty amine.
In one embodiment, said hydrophobic amine be selected from by comprise 6-18 carbon, branching or amine linear, that unsaturated or saturated alkyl chain constitutes.
In one embodiment, said fatty amine is a dodecyl amine.
In one embodiment, said fatty amine is selected from Semen Myristicae amine, cetylamine, stearylamine, cetearyl alcohol amine, butylamine, oleyl amine.
In one embodiment, said hydrophobic amine is selected from the amine that carries aryl.
In one embodiment, the said amine that carries aryl is selected from benzylamine, phenethylamine.
Below described precursor sort out according to the character of its reactive functional groups, said reactive functional groups is at least three on number, but described precursor can comprise four reactive functional groups or more below some.
In one embodiment, tervalent at least precursor R c' and R h' be selected from the aminoacid that carries two acid functional groups.
The said aminoacid that carries two acid functional groups is selected from aspartic acid, glutamic acid, methylaspartic acid, Gla, 2-diaminopimelic acid, 2-aminoadipic acid and O-succinyl homoserine.
In one embodiment, tervalent at least precursor R c' and R h' be aspartic acid.
In one embodiment, tervalent at least precursor R c' and R h' be selected from the aminoacid that carries two amine functional groups.
The said aminoacid that carries two amine functional groups is selected from lysine, 5-hydroxylysine, 2,4-diamino-butanoic, 2,3-diaminopropionic acid, ornithine and p-Aminophenylalanine.
In one embodiment, tervalent at least precursor R c' and R h' be lysine.
In one embodiment, tervalent at least precursor R c' and R h' be selected from the aminoacid that carries alcohol functional group.
The said aminoacid that carries alcohol functional group is selected from serine, threonine and tyrosine, homoserine and Alpha-Methyl serine.
In one embodiment, tervalent at least precursor R c' and R h' be serine.
In one embodiment, tervalent at least precursor R c' and R h' be selected from hydramine.
Said hydramine is selected from trometamol (Tris), 3-amino-1,2-propylene glycol, triethanolamine, methylol tyrosine, cheese ammonia alcohol, serinol (2-amino-1,2-propylene glycol) and Soviet Union's ammonia alcohol.
In one embodiment, tervalent at least precursor R c' and R h' or be trometamol, or be 3-amino-1, the 2-propylene glycol.
In one embodiment, tervalent at least precursor R c' be selected from two acid alcohols.
In one embodiment, said two acid alcohols are selected from 3-hydroxy-3-methylglutaric acid, malic acid and N-(2-hydroxyethyl) iminodiacetic acid.
In one embodiment, tervalent at least precursor R c' be selected from two alkyd.
In one embodiment, said two alkyd are selected from N-two (ethoxy) glycine (bicine), 2, two (methylol) propanoic acid, 2 of 2-, 4-dihydroxycinnamic acid, 3,4-dihydroxy hydrocinnamic acid, 4, two (4-hydroxy phenyl) valeric acids of 4-.
In one embodiment, tervalent at least precursor R c' and R h' be selected from triamine.
In one embodiment, said triamine is selected from 2-(amino methyl)-2-methyl isophthalic acid, 3-propane diamine and three-(2-amino-ethyl) amine.
In one embodiment, said triamine obtains through following manner: react between a dibasic aminoacid and two diamidogen, thereby cause forming the triamine that comprises two amide functional groups.
Said dibasic aminoacid is selected from aspartic acid, glutamic acid, methylaspartic acid, Gla, 2-diaminopimelic acid, 2-aminoadipic acid and O-succinyl homoserine.
In one embodiment, said dibasic aminoacid is an aspartic acid.
In one embodiment, said diamidogen is selected from ethylenediamine and decarboxylation lysine and derivant thereof.
In one embodiment, said diamidogen is selected from diethylene glycol diamidogen and triethylene glycol diamine.
In one embodiment, said triamine is two (2-aminoethyl) aspartic acid amide.
In one embodiment, tervalent at least precursor R c' be selected from three acid alcohols.
In one embodiment, said three acid alcohols are selected from citric acid.
In one embodiment, tervalent at least precursor R c' be selected from triol.
In one embodiment, said triol is selected from 2-methylol-1, ammediol, phloroglucinol and 1,1,1-three (methylol)-propane.
In one embodiment, tervalent at least precursor R c' be selected from triol acid.
In one embodiment, said triol acid is selected from aleuritic acid.
In one embodiment, tervalent at least precursor R c' be selected from polyhydric alcohol.
In one embodiment, said polyhydric alcohol is selected from glycerol, diglycerol, triglycerin, tetramethylolmethane and α, α '-diglycerol.
In one embodiment, polysaccharide according to the present invention carries two group-Hy C1With-Hy C2Perhaps-Hy H1With-Hy H2, they are identical, or different, but have identical reactive functional groups, and key G C1And G C2Perhaps G H1And G H2Be identical.
As an example, implement following combination.
In one embodiment, F cBe ester functional group, G C1And G C2Be ester functional group, R c' be two acid alcohols, and Hy C1And Hy C2For being derived from the group of hydrophobicity alcohol.
In one embodiment, F cBe ester functional group, G C1And G C2Be ester functional group, R c' be triol, and Hy C1And Hy C2For being derived from the group of hydrophobicity acid.
In one embodiment, F cBe ester functional group, G C1And G C2Be amide functional group, R c' be hydro diamine, and Hy C1And Hy C2For being derived from the group of hydrophobicity acid.
In one embodiment, F cBe ester functional group, G C1And G C2Be carbamate-functional, R c' be hydro diamine, and Hy C1And Hy C2For being derived from the group of hydrophobicity alcohol.
In one embodiment, F cBe ester functional group, G C1And G C2Be amide functional group, R c' be pure diacid, and Hy C1And Hy C2For being derived from the group of hydrophobic amine.
In one embodiment, F cBe ester functional group, G C1And G C2Be carbamate-functional, R c' be triol, and Hy C1And Hy C2For being derived from the group of hydrophobic amine.
In one embodiment, F cBe amide functional group, G C1And G C2Be ester functional group, R c' be dibasic aminoacid, and Hy C1And Hy C2For being derived from the group of hydrophobicity alcohol.
In one embodiment, F cBe amide functional group, G C1And G C2Be ester functional group, R c' be glycol amine, and Hy C1And Hy C2For being derived from the group of hydrophobicity acid.
In one embodiment, F cBe amide functional group, G C1And G C2Be amide functional group, R c' be triamine, and Hy C1And Hy C2For being derived from the group of hydrophobicity acid.
In one embodiment, F cBe amide functional group, G C1And G C2Be amide functional group, R c' be dibasic aminoacid, and Hy C1And Hy C2For being derived from the group of hydrophobic amine.
In one embodiment, F cBe amide functional group, G C1And G C2Be carbamate-functional, R c' be glycol amine, and Hy C1And Hy C2For being derived from the group of hydrophobic amine.
In one embodiment, F cBe amide functional group, G C1And G C2Be carbamate-functional, R c' be triamine, and Hy C1And Hy C2For being derived from the group of hydrophobicity alcohol.
In one embodiment, F hBe carbamate-functional, G H1And G H2Be ester functional group, R h' be dibasic aminoacid, and Hy H1And Hy H2For being derived from the group of hydrophobicity alcohol.
In one embodiment, F hBe carbamate-functional, G H1And G H2Be ester functional group, R h' be glycol amine, and Hy H1And Hy H2For being derived from the group of hydrophobicity acid.
In one embodiment, F hBe carbamate-functional, G H1And G H2Be amide functional group, R h' be triamine, and Hy H1And Hy H2For being derived from the group of hydrophobicity acid.
In one embodiment, F hBe carbamate-functional, G H1And G H2Be carbamate-functional, R h' be triamine, and Hy H1And Hy H2For being derived from the group of hydrophobicity alcohol.
In one embodiment, F hBe carbamate-functional, G H1And G H2Be amide functional group, R h' be two acid amides, and Hy H1And Hy H2For being derived from the group of hydrophobic amine.
In one embodiment, F hBe carbamate-functional, G H1And G H2Be carbamate-functional, R h' be glycol amine, and Hy H1And Hy H2For being derived from the group of hydrophobic amine.
In one embodiment, polysaccharide according to the present invention carries two group Hy C1And Hy C2Perhaps Hy H1And Hy H2, they are different, but key G C1And G C2Perhaps G H1And G H2Be identical.
As an example, implement following combination.
In one embodiment, F cBe ester functional group, G C1And G C2Be ester functional group, R c' be two alkyd, and Hy C1For being derived from the group and the Hy of hydrophobicity alcohol C2For being derived from the group of hydrophobicity acid.
In one embodiment, F cBe ester functional group, G C1And G C2Be amide functional group, R c' be acid alcohol amine, and Hy C1For being derived from the group and the Hy of hydrophobicity acid C2For being derived from the group of hydrophobic amine.
In one embodiment, F cBe amide functional group, G C1And G C2Be ester functional group, R c' be acid alcohol amine, and Hy C1For being derived from the group and the Hy of hydrophobicity alcohol C2For being derived from the group of hydrophobicity acid.
In one embodiment, F cBe amide functional group, G C1And G C2Be amide functional group, R c' be two amino acids, and Hy C1For being derived from the group and the Hy of hydrophobicity acid C2For being derived from the group of hydrophobic amine.
In one embodiment, F hBe carbamate-functional, G H1And G H2Be ester functional group, R h' be acid alcohol amine, and Hy H1For being derived from the group and the Hy of hydrophobicity alcohol H2For being derived from the group of hydrophobicity acid.
In one embodiment, F hBe carbamate-functional, G H1And G H2Be amide functional group, R h' be two acid amides, and Hy H1For being derived from the group and the Hy of hydrophobicity acid H2For being derived from the group of hydrophobic amine.
In one embodiment, F hBe carbamate-functional, G H1And G H2Be carbamate-functional, R h' be diamidogen alcohol, and Hy H1For being derived from the group and the Hy of hydrophobicity alcohol H2For being derived from the group of hydrophobic amine.
In one embodiment, polysaccharide according to the present invention carries two group Hy C1And Hy C2Perhaps Hy H1And Hy H2, they are identical, or different, but have identical reactive functional groups, and key G C1And G C2Perhaps G H1And G H2Be different.
As an example, implement following combination.
In one embodiment, F cBe ester functional group, G C1Be ester functional group, R c' be glycol amine, G C2Be amide functional group, and Hy C1And Hy C2For being derived from the group of hydrophobicity acid.
In one embodiment, F cBe ester functional group, G C1Be ester functional group, R c' be pure acid amide, G C2Be carbamate-functional, and Hy C1And Hy C2For being derived from the group of hydrophobicity alcohol.
In one embodiment, F cBe amide functional group, G C1Be ester functional group, R c' be diamidogen alcohol, G C2Be amide functional group, and Hy C1And Hy C2For being derived from the group of hydrophobicity acid.
In one embodiment, F cBe amide functional group, G C1Be ester functional group, R c' be two amino acids, G C2Be carbamate-functional, and Hy C1And Hy C2For being derived from the group of hydrophobicity alcohol.
In one embodiment, F cBe ester functional group, G C1Be amide functional group, R c' be two alkyd, G C2Be carbamate-functional, and Hy C1And Hy C2For being derived from the group of hydrophobic amine.
In one embodiment, F hBe carbamate-functional, G H1Be ester functional group, R h' be diamidogen alcohol, G H2Be amide functional group, and Hy H1And Hy H2For being derived from the group of hydrophobicity acid.
In one embodiment, F hBe carbamate-functional, G H1Be ester functional group, R h' be two amino acids, G H2Be carbamate-functional, and Hy H1And Hy H2For being derived from the group of hydrophobicity alcohol.
In one embodiment, F hBe carbamate-functional, G H1Be amide functional group, R h' be pure acid amide, G H2Be carbamate-functional, and Hy H1And Hy H2For being derived from the group of hydrophobic amine.
In one embodiment, polysaccharide according to the present invention carries two group Hy C1And Hy C2Perhaps Hy H1And Hy H2, they are different, and key G C1And G C2Perhaps G H1And G H2Be different.
As an example, implement following combination.
In one embodiment, F cBe ester functional group, G C1Be ester functional group, R c' be glycol amine and Hy C1For being derived from the group of hydrophobicity acid, G C2Be carbamate-functional and Hy C2For being derived from the group of hydrophobicity alcohol.
In one embodiment, F cBe ester functional group, G C1Be ester functional group, R c' be acid alcohol amine and Hy C1For being derived from the group of hydrophobicity alcohol, G C2Be amide functional group and Hy C2For being derived from the group of hydrophobicity acid.
In one embodiment, F cBe ester functional group, G C1Be amide functional group, R c' be hydro diamine and Hy C1For being derived from the group of hydrophobicity acid, G C2Be carbamate-functional and Hy C2For being derived from the group of hydrophobicity alcohol.
In one embodiment, F cBe ester functional group, G C1Be ester functional group, R c' be pure diacid and Hy C1For being derived from the group of hydrophobicity alcohol, G C2Be amide functional group and Hy C2For being derived from the group of hydrophobic amine.
In one embodiment, F cBe ester functional group, G C1Be ester functional group, R c' be two alkyd and Hy C1For being derived from the group of hydrophobicity acid, G C2Be amide functional group and Hy C2For being derived from the group of hydrophobic amine.
In one embodiment, F cBe ester functional group, G C1Be amide functional group, R c' be glycol amine and Hy C1For being derived from the group of hydrophobicity acid, G C2Be carbamate-functional and Hy C2For being derived from the group of hydrophobic amine.
In one embodiment, F cBe ester functional group, G C1Be ester functional group, R c' be triol and Hy C1For being derived from the group of hydrophobicity acid, G C2Be carbamate-functional and Hy C2For being derived from the group of hydrophobic amine.
In one embodiment, F cBe ester functional group, G C1Be ester functional group, R c' be sour glycol and Hy C1For being derived from the group of hydrophobicity alcohol, G C2Be carbamate-functional and Hy C2For being derived from the group of hydrophobic amine.
In one embodiment, F cBe amide functional group, G C1Be ester functional group, R c' be diamino acid and Hy C1For being derived from the group of hydrophobicity alcohol, G C2Be amide functional group and Hy C2For being derived from the group of hydrophobicity acid.
In one embodiment, F cBe amide functional group, G C1Be ester functional group, R c' be hydro diamine and Hy C1For being derived from the group of hydrophobicity acid, G C2Be carbamate-functional and Hy C2For being derived from the group of hydrophobicity alcohol.
In one embodiment, F cBe amide functional group, G C1Be amide functional group, R c' be triamine and Hy C1For being derived from the group of hydrophobicity acid, G C2Be carbamate-functional and Hy C2For being derived from the group of hydrophobicity alcohol.
In one embodiment, F cBe amide functional group, G C1Be ester functional group, R c' be two acid amides and Hy C1For being derived from the group of hydrophobicity alcohol, G C2Be amide functional group and Hy C2For being derived from the group of hydrophobic amine.
In one embodiment, F cBe amide functional group, G C1Be ester functional group, R c' be pure acid amide and Hy C1For being derived from the group of hydrophobicity acid, G C2Be amide functional group and Hy C2For being derived from the group of hydrophobic amine.
In one embodiment, F cBe amide functional group, G C1Be amide functional group, R c' be hydro diamine and Hy C1For being derived from the group of hydrophobicity acid, G C2Be carbamate-functional and Hy C2For being derived from the group of hydrophobic amine.
In one embodiment, F cBe amide functional group, G C1Be ester functional group, R c' be glycol amine and Hy C1For being derived from the group of hydrophobicity acid, G C2Be carbamate-functional and Hy C2For being derived from the group of hydrophobic amine.
In one embodiment, F cBe amide functional group, G C1Be ester functional group, R c' be acid alcohol amine and Hy C1For being derived from the group of hydrophobicity alcohol, G C2Be carbamate-functional and Hy C2For being derived from the group of hydrophobic amine.
In one embodiment, F hBe carbamate-functional, G H1Be ester functional group, R h' be diamino acid and Hy H1For being derived from the group of hydrophobicity alcohol, G H2Be amide functional group and Hy H2For being derived from the group of hydrophobicity acid.
In one embodiment, F hBe carbamate-functional, G H1Be ester functional group, R h' be hydro diamine and Hy H1For being derived from the group of hydrophobicity acid, G H2Be carbamate-functional and Hy H2For being derived from the group of hydrophobicity alcohol.
In one embodiment, F hBe carbamate-functional, G H1Be amide functional group, R h' be triamine and Hy H1For being derived from the group of hydrophobicity acid, G H2Be carbamate-functional and Hy H2For being derived from the group of hydrophobicity alcohol.
In one embodiment, F hBe carbamate-functional, G H1Be ester functional group, R h' be two acid amides and Hy H1For being derived from the group of hydrophobicity alcohol, G H2Be amide functional group and Hy H2For being derived from the group of hydrophobic amine.
In one embodiment, F hBe carbamate-functional, G H1Be ester functional group, R h' be pure acid amide and Hy H1For being derived from the group of hydrophobicity acid, G H2Be amide functional group and Hy H2For being derived from the group of hydrophobic amine.
In one embodiment, F hBe carbamate-functional, G H1Be amide functional group, R h' be hydro diamine and Hy H1For being derived from the group of hydrophobicity acid, G H2Be carbamate-functional and Hy H2For being derived from the group of hydrophobic amine.
In one embodiment, F hBe carbamate-functional, G H1Be ester functional group, R h' be glycol amine and Hy H1For being derived from the group of hydrophobicity acid, G H2Be carbamate-functional and Hy H2For being derived from the group of hydrophobic amine.
In one embodiment, F hBe carbamate-functional, G H1Be ester functional group, R h' be acid alcohol amine and Hy H1For being derived from the group of hydrophobicity alcohol, G H2Be carbamate-functional and Hy H2For being derived from the group of hydrophobic amine.
Said polysaccharide can have the degree of polymerization m of 5-10000.
In one embodiment, said polysaccharide has the degree of polymerization m of 10-1000.
In another embodiment, said polysaccharide has the degree of polymerization m of 10-500.
The invention still further relates to synthesizing according to polysaccharide of the present invention.
The invention still further relates to the synthetic of the polysaccharide that comprises carboxyl, in the said carboxyl at least one through at least two identical or different, be labeled as Hy C1And Hy C2And/or Hy H1And Hy H2Hydrophobic group carry out functionalized.
When said polysaccharide was selected from the polysaccharide of general formula I I, III, IV, obtained to contain amino intermediate [Hy said synthetic comprising c-G c] Rc-R c-NH 2Or ammonium salt [Hy c-G c] Rc-R c-NH 3 +The step of (its counter ion counterionsl gegenions are the anion that is selected from negative halogen ion, sulfate radical, sulfonate radical, carboxylate radical) and this is contained the step of amino intermediate grafting to the carboxyl functional group of polysaccharide, wherein R c, G c, Hy cAnd r cThe definition that provides above meeting.
In one embodiment; The step that the hydroxyl of this polysaccharide is converted into " at least 15 carboxyl functional group/100 sugar units " is through carry out the grafting of the chemical compound of formula Q-L ' at least on " 15 hydroxy functional group/100 sugar units " of this polysaccharide; Wherein Q-L ' is the precursor of chain string Q-L, the definition that provides above Q and L meet.
In a preferred embodiment, formula [Hy c-G c] Rc-R c-NH 2Or [Hy c-G c] Rc-R c-NH 3 +Contain amino intermediate through type [G '] Rc-R c-NH 2The reaction of reactive functional groups of chemical compound (wherein G ' is carboxylic acid, amine or alcohol functional group) and hydrophobic compound obtain R wherein c, G c, Hy cAnd r cThe definition that provides above meeting.
Can also adopt other synthetic methods well known to those skilled in the art, for example use the method for carbodiimide.
If desired,, this acquisition uses protection well known to those skilled in the art/go resist technology in containing the step of amino intermediate.
Preferably, will contain amino intermediate grafting carries out in organic media to the step on the carboxyl of this polysaccharide.
When said polysaccharide was selected from the polysaccharide of general formula V, VI, VII, obtained to contain amino intermediate [Hy said synthetic comprising h-G h] Rh-R h-NH 2Or ammonium salt [Hy h-G h] Rh-R h-NH 3 +The step of (its counter ion counterionsl gegenions are the anion that is selected from negative halogen ion, sulfate radical, sulfonate radical, carboxylate radical) and this is contained the step of amino intermediate grafting to the hydroxyl of polysaccharide, wherein R h, G h, Hy hAnd r hThe definition that provides above meeting.
In one embodiment; The step that the hydroxyl of this polysaccharide is converted into " at least 15 carboxyl/100 sugar units " is through carry out the grafting of the chemical compound of formula Q-L ' at least on " 15 hydroxyl/100 sugar units " of this polysaccharide; Wherein Q-L ' is the precursor of chain string Q-L, the definition that provides above Q and L meet.
In a preferred embodiment, formula [Hy h-G h] Rh-R h-NH 2Or [Hy h-G h] Rh-R h-NH 3 +Contain amino intermediate through type [G h'] Rh-R h-NH 2Chemical compound (G wherein h' be carboxylic acid, amine or alcohol functional group) obtain R wherein with the reaction of the reactive functional groups of hydrophobic compound h, G h, Hy hAnd r hThe definition that provides above meeting.
Can also adopt other synthetic methods well known to those skilled in the art, for example use the method for carbodiimide.
If desired,, this acquisition uses protection well known to those skilled in the art/go resist technology in containing the step of amino intermediate.
Preferably, will contain amino intermediate grafting carries out in organic media to the step on the carboxyl of this polysaccharide.
In one embodiment, the present invention relates to be selected from the polysaccharide of following polysaccharide:
-dextran methyl carboxylic acids the sodium modified through the aspartic acid dihexyl.
-dextran methyl carboxylic acids the sodium modified through the aspartic acid dibenzyl ester.
-dextran methyl carboxylic acids the sodium (10kDa dextran) modified through aspartic acid two lauryls.
-through 3-amino-1, the dextran methyl carboxylic acids sodium that 2-propylene glycol dilaurate is modified.
-dextran methyl carboxylic acids the sodium modified through the aspartic acid dioctyl ester.
-dextran methyl carboxylic acids the sodium (5kDa dextran) modified through aspartic acid two lauryls.
-dextran methyl carboxylic acids the sodium modified through 2-[(2-lauroyl amino-6-lauroyl amino) caproyl is amino] ethamine.
-dextran the sodium succinate modified through the aspartic acid dioctyl ester.
-through 2,2 ', 2 " the dextran methyl carboxylic acids sodium that (amino-two [methyl-phenylacetates]) ethyl-phenylacetate is modified.
-dextran methyl carboxylic acids the sodium modified through the hot acyloxy-benzyl propionate of 2-amino-3-.
-dextran carbamate N-methyl carboxylic acids the sodium modified through the aspartic acid dioctyl ester.
-the dextran modified through carbamate N-methyl carboxylic acids sodium and carbamate aspartic acid dihexyl.
-dextran methyl carboxylic acids the sodium modified through the dilaurylamine (DLA) amide glutaminate.
-dextran methyl carboxylic acids the sodium modified through two (2-dodecane amide-ethamine) aspartic acid amide.
Embodiment 1: the dextran methyl carboxylic acids sodium of modifying through the aspartic acid dihexyl (polymer 1)
The dextran (Pharmacosmos) that 16g (being the hydroxyl of 296mmol) is had the weight-average molar mass of about 40kg/mol is dissolved in the water with 42g/L.In this solution, add 30mL 10N NaOH (296mmol NaOH).Mixture is brought to 35 ℃, add 46g (396mmol) sodium chloroacetate subsequently.The temperature of reaction medium is brought to 60 ℃ with 0.5 ℃/minute, maintain subsequently 60 ℃ 100 minutes.With 200mL water diluting reaction medium,, and carry out ultrafiltration through water and implement purification at the PES of 5kD film superinverse 6 volumes with the acetic acid neutralization.Final solution measures through dry extract, to measure the concentration of polymer; Measure through the acid/alkali content in the water/acetone of 50/50 (V/V) subsequently and measure, be converted into the degree of methyl carboxylic acids root with mensuration.
According to dry extract: [polymer]=31.5mg/g.
Measure according to acid/alkali content: degree/glycosyl unit that hydroxyl is converted into the methyl carboxylic acids root is 1.07.
Make dextran methyl carboxylic acids sodium solution through Purolite resin (anionic) obtaining the dextran methyl carboxylic acids, its lyophilizing 18 hours then.
According to (method described in US4826818) obtains aspartic acid dihexyl, tosilate for Kenji, people such as M in patent.
10g dextran methyl carboxylic acids (being the methyl carboxylic acids of 47.76mmol) is dissolved among the DMF with 60g/L, is cooled to 0 ℃ subsequently.2.0g aspartic acid dihexyl tosilate (4.46mmol) is suspended among the DMF with 100g/L.Then, in this suspension, add 0.45g triethylamine (4.46mmol).In case polymer solution reaches 0 ℃, add NMM (1.35g, 13.39mmol) solution in DMF (530g/L) and 1.45g (13.39mmol) EtOCOCl immediately.After reaction 10 minutes, add the suspension of aspartic acid dihexyl.Then, with this medium maintain 10 ℃ 45 minutes.Then, this medium is heated to 30 ℃.In this reaction medium, add imidazoles solution (3.04g is in 9mL water) and 52mL water.This polymer solution is carried out ultrafiltration at the 0.9%NaCl solution of 10kD PES film superinverse 15 volumes and the water of 5 volumes.Measure the concentration of polymer solution through dry extract.With a part of solution lyophilizing, and at D 2Pass through among the O 1H NMR analyzes, and is converted into the ratio of the carboxyl of aspartic acid dihexyl amide with mensuration.
According to dry extract: [polymer 1]=31.1mg/g.
According to 1H NMR: it is 0.075 that acid is carried out functionalized degree/sugar unit through the aspartic acid dihexyl.
Embodiment 2: the dextran methyl carboxylic acids sodium of modifying through the aspartic acid dibenzyl ester (polymer 2)
According to (method described in US4826818) obtains aspartic acid dibenzyl ester, tosilate for Kenji, people such as M in patent.
Through with method similar methods described in embodiment 1, obtain the dextran methyl carboxylic acids sodium of modifying through the aspartic acid dibenzyl ester.
According to dry extract: [polymer 2]=35mg/g.
According to 1H NMR: it is 0.085 that acid is carried out functionalized degree through the aspartic acid dibenzyl ester.Embodiment 3: the dextran methyl carboxylic acids sodium of modifying through aspartic acid two lauryls (10kDa dextran) (polymer 3)
According to (method described in US4826818) obtains aspartic acid two lauryls, tosilate for Kenji, people such as M in patent.
Through with method similar methods described in embodiment 1, the dextran (Pharmacosmos) that obtains to modify through aspartic acid two lauryls, have the weight average molecular mass of about 10kg/mol through use is according to the synthetic dextran methyl carboxylic acids of the method sodium described in embodiment 1.
According to dry extract: [polymer 3]=17.8mg/g.
According to 1H NMR: it is 0.05 that acid is carried out functionalized degree through aspartic acid two lauryls.Embodiment 4: through 3-amino-1, the dextran methyl carboxylic acids sodium (polymer 4) that 2-propylene glycol dilaurate is modified
According to (method described in US4826818) obtains 3-amino-1,2-propylene glycol dilaurate, tosilate for Kenji, people such as M in patent.
Through with method similar methods described in embodiment 1, obtain through 3-amino-1, the dextran methyl carboxylic acids sodium that 2-propylene glycol dilaurate is modified.
According to dry extract: [polymer 4]=18.5mg/g.
According to 1H NMR: acid is through 3-amino-1, and it is 0.045 that 2-propylene glycol dilaurate carries out functionalized degree/sugar unit.
Embodiment 5: the dextran methyl carboxylic acids sodium of modifying through the aspartic acid dioctyl ester (polymer 5)
According to (method described in US4826818) obtains aspartic acid dioctyl ester, tosilate for Kenji, people such as M in patent.
Through with method similar methods described in embodiment 1, the dextran (Pharmacosmos) that obtains to modify through the aspartic acid dioctyl ester, have the weight average molecular mass of about 10kg/mol through use is according to the synthetic dextran methyl carboxylic acids of the method sodium described in embodiment 1.
According to dry extract: [polymer 5]=22.2mg/g.
According to 1H NMR: it is 0.05 that acid is carried out functionalized degree through the aspartic acid dioctyl ester.Embodiment 6: the dextran methyl carboxylic acids sodium of modifying through aspartic acid two lauryls (5kDa dextran) (polymer 6)
According to (method described in US4826818) obtains aspartic acid two lauryls, tosilate for Kenji, people such as M in patent.
Through with method similar methods described in embodiment 1, the dextran (Pharmacosmos) that obtains to modify through aspartic acid two lauryls, have the weight average molecular mass of about 5kg/mol through use is according to the synthetic dextran methyl carboxylic acids of the method sodium described in embodiment 1.
According to dry extract: [polymer 6]=8.9mg/g.
According to 1H NMR: it is 0.05 that acid is carried out functionalized degree through aspartic acid two lauryls.
Embodiment 7: the dextran methyl carboxylic acids sodium of modifying through 2-[(2-lauroyl amino-6-lauroyl amino) caproyl is amino] ethamine (polymer 7)
According to (Tetrahedron 2007,63 for Pal, people such as A, and the method described in 7334-7348) begins to obtain N from L-ethyl ester of lysine hydrochlorate (Bachem) and dodecylic acid (Sigma), two (lauroyl) lysines of N-at publication.
According at publication (Paul, people such as R, J.Org.Chem.1962; 27,2094-2099 and Dale, people such as D.J.; Org.Proces s.Res.Dev.2002,6, the method described in 767-772); From N, two (lauroyl) lysines of N-and ethylenediamine (Roth) begin to obtain 2-[(2-lauroyl amino-6-lauroyl is amino) caproyl is amino] ethamine, hydrochlorate.
Through with method similar methods described in embodiment 1, the method synthetic dextran methyl carboxylic acids sodium of dextran (Pharmacosmos) basis described in embodiment 1 that obtains to modify, have the weight average molecular mass of about 10kg/mol through use through 2-[(2-lauroyl amino-6-lauroyl is amino) caproyl is amino] ethamine.
According to dry extract: [polymer 7]=16.9mg/g.
According to 1H NMR: it is 0.02 that acid is carried out functionalized degree through 2-[(2-lauroyl amino-6-lauroyl is amino) caproyl is amino] ethamine.
Embodiment 8: the dextran sodium succinate of modifying through the aspartic acid dioctyl ester (polymer 8)
According to (method described in US4826818) obtains aspartic acid dioctyl ester, tosilate for Kenji, people such as M in patent.
According to article (Sanchez-Chaves people such as Sanchez-Chaves; People such as Manuel, Polymer 1998,39 (13); Method 2751-2757), (Pharmacosmos) begins to obtain the dextran sodium succinate from Dextran 10.According at D 2Among the O/NaOD 1H NMR, the ratio of carboxyl/glycoside units are 1.41.
Through with method similar methods described in embodiment 1, obtain the dextran sodium succinate of modifying through the aspartic acid dioctyl ester.
According to dry extract: [polymer 8]=19.3mg/g.
According to 1H NMR: it is 0.05 that acid is carried out functionalized degree/sugar unit through the aspartic acid dioctyl ester.
Embodiment 9: through 2,2 ', 2 " the dextran methyl carboxylic acids sodium (polymer 9) that (amino-two [methyl-phenylacetates]) ethyl-phenylacetate is modified
According at patent (Kenji; People such as M, the method described in US4826818) is from 2-amino-2-(methylol)-1; Ammediol (Tris) (Aldrich) and phenylacetic acid (Aldrich) begin to obtain 2; 2 ', 2 " (amino-two [methyl-phenylacetates]) ethyl-phenylacetate, tosilate.
Through with method similar methods described in embodiment 1; Obtain through 2; 2 ', 2 " (amino-two [methyl-phenylacetates]) ethyl-phenylacetate dextran (Pharmacosmos) that modify, that have the weight average molecular mass of about 10kg/mol through use is according to the synthetic dextran methyl carboxylic acids of the method sodium described in embodiment 1.
According to dry extract: [polymer 9]=15.4mg/g.
According to 1H NMR: acid through 2,2 ', 2 " it is 0.04 that (amino-two [methyl-phenylacetates]) ethyl-phenylacetate carries out functionalized degree.
Embodiment 10: through the dextran methyl carboxylic acids sodium (polymer 10) that 2-amino-3-suffering acyloxy-benzyl propionate is modified
According to (method described in US4826818) is from L-serine benzyl ester hydrochloride with sadly begin to obtain the hot acyloxy-benzyl propionate of 2-amino-3-, tosilate for Kenji, people such as M in patent.
Through with method similar methods described in embodiment 1, obtain through the hot acyloxy-benzyl propionate of 2-amino-3-dextran (Pharmacosmos) that modify, that have the weight average molecular mass of about 10kg/mol through use according to the synthetic dextran methyl carboxylic acids of the method sodium described in embodiment 1.
According to dry extract: [polymer 10]=21.2mg/g.
According to 1H NMR: it is 0.045 that acid is carried out functionalized degree/sugar unit through the hot acyloxy-benzyl propionate of 2-amino-3-.
Embodiment 11: the dextran carbamate N-methyl carboxylic acids sodium of modifying through the aspartic acid dioctyl ester (polymer 11)
According to (method described in US4826818) obtains aspartic acid dioctyl ester, tosilate for Kenji, people such as M in patent.
The dextran (Bachem) that 11.5g (being the hydroxyl of 0.21mol) is had the weight-average molar mass of about 10kg/mol is dissolved in the DMF/DMSO mixture.Under agitation mixture is brought to 130 ℃, and introduce 13.75g (0.11mol) isocyanato-ethyl acetate step by step.After reaction 1 hour, this medium is diluted in water, and implement purification through carrying out diafiltration at the PES of 5kD film superinverse 0.1N NaOH, 0.9%NaCl and water.Final solution measures through dry extract, to measure the concentration of polymer; Measure through the acid/alkali content in the water/acetone of 50/50 (V/V) subsequently and measure, to measure the degree that hydroxyl is converted into carbamate N-methyl carboxylic acids root.
According to dry extract: [polymer]=38.9mg/g.
Measure according to acid/alkali content: degree/glycosyl unit that hydroxyl is converted into carbamate N-methyl carboxylic acids root functional group is 1.08.
Make dextran carbamate N-methyl carboxylic acids sodium solution through Purolite resin (anionic) obtaining dextran carbamate N-methyl carboxylic acids, its lyophilizing 18 hours then.
5g dextran carbamate N-methyl carboxylic acids (being the N-methyl carboxylic acids of 20mmol) is dissolved among the DMF with 50g/L, is cooled to 0 ℃ subsequently.0.95g aspartic acid dioctyl ester tosilate (0.18mmol) is suspended among the DMF with 100g/L.Then, in this suspension, add 0.02g triethylamine (0.18mmol).Then, add 2.22g (22mmol) NMM and 2.38g (22mmol) EtOCOCl.After reaction 10 minutes, add the suspension of aspartic acid dioctyl ester.Then, with this medium maintain 10 ℃ 45 minutes.Then, this medium is heated to 50 ℃.Under 30 ℃, add imidazoles aqueous solution and the 25mL water of 600g/L.After stirring 1 hour 30 minutes under 50 ℃, the solution that is obtained is carried out ultrafiltration at 10kDPES film superinverse 0.1N NaOH, 0.9%NaCl and water.Measure the concentration of polymer solution through dry extract.With a part of solution lyophilizing, and at D 2Pass through among the O 1H NMR analyzes, and is converted into the ratio of the carboxyl of aspartic acid dioctyl ester amide with mensuration.
According to dry extract: [polymer 11]=21.2mg/g.
According to 1H NMR: it is 0.09 that acid is carried out functionalized degree/sugar unit through the aspartic acid dioctyl ester.
Embodiment 12: the dextran of modifying through carbamate N-methyl carboxylic acids sodium and carbamate aspartic acid dihexyl (polymer 12)
According to (method described in US4826818) obtains aspartic acid dihexyl, tosilate for Kenji, people such as M in patent.
According at publication (
Figure BDA00002089881000331
; H.-J. wait the people; Synlett 1997; Method 925-928) begins to obtain 2-isocyanato-succinic acid dihexyl from the aspartic acid dihexyl.
The dextran (Bachem) that 2.7g (being the hydroxyl of 50mmol) is had the weight-average molar mass of about 10kg/mol is dissolved in the DMF/DMSO mixture.Under agitation mixture is brought to 130 ℃, and introduce 3.2g (25mmol) isocyanato-ethyl acetate step by step, subsequently 3.9g (8mmol) 2-isocyanato-succinic acid dihexyl.After reaction 1 hour, this medium is diluted in water, and implement purification through carrying out diafiltration at the PES of 5kD film superinverse 0.1NNaOH, 0.9%NaCl and water.Final solution measures through dry extract, to measure the concentration of polymer.With a part of solution lyophilizing, and at D 2Pass through among the O 1H NMR analyzes, and is converted into the degree of carbamate N-methyl carboxylic acids sodium and the degree that hydroxyl-functional turns to the carbamate aspartic acid dihexyl to measure hydroxyl.
According to dry extract: [polymer 12]=8.2mg/g.
According to 1H NMR: the degree that hydroxyl is converted into carbamate N-methyl carboxylic acids sodium be 1.1 and the hydroxyl-functional degree that turns to the carbamate aspartic acid dihexyl be 0.05.
Embodiment 13: the dextran methyl carboxylic acids sodium of modifying through aspartic acid two lauryls (5kDa dextran) (polymer 13)
According to (method described in US4826818) obtains aspartic acid two lauryls, tosilate for Kenji, people such as M in patent.
The dextran (Pharmacosmos) that has the weight average molecular mass of about 5kg/mol through use; Through repeating the methyl carboxylic acids method of twice dextran described in the embodiment 1, obtaining " degree/glycosyl unit that hydroxyl is converted into the methyl carboxylic acids root " is 1.66 dextran methyl carboxylic acids sodium.Begin from this dextran methyl carboxylic acids sodium, through with method similar methods described in embodiment 1, obtain the dextran methyl carboxylic acids sodium of modifying through aspartic acid two lauryls.
According to dry extract: [polymer 13]=10.1mg/g.
According to 1H NMR: it is 0.05 that acid is carried out functionalized degree through aspartic acid two lauryls.
Embodiment 14: the dextran methyl carboxylic acids sodium of modifying through the dilaurylamine (DLA) amide glutaminate (polymer 14)
According to (Tetrahedron 2007,63 for Pal, people such as A, and the method described in 7334-7348) begins to obtain the dilaurylamine (DLA) L-amide glutaminate of its α-amine through the Fmoc protection from Fmoc-L-glutamic acid (Bachem) and dodecyl amine at publication.Then, remove the Fmoc group, to obtain the dilaurylamine (DLA) amide glutaminate through in piperidine solution, handling.
Through with method similar methods described in embodiment 1, the dextran (Pharmacosmos) that obtains to modify through the dilaurylamine (DLA) amide glutaminate, have the weight average molecular mass of about 10kg/mol through use is according to the synthetic dextran methyl carboxylic acids of the method sodium described in embodiment 1.
According to dry extract: [polymer 14]=15.6mg/g.
According to 1H NMR: it is 0.07 that acid is carried out functionalized degree through the dilaurylamine (DLA) amide glutaminate.
Embodiment 15: the dextran methyl carboxylic acids sodium of modifying through two (2-dodecane amide-ethamine) aspartic acid amide (polymer 15)
According to (method described in US2387201) begins to obtain N-(2-amino-ethyl) dodecane amide from methyl laurate (Sigma) and ethylenediamine (Roth) for Weiner, people such as N. in patent.
According at publication (Pal; People such as A; Tetrahedron 2007; 63, the method described in 7334-7348) begins to obtain its α-amine two (2-dodecane amide-ethamine) L-aspartic acid amide through the Fmoc protection from Fmoc-L-aspartic acid (Bachem) and N-(2-amino-ethyl) dodecane amide.Then, remove the Fmoc group, to obtain two (2-dodecane amide-ethamine) aspartic acid amide through in piperidine solution, handling.
Through with method similar methods described in embodiment 1, the method synthetic dextran methyl carboxylic acids sodium of dextran (Pharmacosmos) basis described in embodiment 1 that obtains to modify, have the weight average molecular mass of about 5kg/mol through use through two (2-dodecane amide-ethamine) aspartic acid amide.
According to dry extract: [polymer 15]=9.2mg/g.
According to 1H NMR: it is 0.05 that acid is carried out functionalized degree through two (2-dodecane amide-ethamine) aspartic acid amide.
The invention still further relates to according to of the present invention through the purposes of functionalized polysaccharide in pharmaceutical compositions.
The invention still further relates to pharmaceutical composition, it comprises described above according to one of polysaccharide of the present invention and at least a active component.
The invention still further relates to and described abovely it is characterized in that according to pharmaceutical composition of the present invention said active component is selected from protein, glycoprotein, peptide and non-peptide therapeutic molecules.
" active component " is meant with the form of independent chemical entities or with the product of the form of combination with physiologically active.Said active component can be an external source, and promptly it is provided by compositions according to the present invention.It can also be endogenous, somatomedin for example, and it will be secreted in the wound during the synulotic phase I and can be retained on the said wound through compositions according to the present invention.
Based on the pathological conditions that is directed against, it is used for the treatment of part or whole body.
Under the situation that local and whole body discharge, the method for application of being considered is for passing through the approach of intravenous, subcutaneous, Intradermal, transdermal, intramuscular, oral, nose, vagina, eye, cheek, lung etc.
Exist according to pharmaceutical composition of the present invention or with the form (with aqueous solution) of liquid, or exist with the form of powder, implant or thin film.In addition, they also comprise the pharmaceutical excipient of routine well known to those skilled in the art.
According to pathological conditions and method of application, said pharmaceutical composition advantageously can also comprise permission in addition they are mixed with the excipient of gel, sponge, injectable solution, drinkable solution, lyophilizing sheet forms such as (lyoc).
The invention still further relates to and described abovely it is characterized in that according to pharmaceutical composition of the present invention, said pharmaceutical composition is to use with the form of the thin film of support, implantable biomaterial or " coating ", implant.

Claims (32)

1. anion polysaccharide; It is characterized in that; It is selected from the polysaccharide that comprises carboxyl, said polysaccharide or be selected from the polysaccharide that carries carboxyl natively, or be selected from from the polysaccharide that comprises carboxyl natively and obtain or be converted into the synthetic polysaccharide that the neutral polysaccharide of carboxyl obtains from its hydroxyl; With in its hydroxyl that is selected from formula I at least one by at least two identical or different, be labeled as Hy hHydrophobic group replace or its carboxyl at least one by at least two identical or different, be labeled as Hy cThe substituted polysaccharide of hydrophobic group:
Figure FDA00002089880900011
Formula I
Wherein, n cAnd n hThe sugar unit of representing this polysaccharide passes through-F c-R c-[G c-Hy c] RcAnd/or-F h-R h-[G h-Hy h] RhCarry out functionalized degree, and n h>=0 and n c>=0,0.01≤n wherein h+ n c≤0.5,
● F cBe amide functional group, or be ester functional group,
● F hBe carbamate-functional,
● the carboxyl of not functionalized anion polysaccharide exists with the form of cationic carboxylate, and said cation is preferably alkali metal cation, for example Na +Or K +,
● G hOr G cBe amide functional group, or be ester functional group, or be carbamate-functional that it is because hydrophobic compound (Hy h' or Hy c') reactive functional groups and linking arm precursor R h' or R c' reactive functional groups between coupling and produce,
● Hy hOr Hy cFor because hydrophobic compound (Hy h' or Hy c') reactive functional groups and linking arm precursor R h' or R c' reactive functional groups between coupling and the identical or different group that produces, Hy hOr Hy cChain by comprising 4-50 carbon constitutes, and said chain randomly is branching and/or undersaturated, randomly comprises one or more hetero atoms, and for example O, N be or/and S, randomly comprises one or more saturated, undersaturated or aromatic rings or heterocycle,
● R cThe trivalent group that the chain that comprises 1-15 carbon of serving as reasons constitutes; Said chain randomly is branching and/or undersaturated; Randomly comprise one or more hetero atoms; For example O, N be or/and S, randomly comprises one or more saturated, undersaturated or aromatic rings or heterocycle, and owing to have the precursor R of at least three identical or different reactive functional groups c' reaction and produce, said at least three identical or different reactive functional groups are selected from alcohol functional group, acid functional group and amine functional group,
● R hThe trivalent group that the chain that comprises 1-15 carbon of serving as reasons constitutes; Said chain randomly is branching and/or undersaturated; Randomly comprise one or more hetero atoms; For example O, N be or/and S, randomly comprises one or more saturated, undersaturated or aromatic rings or heterocycle, and owing to have the precursor R of at least three reactive functional groups h' reaction and produce, a reactive functional groups in said at least three reactive functional groups is that amine and other reactive functional groups are selected from alcohol functional group, acid functional group and amine functional group,
● r hBe integer, its expression grafting is at tervalent at least linking arm R hOn the number of hydrophobic group, and 2≤r h≤4,
● r cBe integer, its expression grafting is at tervalent at least linking arm R cOn the number of hydrophobic group, and 2≤r c≤4.
2. according to the polysaccharide of claim 1, it is characterized in that said polysaccharide according to the present invention is selected from the polysaccharide of formula II:
Figure FDA00002089880900031
Formula II
Wherein,
-n cThe carboxyl of representing this polysaccharide is through chain string-F c-R c-[G C-Hy c] RcCarry out functionalized degree, and be 0.01-0.5,
-F c, R c, G c, Hy cAnd r cThe definition that provides above meeting,
-when the carboxyl of this polysaccharide through-F c-R c-[G C-Hy c] RcCarry out when functionalized, the said carboxyl of this polysaccharide is cationic carboxylate so, and said cation is preferably alkali metal cation, for example Na +Or K +, and
-as not functionalized linking arm R cReactive functional groups when being acid functional group, it is also with salifiable form, exists with the form of cationic carboxylate, said cation is preferably alkali metal cation, for example Na +Or K +With linking arm R that ought be not functionalized cReactive functional groups when being amine functional group, it exists with the form of anionic salt, said anion is preferably negative halogen ion.
3. according to the polysaccharide of claim 1, it is characterized in that said polysaccharide is selected from the polysaccharide of formula III:
Figure FDA00002089880900041
Formula III
Wherein,
-n c, F cAnd R cThe definition that provides above meeting,
-identical or different G C1And G C2Meet G cDefinition,
-identical or different Hy C1And Hy C2Meet Hy CDefinition.
4. according to the polysaccharide of claim 1, it is characterized in that said polysaccharide is selected from the polysaccharide of formula V:
Figure FDA00002089880900042
Formula V
Wherein,
-n hThe hydroxyl of representing this polysaccharide is through chain string-F h-R h-[G h-Hy h] RhCarry out functionalized degree, and be 0.01-0.5,
-F h, R h, G h, Hy hAnd r hThe definition that provides above meeting,
The carboxyl of-this polysaccharide exists with the form of cationic carboxylate, and said cation is preferably alkali metal cation, for example Na +Or K +, and
-as not functionalized linking arm R hReactive functional groups when being acid functional group, it is also with salifiable form, exists with the form of cationic carboxylate, said cation is preferably alkali metal cation, for example Na +Or K +With linking arm R that ought be not functionalized hReactive functional groups when being amine functional group, it exists with the form of anionic salt, said anion is preferably negative halogen ion.
5. according to the polysaccharide of claim 1, it is characterized in that said polysaccharide is selected from the polysaccharide of formula VI:
Figure FDA00002089880900051
Formula VI
Wherein,
-n h, F hAnd R hThe definition that provides above meeting,
-identical or different G H1And G H2Meet G hDefinition,
-identical or different Hy H1And Hy H2Meet Hy hDefinition.
6. according to each polysaccharide in the claim 1 to 5; It is characterized in that; It is selected from synthetic polysaccharide, and said synthetic polysaccharide perhaps is equal to or greater than 0.15 neutral polysaccharide acquisition from general formula VIII wherein " hydroxyl is converted into the degree/sugar unit of carboxyl " from the polysaccharide acquisition that comprises carboxyl natively:
Formula VIII
Wherein,
-said natural polysaccharide is selected from the polysaccharide that the monomer that is connected by the glycosidic bond through (1,6) and/or (1,4) and/or (1,3) and/or (1,2) type constitutes with occupying the majority,
-L for owing to the precursor of linking arm Q and this polysaccharide-key that coupling between the OH functional group produces, and be ester functional group, carbamate-functional or ether functional group,
-i representes this polysaccharide " hydroxyl is converted into degree/sugar unit of chain string L-Q ",
-Q is selected from the group of general formula I X:
Figure FDA00002089880900062
Formula IX
Wherein:
1≤a+b+c≤6,0≤a≤3,0≤b≤3 and 0≤c≤3,
R 3And R 4Be identical or different, and be selected from-H, the C1-C3 alkyl of linearity or branching ,-group of COOH and general formula X:
Figure FDA00002089880900063
Formula X
Wherein:
1≤d≤3, and
R ' 3And R ' 4Be identical or different, and be selected from-the C1-C3 alkyl group of H and linearity or branching.
7. according to the polysaccharide of claim 6, it is characterized in that the monomer that said polysaccharide is connected by the glycosidic bond through (1,6) type with occupying the majority constitutes.
8. according to the polysaccharide of claim 7, it is characterized in that the polysaccharide that the said monomer that is connected by the glycosidic bond through (1,6) type constitutes with occupying the majority is a dextran.
9. according to the polysaccharide of claim 6, it is characterized in that the monomer that said polysaccharide is connected by the glycosidic bond through (1,4) type with occupying the majority constitutes.
10. according to the polysaccharide of claim 9; It is characterized in that; The polysaccharide that the said monomer that is connected by the glycosidic bond through (1,4) type constitutes with occupying the majority is selected from Aureobasidium pullulans polysaccharide, alginate, hyaluronan, xylan, polygalacturonic acid or water-soluble cellulose.
11. according to each polysaccharide in the claim 6 to 10, it is characterized in that it is selected from the following polysaccharide of its characteristic: chain string L-Q is selected from following chain string, the implication that provides above wherein L has,
Figure FDA00002089880900071
12. according to each polysaccharide in the claim 6 to 10, it is characterized in that it is selected from the following polysaccharide of its characteristic: chain string L-Q is selected from following chain string, the implication that provides above wherein L has,
Figure FDA00002089880900081
13., it is characterized in that it is selected from the polysaccharide of formula II, III or IV, wherein group-Hy according to each polysaccharide in the claim 1 to 12 cFor being derived from the group of hydrophobicity alcohol, it is owing to this pure hydroxy functional group and at least one is by tervalent at least radicals R cPrecursor R cCoupling between the ' entrained reactive functional groups and producing, and
-G cBe ester functional group, or be carbamate-functional,
-R cAnd F cThe definition that provides above having.
14., it is characterized in that it is selected from the polysaccharide of formula V, VI or VII, wherein group-Hy according to each polysaccharide in the claim 1 to 12 hFor being derived from the group of hydrophobicity alcohol, itself since the hydroxy functional group of this hydrophobicity alcohol with at least one by tervalent at least radicals R hPrecursor R hCoupling between the ' entrained reactive functional groups and producing, and
-G hBe ester functional group, or be carbamate-functional,
-R hAnd F hThe definition that provides above having.
15., it is characterized in that said hydrophobicity alcohol is selected from by comprising alcohol 4-18 carbon, that branching or alkyl chain non-branching, unsaturated or saturated constitute according to each polysaccharide in claim 13 or 14.
16., it is characterized in that said hydrophobicity alcohol is selected from by comprising more than alcohol 18 carbon, that branching or alkyl chain non-branching, unsaturated or saturated constitute according to each polysaccharide in claim 13 or 14.
17., it is characterized in that it is selected from the polysaccharide of formula II, III or IV, wherein group-Hy according to each polysaccharide in the claim 1 to 12 cFor being derived from the group of hydrophobicity acid, itself since the carboxyl functional group of this hydrophobicity acid with at least one by tervalent at least radicals R cPrecursor R cCoupling between the ' entrained reactive functional groups and producing, and
-G cBe ester functional group, or be amide functional group,
-R cAnd F cThe definition that provides above having.
18., it is characterized in that it is selected from the polysaccharide of formula V, VI or VII, wherein group-Hy according to each polysaccharide in the claim 1 to 12 hFor being derived from the group of hydrophobicity acid, itself since the carboxyl functional group of this hydrophobicity acid with at least one by tervalent at least radicals R hPrecursor R hCoupling between the ' entrained reactive functional groups and producing, and
-G hBe ester functional group, or be amide functional group,
-R hAnd F hThe definition that provides above having.
19., it is characterized in that said hydrophobicity acid is selected from by comprising fatty acid 6-50 carbon, that branching or alkyl chain non-branching, unsaturated or saturated constitute according to each polysaccharide in claim 17 or 18.
20., it is characterized in that it is selected from the polysaccharide of formula II, III or IV, wherein group-Hy according to each polysaccharide in the claim 1 to 12 cFor being derived from the group of hydrophobic amine, itself since the amine functional group of this hydrophobic amine with at least one by tervalent at least radicals R cPrecursor R cCoupling between the ' entrained reactive functional groups and producing, and
-G cBe amide functional group, or be carbamate-functional,
-R cAnd F cThe definition that provides above having.
21., it is characterized in that it is selected from the polysaccharide of formula V, VI or VII, wherein group-Hy according to each polysaccharide in the claim 1 to 12 hFor being derived from the group of hydrophobic amine, itself since the amine functional group of this hydrophobic amine with at least one by tervalent at least radicals R hPrecursor R hCoupling between the ' entrained reactive functional groups and producing, and
-G hBe amide functional group, or be carbamate-functional,
-R hAnd F hThe definition that provides above having.
22., it is characterized in that said hydrophobic amine is selected from fatty amine according to each polysaccharide in claim 20 or 21.
23. according to each polysaccharide in claim 20 or 21, it is characterized in that, said hydrophobic amine be selected from by comprise 6-18 carbon, branching or amine linear, that unsaturated or saturated alkyl chain constitutes.
24., it is characterized in that it is selected from wherein tervalent at least precursor R according to each polysaccharide in the claim 1 to 23 c' and R h' be selected from the amino acid whose polysaccharide that carries two acid functional groups.
25., it is characterized in that it is selected from wherein tervalent at least precursor R according to each polysaccharide in the claim 1 to 21 c' and R h' be selected from the amino acid whose polysaccharide that carries two amine functional groups.
26., it is characterized in that it is selected from wherein tervalent at least precursor R according to each polysaccharide in the claim 1 to 21 c' and R h' be selected from the amino acid whose polysaccharide that carries alcohol functional group.
27., it is characterized in that it is selected from wherein tervalent at least precursor R according to each polysaccharide in the claim 1 to 21 c' and R h' be selected from the polysaccharide of hydramine.
28., it is characterized in that it is selected from wherein tervalent at least precursor R according to each polysaccharide in the claim 1 to 21 c' and R h' be selected from the polysaccharide of triamine.
29., it is characterized in that it is selected from wherein tervalent at least precursor R according to each polysaccharide in the claim 1 to 21 c' and R h' be selected from the polysaccharide of two acid alcohols.
30. pharmaceutical composition, it comprises according to each polysaccharide and at least a active component in the claim 1 to 29.
31. the pharmaceutical composition according to claim 30 is characterized in that, it is that administered through oral, nose, vagina, cheek approach can be used.
32. the pharmaceutical composition according to one of claim 30 or 31 is characterized in that, said active component is selected from protein, glycoprotein, peptide and non-peptide therapeutic molecules.
CN201180011939.2A 2010-02-09 2011-02-09 Functionalized anion polysaccharide is carried out by least two hydrophobic group entrained by the sept of at least trivalent Expired - Fee Related CN102834117B (en)

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