WO2016150342A1 - 多糖-聚氨共聚物及其在降低血浆中低密度脂蛋白浓度的应用 - Google Patents

多糖-聚氨共聚物及其在降低血浆中低密度脂蛋白浓度的应用 Download PDF

Info

Publication number
WO2016150342A1
WO2016150342A1 PCT/CN2016/076716 CN2016076716W WO2016150342A1 WO 2016150342 A1 WO2016150342 A1 WO 2016150342A1 CN 2016076716 W CN2016076716 W CN 2016076716W WO 2016150342 A1 WO2016150342 A1 WO 2016150342A1
Authority
WO
WIPO (PCT)
Prior art keywords
polysaccharide
polyamine
copolymer
selectively oxidized
functional group
Prior art date
Application number
PCT/CN2016/076716
Other languages
English (en)
French (fr)
Inventor
杨达志
Original Assignee
杨达志
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 杨达志 filed Critical 杨达志
Priority to CN201680017196.2A priority Critical patent/CN107428850B/zh
Priority to US15/559,221 priority patent/US10925893B2/en
Publication of WO2016150342A1 publication Critical patent/WO2016150342A1/zh

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B15/00—Preparation of other cellulose derivatives or modified cellulose, e.g. complexes
    • C08B15/05—Derivatives containing elements other than carbon, hydrogen, oxygen, halogens or sulfur
    • C08B15/06—Derivatives containing elements other than carbon, hydrogen, oxygen, halogens or sulfur containing nitrogen, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/738—Cross-linked polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/26—Synthetic macromolecular compounds
    • B01J20/264—Synthetic macromolecular compounds derived from different types of monomers, e.g. linear or branched copolymers, block copolymers, graft copolymers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/26—Synthetic macromolecular compounds
    • B01J20/265—Synthetic macromolecular compounds modified or post-treated polymers
    • B01J20/267—Cross-linked polymers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28002—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their physical properties
    • B01J20/28004—Sorbent size or size distribution, e.g. particle size
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
    • B01J20/28078—Pore diameter
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28054—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their surface properties or porosity
    • B01J20/28078—Pore diameter
    • B01J20/28085—Pore diameter being more than 50 nm, i.e. macropores
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/3085—Chemical treatments not covered by groups B01J20/3007 - B01J20/3078
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F251/00—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof
    • C08F251/02—Macromolecular compounds obtained by polymerising monomers on to polysaccharides or derivatives thereof on to cellulose or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
    • C08G73/02—Polyamines
    • C08G73/0206—Polyalkylene(poly)amines
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G81/00—Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
    • C08G83/002—Dendritic macromolecules
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
    • C08J9/16—Making expandable particles
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L1/00—Compositions of cellulose, modified cellulose or cellulose derivatives
    • C08L1/08—Cellulose derivatives
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L3/00—Compositions of starch, amylose or amylopectin or of their derivatives or degradation products
    • C08L3/14—Amylose derivatives; Amylopectin derivatives
    • C08L3/20—Oxidised amylose; Oxidised amylopectin
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/02—Dextran; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2101/00—Manufacture of cellular products
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2210/00—Compositions for preparing hydrogels
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2205/00—Foams characterised by their properties
    • C08J2205/02—Foams characterised by their properties the finished foam itself being a gel or a gel being temporarily formed when processing the foamable composition
    • C08J2205/022—Hydrogel, i.e. a gel containing an aqueous composition
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2207/00—Foams characterised by their intended use
    • C08J2207/10—Medical applications, e.g. biocompatible scaffolds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2387/00—Characterised by the use of unspecified macromolecular compounds, obtained otherwise than by polymerisation reactions only involving unsaturated carbon-to-carbon bonds

Definitions

  • the present disclosure relates to polysaccharide-polyaluminum copolymers and their use in reducing the concentration of low density lipoprotein in plasma.
  • Lipid substances in the blood include cholesterol, phospholipids, triglycerides, and fatty acids.
  • Cholesterol and triglycerides (TG) in circulating blood must combine with a specific protein, apolipoprotein, to form lipoproteins that can be transported to tissues for metabolism.
  • Cholesterol and other plasma lipids are present in the blood in the form of complexes with apolipoproteins, including plasma lipoproteins: chylomicron (CM), very low density lipoprotein (VLDL). , intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL).
  • CM chylomicron
  • VLDL very low density lipoprotein
  • IDL intermediate density lipoprotein
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • hyperlipidemia mainly refers to blood cholesterol. And / or triglycerides elevated.
  • Hyperlipidemia is a manifestation of abnormal body fat metabolism. It is mainly divided into three categories: hypercholesterolemia, hypertriglyceridemia, and mixed hyperlipidemia. World 2008 WHO statistics show that total cholesterol is greater than 5mmol/L. About 37% of adults worldwide have hypercholesterolemia, including 54% in Europe, 48% in the Americas, 22.6% in Africa, and 29% in Southeast Asia. There are seven in the United States in 2014. 13.5 million people (about 37% of the population) suffer from high and low density lipoprotein (LDL). The proportion of critical hypercholesterolemia and hypercholesterolemia in China is 22.5%. 9.0%, whereby estimates China currently has 300 million threshold in patients with hypercholesterolemia and 120 million patients with hypercholesterolemia.
  • LDL low density lipoprotein
  • Low-density lipoproteins mainly carry cholesterol and can be used to synthesize cell membranes and steroid hormones.
  • Low-density lipoprotein cholesterol is also known as "bad cholesterol" because low-density lipoprotein is a major atherosclerotic particle, and oxidized or chemically-modified LDL-cholesterol cannot be used by tissues and cleared by the liver. Deposition on the wall of the arterial tube forms plaque, causing atherosclerosis. Two-thirds of LDL particles in the blood circulation of healthy people are cleared by LDL receptors in the liver. For example, long-term intake of high-fat and high-cholesterol foods inhibits LDL receptor activity and increases LDL-cholesterol levels.
  • LDL-C low-density lipoprotein cholesterol
  • Elevation is the key to the formation of atherosclerosis.
  • LDL-increased cholesterol can cause coronary heart disease.
  • a large number of randomized clinical studies have demonstrated that lowering LDL-C significantly reduces the risk of atherosclerotic cardiovascular disease events.
  • the level of total cholesterol (TC) in the blood generally reflects the level of LDL-cholesterol.
  • Clinical trial results for a 1% reduction in total cholesterol can reduce the incidence of coronary heart disease by 2 to 3%. Therefore, LDL-C is the most important target for lipid-lowering therapy. In lipid-lowering therapy, LDL-C also serves as a primary intervention target.
  • Covalently crosslinked copolymers are described herein. More specifically, polysaccharide-polyamine copolymer matrices and cationic polymer matrices are described herein. Upon protonation, the polysaccharide-polyamine copolymer can form a cationic polymer matrix having very high density cationic sites. In one form, the polysaccharide-polyamine copolymer has a three dimensional structure, especially when hydrated.
  • the polysaccharide-polyamine copolymer matrix is the result of a reaction of two pre-existing polymers or macromolecules.
  • the polysaccharide-polyamine copolymer may be considered a diblock copolymer.
  • the polysaccharide-polyamine copolymer is a selectively oxidized polysaccharide polymer having a 2,3-dialdehyde group and having a plurality of multifunctional amino groups capable of reacting with an aldehyde group. The reaction product of a functional group of a polyamine.
  • the latter reaction product includes a hydrogel or a particulate covalently crosslinked polymer which is a polysaccharide-polyamine copolymer, such as a cellulose-polyamine copolymer, having a three-dimensional structure.
  • a polysaccharide-polyamine copolymer such as a cellulose-polyamine copolymer, having a three-dimensional structure.
  • the primary amine, secondary amine, tertiary amine in the polysaccharide-polyamine copolymer material can be protonated.
  • the primary amine is most prone to protonation, the secondary amine is second, and the tertiary amine is again.
  • a primary amine in the polysaccharide-polyamine copolymer material is preferred, followed by a secondary amine, again a tertiary amine.
  • the primary amine in the polysaccharide-polyamine copolymer material comprises more than 20%, or more than 40%, or more than 53% of all amine groups.
  • the sum of the primary amine and the secondary amine in the polysaccharide-polyamine copolymer material accounts for more than 30%, or more than 50%, or more than 70% of all amine groups.
  • the polysaccharide polymer is selected from the group consisting of selectively oxidized cellulose, selectively oxidized starch, chitosan selectively oxidized, and selectively A group consisting of oxidized dextran, selectively oxidized glycogen, selectively oxidized chitin, and mixtures thereof.
  • Selective oxidation means C2 and Oxidation of the hydroxyl group at the position of C3, accompanied by cleavage of the C2-C3 bond, forms an aldehyde group, wherein the oxidation produces only an aldehyde group without generating a carboxyl group, and does not cleave the polysaccharide chain.
  • the polysaccharide is a cellulosic polymer selected from the group consisting of selectively oxidized cellulose, selectively oxidized chitosan, and mixtures thereof.
  • selectively oxidized cellulose, selectively oxidized starch, selectively oxidized chitosan, selectively oxidized dextran, selectively oxidized glycogen are selectively oxidized Chitin, in which "selectively oxidized”, refers to oxidation to dialdehyde.
  • the subsequently selectively oxidized cellulose, selectively oxidized chitosan is important for polysaccharide-polyamine copolymers used as pharmaceuticals because they contain ⁇ -1,4-glycosidic bonds that cannot be digested by humans. .
  • Polymers such as cellulose, starch, chitosan, dextran, glycogen, chitin, etc. are oxidized to effectively provide a 2,3-dialdehyde group capable of reacting sufficiently with the polyamine to allow water-soluble cellulose polymers Reacting with the polyamine-functional polymer provides a covalently crosslinked matrix or three-dimensional structure with protonatable amine functionality.
  • the latter polysaccharide-polyamine copolymer matrix and cationic matrix are not easily digested by humans.
  • the polysaccharide-polyamine copolymer matrix is a three-dimensional covalently crosslinked matrix formed by the association of a polysaccharide polymer with a polyamine, especially when hydrated.
  • the three-dimensional structure of these covalently crosslinked polymers is in the form of particles having a size ranging from about 100 ⁇ m to about 10 mm.
  • the dehydrated form of the polysaccharide-polyamine copolymer or copolymer matrix does not carry any permanent charge. These copolymers are rich in amine groups and small amounts of imine groups.
  • the amine group and the imine group belong to a weak base having a pKa value in the range of 9 to 11.
  • the polysaccharide-polyamine copolymer or copolymer matrix When exposed to an aqueous environment having a pH below 9.0, the polysaccharide-polyamine copolymer or copolymer matrix will be rehydrated, expanded, protonated and formed into a cationic polymer matrix.
  • the structure of the polysaccharide-polyamine copolymer particles and the cationic polymer particles is porous.
  • the polysaccharide-polyamine copolymer structure has a large number of primary, secondary and tertiary substituted amines.
  • the water-gel or granular polysaccharide-polyamine copolymer is formed by a covalent cross-linking of a polysaccharide macromolecule and a polyamine macromolecule to form a three-dimensional dense network structure.
  • This dense network structure in which a polysaccharide macromolecule and a polyamine macromolecule are covalently crosslinked to form a three-dimensional solid is substantially different from an amino or amine group and a carboxylic acid reaction product encapsulated by a cellulose outer shell.
  • the pores in the polysaccharide-polyamine copolymer matrix and/or the protonated polysaccharide-polyamine copolymer matrix are in the size range of less than 50 microns, and in an important aspect of the invention, the pores have Sizes from about a few hundred nanometers to about 50 microns.
  • the pores have a size of 100 nm to 50 ⁇ m, or the pores have a size of 200 nm to 40 ⁇ m, or the pores have a size of 300 nm to 30 ⁇ m, or the pores have a size of 400 nm to 20 ⁇ m, or the pores have The size is from 500 nm to 10 microns, or the pores have a size of from 800 nm to 5 microns.
  • the outermost layer of LDL LDL, 85% of the protein constitutes the framework, the non-polar part of the phospholipid is embedded in the framework, and the polar part and the hydrophilic group such as water-soluble protein protrude into the surrounding water phase, making it
  • the lipoprotein is stably dispersed in an aqueous solution. Therefore, the outer layer of LDL contains organic phosphate. Since the polysaccharide-polyamine copolymer provided by the embodiment of the present invention has the above-mentioned larger pores, it is suitable for adsorbing negatively charged particles having a large volume, such as the above-described low density lipoprotein.
  • a large volume of negatively charged particles such as LDL can be adsorbed into the pores, making full use of the large surface area brought about by the porous structure of the polysaccharide-polyamine copolymer.
  • common bile acid sequestrants for the treatment of hypercholesterolemia do not have a porous structure or have a pore diameter of several nanometers to ten nanometers, which is disadvantageous for adsorbing bulky anions such as low density lipoprotein.
  • the polysaccharide-polyamine copolymer structure provides amine substituents having a high density, such as primary, secondary and quaternary amines.
  • the gel and polymer particles can be provided by the compositions of the invention.
  • the gel and polymer particles may comprise a backbone that is covalently crosslinked by a copolymer region of a polyamine to have a three-dimensional dense interlocking network, such as a cellulose chain.
  • the intricate three-dimensional network matrix formed by covalent cross-linking of a cellulosic polymer and a polyamine crosslinker is in contrast to the reaction of a polymer amine group of a cellulose shell entrapped amine compound with a carboxylic acid.
  • Polysaccharide polymers such as cellulose, starch, chitosan, dextran, glycogen, and chitin, are oxidized to a 2,3-dialdehyde group effective to provide reaction with polyamines to allow for the above oxidation.
  • the polysaccharide polymer is reacted with a polyamine having an amine functional group to provide a covalently crosslinked structure having a protonated nitrogen content of at least 12.5% (based on the weight of the polysaccharide-polyamine copolymer).
  • a polyamine crosslinked polysaccharide polymer such as a water soluble cellulosic polymer (having a dialdehyde group) provides a three dimensional structure of a polysaccharide derived "backbone” in which a plurality of polysaccharide chains are attached to a plurality of polyamine chains.
  • These polysaccharide polymers are pre-existing polymer "blocks” or “skeletons” which are joined together by pre-existing polyamines which are also discrete amine-based "blocks".
  • the polysaccharide-polyamine copolymer can be considered a diblock copolymer.
  • the linked backbone is a covalently crosslinked product of polyamines (forming covalently crosslinked blocks) and selectively oxidized polysaccharides to provide covalent cross-linking with a high percentage of protonated nitrogen content. Segment copolymer and copolymer matrix.
  • the latter polysaccharide-polyamine copolymer forming the amino-based polysaccharide structural particles can be protonated (in the human body, or by hydrogenation reduction by lowering the pH or by a reaction such as a cross-linking reaction in vitro).
  • the charge density of the cationic polymer structure For example, when exposed to water with a pH below 9.0 In the environment, the subsequent polysaccharide-polyamine copolymer forming the copolymer matrix can be protonated.
  • the polysaccharide-polyamine copolymer can be protonated to effectively provide the cationic copolymer matrix with an ammonium content (based on the weight of the cationic copolymer) of at least 12.5% by weight.
  • the obtained polysaccharide-polyamine copolymer is insoluble in water. Therefore, the polysaccharide-polyamine copolymer of the present invention is clearly distinguished from the water-soluble polysaccharide-polyamine copolymer which has been previously available in the present invention.
  • the previously water-soluble polysaccharide-polyamine copolymer of the present invention can form a stable, transparent and uniform colloidal solution in water, and has a small volume and can be absorbed by cells; and the polysaccharide-polyamine copolymer of the present invention is composed of A plurality of oxidized polysaccharides containing an aldehyde group and a plurality of polyamine polymers containing a polyamine group form a covalent bond and are formed by repeated covalent crosslinking. Therefore, the copolymer has a large molecular weight, is easily precipitated in water, and has a volume of more than 30 ⁇ m, and is not absorbed by cells at all.
  • the polysaccharide-polyamine copolymer has an ammonium cation which is a substituted amine having a positive charge or a protonation, such as RMH 3 + , R 2 formed by protonation of substituted amines RNH 2 , R 2 NH and R 3 N. NH 2 + and R 3 NH + and the like.
  • the polyamine matrix is positively or protonated at the position of the amine to form a quaternary ammonium cation (HNR 3 + ) wherein one or more hydrogen atoms may be replaced by an organic group (represented by R).
  • the high charge density can effectively bind at least about 2.58 ⁇ 0.43 mmol/g phosphate at pH 7.0 and a phosphate concentration of 6.25 mM.
  • the cationic matrix acts as a scavenger to remove phosphate from mammals including humans.
  • the polyamines are dendrimers which are macromolecular amines having a core or a center, including amine groups and branches, which can start from the core or central functional group of the macromolecular amine through a series of The reaction is iteratively provided to provide a highly branched amine polymer.
  • the dendrimer molecule can be circular, or substantially circular, or have a spherical shape or have a three-dimensional morphology with an outer perimeter that is curved or defined by a curve.
  • the dendrimer has a nitrogen content of at least 24.5 wt%, preferably 25-80 wt% (based on the weight of the dendrimer), such that when the polysaccharide-polyamine copolymer material is protonated (Formation of the cationic polymer matrix) has an ammonium ion content (calculated on a N atom basis) of at least about 12.3 wt%.
  • the branched polyamine can be used alone or in combination with a polyamine having a dendritic morphology.
  • Polyamines include polymers of branched amines, dendritic polyamines, and polyamines disclosed in U.S. Patent Nos. 8,888,738 and WO 2014/029888 (all of which are incorporated herein by reference).
  • the polysaccharide-polyamine copolymer material is provided with an amine function (and provides a cationic officer upon protonation after covalently crosslinking the polysaccharide polymer)
  • a polyamine selected from the group consisting of polyethyleneimine (PEI), polyallylamine, polypropyleneimine, and mixtures thereof.
  • the polyethyleneimine (PEI), polyallylamine, and polypropyleneimine may be in the form of a branch or a dendrimer, as shown in the accompanying drawings.
  • the present invention also provides a method of preparing a polysaccharide-polyamine copolymer material and a cationic polymer material.
  • the method comprises oxidizing a polysaccharide polymer, and then reacting the polysaccharide-derived polymer having a 2,3-dialdehyde group as described above with a polyamine to provide a polysaccharide-polyamine copolymer material. If the primary amine of the polyamine is reacted with the aldehyde group of the selectively oxidized polysaccharide to obtain the reaction product imine, the carbonamine bond can be reduced to a single bond by a reduction reaction such as a hydrogenation reduction reaction, thereby converting the imine to a substitution. Secondary amine.
  • the selectively oxidized polysaccharide has at least 50% by weight, preferably more than 80%, of oxidized glucose units.
  • PVA polyallylamine
  • PEI polyethyleneimine
  • the molecular weight ranges from about 25,000 to about 750,000, preferably from about 60,000 to about 750,000.
  • the ratio of polysaccharide polymer to polyamine is from about 1:1 to about 1:3 (by weight).
  • the ratio of polysaccharide polymer to polyamine is from about 1:5 to about 1:30 by weight.
  • a biocompatible cationic polymer that maintains a high positive charge density to strongly bind to a polyvalent anion including phosphate, phospholipids (the lipoprotein surface is the phosphate head of the phospholipid.
  • hydrophilic Negatively charged polynucleotides, negatively charged peptides, and metal anions.
  • the polysaccharide-polyamine copolymer can also be used to remove or remove other inorganic anions and/or organic solutes or particles, such as chlorides, nitrites, bicarbonates, polynucleotides, polypeptides. , bile acids, and compounds or ions containing oxalic acid. In one form of the invention, this (removing the above substances) can be used to remove from the body.
  • 1 is an exemplary form of a general chemical structure of a covalently crosslinked copolymer, such as a polysaccharide-polyamine copolymer, in an embodiment of the present invention
  • FIG. 2 is an exemplary schematic view of covalently combining a polysaccharide backbone to form a polysaccharide-polyamine copolymer according to an embodiment of the present invention
  • Figure 3A is an example of a branched polyethyleneimine, and B is an example of a dendritic polyethyleneimine;
  • Figure 6 is a blood biochemical test result after three weeks of administration of the polysaccharide-polyamine copolymer provided by the embodiment of the present invention.
  • Fig. 7 is a graph showing the change in body weight during the test of the polysaccharide-polyamine copolymer provided by the embodiment of the present invention.
  • covalently crosslinked copolymers are described herein and can be used for a variety of purposes including, but not limited to, removal of phosphate.
  • the covalently crosslinked copolymer generally comprises two moieties, namely one backbone molecule and one functional group polymer covalently crosslinked to the backbone molecule.
  • a stable covalent bond is formed between the polysaccharide polymer and the large polymer molecule to provide a covalently crosslinked copolymer in which the amine and/or imine functions of the covalently crosslinked copolymer are When protonated, it has a cationic function.
  • the covalently crosslinked copolymer is a polysaccharide-polyamine copolymer.
  • the polysaccharide-polyamine copolymer When the polysaccharide-polyamine copolymer is protonated, it can form a cationic polymerization with a very high density of cationic sites. Substrate.
  • the covalently crosslinked copolymer provides a three dimensional structure, particularly when hydrated.
  • the covalently crosslinked copolymer can be more specifically described as a cellulose polyamine copolymer comprising a cellulose derived material to form a polysaccharide component.
  • the methods of making a water-insoluble cationic polymer described herein include an oxidation reaction and a carbonyl nucleophilic addition reaction.
  • the oxidation reaction may include oxidation of a saccharide such as microcrystalline cellulose, amylopectin, starch, chitosan, chitin, dextran, glycogen or the like.
  • the polysaccharide polymer is selected from the group consisting of selectively oxidized cellulose, selectively oxidized starch, selectively oxidized chitosan, selectively oxidized dextran, a group consisting of selectively oxidized glycogen, selectively oxidized chitin, and mixtures thereof.
  • Selective oxidation refers to the oxidation of a hydroxyl group at the C2 and C3 positions to an aldehyde group accompanied by a cleavage of a C2-C3 bond, but the oxidation produces only an aldehyde group without generating a carboxyl group and does not cause breakage of the polysaccharide chain.
  • a preferred polysaccharide suitable for synthesis into a copolymer is an insoluble polysaccharide formed by a-D-glucose unit or a D-glucosamine unit bonded to each other by a ⁇ -1,4-glycosidic bond.
  • cellulose amylopectin, chitosan, and chitin.
  • the hydroxyl groups on the glucose units of these polysaccharides C-2 and C-3 are selectively oxidized to produce a rich aldehyde group.
  • These newly added hydrophilic aldehyde groups significantly increase the water solubility of the selectively oxidized polysaccharide.
  • the polysaccharide polymer is selected from the group consisting of selectively oxidized cellulose, selectively oxidized starch, selectively oxidized chitosan, selectively oxidized dextran, selectively oxidized glycogen, and A group consisting of selective chitosan and a mixture thereof.
  • Cellulose, amylopectin and chitosan cannot be digested by mammals due to the presence of beta-1,4 glycosidic linkages.
  • Starch, dextran and glycogen contain beta-1,6 glycosidic bonds and are thus digestible by humans.
  • the polysaccharide-polyamine copolymer matrix described herein is not digestible, depending on the starting polysaccharide material.
  • the polysaccharide-polyamine copolymer can be prepared in a variety of ways.
  • the method of preparation may comprise three steps.
  • a rich aldehyde group is produced by an oxidation reaction by selectively oxidizing hydroxyl groups on the glucose units C2 and C3 of the polysaccharide.
  • selective oxidation refers to the oxidation of a hydroxyl group at the C2 and C3 positions to an aldehyde group accompanied by a cleavage of a C2-C3 bond, but the oxidation produces only an aldehyde group without generating a carboxyl group and does not cause a polysaccharide. The break of the chain.
  • the carboxyl group cannot covalently crosslink the polyamine, and if a carboxyl group is formed, the carboxyl group in the aqueous environment will undesirably form a carboxylic acid. If further formed (carboxylic acid), the carboxylic acid will carry a negative The charge, which will adversely interfere with the cationic charge formed upon the amine matrix.
  • the aldehyde group formed by the selective oxidation of the polysaccharide reacts with an amine (e.g., a primary amine) in the polyamine to form an imine derivative, and the intermediate polysaccharide-polyamine copolymer has an unstable carbon-nitrogen double bond.
  • these are considered to be diblock copolymers.
  • the carbon-nitrogen double bond of the imine is converted into a carbon-nitrogen single bond of the amine by a reduction reaction to produce a stable polysaccharide-polyamine copolymer.
  • the polysaccharide-polyamine copolymer matrix is the result of two pre-existing polymers or macromolecule reactions.
  • the polysaccharide-polyamine copolymer can be considered a diblock copolymer.
  • the polysaccharide-polyamine copolymer is the reaction product of a polysaccharide polymer having a 2,3-dialdehyde group and a polyamine having a polyfunctional amine group reactive with an aldehyde group.
  • the latter reaction product includes a particulate covalently crosslinked polymer which is a polysaccharide-polyamine copolymer such as a cellulose polyamine copolymer having a three-dimensional structure.
  • covalently crosslinked copolymers described herein can also be prepared by other methods than oxidizing polysaccharides.
  • the intermediate polymer obtained from the above discussion of the oxidation reaction may have the following general formula:
  • Reaction 1 is a schematic representation of a process for obtaining an exemplary polymer from cellulose.
  • Cellulose is a naturally occurring polymer comprising glucose units interconnected by beta-1,4 glycosidic linkages.
  • the molecular structure of the cellulose forming the main chain of the cellulose derivative polymer is generally expressed as follows:
  • a polysaccharide such as microcrystalline cellulose can be oxidized to form an intermediate cellulose.
  • a carbonyl-rich intermediate such as an aldehyde is produced by oxidation of the polysaccharide backbone.
  • a reactive aldehyde group can be formed by opening a cellulose ring at a plurality of sites along the polysaccharide backbone.
  • the formula "A” generally means cellulose, which may be any commercially available cellulose; and the formula “B” generally means 2,3-dialdehyde formed by oxidation of cellulose.
  • the 2,3-dialdehyde cellulose described above is a linear polymer having a cellulose-like structure and includes one or more (two in the illustrated manner) reaction. Aldehyde. In one mode, the cellulose can be pretreated with sulfuric acid to reduce crystallinity and size. In another mode, the cellulose can be treated with hydrochloric acid.
  • oxidation of cellulose can be by periodic acid, potassium periodate or other cationic derivatives and periodate or the like.
  • Other oxidizing agents include chlorine, hydrogen peroxide, peracetic acid, chlorine dioxide, nitrogen dioxide, persulfate, permanganate, dichromate-sulfuric acid, hypochlorous acid, hypohalite or periodate Various metal catalysts.
  • the oxidized polysaccharides may also contain carboxylic acid, aldehyde and/or ketone groups depending on the nature of the oxidizing agent and the reaction conditions.
  • Periodate is a unique oxidant.
  • the periodate-mediated oxidation of polysaccharides is well known for the selective oxidation of hydroxyl groups of C2 and C3 to the corresponding aldehyde groups with C2-C3 bond cleavage and is modified for polysaccharides.
  • One of the most effective methods Other oxidants produce more carboxyl groups than the aldehyde groups and cause breakage of the polysaccharide backbone.
  • the carboxyl group cannot covalently crosslink the amine polymer under the reaction conditions as described.
  • it will ionize and form carboxylic acids in aqueous solution.
  • Carboxylic acids carry a negative charge that disrupts the cationic function of our copolymers.
  • the polymeric intermediate obtained by oxidation of the polysaccharide described above can then be subjected to a carbonyl nucleophilic addition (e.g., hydride reduction) reaction with one or more branched cationic functional groups such as an amine/imine polymer.
  • a polyfunctional primary amine-containing molecule can be covalently crosslinked with an aldehyde-containing oligosaccharide derived from a polysaccharide such as cellulose or the like or a glycoprotein.
  • Large molecular weight polyfunctional primary amine reagent by one method It can be used to provide a high density of cationic sites for polysaccharide derivatives upon subsequent protonation. For most processes, any polyamine (including both linear and branched) containing multiple primary amines can be used as a nucleophile.
  • the reactive aldehyde group-containing cellulose intermediate obtained as a result of the oxidation reaction of cellulose with sodium periodate is further subjected to a carbonyl nucleophilic addition reaction, and
  • a hydride reduction reaction is carried out using a cationic functional polymer such as polyethyleneimine to derive an exemplary insoluble cationic cellulose derivative polymer, generally represented by the formula "C".
  • exemplary reaction described above uses polyethyleneimine as the nucleophile
  • other exemplary polymers may also be used as nucleophiles in the reaction with the above-described cellulose intermediates including reactive aldehyde groups.
  • Some exemplary cationic functional polymers include, for example, poly(allylamine), poly(amidoamine), polypropyleneiminetetramine, and the like.
  • polyethyleneimine, poly(allylamine) and polypropyleneiminetetraamine can be used in the form of a branched and/or dendrimer.
  • the resulting product can be dried by evaporation, precipitation or other suitable technique.
  • a uniform particle size polysaccharide-polyamine copolymer material can be achieved by sieving the dried material through a suitable screen.
  • the polysaccharide-polyamine copolymer matrix and/or the protonated polysaccharide-polyamine copolymer matrix have pores having a size of less than 50 microns, and in an important aspect, the pore size is from about several hundred nanometers. Up to about 50 microns.
  • the amine group density of the cationic polymer product can also be controlled by the degree of polymerization, the size of the nucleophile, and the relative proportions of the polysaccharide substrate backbone and nucleophile.
  • charge density refers to the amount of primary, secondary, and tertiary ammonium cations in the cationic polymer. More specifically, charge carrier density refers to the number of charge carriers (eg, electrons, ions) per unit volume of material (eg, cationic polymer), rather than the actual amount of charge on the carrier.
  • the amine-based polysaccharide is prepared to provide at least 12.5 wt% of the amine functionality (calculated as N atom weight) based on the total weight of the polysaccharide copolymer for the covalently crosslinked structure.
  • the dendrimer has at least 24.5 wt%, preferably 25-80 wt%, based on the weight of the dendrimer, of an amine group (calculated as N atom weight) to be a polysaccharide-poly
  • the amine copolymer material effectively provides a cationic content (calculated as N atomic weight) based on at least 12.3 weight percent of the cationic material upon protonation to form the cationic polymer matrix.
  • the range of ratios of nucleophiles containing aldehyde polysaccharide derivatives and functional primary amines can be qualitatively described as low, medium and high.
  • the amount of aldehyde and the primary amine content of the reactant are determined by quantitative titration, and the NH 2 + content of the final product is determined by nuclear magnetic resonance (NMR).
  • Figure 2 provides an illustration of another exemplary process showing the reaction of a polysaccharide with a polyamine.
  • the physical properties of the covalently crosslinked copolymer obtained from the above oxidation reaction and carbonyl nucleophilic addition reaction can be controlled by manipulating the conditions of the above reaction, for example, by changing the selective oxidation of the aldehyde group to the polysaccharide and nucleophilic
  • the relative proportion of the reagents, the type of functional group that reacts with the oxidatively-selectively oxidized polysaccharide, and/or the change in reaction time, pH, and/or reaction temperature, and the like For example, increasing the temperature of the reaction can result in a corresponding increase in the size of the resulting water insoluble cationic polymer.
  • the reaction time can result in a corresponding increase in the size of the resulting water insoluble cationic polymer.
  • the increased pH of the reaction conditions can result in a corresponding increase in the size of the resulting covalently crosslinked copolymer.
  • the size of the covalently crosslinked copolymer product obtained can be selected by selecting two primary reactants, namely a polysaccharide derivative (eg, 2,3-dialdehyde cellulose) and a polyamine nucleophile (eg, Polyethyleneimine), the molecular weight and the ratio to control.
  • a polysaccharide derivative eg, 2,3-dialdehyde cellulose
  • a polyamine nucleophile eg, Polyethyleneimine
  • a polyallylamine (PLA) having an average molecular weight of from about 15,000 Da (Dalton) to about 900,000 Da or a polyethyleneimine (PEI) having an average molecular weight of from about 25,000 Da to about 750,000 Da can be used.
  • PVA polyallylamine
  • PEI polyethyleneimine
  • polyallylamines having an average molecular weight of about 15,000 Daltons, 17,000 Daltons, 65,000 Daltons, or 900,000 Daltons, or having an average molecular weight of about 25,000 Daltons, available from Sigma-Aldrich can be used. Or 750,000 Daltons of polyacetimide.
  • the ratio of the backbone portion of the polysaccharide (e.g., cellulose) to the cationic site forming functional polymer (e.g., polyethyleneimine) can depend on the molecular weight of the cationic site to form the functional polymer.
  • the ratio of the cellulose derivative to the polyamine can range from about 1:1 to about 1:8. (weight ratio).
  • the ratio of the cellulose derivative to the polyamine is about 1:5. It is about 1:20 (weight ratio).
  • the polyamine is a dendrimer having a core or a center, including an amine group and a branch, which can start from the core or central functional group, through a series of iterative reactions to provide a highly branched Amine polymer.
  • the dendrimer molecule can be circular or substantially circular or have a three-dimensional morphology, which is spherical or has an outer perimeter that is curved or curved Line definition.
  • the dendrimer has at least 24.5 wt%, preferably 25-80 wt%, based on the weight of the dendrimer, of an amine group (calculated as N atom weight) to be a polysaccharide-polyamine
  • the copolymer material effectively provides a cationic content based on at least 12.3 wt% (calculated as N atom weight) of the cationic material upon protonation to form the cationic polymer matrix.
  • the particle size of the covalently crosslinked copolymer product can be achieved by crosslinking a cross-linked polyfunctional primary amine (e.g., polyethyleneimine) with a low, medium, and very high molecular weight (e.g., ranging from about 15,000 Daltons to about A polysaccharide derivative of 750000 Daltons (for example, 2,3-dialdehyde cellulose) is reacted to adjust to obtain nanoparticles, microparticles, and millimeter-sized particles.
  • a cross-linked polyfunctional primary amine e.g., polyethyleneimine
  • a low, medium, and very high molecular weight e.g., ranging from about 15,000 Daltons to about
  • a polysaccharide derivative of 750000 Daltons for example, 2,3-dialdehyde cellulose
  • the polysaccharide-polyamine copolymer matrix is a three-dimensional covalently crosslinked matrix formed by interconnecting a polysaccharide polymer and a polyamine, especially in a hydrated state.
  • the three dimensional structure of these covalently crosslinked polymers is in the form of particles having a size ranging from about 100 [mu]m to about 10 mm.
  • the dehydrated form of the polysaccharide-polyamine copolymer or copolymer matrix does not carry any permanent charge.
  • These copolymers are rich in amine groups and small amounts of imine groups. Amines and imines are classified as weak bases with pKa values in the range of 9 to 11.
  • the polysaccharide-polyamine copolymer or copolymer matrix Upon exposure to an aqueous environment at a pH below 9.0, the polysaccharide-polyamine copolymer or copolymer matrix will be rehydrated, swelled, protonated and formed into a cationic polymer matrix.
  • Polysaccharide polymers such as cellulose, starch, chitosan, dextran, glycogen and chitin, are oxidized to form a sufficient amount of 2,3-dialdehyde groups reactive with polyamines to allow oxidative polymers Reaction with a polyamine-based polyamine, which in turn provides a covalently crosslinked structure having at least 12.5 wt% of amine functionality (calculated as N atom weight) based on the weight of the polysaccharide copolymer.
  • a polyamine crosslinked polysaccharide polymer such as a water soluble cellulosic polymer (having a dialdehyde moiety) provides a three dimensional structure of a polysaccharide derived "backbone” in which a plurality of polysaccharide chains are attached to a plurality of polyamine chains.
  • These polysaccharide polymers are pre-existing polymer "blocks” or “skeletons” which are joined together by a pre-existing polyamine "block”.
  • the polysaccharide-polyamine copolymer can be considered a diblock copolymer.
  • the attached backbone is bonded together as an amine polymer (forming a covalently crosslinked mass) and a covalently crosslinked product of the selectively oxidized polysaccharide to provide a covalently protonated, high percentage of amine content.
  • Crosslinked block copolymer and copolymer matrix are bonded together as an amine polymer (forming a covalently crosslinked mass) and a covalently crosslinked product of the selectively oxidized polysaccharide to provide a covalently protonated, high percentage of amine content.
  • the resulting covalently crosslinked copolymer such as a polysaccharide-polyamine copolymer
  • the covalently crosslinked copolymer may have a phosphate binding ability of 2.59 ⁇ 0.43 mmol/g.
  • covalent cross-linking at pH 6 under physiological phosphate levels at a phosphate concentration of 5 mm in vitro The copolymer has a maximum phosphate binding capacity of 2.56 ⁇ 0.27 mmol / g.
  • the covalently crosslinked copolymer can exhibit stable phosphate binding properties after storage for at least 3 months in water at room temperature.
  • the coefficient of expansion of the covalently crosslinked copolymer may be 6.43 ⁇ 0.36 times or more.
  • statins There are five clinically available treatments for hypercholesterolemia, including statins, fibrates, niacin, bile acid sequestrants, and cholesterol absorption inhibitors.
  • Statins, cholesterol absorption inhibitors and resins are mainly targeted at high-low-density lipoprotein cholesterol.
  • statins (3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor) are very important drugs for the prevention and treatment of hypercholesterolemia and atherosclerotic diseases.
  • Epidemiological studies and existing clinical trials show that due to differences in genetic background, the Chinese population is less tolerant and safe for high-dose, high-intensity statin therapy, and the risk of hepatotoxicity and muscle toxicity is significantly higher. Patients in European and American countries.
  • Statins can also increase blood glucose levels in patients and increase the risk of type 2 diabetes.
  • Cholesterol absorption inhibitors act on the brush border of small intestinal cells, effectively inhibiting the absorption of cholesterol and plant sterols. Although such drugs are safe and well tolerated, administration alone can only reduce LDL-C by about 18%.
  • the bile acid sequester is also called a resin lipid-lowering drug.
  • These drugs are basic anion exchange resins, which can irreversibly bind to bile acids in the intestine, thus hindering the enterohepatic circulation of bile acids, promoting the excretion of bile acids with stools, and blocking the reabsorption of cholesterol in bile acids.
  • the LDL receptor on the surface of the hepatocyte membrane is stimulated by a feedback mechanism to accelerate the clearance of LDL in the blood of LDL, and the serum LDL-C level is lowered.
  • the bile acid sequestrant can reduce TC by 15% to 20%, LDL-C by 15% to 30%, and HDL-C by 3% to 5%.
  • bile acid sequestrants include quercetin (Cholestyramine), cholestyramine (Colestatin), and colesevelam hydrochloride powder. Although they have a good effect on high and low density lipoprotein cholesterol.
  • cholestyramine-containing benzene ring structure polymer can affect the absorption of various drugs; (2) Colestipol-containing cyclic structure polymer can affect many Drug absorption, containing carcinogenic teratogenic chemical epichlorohydrin; (3) coleseverol hydrochloride powder, 10% of patients with gastrointestinal disorders, containing carcinogenic teratogenic chemical substances epichlorohydrin.
  • Sevelam and Bisallom are non-calcium non-metallic phosphorus binders of basic anion exchange resins. A large number of clinical studies have found that sevelamer reduces plasma total cholesterol by about 20% and plasma LDL-C by about 23%.
  • epichlorohydrin a well-known carcinogen and teratogen synthetic substrate, and the drug is expensive, it is not used as a lipid-lowering drug.
  • the inventors of the present invention have found in the research that the polysaccharide-polyamine copolymer provided by the embodiment of the present invention can be used as a good drug for treating hypercholesterolemia, because the polysaccharide-polyamine copolymer provided by the embodiment of the present invention is rich in An amine group and a small amount of an imine group, when exposed to an aqueous environment having a pH below 9.0, the polysaccharide-polyamine copolymer or copolymer matrix will be rehydrated, swollen, protonated and form a cationic polymer matrix, the cation
  • the surface of the polymer matrix has a high density of positive charges and can be combined with negatively charged lipoproteins and bile acids.
  • protonated polysaccharide-polyamine copolymers block in the intestine by binding to lipoproteins and bile acids.
  • the enterohepatic circulation of lipoproteins and bile acids promotes the excretion of lipoproteins, cholesterol and bile acids with stools, and blocks the absorption of lipoproteins and cholesterol in the small intestine.
  • the LDL receptor on the surface of the liver cell membrane was stimulated by a feedback mechanism to accelerate the clearance of LDL in the blood of LDL, and the serum LDL-C level was lowered.
  • the drug which is orally administered with the polysaccharide-polyamine copolymer provided by the embodiment of the present invention as an active ingredient does not have the above disadvantages.
  • the polysaccharide-polyamine copolymer provided by the embodiment of the present invention contains almost no benzene ring structure, does not affect the absorption of other drugs, that is, there is little drug interference; second, the polysaccharide-polyamine copolymer does not cause carcinogenesis.
  • the structure, composition and preparation method of the polysaccharide-polyamine copolymer of the present invention are more specifically described below by way of specific examples.
  • the characterization of the polysaccharide-polyamine copolymers of the present invention employs established means in the art.
  • the nitrogen content of the polyamine, polysaccharide-polyamine copolymer can be determined by molecular formula and by elemental analysis; the pore size of the polysaccharide-polyamine copolymer is measured by an optical microscope; FI-IR is measured by a Thermo Nicolet 4700 FT-IR Spectrometer;
  • the collected supernatant is lyophilized (optional).
  • the washed insoluble DAC will be redispersed with DI water.
  • Poly(allylamine hydrochloride) PLA poly(acrylamide hydrochloride) / polyallylamine hydrochloride /
  • PEI polyethyleneimine PEI polyethyleneimine
  • PEI molecular weight 750K, 50% by weight aqueous solution
  • PEI molecular weight 750K, 50% by weight aqueous solution
  • the suspension of hydrogel particles is further incubated at 70 ° C for 60 minutes, the pH of the suspension is measured every 10 minutes, and adjusted to 8.5 with 5M sodium hydroxide solution;
  • the gel particles are precipitated by gravity at room temperature;
  • the particles were incubated with 4 liters of 100 mM sodium bicarbonate solution of pH 8.5 for 60 minutes with stirring, and precipitated by gravity at room temperature;
  • the precipitated gel particles were reduced by adding 10 g of sodium borohydride and incubated at room temperature for 72 hours;
  • the reduced gel particles are washed with deionized water to remove excess sodium borohydride and PEI until the pH of the solution is between 5 and 6;
  • the washed gel particles are freeze-dried (optional).
  • the final product obtained is a white or light yellow water colloidal particle having a synthetic yield of 70-80% and a nitrogen content of about 20%.
  • the reaction conditions were the same as in Example 1, except that the PEI molecular weight was 750 K and the weight ratio of DAC to PEI was 1:20.
  • the final product obtained is a white or light yellow water colloidal particle having a synthetic yield of 50-60% and a nitrogen content of about 21.5%.
  • the reaction conditions were the same as in Example 1, except that the weight ratio of DAC to PEI was 1:30.
  • the final product obtained is a white or light yellow water colloidal particle having a synthetic yield of 20-40% and a nitrogen content of about 22%.
  • the reaction conditions were the same as in Example 1, except that the PEI molecular weight was 25 K and the weight ratio of DAC to PEI was 1:1.
  • the final product obtained was white or light yellow solid particles with a synthetic yield of 60-70% and a nitrogen content of about 12.5%.
  • the reaction conditions were the same as in Example 1, except that the PEI molecular weight was 25 K and the weight ratio of DAC to PEI was 1:2.
  • the final product obtained was white or light yellow solid particles with a synthetic yield of 20-40% and a nitrogen content of about 15%.
  • the reaction conditions were the same as in Example 3, except that the weight ratio of DAC to PEI was 1:3.
  • the final product obtained was white or light yellow water gel particles with a synthetic yield of 10-20% and a nitrogen content of about 16.9%.
  • poly(allylamine hydrochloride) (molecular weight 58K and 15K) or polyethyleneimine (molecular weight 750K and 25K) dispersed in deionized water to reach a total volume of 100 ml;
  • the insoluble DAC suspension was added to the polyamine solution at a speed of 10 ml/min under stirring at 500 rpm, and then incubated at 70 ° C for 60 minutes;
  • the suspension of gel particles was incubated at 70 ° C for another 60 minutes, the pH of the suspension was measured every 10 minutes, and adjusted to 8.5 with 5M sodium hydroxide solution;
  • the gel particles are precipitated by gravity at room temperature;
  • the particles were incubated with 4 liters of 100 mM sodium bicarbonate solution of pH 8.5 for 60 minutes with stirring, and precipitated by gravity at room temperature;
  • the precipitated gel particles were reduced by adding 10 g of sodium borohydride and incubated at room temperature for 72 hours;
  • the reduced gel particles are washed with deionized water to remove excess sodium borohydride and polyamine until the pH of the solution is between 5 and 6;
  • the final product obtained is white or light yellow solid particles, the synthesis yield is 50-80%, and the nitrogen content is about 12.5%.
  • the reaction conditions were the same as in Example 7, except that the polyamine was PLA (MW 58K) and the weight ratio of DAC to PLA was 1:5.
  • the final product was obtained, and the final product obtained was white or pale yellow solid particles with a synthetic yield of 50-80% and a nitrogen content of about 18%.
  • the reaction conditions were the same as in Example 8, except that the weight ratio of DAC to PLA was 1:10.
  • the final product obtained was white or light yellow water gel particles with a synthetic yield of 40-60% and a nitrogen content of about 20%.
  • the reaction conditions were the same as in Example 8, except that the weight ratio of DAC to PLA was 1:20.
  • the final product obtained was white or light yellow water gel particles with a synthetic yield of 30-50% and a nitrogen content of about 21%.
  • the reaction conditions were the same as in Example 8, except that the weight ratio of DAC to PLA was 1:2.
  • the final product obtained was white or light yellow water gel particles with a synthetic yield of 25-45% and a nitrogen content of about 12.8%.
  • the reaction conditions were the same as in Example 8, except that the weight ratio of DAC to PLA was 1:3.
  • the final product obtained was white or light yellow water gel particles with a synthetic yield of 30-55% and a nitrogen content of about 13.0%.
  • FIG. 4 shows the appearance of the product of the invention.
  • 4A is a cationic copolymer CelloPhos formed after the positive electropolymerization of the polysaccharide-polyamine copolymer;
  • FIG. 4B is a granular CelloPhos after reduction;
  • FIG. 4C is a granular CelloPhos after the product obtained by the procedure of Example 1 is dried in the air.
  • DAC: PEI 750K 1:20
  • Figure 4E is a granular form stained with eosin Eosin CelloPhos phase comparison chart.
  • the polysaccharide-polyamine copolymer of the present invention is a hydrophilic material hydrogel obtained under special copolymerization conditions;
  • positively charged polysaccharide-polyamine copolymer particles can be combined with dye blush Eosin;
  • the polysaccharide-polyamine copolymer particles have a porous, multi-layered structure, which enhances their adsorption and binding ability to phosphate.
  • Figure 5 shows the FT-IR spectrum of the product of the invention.
  • the FT-IR spectrum of the polysaccharide-polyamine copolymer CelloPhos is clearly distinguished from the FT-IR spectrum of the reactants.
  • the novel substance polysaccharide-polyamine copolymer CelloPhos obtained by the present invention has a unique FT-IR absorption spectrum.
  • “Siloxi” is a drug name in which the polysaccharide-polyamine copolymer provided by the embodiment of the present invention is an active ingredient.
  • celoxi is 100% a polysaccharide-polyamine copolymer active ingredient.
  • Rodent 5008 Fomulab (LabDiet, Louis, MO) as a standard food.
  • Female and male rats (Sprague Dawley) were fed standard food for 14 days. On day 14, plasma total cholesterol and low density lipoprotein levels were determined as baseline by drawing blood samples. The standard diet was then replaced with a test diet and a negative control diet. Blood samples were taken again on the 21st day after food replacement to determine plasma total cholesterol and low density lipoprotein levels. The test results are listed in Tables 1 and 2 below. As can be seen from the table, Xelox significantly reduced the total cholesterol concentration and LDL-C concentration in rat plasma.
  • Figure 6 shows the results of blood biochemical tests after three weeks of administration of the polysaccharide-polyamine copolymer provided by the examples of the present invention. It can be seen that the administration of the polysaccharide-polyamine copolymer provided by the embodiment of the present invention has no significant effect on the levels of various enzymes in the blood of the rat, thereby demonstrating the plurality of embodiments provided by the embodiments of the present invention.
  • the sugar-polyamine copolymer is safe and non-toxic.
  • Figure 7 shows the changes in animal body weight during the test. As can be seen from the figure, all animals gained weight throughout the trial. This data indirectly indicates that 1% of the polysaccharide-polyamine copolymer provided by the examples of the present invention does not have any significant side effects on the gastrointestinal tract of the test animals.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Analytical Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Materials Engineering (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Nanotechnology (AREA)
  • Diabetes (AREA)
  • Biochemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Compositions Of Macromolecular Compounds (AREA)
  • Macromolecular Compounds Obtained By Forming Nitrogen-Containing Linkages In General (AREA)

Abstract

用于治疗高胆固醇血症的药物组合物，药物组合物包括作为活性成分的多糖-聚胺共聚物及其药学上可接受的盐，多糖-聚胺共聚物由以下两部分共聚形成：具有2,3-二醛基的被选择性氧化的多糖，和具有胺基功能团的聚胺；具有胺基功能团的聚胺与所述具有2,3-二醛基的被选择性氧化的多糖共价交联形成网状结构，得到具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物，具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物中的胺基功能团可被质子化而形成具有质子化位点的三维网状结构阳离子共聚物，阳离子共聚物的氮含量和所述多糖-聚胺共聚物的氮含量在12.3wt％以上，阳离子共聚物和所述多糖-聚胺共聚物均不溶于水。

Description

多糖-聚氨共聚物及其在降低血浆中低密度脂蛋白浓度的应用 技术领域
本公开涉及多糖-聚氨共聚物及其在降低血浆中低密度脂蛋白浓度的应用。
背景技术
血液中的脂质物质包括胆固醇、磷脂、甘油三酯和脂肪酸等。循环血液中的胆固醇和甘油三酯(TG)必须与特殊的蛋白质即载脂蛋白结合形成脂蛋白，才能被运输至组织进行代谢。胆固醇和其他血浆脂质在血液中是以和载脂蛋白形成复合物的形式存在包括可将血浆脂蛋白分为：乳糜微粒(chylomicron，CM)、极低密度脂蛋白(very low density lipoprotein，VLDL、中间密度脂蛋白(intermediate density lipoprotein，IDL)、低密度脂蛋白(low density lipoprotein，LDL)和高密度脂蛋白(high density lipoprotein，HDL)。通常所说的高脂血症主要是指血胆固醇和/或甘油三酯升高。高脂血症是人体脂肪代谢异常的表现。主要分为三类：高胆固醇血症、高甘油三酯血症、和混合性高脂血症。2008年世界卫生组织统计以总胆固醇大于5mmol/L为标准，全世界约有37％成人患有高总胆固醇血症。其中欧洲54％，美洲48％，非洲22.6％，东南亚29％。2014年全美有七千三百五十万人(约人口的37％)患有高低密度脂蛋白(LDL)血症。中国国内临界高胆固醇血症及高胆固醇血症的比例分别为22.5％及9.0％。由此估算中国目前有3亿的临界高胆固醇血症患者以及1.2亿的高胆固醇血症患者。
低密度脂蛋白主要携带胆固醇，可用来合成细胞膜和固醇类激素。低密度脂蛋白胆固醇也被称为“坏胆固醇"，因为低密度脂蛋白是主要致动脉粥样硬化的微粒，氧化的或被化学修饰的LDL-胆固醇不能被组织利用和被肝脏清除，就会沉积到动脉管壁上形成斑块，引起动脉粥样硬化。健康人血液循环中2/3的LDL微粒被肝脏的LDL受体清除，如长期摄入高脂肪和高胆固醇的食物就会抑制LDL受体的活性，而使LDL-胆固醇水平升高。
大量的动物和人类试验研究资料均显示低密度脂蛋白胆固醇(LDL-C) 升高是致动脉粥样硬化形成的关键。LDL-胆固醇升高可引起冠心病的发生。大量随机临床研究证实，降低LDL-C可显著降低动脉粥样硬化性心血管疾病事件风险。血中总胆固醇(TC)的水平一般可反应LDL-胆固醇的水平。临床试验结果总胆固醇每减少1％，可减少2～3％的冠心病的事件。因此LDL-C是最主要的调脂治疗的靶点。在降脂治疗中，LDL-C也作为主要干预靶点。
发明内容
本文描述共价交联共聚物。更具体地，本文描述多糖-聚胺共聚物基体(matrices)和阳离子聚合物基体(matrices)。质子化时，多糖-聚胺共聚物可以形成具有非常高密度阳离子位点的阳离子聚合物基体。在一种形式中，多糖-聚胺共聚物具有一种三维结构，水合时尤其如此。
根据本发明的一种实施方式，所述多糖-聚胺共聚物基体是两个预存聚合物或大分子的反应的结果。根据本发明的一种实施方式，所述多糖-聚胺共聚物可以被认为是二嵌段共聚物。根据本发明的一种实施方式，所述多糖-聚胺共聚物是具有2,3-二醛基的被选择性氧化的多糖聚合物与具有多个能与醛基反应的多功能-胺基官能团的聚胺的反应产物。后者反应产物包括水凝胶或颗粒状共价交联的聚合物，其是多糖-聚胺共聚物，如纤维素-聚胺共聚物，具有三维结构。当多糖-聚胺共聚物材料的胺基官能被质子化时，胺基官能为阳离子聚合物提供阳离子官能。
在本发明的一个方面，多糖-聚胺共聚物材料中的一级胺、二级胺、三级胺均可被质子化。其中一级胺最容易被质子化，二级胺其次，三级胺再次。因此，多糖-聚胺共聚物材料中的一级胺是优选的，其次二级胺，再次三级胺。例如，多糖-聚胺共聚物材料中的一级胺占所有胺基团的20％以上，或者40％以上，或者53％以上。或者，多糖-聚胺共聚物材料中的一级胺、二级胺之和占所有胺基团的30％以上，或者50％以上，或者70％以上。
在本发明的一个方面，所述多糖聚合物选自被选择性氧化的纤维素(cellulose)、被选择性氧化的淀粉(starch)、被选择性氧化的壳聚糖(chitosan)、被选择性氧化的葡聚糖(dextran)、被选择性氧化的糖原(glycogen)、被选择性氧化的甲壳素(chitin)和它们的混合物组成的组。被选择性氧化是指将C2和 C3的位置的羟基氧化，伴随C2-C3键的断裂而形成醛基，其中该氧化只会生成醛基而不会生成羧基，并且不会裂解多糖链。
在本发明非常重要的一个方面，多糖是选自由被选择性氧化的纤维素、被选择性氧化的壳聚糖以及它们的混合物组成的组的纤维素聚合物。本文所使用的，被选择性氧化的纤维素、被选择性氧化的淀粉、被选择性氧化的壳聚糖、被选择性氧化的葡聚糖、被选择性氧化的糖原、被选择性氧化的甲壳素，其中所谓“被选择性氧化”是指氧化成二醛。在后的被选择性氧化的纤维素、被选择性氧化的壳聚糖对于用作药物的多糖-聚胺共聚物是重要的，因为它们含有不能被人类消化的β-1,4-糖苷键。聚合物如纤维素、淀粉、壳聚糖、葡聚糖、糖原、甲壳素等被氧化到有效提供能与聚胺充分反应的2,3-二醛基，以允许水溶性纤维素聚合物与多胺基官能聚合物反应，进而提供具有可质子化胺基官能的共价交联的基体或三维结构。
在后的多糖-聚胺共聚物基体和阳离子基体是不易被人类消化的。多糖-聚胺共聚物基体是多糖聚合物与聚胺连接在一起形成的三维共价交联基体，水合时尤其如此。这些共价交联聚合物的三维结构是颗粒形式，颗粒具有从约100μm至约10mm的范围内的尺寸。脱水形式的多糖-聚胺共聚物或共聚基体并不携带任何永久的电荷。这些共聚物含有丰富的胺基和少量的亚胺基。胺基和亚胺基属于pKa值在9至11的范围内的弱碱。当暴露于pH低于9.0的水性环境中时，多糖-聚胺共聚物或共聚物基体将被再水合、膨胀、质子化并形成阳离子聚合物基体。
多糖-聚胺共聚物颗粒和阳离子聚合物颗粒的结构是多孔的。从一方面讲，多糖-聚胺共聚物结构中俱有大量一级，二级和三级取代胺。无论是水胶状还是颗粒状的多糖-聚胺共聚物，均由多糖大分子与聚胺大分子通过共价交联形成三维立体的致密的网状结构。这种由多糖大分子与聚胺大分子通过共价交联形成三维立体的致密的网状结构与由纤维素外壳包裹的氨基或胺基与羧酸反应产物有着本质区别。当以颗粒形式存在时，多糖-聚胺共聚物基体和/或质子化的多糖-聚胺共聚物基体中的孔在小于50微米的尺寸范围内，并且在本发明的一个重要方面，孔具有从约数百纳米至约50微米的尺寸。例如，孔具有100nm-50微米的尺寸，或者孔具有200nm-40微米的尺寸，或者孔具有300nm-30微米的尺寸，或者孔具有400nm-20微米的尺寸，或者孔具有 500nm-10微米的尺寸，或者孔具有800nm-5微米的尺寸。低密度脂蛋白LDL的最结构外层，85％的蛋白质构成框架，磷脂的非极性部分镶嵌在框架中，其极性部分与水溶性的蛋白质等亲水基团突入周围水相，使其脂蛋白稳定地分散于水溶液中。因此LDL外层含有机磷酸根。由于本发明实施例提供的多糖-聚胺共聚物具有上述的较大的孔，其适合于吸附具有较大体积的带负电荷颗粒，例如上述的低密度脂蛋白。更详细地说，由于孔较大，LDL等具有较大体积的带负电荷颗粒能够被吸附进入孔中，充分利用了多糖-聚胺共聚物多孔结构所带来的大的表面积。如下文所述，常见的胆酸螯合剂类治疗高胆固醇血症的药物，其不具有多孔结构或者其孔径为几个纳米至十纳米，不利于吸附低密度脂蛋白等体积较大的阴离子。
在本发明的一个方面，多糖-聚胺共聚物结构提供了具有高密度的胺取代基，如伯胺、仲胺和季胺。根据本发明的一个方面，凝胶和聚合物颗粒可以由本发明的组合物提供。凝胶和聚合物颗粒可以包含被聚胺的共聚物区域共价交联而具有三维密集互锁网络的主链，例如纤维素链。纤维素聚合物和多聚胺交联剂共价交联形成的这种错综复杂的三维网状基体与纤维素壳包住胺基化合物的聚合物胺基与羧酸的反应形成了对比。
多糖聚合物，例如纤维素、淀粉、壳聚糖、葡聚糖、糖原、和甲壳素，被氧化到能够有效提供可与聚胺反应的2,3-二醛基，以允许上述氧化的多糖聚合物与具有胺基官能团的聚胺反应，进而提供具有至少12.5％(基于所述多糖-聚胺共聚物重量百分比)可被质子化氮含量的共价交联结构。聚胺交联多糖聚合物(如水溶性纤维素聚合物(具有二醛基))来提供多糖衍生的“骨架”的三维结构，其中多个多糖链与多个聚胺链连接。这些多糖聚合物是预先存在的聚合物“块”或“骨架”，其由同样属于离散的胺基“块”的预先存在的聚胺连接在一起。在本发明的一种实施方式中，所述多糖-聚胺共聚物可被认为是二嵌段共聚物。连接的骨架是作为聚胺(形成共价交联的块)和被选择性氧化的多糖的共价交联的产品，以提供具有高百分比的可被质子化的氮含量的共价交联嵌段共聚物和共聚物基体。
在后的形成胺基多糖结构颗粒的多糖-聚胺共聚物可以被质子化(在人体内，或通过降低pH或在体外通过反应如交联反应后对胺进行加氢还原)成具有极高的电荷密度阳离子聚合物结构。例如，当暴露于pH低于9.0的水性 环境中，在后的形成共聚物基体的多糖-聚胺共聚物可以被质子化。多糖-聚胺共聚物可以被质子化以有效地为阳离子共聚物基体提供至少12.5重量％铵含量(基于所述阳离子共聚物的重量)。此外如前所述，所得到的多糖-聚胺共聚物不溶于水。因此，本发明的多糖-聚胺共聚物明显区别于在本发明以前已有的水溶性的多糖-聚胺共聚物。本发明以前已有的水溶性的多糖-聚胺共聚物在水中可以形成稳定、透明、均一的胶体溶液，且体积较小，可被细胞吸收；而本发明的多糖-聚胺共聚物是由含有醛基的众多氧化多糖和含有多胺基的众多聚胺聚合物之间形成共价键并反复共价交联形成。因此共聚物分子量巨大，在水中极易沉淀，体积大于30微米，根本无法被细胞吸收。
该多糖-聚胺共聚物具有铵阳离子，该铵阳离子为具有正电荷或质子化的取代胺，如取代胺RNH2、R2NH和R3N等质子化而形成的RNH3 +、R2NH2 +和R3NH+等。聚胺基体在胺的位置上带正电或质子化，以形成季铵阳离子(HNR3 +)，其中一个或多个氢原子可以被有机基团取代(由R表示)。该高电荷密度可以在pH 7.0、磷酸盐浓度6.25mM的条件有效结合至少约2.58±0.43mmol/g磷酸根。实际上，阳离子基体可以作为清除剂，以从包括人类的哺乳动物体内去除磷酸盐。
在本发明的一个方面，聚胺是树枝状聚合物，它们是具有核或中心、包括胺基团和分支的大分子胺，其可从大分子胺的核或中心的官能团开始，通过一系列迭代反应来提供高度分支化的胺聚合物。在本发明的一方面，树枝状聚合物分子可以是圆形，或基本上是圆形，或是具有球形的或具有一个外周边是弯曲的或是由曲线界定的三维的形态。在本发明的一个重要的方面，树枝状聚合物具有至少24.5wt％，优选在25-80wt％(基于树枝状聚合物的重量)的氮含量，以使得多糖-聚胺共聚物材料质子化时(生成所述阳离子聚合物基体)具有至少约12.3wt％的铵离子含量(以N原子为基准计算)。在本发明的另一种形式中，支链型的聚胺可以单独或与具有树枝状形态的聚胺组合使用。
聚胺包括支链胺的聚合物、树枝状聚胺、以及在专利号US8889738和WO2014/029888中公开的聚胺(上述两篇专利文献中记载的聚胺全部包括进本文)。在本发明一个非常重要的实施方案中，为多糖-聚胺共聚物材料提供了胺基官能(以及在共价交联了多糖聚合物后在质子化时提供了阳离子官 能)的聚胺，选自聚乙烯亚胺(PEI)、聚烯丙基胺、聚丙烯亚胺和它们的混合物。所述聚乙烯亚胺(PEI)、聚烯丙基胺、聚丙烯亚胺可以为支链形式或树枝状的形式，如附图中所示。
本发明还提供一种制备多糖-聚胺共聚物材料和阳离子聚合物材料的方法。该方法包括氧化多糖聚合物，然后将如上所述的具有2,3-二醛基团的多糖衍生的聚合物与聚胺反应，以提供多糖-聚胺共聚物材料。如果聚胺的伯胺与被选择性氧化的多糖的醛基反应得到反应产物亚胺，可以通过还原反应例如加氢还原反应，将碳氮双键还原为单键，从而将亚胺转化为取代的仲胺。
Figure PCTCN2016076716-appb-000001
多糖的氧化水平、聚胺中胺的百分含量、聚胺的大小、和被选择性氧化的多糖与聚胺的比例都会影响到多糖-聚胺共聚物和共聚基体的形成。在本发明一个重要的方面，被选择性氧化的多糖具有至少50wt％，优选80％以上的氧化的葡萄糖单元。对于聚烯丙基胺(PLA)，分子量在约17000至约900000的范围内，对于聚乙烯亚胺(PEI)，分子量在约25000至约750000的范围内，优选在约60000至约750000的范围内。对于分子量在15000至25000道尔顿之间的PEI和/或PLA，多糖聚合物与聚胺的比率在约1：1至约1：3(重量比)。当分子量在65000至750000道尔顿之间时，多糖聚合物与聚胺的比率在约1：5至约1：30(重量比)。
生产出保持高正电荷密度的生物相容的阳离子聚合物，以与多价阴离子强烈结合，所述多价阴离子包括磷酸根、磷脂(脂蛋白表面为磷脂的磷酸根头部。因此亲水且带负电)、多聚核苷酸、带负电荷的肽和金属阴离子等。
在本发明的另一个方面，所述多糖-聚胺共聚物也可用于去除或清除其他无机阴离子和/或有机溶质或粒子，如氯化物、亚硝酸盐、碳酸氢盐、多核苷酸、多肽、胆汁酸、以及含草酸的化合物或离子等。在本发明的一种形式中，这(去除上述物质)可以用于从人体去除。
上述发明内容可以结合下面的描述和附图更容易地理解。
附图说明
为了更清楚地说明本发明实施例的技术方案，下面将对实施例的附图作简单地介绍，显而易见地，下面描述中的附图仅仅涉及本发明的一些实施例，而非对本发明的限制。
图1为本发明一实施方式中的共价交联共聚物，如多糖-聚胺共聚物的一般化学结构的一个示例性形式；
图2为本发明一实施方式中使用多糖主链共价交联合成多糖-聚胺共聚物的示例性的示意图；
图3A是支链的聚乙烯亚胺的实例，B是树突状聚乙烯亚胺的一个例子；
图4是本发明一些实施方式中的产品的表面形貌图；
图5是本发明一些实施方式中的反应物和产物的红外光谱FT-IR图；
图6是大鼠服用本发明实施例提供的多糖-聚胺共聚物三周后血液生化测试结果；
图7是大鼠服用本发明实施例提供的多糖-聚胺共聚物试验过程中体重的变化。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合本发明实施例的附图，对本发明实施例的技术方案进行清楚、完整地描述。显然，所描述的实施例是本发明的一部分实施例，而不是全部的实施例。基于所描述的本发明的实施例，本领域普通技术人员在无需创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
除非另作定义，本公开中百分比均为质量(重量)百分比。
一般地，共价交联共聚物在本文中描述并且可以被用于各种目的，包括但不限于：去除磷酸盐。共价交联共聚物通常包括两个部分，即，一个骨架分子和一个共价交联到骨架分子的官能团聚合物。在一种方法中，多糖聚合物和大的聚合物分子之间形成稳定的共价键以提供共价交联共聚物，该共价交联共聚物在其中的胺基和/或亚胺官能度质子化时，具有阳离子官能。
在本发明的一种实施方式中，共价交联共聚物是多糖-聚胺共聚物。多糖-聚胺共聚物在质子化时，可以形成具有非常高密度阳离子位点的阳离子聚合 物基体。在本发明的一种形式中，共价交联共聚物提供了一种三维结构，水合时尤其如此。在本发明的一些形式中，共价交联共聚物可以被更具体地描述为一个纤维素聚胺共聚物，其包括纤维素衍生材料形成多糖组分。
在本发明的一种实施方式中，本文所描述的制造不溶于水的阳离子聚合物的方法，包括氧化反应和羰基亲核加成反应。例如，氧化反应可以包括糖类的氧化，多糖可以列举如微晶纤维素、支链淀粉、淀粉、壳聚糖、甲壳素、葡聚糖、糖原或类似物。
在本发明的一种实施方式中，所述多糖聚合物选自被选择性氧化的纤维素、被选择性氧化的淀粉、被选择性氧化的壳聚糖、被选择性氧化的葡聚糖、被选择性氧化的糖原、被选择性氧化的甲壳素和它们的混合物组成的组。被选择性氧化是指将C2和C3位置的羟基氧化为醛基并伴随C2-C3键的断裂，但该氧化只生成醛基而不会产生羧基、也不会导致多糖链的断裂。
在本发明的一种实施方式中，适用于合成到共聚物的优选的多糖是α-D-葡萄糖单元或D-葡糖胺单元通过β-1,4-糖苷键彼此结合而形成的不溶性多糖，如纤维素(cellulose)、支链淀粉(Amylopectin)、壳聚糖(chitosan)、和甲壳素(chitin)。通过氧化反应，这些多糖C-2和C-3的葡萄糖单元上的羟基被选择性地氧化而产生丰富的醛基。这些新添加的亲水性醛基显著增加了被选择性氧化的多糖的水溶性。另外，该多糖聚合物选自由被选择性氧化的纤维素、被选择性氧化的淀粉、被选择性氧化的壳聚糖、被选择性氧化的葡聚糖、被选择性氧化的糖原、被选择性壳聚糖和它们的混合物组成的组。纤维素、支链淀粉和壳聚糖由于含有β-1,4糖苷键而不能被哺乳动物消化。淀粉、葡聚糖和糖原含有β-1,6糖苷键因而是可被人类消化的。因而，本文所述的多糖-聚胺共聚物基体是不是易消化的，取决于起始的多糖材料。
该多糖-聚胺共聚物可以以各种方式来制备。在本发明的一种实施方式中，例如该制备方法可以包括三个步骤。首先，通过氧化反应，通过选择性地氧化多糖的葡萄糖单元C2和C3上的羟基产生丰富的醛基。在一种方式中，被选择性氧化是指将C2和C3位置的羟基氧化为醛基并伴随C2-C3键的断裂，但该氧化只生成醛基而不会产生羧基、也不会导致多糖链的断裂。在该氧化反应的条件下，羧基不能共价交联聚胺，以及如果形成羧基，含水环境中羧基将会不合需要地形成羧酸。如果进一步形成(羧酸)，羧酸将携带负 电荷，这将对胺基质子化时形成的阳离子电荷产生不利的干扰。
其次，由多糖的选择性氧化生成的醛基与聚胺中的胺(例如伯胺)反应以形成亚胺衍生物，中间产物多糖-聚胺共聚物具有不稳定的碳-氮双键。在一种形式中，这些被认为是二嵌段共聚物。然后，通过还原反应，将亚胺的碳-氮双键转化为胺的碳-氮单键，以便产生稳定的多糖-聚胺共聚物。
根据本发明的一种方式，所述多糖-聚胺共聚物基体是两个预存聚合物或大分子反应的结果。按照一种形式，所述多糖-聚胺共聚物可以被认为二嵌段共聚物。在一种形式中，所述多糖-聚胺共聚物是具有2,3-二醛基的多糖聚合物与具有可与醛基反应的、多官能的胺基基团的聚胺的反应产物。后者反应产物包括颗粒状共价交联的聚合物，其是多糖-聚胺共聚物，如具有三维结构的纤维素聚胺共聚物。在多糖-聚胺共聚物材料中的胺基官能被质子化时，胺基官能为阳离子聚合物提供阳离子官能。
应该理解的是，本文所述的共价交联的共聚物也可以通过氧化多糖以外的其他方法制备。
从上述讨论氧化反应所得的中间聚合物可具有下列通式：
Figure PCTCN2016076716-appb-000002
下面的反应1是从纤维素获得示例性聚合物的方法的示意图。
纤维素是一种包括由β-1,4糖苷键相互连接的葡萄糖单元的天然存在的聚合物。形成纤维素衍生物聚合物的主链的纤维素的分子结构一般表示如下：
Figure PCTCN2016076716-appb-000003
正如反应1中所示，多糖如微晶纤维素可以被氧化以形成中间体纤维素。在一种方法中，由多糖主链的氧化产生富羰基中间体如醛。特别是，反应性醛基可以沿多糖骨架在多个位点打开纤维素环而形成。示例性纤维素的氧化反应可以如下：
Figure PCTCN2016076716-appb-000004
在上述示出的化学反应中，式“A”通常表示纤维素，其可以是任何市售的纤维素；式“B”通常表示纤维素的氧化生成的2,3-二醛。从上面可以看出，以上所述的2,3-二醛纤维素是一种具有类似于纤维素结构的线性聚合物，并且包括一个或多个(在图示的方式中是2个)反应性醛基。在一种方式中，纤维素可以用硫酸预处理以降低结晶度和尺寸。在另一种方式中，纤维素可以用盐酸处理。
尽管上述示例性化学反应利用高碘酸钠(NaIO4)作为氧化剂，应当理解的是，纤维素的氧化可以通过高碘酸、高碘酸钾或其它阳离子衍生物和高碘酸盐或类似物来替代地催化。其它氧化剂包括氯、过氧化氢、过乙酸、二氧化氯、二氧化氮、过硫酸盐、高锰酸盐、重铬酸盐-硫酸、次氯酸、次卤酸盐或高碘酸盐以及各种金属催化剂。除了原料的原有的羟基外，氧化的多糖(包括氧化的纤维素)还可以含有羧酸、醛和/或酮基团，这取决于氧化剂的性质和反应条件。
高碘酸盐是一种独特的氧化剂。多糖(包括纤维素)的高碘酸盐介导的氧化反应是公知的在C2和C3的羟基氧化为相应的醛基并伴随C2-C3键裂解的选择性氧化，并且是为多糖改性的最有效的方法之一。其它氧化剂会产生比醛基更多的羧基，并导致多糖主链的断裂。羧基不能在如我们所描述的反应条件下共价交联胺聚合物。此外，它还将电离并在水溶液中形成羧酸。羧酸携带负电荷，扰乱我们的共聚物的阳离子功能。
在一种方法中，如上述多糖氧化得到的聚合物中间体随后可与一种或多种支链阳离子官能团如胺基/亚胺聚合物进行羰基亲核加成(例如氢化物还原)反应。一般地，含多官能伯胺的分子可以与衍生自多糖如纤维素等或糖蛋白等的含醛的寡糖共价交联。通过一种方法，大分子量的多官能伯胺试剂 可以用来在后续质子化时为多糖衍生物提供高密度的阳离子位点。对于大多数方法，包含多个伯胺的任何多胺(包括直链和支链的)都可以用作亲核试剂。
以上所述的高分子量聚胺如聚乙烯亚胺与含醛基的多糖衍生物反应导致聚胺和多糖衍生物分子之间稳定的共价键形成。在一种形式中，这提供了上述通常用式“C”表示的和下面更详细讨论的共价交联的共聚物。另外，在上述示出的示例性反应中，作为纤维素与高碘酸钠的氧化反应的结果而得到的含反应性醛基的纤维素中间体进一步经受羰基亲核加成反应，以及在本实施例中，经历氢化物还原反应，用阳离子官能聚合物如聚乙烯亚胺来导出示例性的、通常由式“C”表示的不溶性阳离子纤维素衍生物聚合物。
尽管上述的示范性反应使用聚乙烯亚胺作为亲核试剂，在与上述包括反应性醛基团的纤维素中间体的反应中，其他示例性的聚合物也可以作为亲核试剂使用。一些示例性的阳离子官能聚合物包括，例如，聚(烯丙胺)、聚(酰胺基胺)、聚丙烯亚胺四胺等。作为含有合成聚胺的聚合物，聚乙烯亚胺、聚(烯丙胺)和聚丙烯亚胺四胺可以以支链和/或树枝状聚合物的形式使用。
此外，国际公开号WO 2014/029888的内容以引用的方式全部包括进本文，其中描述的支链或大环聚胺全部可适合用于本文所述的反应。此外，适合于本文描述的反应的一些示例性线性多胺列举如下：
Figure PCTCN2016076716-appb-000005
多糖衍生物与亲核试剂经历上述反应后，将所得产物可通过蒸发、沉淀或其它合适的技术进行干燥。通过一种方法，粒径均匀的多糖-聚胺共聚物材料可以由通过合适的筛网筛分干燥后的材料来实现。当以颗粒形式存在时，所述多糖-聚胺共聚物基体和/或质子化的多糖-聚胺共聚物基体具有小于50微米尺寸的孔，并且在一个重要方面，孔尺寸从约数百纳米至约50微米范围内。
通过一种方法，阳离子聚合物产物的胺基密度也可以通过聚合度、亲核试剂的尺寸和多糖衬底主链和亲核试剂的相对比例来控制。在本申请中，电荷密度是指阳离子聚合物中的一级、二级、三级铵阳离子的数量。更具体地，电荷载体密度是指每单位体积材料(例如，阳离子聚合物)中电荷载体(例如，电子、离子)的数量，而不是在载体上的实际电荷数量。根据一种形式，制备所述胺基多糖以为共价交联的结构提供基于所述多糖共聚物总重量的至少12.5(重量)％的胺基官能(以N原子重量进行计算)。在一个重要的方面，树枝状聚合物具有基于所述树枝状聚合物重量至少24.5(重量)％，优选25-80(重量)％的胺基(以N原子重量进行计算)，以为多糖-聚胺共聚物材料在质子化形成阳离子聚合物基体时有效地提供基于阳离子材料的至少12.3(重量)％的阳离子含量(以N原子重量进行计算)。
含醛多糖衍生物和官能伯胺的亲核试剂的比例范围，可定性地描述为低、中、高。在一种方法中，醛的含量和反应物的伯胺含量是通过定量滴定法测定，而最终产物的NH2 +含量是由核磁共振技术(NMR)确定的。
图2提供了另一示例性过程的图示，展示了多糖与聚胺的反应。
从上述的氧化反应和羰基亲核加成反应得到的共价交联的共聚物的物理特性可通过操纵上述反应的条件加以控制，例如，通过改变含醛基的选择性氧化的多糖与亲核试剂的相对比例、改变与含醛基的选择性氧化的多糖反应的官能团的种类、和/或改变反应时间、pH和/或反应温度等。例如，增加该反应的温度可导致所得的水不溶性阳离子聚合物的大小相应地增加。在另一实例中，增加反应时间可导致所得的水不溶性阳离子聚合物的大小相应地增加。在又一实例中，增加的反应条件的pH可导致所得共价交联的共聚物的尺寸的相应增加。在又一示例中，得到的共价交联的共聚物产品的尺寸可以通过选择两个主要反应物，即多糖衍生物(例如2,3-二醛纤维素)和聚胺亲核试剂(例如聚乙烯亚胺)，的分子量和的比率来控制。
在一种方法中，可以使用具有平均分子量约15000Da(道尔顿)至约900000Da的聚烯丙基胺(polyallylamine，PLA)或具有平均分子量约25000Da至约750000Da的聚乙烯亚胺(PEI)。例如，可以使用自Sigma-Aldrich获得的具有平均分子量大约15000道尔顿、17000道尔顿、65000道尔顿、或900000道尔顿的聚烯丙基胺，或具有平均分子量大约25000道尔顿或750000道尔顿的聚乙酰亚胺。多糖主链部分(例如纤维素)与阳离子位点形成功能性聚合物(例如聚乙烯亚胺)的比例可取决于阳离子位点形成功能性聚合物的分子量。例如，对于分子量为约15000Da至约25000Da的聚乙烯亚胺(PEI)和聚烯丙基胺(PLA)，该纤维素衍生物与聚胺的比例范围可为约1：1至约1：8(重量比)。在一种方法中，当聚乙烯亚胺(PEI)和聚烯丙基胺(PLA)分子量范围为约65000Da至约750000Da的情况下，该纤维素衍生物与聚胺的比例为约1:5到约1:20(重量比)。
在一个方面，聚胺是具有核心或中心的、包括胺基团和分支的树枝状高分子，其可从所述核心或中心的功能基团开始，通过一系列迭代反应以提供高度分支化的胺聚合物。在一个方面，树枝状聚合物分子可以是圆形或基本上圆形或具有三维的形态，其是球形的或具有一个外周边是弯曲的或是由曲 线界定。在一个重要的方面，树枝状聚合物具有基于所述树枝状聚合物重量至少24.5(重量)％，优选25-80(重量)％的胺基(以N原子重量计算)，以为多糖-聚胺共聚物材料在质子化形成阳离子聚合物基体时有效地提供基于阳离子材料的至少12.3(重量)％(以N原子重量计算)的阳离子含量。
该共价交联的共聚物产品的粒径可以通过将交联多官能伯胺(例如聚乙烯亚胺)与具有低、中、和非常高的分子量(例如范围从约15,000道尔顿至约750000道尔顿)的多糖衍生物(例如2,3-二醛纤维素)进行反应来调节，以获得纳米颗粒、微米颗粒、和毫米大小的颗粒。
多糖-聚胺共聚物基体是多糖聚合物与聚胺相互连接形成的三维共价交联基体，尤其是在水合状态下。这些共价交联聚合物的三维结构是颗粒形式，这些颗粒具有从约100μm至约10毫米范围内的尺寸。脱水形式的多糖-聚胺共聚物或共聚基体并不携带任何永久的电荷。这些共聚物含有丰富胺基和少量的亚胺基。胺和亚胺被归类为pKa值在9至11范围内的弱碱。当暴露于pH低于9.0下水性环境中，多糖-聚胺共聚物或共聚物基体将被再水合、膨润、质子化并形成阳离子聚合物基体。
多糖聚合物，例如纤维素、淀粉、壳聚糖、葡聚糖、糖原和甲壳素，被氧化生成足够量的、能与聚胺反应的2,3-二醛基，以允许氧化聚合物与多胺基官能聚胺反应，这反过来提供具有基于多糖共聚物重量的至少12.5(重量)％的胺基官能(以N原子重量计算)的共价交联的结构。聚胺交联多糖聚合物，如水溶性纤维素聚合物(具有二醛部分)来提供多糖衍生的“骨架”的三维结构，其中多个多糖链与多个聚胺链连接。这些多糖聚合物是预先存在的聚合物“块”或“骨架”，其被同样是预先存在的聚胺“块”连接在一起。在一种形式中，所述多糖-聚胺共聚物可被认为是二嵌段共聚物。连接的骨架作为胺聚合物(形成共价交联的块)和选择性氧化多糖的共价交联的产品键合在一起，以提供可被质子化的、具有高百分比的胺含量的共价交联的嵌段共聚物和共聚物基体。
得到的共价交联共聚物，如多糖-聚胺共聚物，可以制备为固体粉末、凝胶和类似的形式。另外，当体外pH为7条件下磷酸盐水平是6.25mM时，共价交联共聚物可以具有2.59±0.43mmol/g的磷酸盐结合能力。在一种形式中，体外在pH 6下，当磷酸盐浓度是5mm的生理磷酸盐水平下，共价交联 共聚物具有最大磷酸盐结合能力2.56±0.27mmol/g。根据一种形式，在室温下，在水中至少贮存3个月后，所述共价交联的共聚物可显示稳定的磷酸盐结合性质。根据一种形式中，该共价交联的共聚物的膨胀系数可以是6.43±0.36倍以上。
现有临床上供选用的治疗高胆固醇血症药物共有5类包括：他汀类、贝特类、烟酸类、胆酸螯合剂、胆固醇吸收抑制剂。他汀类、胆固醇吸收抑制剂和树脂类主要针对高低密度脂蛋白胆固醇血症。其中他汀类(3-羟基-3-甲基-戊二酰辅酶A还原酶抑制剂)是当前防治高胆固醇血症和动脉粥样硬化性疾病非常重要的药物。流行病学研究与现有临床试验显示，由于遗传学背景的差异，我国人群对于大剂量、高强度他汀类药物治疗的耐受性和安全性较差，发生肝毒性、肌肉毒性的风险明显高于欧美国家患者。他汀类药物还可增高服用者血糖水平，增加II型糖尿病风险。胆固醇吸收抑制剂作用于小肠细胞的刷状缘，有效地抑制胆固醇和植物固醇的吸收。尽管此类药物安全性和耐受性良好，但是单独服用仅能使LDL-C约降低18％。
胆酸螯合剂又称树脂类调脂药物。此类药物为碱性阴离子交换树脂，在肠道内能与胆酸呈不可逆结合，因而阻碍胆酸的肠肝循环，促进胆酸随大便排出体外，阻断胆汁酸中胆固醇的重吸收。通过反馈机制刺激肝细胞膜表面的LDL受体，加速LDL血液中LDL清除，结果使血清LDL-C水平降低。胆酸螯合剂可使TC降低15％～20％，LDL-C降低15％～30％；HDL-C升高3％～5％。临床试验证实这类药物能降低主要冠状动脉事件和冠心病死亡。现有胆酸螯合剂包括沁心青(考来烯胺，Cholestyramine)，降胆宁(考来替泊，Colestipol)和盐酸考来维仑粉剂。尽管它们对高低密度脂蛋白胆固醇血症均有明显良好疗效。但是这三种药物均存在不足：(1)考来烯胺-含苯环结构多聚物，可影响多种药物吸收；(2)考来替泊-含环状结构多聚物可影响多种药物吸收，含致癌致畸化学物质表氯醇；(3)盐酸考来维仑粉剂，有10％病人出现胃肠功能紊乱，含致癌致畸化学物质表氯醇。司维拉姆和比沙洛姆是碱性阴离子交换树脂类的非钙非金属类磷结合剂。大量临床研究发现司维拉姆可降低血浆总胆固醇约20％，降低血浆LDL-C约23％。但因其含有表氯醇这种众所周知的致癌剂和致畸剂合成底物存留且药物价格昂贵，并未作为降脂药使用。
本发明的发明人在研究中发现，本发明实施例提供的多糖-聚胺共聚物可作为很好的治疗高胆固醇血症药物，原因在于本发明实施例提供的多糖-聚胺共聚物含有丰富胺基和少量的亚胺基，当暴露于pH低于9.0下水性环境中，多糖-聚胺共聚物或共聚物基体将被再水合、膨润、质子化并形成阳离子聚合物基体，该阳离子聚合物基体表面具有高密度的正电荷，可以与带负电的脂蛋白及胆酸结合，同样的，质子化的多糖-聚胺共聚物在肠道内通过与脂蛋白和胆酸的结合，从而阻碍脂蛋白和胆酸的肠肝循环，促进脂蛋白，胆固醇及胆酸随大便排出体外，阻断脂蛋白和胆固醇的在小肠吸收。并通过反馈机制刺激肝细胞膜表面的LDL受体，加速LDL血液中LDL清除，结果使血清LDL-C水平降低。同时，与常规的胆酸螯合剂(树脂类调脂药物)相比，口服本发明实施例提供的多糖-聚胺共聚物为有效成分的药物不存在上述不足。第一，本发明实施例提供的多糖-聚胺共聚物几乎不含苯环结构，不会影响其他药物吸收，也即很少存在药物干扰；第二，多糖-聚胺共聚物不含致癌致畸化学物质表氯醇；第三，实验发现，口服本发明实施例提供的多糖-聚胺共聚物几乎不会对正常的肠胃功能带来任何干扰；第四，本发明实施例提供的多糖-聚胺共聚物制造成本低。
下面通过具体的实例来更具体地描述本发明多糖-聚胺共聚物的结构、组成以及制备方法。本发明多糖-聚胺共聚物的表征均采用本领域的成熟手段。例如，聚胺、多糖-聚胺共聚物的氮含量可以通过分子式推算以及通过元素分析测量；多糖-聚胺共聚物的孔径由光学显微镜测量；FI-IR通过Thermo Nicolet 4700FT-IR Spectrometer测量；
实施例1多糖-聚胺共聚物的制备
1.由高碘酸钠氧化合成2,3-二醛纤维素(DAC)：
1.1.由高碘酸钠氧化纤维素制备可溶性2,3-二醛纤维素(2,3-dialdehyde cellulose，DAC)(氧化的葡萄糖单元>80％)
1).用200毫升去离子水分散10克纤维素(粒度<100nm、20微米或50微米或纤维)；
2).添加20克高碘酸钠；
3).用6x的HCl调节pH至3.0；
4).用氮气脱气并吹扫；
5).在黑暗中、60℃、pH＝3下搅拌反应4小时；
6).通过添加10毫升乙二醇停止反应；
7).用去离子水对产品进行透析3天；
8).在40,000g下离心30分钟，收集作为上清的可溶的DAC，以除去不溶性的DAC；
9).收集的上清进行冷冻干燥(可选)。
1.2.由高碘酸钠氧化纤维素(氧化的葡萄糖单元数<80％)合成不溶的2,3-二醛纤维素(DAC)：
1).分散10克纤维素(尺寸：<100nm、20微米、50微米或纤维)于200毫升去离子水中；
2).添加10克高碘酸钠；
3).用6x的HCl调节pH至3.0；
4).用氮气脱气并吹扫；
5).在黑暗中、60℃、pH＝3下搅拌反应4小时；
6).通过添加10毫升乙二醇停止反应；
7).产物用去离子水洗涤；
8).在2000g下离心分离10分钟，收集不溶的DAC；
9).洗涤后的不溶DAC将用去离子水(DI water)进行再分散。
10).洗涤后的不溶DAC进行冷冻干燥(可选)。
Poly(allylamine hydrochloride):PLA聚(丙烯胺盐酸盐)/聚烯丙基胺盐酸盐/
Polyethyleneimine:PEI聚乙烯亚胺
Figure PCTCN2016076716-appb-000006
2.由可溶的DAC与PEI制备多糖-聚胺共聚物
PEI分子量750K，DAC与PEI重量比例1：10
1).将45克支链状聚乙烯亚胺PEI(分子量750K，50重量％的水溶液)添加到500mL烧杯中；
2).用37％HCl调整PEI的pH为1.0；
3).将5克上述支链状聚乙烯亚胺PEI(分子量750K，50重量％的水溶液)加入到50ml离心管中并用等体积的去离子水稀释；
4).通过加入6X HCl调节上述含有5克可溶性DAC的100毫升溶液的pH值至1.0；
5).PEI的溶液和DAC的溶液在冰上温育10分钟；
6).将含有45克PEI的溶液和含有5g DAC的溶液混合，并在冰上温育10分钟，同时搅拌；
7).将含5克稀释的PEI的溶液快速加入到上述PEI-DAC混合物中，在冰上温育并在1000rpm搅拌5分钟；
8).将混合物保持在冰上不搅拌直到水凝胶完全形成；
9).将上述水凝胶在70℃温育60分钟；
10).通过网筛筛分水凝胶以实现凝胶颗粒具有均匀的尺寸；
11).加入去离子水，使水凝胶颗粒悬浮液的总体积至1000ml；
12).水凝胶颗粒的悬浮液在70℃另外温育60分钟，每隔10分钟检测该悬浮液的pH值，并用5M氢氧化钠溶液调整到8.5；
13).凝胶颗粒通过重力在室温下沉淀；
14).吸出上清液后，将颗粒用4升100mM、pH 8.5的碳酸氢钠溶液在搅拌下孵育60分钟，并在室温通过重力沉淀；
15).吸出上清液后，将沉淀的凝胶颗粒物用4升去离子水洗涤两次并通过重力沉淀；
16).吸出上清液后，通过加入10克硼氢化钠还原沉淀的凝胶颗粒，并在室温下温育72小时；
17).还原的凝胶颗粒用去离子水洗涤以除去过量的硼氢化钠和PEI直到溶液的pH在5和6之间；
18).洗涤后的凝胶颗粒冷冻干燥(可选)。所获最终产品为白色或淡黄色水胶状颗粒，合成产率为70-80％，含氮量约为20％。
实施例2多糖-聚胺共聚物的制备
反应条件与实施例1相同，不同的是PEI分子量750K，DAC与PEI重量比例1：20。所获最终产品为白色或淡黄色水胶状颗粒，合成产率为50-60％，含氮量约为21.5％。
实施例3多糖-聚胺共聚物的制备
反应条件与实施例1相同，不同的是DAC与PEI重量比例1：30。所获最终产品为白色或淡黄色水胶状颗粒，合成产率为20-40％，含氮量约为22％。
实施例4多糖-聚胺共聚物的制备
反应条件与实施例1相同，不同的是PEI分子量为25K，DAC与PEI重量比例1：1。所获最终产品为白色或淡黄色固体颗粒，合成产率为60-70％，含氮量约为12.5％。
实施例5多糖-聚胺共聚物的制备
反应条件与实施例1相同，不同的是PEI分子量为25K，DAC与PEI重量比例1：2。所获最终产品为白色或淡黄色固体颗粒，合成产率为20-40％，含氮量约为15％。
实施例6多糖-聚胺共聚物的制备
反应条件与实施例3相同，不同的是DAC与PEI重量比例1：3。所获最终产品为白色或淡黄色水胶颗粒，合成产率为10-20％，含氮量约为16.9％。
实施例7多糖-聚胺共聚物的制备
由不可溶的DAC与聚胺制备颗粒状的多糖-聚胺共聚物
1).50g聚(烯丙胺盐酸盐)(分子量58K和15K)或聚乙烯亚胺(分子量750K和25K)分散于去离子水中以达到总体积100毫升；
2).用37％HCl或NaOH调节溶液pH至9.0并通过加入去离子水使总体积至300毫升；
3).用100mL去离子水分散该不溶DAC；
4).用6N盐酸调节pH至2后，将不溶性的DAC悬浮液在500rpm搅拌下、以10ml/min的速度加入到聚胺溶液中，然后在70℃温育60分钟；
5).通过网筛筛分水凝胶以实现凝胶颗粒具有均匀的尺寸；
6).用5M氢氧化钠溶液滴定颗粒悬浮液至pH 8.5；
7).加入去离子水，使凝胶颗粒悬浮液的总体积在500ml、pH至8.5；
8).凝胶颗粒的悬浮液在70℃温育另外60分钟，每隔10分钟检测悬浮液的pH，并用5M氢氧化钠溶液调整到8.5；
9).凝胶颗粒通过重力在室温下沉淀；
10).吸出上清液后，将颗粒用4升100mM、pH 8.5的碳酸氢钠溶液在搅拌下孵育60分钟，并在室温通过重力沉淀；
11).吸出上清液后，将沉淀的凝胶颗粒物用4升去离子水洗涤两次并通过重力沉淀；
12).通过加入10克硼氢化钠还原沉淀的凝胶颗粒，并在室温下温育72小时；
13).还原的凝胶颗粒用去离子水洗涤以除去过量的硼氢化钠和聚胺直到溶液的pH在5和6之间；
14.对洗涤后的凝胶颗粒冷冻干燥(可选)，所获最终产品为白色或淡黄色固体颗粒，合成产率为50-80％，含氮量约为12.5％。
实施例8多糖-聚胺共聚物的制备
反应条件与实施例7相同，不同的是聚胺为PLA(MW 58K)，DAC与PLA重量比例1：5。获得最终产品，所获最终产品为白色或淡黄色固体颗粒，合成产率为50-80％，含氮量约为18％。
实施例9多糖-聚胺共聚物的制备
反应条件与实施例8相同，不同的是DAC与PLA重量比例1：10。所获最终产品为白色或淡黄色水胶颗粒，合成产率为40-60％，含氮量约为20％。
实施例10多糖-聚胺共聚物的制备
反应条件与实施例8相同，不同的是DAC与PLA重量比例1：20。所获最终产品为白色或淡黄色水胶颗粒，合成产率为30-50％，含氮量约为21％。
实施例11多糖-聚胺共聚物的制备
反应条件与实施例8相同，不同的是DAC与PLA重量比例1：2。所获最终产品为白色或淡黄色水胶颗粒，合成产率为25-45％，含氮量约为12.8％。
实施例12多糖-聚胺共聚物的制备
反应条件与实施例8相同，不同的是DAC与PLA重量比例1：3。所获最终产品为白色或淡黄色水胶颗粒，合成产率为30-55％，含氮量约为13.0％。
实施例13多糖-聚胺共聚物的形貌
图4显示了本发明产品的外观形貌。图4A是多糖-聚胺共聚物正电化后形成的阳离子共聚物CelloPhos；图4B是还原后的颗粒状CelloPhos；图4C是按照实施例1的步骤获得的产品在空气中干燥后的颗粒状CelloPhos(DAC:PEI 750K＝1:20)；图4D是按照实施例2获得的产品空气中干燥后的颗粒状CelloPhos(DAC:PEI750K＝1:20)；图4E是用曙红Eosin染色的颗粒状CelloPhos相位对比图。从结果可以得到的结论有：
1)本发明的多糖-聚胺共聚物是在特殊的共聚反应条件下得到的亲水材料水凝胶；
2)通过筛分获得均一的、小粒径的水凝胶；
3)空气干燥可以获得黄色粉末状颗粒；
4)正电化的多糖-聚胺共聚物颗粒可以结合染料曙红Eosin；
5)多糖-聚胺共聚物颗粒具有多孔、多层的结构，这增强了其对磷酸根的吸附、结合能力。
实施例14多糖-聚胺共聚物的FT-IR图谱
图5显示了本发明产品的FT-IR图谱。其中，图5A，1：纤维素；2：被选择性氧化的2,3-二醛纤维素；3：分支状的PEI(MW 750K and 25K)；4：多糖-聚胺共聚物CelloPhos(PEI MW 750K，DAC:PEI＝1:20)。图5B，5：纤维素；6：被选择性氧化的2,3-二醛纤维素；7：分支状的PLA(MW 58K)；8：多糖-聚胺共聚物CelloPhos(PLA MW 58K，DAC:PLA＝1:20)。图5C，9：多糖-聚胺共聚物CelloPhos(PEI MW 25K，DAC:PEI＝1:10)；10：多糖-聚胺共聚物CelloPhos(PEI MW 750K，DAC:PEI＝1:20)；11：多糖-聚胺共聚物CelloPhos(PLA MW 58K，DAC:PLA＝1:20)。
从图5可以看出，多糖-聚胺共聚物CelloPhos的FT-IR谱图明显区别于反应物的FT-IR谱图。由图可见，本发明得到的新物质多糖-聚胺共聚物CelloPhos具有独特的FT-IR吸收光谱。
实施例15降总胆固醇和低密度脂蛋白胆固醇(LDL-C)动物实验
“赛洛喜”即以本发明实施例提供的多糖-聚胺共聚物为活性成分的药品名称。在本实施例中，赛洛喜100％为多糖-聚胺共聚物活性成分。
Rodent 5008 Fomulab(LabDiet,Louis,MO)作为标准食物。赛洛喜(即CelloPhos(PEI MW 750K,DAC:PEI＝1:20))以1％重量比加入标准食物作为实 验食物。纤维素也以1％的重量比加入标准食物作为负控制(阴性对照)食物。雌性和雄性大鼠(Sprague Dawley)先以标准食物喂养14天。在第14天，通过抽取血液样品测定血浆总胆固醇和低密度脂蛋白含量作为基线。随后将标准饮食替换为试验饮食和阴性对照组饮食。并于食物替换后的第21天再次抽取血液样品测定血浆总胆固醇和低密度脂蛋白含量。试验结果列于下表一和二。由表可见，赛洛喜明显降低了大鼠血浆中总胆固醇浓度和LDL-C浓度。
表一、赛洛喜降总胆固醇试验结果
Figure PCTCN2016076716-appb-000007
表二、赛洛喜降LDL-C试验结果
Figure PCTCN2016076716-appb-000008
实施例16副作用
附图6显示了大鼠服用本发明实施例提供的多糖-聚胺共聚物三周后血液生化测试结果。由图可见，服用本发明实施例提供的多糖-聚胺共聚物对于大鼠血液中各种酶的水平没有明显的影响，由此证明本发明实施例提供的多 糖-聚胺共聚物是安全无毒的。图7则显示了试验过程中动物体重的变化。由图可见，在整个试验过程中，所有动物体重都增加了。这个数据间接表明了口服1％的本发明实施例提供的多糖-聚胺共聚物对于试验动物的胃肠道没有任何明显的副作用。
以上所述仅是本发明的示范性实施方式，而非用于限制本发明的保护范围，本发明的保护范围由所附的权利要求确定。
本申请要求于2015年3月20日递交的美国专利申请第62136220号的优先权，在此全文引用上述美国专利申请公开的内容以作为本申请的一部分。

Claims (61)

  1. 一种多糖-聚胺共聚物，所述多糖-聚胺共聚物由以下两部分共聚形成：
    具有2,3-二醛基的被选择性氧化的多糖，和具有胺基功能团的聚胺；
    所述具有胺基功能团的聚胺与所述具有2,3-二醛基的被选择性氧化的多糖共价交联形成网状结构，得到具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物，所述具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物中的胺基功能团可被质子化而形成具有质子化位点的三维网状结构阳离子共聚物，所述阳离子共聚物的氮含量和所述多糖-聚胺共聚物的氮含量在12.3wt％以上，或者在15wt％以上，或者在22wt％以上，或者在40wt％以上，所述阳离子共聚物和所述多糖-聚胺共聚物均不溶于水。
  2. 根据权利要求1所述的多糖-聚胺共聚物，其中所述具有胺基功能团的聚胺的氮含量在24.5wt％以上，或者在30wt％以上，或者在44wt％以上，或者在80wt％以上。
  3. 根据权利要求1或2所述的多糖-聚胺共聚物，其中所述具有胺基功能团的聚胺的分子量为约15000-约900000。
  4. 根据权利要求1-3的任一项所述的多糖-聚胺共聚物，其中所述具有2,3-二醛基的被选择性氧化的多糖选自下述物质中的一种或多种：被选择性氧化的纤维素、被选择性氧化的淀粉(starch)、被选择性氧化的支链淀粉(Amylopectin)、被选择性氧化的壳聚糖、被选择性氧化的葡聚糖、被选择性氧化的糖元、被选择性氧化的甲壳素。
  5. 根据权利要求1-3的任一项所述的多糖-聚胺共聚物，其中所述具有2,3-二醛基的被选择性氧化的多糖中被氧化的葡萄糖单位数量占所有葡萄糖单位数量的50％以上，优选70％以上，更优选80％以上。
  6. 根据权利要求1-5的任一项所述的多糖-聚胺共聚物，其中所述具有2,3-二醛基的被选择性氧化的多糖具有β-1,4-糖苷键和β-1,6-糖苷键的至少之一。
  7. 根据权利要求6所述的多糖-聚胺共聚物，其中所述具有2,3-二醛基的被选择性氧化的多糖具有β-1,4-糖苷键且不具有β-1,6-糖苷键。
  8. 根据权利要求1-7的任一项所述的多糖-聚胺共聚物，其中所述具有 2,3-二醛基的被选择性氧化的多糖选自下述物质中的一种或多种：被选择性氧化的纤维素、被选择性氧化的支链淀粉(Amylopectin)、被选择性氧化的壳聚糖、被选择性氧化的甲壳素。
  9. 根据权利要求1-8的任一项所述的多糖-聚胺共聚物，其中所述具有胺基功能团的聚胺选自下述物质中的一种或多种：聚乙烯亚胺(PEI)、聚烯丙基胺、聚丙烯亚胺、聚丙烯亚胺四胺。
  10. 根据权利要求1-9的任一项所述的多糖-聚胺共聚物，其中所述具有胺基功能团的聚胺具有支链结构或者树枝状结构。
  11. 根据权利要求1-10的任一项所述的多糖-聚胺共聚物，其中所述具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物和所述阳离子共聚物的尺寸在30μm-10mm之间，优选100μm-10mm之间，更优选300μm-5mm之间。
  12. 根据权利要求1-11的任一项所述的多糖-聚胺共聚物，其中所述具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物和所述阳离子共聚物具有直径小于50μm的孔。
  13. 一种多糖-聚胺共聚物的制备方法，包括：
    将具有2,3-二醛基的被选择性氧化的多糖与具有胺基功能团的聚胺发生共价交联反应形成网状结构，得到具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物，所述具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物中的胺基功能团可被质子化而形成具有质子化位点的三维网状结构阳离子共聚物，所述阳离子共聚物的氮含量和所述多糖-聚胺共聚物的氮含量在12.3wt％以上，或者在15wt％以上，或者在22wt％以上，或者在40wt％以上，所述阳离子共聚物和所述多糖-聚胺共聚物均不溶于水。
  14. 根据权利要求13所述的方法，其中所述具有胺基功能团的聚胺的氮含量在24.5wt％以上，或者在30wt％以上，或者在44wt％，或者在80wt％以上。
  15. 根据权利要求13或14所述的方法，其中所述具有胺基功能团的聚胺的分子量为约15000-约900000。
  16. 根据权利要求13-15的任一项所述的方法，其中所述具有2,3-二醛基的被选择性氧化的多糖选自下述物质中的一种或多种：被选择性氧化的纤 维素、被选择性氧化的淀粉、被选择性氧化的支链淀粉、被选择性氧化的壳聚糖、被选择性氧化的葡聚糖、被选择性氧化的糖元、被选择性氧化的甲壳素。
  17. 根据权利要求13-16的任一项所述的方法，其中所述具有2,3-二醛基的被选择性氧化的多糖中被氧化的葡萄糖单位数量占所有葡萄糖单位数量的50％以上，优选70％以上，更优选80％以上。
  18. 根据权利要求13-17的任一项所述的方法，其中所述具有2,3-二醛基的被选择性氧化的多糖具有β-1,4-糖苷键和β-1,6-糖苷键的至少之一。
  19. 根据权利要求13-18的任一项所述的方法，其中所述具有2,3-二醛基的被选择性氧化的多糖具有β-1,4-糖苷键且不具有β-1,6-糖苷键。
  20. 根据权利要求13-19的任一项所述的方法，其中所述具有2,3-二醛基的被选择性氧化的多糖选自下述物质中的一种或多种：被选择性氧化的纤维素、被选择性氧化的支链淀粉、被选择性氧化的壳聚糖、被选择性氧化的甲壳素。
  21. 根据权利要求13-20的任一项所述的方法，其中所述具有胺基功能团的聚胺选自下述物质中的一种或多种：聚乙烯亚胺(PEI)、聚烯丙基胺、聚丙烯亚胺、聚丙烯亚胺四胺。
  22. 根据权利要求13-21的任一项所述的方法，其中所述具有胺基功能团的聚胺具有支链结构或者树枝状结构。
  23. 根据权利要求13-22的任一项所述的方法，其中所述具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物和所述阳离子共聚物的尺寸在30μm-10mm之间，优选100μm-10mm之间，更优选300μm-5mm之间。
  24. 根据权利要求13-23的任一项所述的方法，其中所述具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物和所述阳离子共聚物具有直径小于50μm的孔。
  25. 根据权利要求13-24的任一项所述的方法，其中该方法可以包括三个步骤，步骤一，通过氧化反应，通过选择性地氧化多糖的葡萄糖单元C2和C3上的羟基产生醛基，得到所述的具有2,3-二醛基的被选择性氧化的多糖；步骤二，所述具有2,3-二醛基的被选择性氧化的多糖中的醛基与所述聚胺中的胺基反应形成亚胺衍生物；步骤三，通过还原反应，将所述亚胺衍生 物中亚胺的碳-氮双键转化为胺的碳-氮单键，得到所述多糖-聚胺共聚物。
  26. 根据权利要求25所述的方法，其中步骤一中选择性地氧化用到的氧化剂包括高碘酸、高碘酸钠、高碘酸钾或其阳离子衍生物、氯、过氧化氢、过乙酸、二氧化氯、二氧化氮、过硫酸盐、高锰酸盐、重铬酸盐-硫酸、次氯酸、次卤酸盐或高碘酸盐以及各种金属催化剂。
  27. 根据权利要求25所述的方法，其中步骤三的所述还原反应为加氢还原反应，所用的还原剂包括硼氢化钠或硼氢化钾。
  28. 一种阳离子共聚物，所述阳离子共聚物包括质子化的多糖-聚胺共聚物，所述多糖-聚胺共聚物由以下两部分共聚形成：
    具有2,3-二醛基的被选择性氧化的多糖，和具有胺基功能团的聚胺；
    所述具有胺基功能团的聚胺与所述具有2,3-二醛基的被选择性氧化的多糖共价交联形成网状结构，得到具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物，所述具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物中的胺基功能团被质子化而形成具有质子化位点的三维网状结构阳离子共聚物，所述阳离子共聚物的氮含量在12.3wt％以上，或者在15wt％以上，或者在22wt％以上，或者在40wt％以上，所述阳离子共聚物和所述多糖-聚胺共聚物均不溶于水。
  29. 根据权利要求28所述的阳离子共聚物，其中所述具有胺基功能团的聚胺中的氮含量在24.5wt％以上，或者在30wt％以上，或者在44wt％以上，或者在80wt％以上。
  30. 根据权利要求28或29所述的阳离子共聚物，其中所述具有胺基功能团的聚胺的分子量为约15000-约900000。
  31. 根据权利要求28-30的任一项所述的阳离子共聚物，其中所述具有2,3-二醛基的被选择性氧化的多糖选自下述物质中的一种或多种：被选择性氧化的纤维素、被选择性氧化的淀粉、被选择性氧化的支链淀粉、被选择性氧化的壳聚糖、被选择性氧化的葡聚糖、被选择性氧化的糖元、被选择性氧化的甲壳素。
  32. 根据权利要求28-31的任一项所述的阳离子共聚物，其中所述具有2,3-二醛基的被选择性氧化的多糖中被氧化的葡萄糖单位数量占所有葡萄糖单位数量的50％以上，优选70％以上，更优选80％以上。
  33. 根据权利要求28-32的任一项所述的阳离子共聚物，其中所述具有2,3-二醛基的被选择性氧化的多糖具有β-1,4-糖苷键和β-1,6-糖苷键的至少之一。
  34. 根据权利要求28-33的任一项所述的阳离子共聚物，其中所述具有2,3-二醛基的被选择性氧化的多糖具有β-1,4-糖苷键且不具有β-1,6-糖苷键。
  35. 根据权利要求28-34的任一项所述的阳离子共聚物，其中所述具有2,3-二醛基的被选择性氧化的多糖选自下述物质中的一种或多种：被选择性氧化的纤维素、被选择性氧化的支链淀粉、被选择性氧化的壳聚糖、被选择性氧化的甲壳素。
  36. 根据权利要求28-35的任一项所述的阳离子共聚物，其中所述具有胺基功能团的聚胺选自下述物质中的一种或多种：聚乙烯亚胺(PEI)、聚烯丙基胺、聚丙烯亚胺、聚丙烯亚胺四胺。
  37. 根据权利要求28-36的任一项所述的阳离子共聚物，其中所述具有胺基功能团的聚胺具有支链结构或者树枝状结构。
  38. 根据权利要求28-37的任一项所述的阳离子共聚物，其中所述具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物和所述阳离子共聚物的尺寸在30μm-10mm之间，优选100μm-10mm之间，更优选300μm-5mm之间。
  39. 根据权利要求28-38的任一项所述的阳离子共聚物，其中所述具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物和所述阳离子共聚物具有直径小于50μm的孔。
  40. 一种用于治疗高胆固醇血症的药物组合物，所述药物组合物包括作为活性成分的多糖-聚胺共聚物及其药学上可接受的盐，所述多糖-聚胺共聚物由以下两部分共聚形成：
    具有2,3-二醛基的被选择性氧化的多糖，和具有胺基功能团的聚胺；
    所述具有胺基功能团的聚胺与所述具有2,3-二醛基的被选择性氧化的多糖共价交联形成网状结构，得到具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物，所述具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物中的胺基功能团可被质子化而形成具有质子化位点的三维网状结构阳离子共聚物，所述阳离子共聚物的氮含量和所述多糖-聚胺共聚物的氮含量在12.3wt％以上，或者在15wt％以上，或者在22wt％以上，或者在40wt％以上，所述 阳离子共聚物和所述多糖-聚胺共聚物均不溶于水。
  41. 根据权利要求40所述的药物组合物，其中所述具有胺基功能团的聚胺的氮含量在24.5wt％以上，或者在30wt％以上，或者在44wt％以上，或者在80wt％以上。
  42. 根据权利要求40或41所述的药物组合物，其中所述具有胺基功能团的聚胺的分子量为约15000-约900000。
  43. 根据权利要求40-42的任一项所述的药物组合物，其中所述具有2,3-二醛基的被选择性氧化的多糖选自下述物质中的一种或多种：被选择性氧化的纤维素、被选择性氧化的支链淀粉、被选择性氧化的壳聚糖(chitosan)。
  44. 根据权利要求40-43的任一项所述的药物组合物，其中所述具有2,3-二醛基的被选择性氧化的多糖中被氧化的葡萄糖单位数量占所有葡萄糖单位数量的50％以上，优选70％以上，更优选80％以上。
  45. 根据权利要求40-44的任一项所述的药物组合物，其中所述具有2,3-二醛基的被选择性氧化的多糖具有β-1,4-糖苷键和β-1,6-糖苷键的至少之一。
  46. 根据权利要求40-45所述的药物组合物，其中所述具有2,3-二醛基的被选择性氧化的多糖具有β-1,4-糖苷键且不具有β-1,6-糖苷键。
  47. 根据权利要求40-46的任一项所述的药物组合物，其中所述具有胺基功能团的聚胺选自下述物质中的一种或多种：聚乙烯亚胺(PEI)、聚烯丙基胺、聚丙烯亚胺、聚丙烯亚胺四胺。
  48. 根据权利要求40-47的任一项所述的药物组合物，其中所述具有胺基功能团的聚胺具有支链结构或者树枝状结构。
  49. 根据权利要求40-48的任一项所述的药物组合物，其中所述具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物和所述阳离子共聚物的尺寸在30μm-10mm之间，优选100μm-10mm之间，更优选300μm-5mm之间。
  50. 根据权利要求40-49的任一项所述的药物组合物，其中所述具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物和所述阳离子共聚物具有直径小于50μm的孔，或者孔具有100nm-50微米的尺寸，或者孔具有200nm-40微米的尺寸，或者孔具有300nm-30微米的尺寸，或者孔具有400nm-20微米的尺寸，或者孔具有500nm-10微米的尺寸，或者孔具有800nm-5微米的尺寸。
  51. 包含作为活性成分的多糖-聚胺共聚物及其药学上可接受的盐的药物组合物在制备用于治疗高胆固醇血症的药物中的用途，其中，所述多糖-聚胺共聚物由以下两部分共聚形成：
    具有2,3-二醛基的被选择性氧化的多糖，和具有胺基功能团的聚胺；
    所述具有胺基功能团的聚胺与所述具有2,3-二醛基的被选择性氧化的多糖共价交联形成网状结构，得到具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物，所述具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物中的胺基功能团可被质子化而形成具有质子化位点的三维网状结构阳离子共聚物，所述阳离子共聚物的氮含量和所述多糖-聚胺共聚物的氮含量在12.3wt％以上，或者在15wt％以上，或者在22wt％以上，或者在40wt％以上，所述阳离子共聚物和所述多糖-聚胺共聚物均不溶于水。
  52. 根据权利要求51所述的用途，其中所述具有胺基功能团的聚胺的氮含量在24.5wt％以上，或者在30wt％以上，或者在44wt％以上，或者在80wt％以上。
  53. 根据权利要求51或52所述的用途，其中所述具有胺基功能团的聚胺的分子量为约15000-约900000。
  54. 根据权利要求51-53的任一项所述的用途，其中所述具有2,3-二醛基的被选择性氧化的多糖选自下述物质中的一种或多种：被选择性氧化的纤维素、被选择性氧化的支链淀粉、被选择性氧化的壳聚糖(chitosan)。
  55. 根据权利要求51-54的任一项所述的用途，其中所述具有2,3-二醛基的被选择性氧化的多糖中被氧化的葡萄糖单位数量占所有葡萄糖单位数量的50％以上，优选70％以上，更优选80％以上。
  56. 根据权利要求51-55的任一项所述的用途，其中所述具有2,3-二醛基的被选择性氧化的多糖具有β-1,4-糖苷键和β-1,6-糖苷键的至少之一。
  57. 根据权利要求51-56所述的用途，其中所述具有2,3-二醛基的被选择性氧化的多糖具有β-1,4-糖苷键且不具有β-1,6-糖苷键。
  58. 根据权利要求51-57的任一项所述的用途，其中所述具有胺基功能团的聚胺选自下述物质中的一种或多种：聚乙烯亚胺(PEI)、聚烯丙基胺、聚丙烯亚胺、聚丙烯亚胺四胺。
  59. 根据权利要求51-58的任一项所述的用途，其中所述具有胺基功能 团的聚胺具有支链结构或者树枝状结构。
  60. 根据权利要求51-59的任一项所述的用途，其中所述具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物和所述阳离子共聚物的尺寸在30μm-10mm之间，优选100μm-10mm之间，更优选300μm-5mm之间。
  61. 根据权利要求51-60的任一项所述的用途，其中所述具有胺基功能团的水凝胶或颗粒状的多糖-聚胺共聚物和所述阳离子共聚物具有直径小于50μm的孔，或者孔具有100nm-50微米的尺寸，或者孔具有200nm-40微米的尺寸，或者孔具有300nm-30微米的尺寸，或者孔具有400nm-20微米的尺寸，或者孔具有500nm-10微米的尺寸，或者孔具有800nm-5微米的尺寸。
PCT/CN2016/076716 2015-03-20 2016-03-18 多糖-聚氨共聚物及其在降低血浆中低密度脂蛋白浓度的应用 WO2016150342A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201680017196.2A CN107428850B (zh) 2015-03-20 2016-03-18 多糖-聚氨共聚物及其在降低血浆中低密度脂蛋白浓度的应用
US15/559,221 US10925893B2 (en) 2015-03-20 2016-03-18 Polysaccharide-polyamine copolymer and use thereof in reducing low density lipolipoprotein (LDL) concentration in plasma

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562136220P 2015-03-20 2015-03-20
US62/136,220 2015-03-20

Publications (1)

Publication Number Publication Date
WO2016150342A1 true WO2016150342A1 (zh) 2016-09-29

Family

ID=56976949

Family Applications (3)

Application Number Title Priority Date Filing Date
PCT/CN2016/076716 WO2016150342A1 (zh) 2015-03-20 2016-03-18 多糖-聚氨共聚物及其在降低血浆中低密度脂蛋白浓度的应用
PCT/CN2016/076715 WO2016150341A1 (zh) 2015-03-20 2016-03-18 多糖-聚氨共聚物及其在降低血浆中尿酸浓度的应用
PCT/US2016/023237 WO2016154043A1 (en) 2015-03-20 2016-03-18 Polysaccharide-polyamine copolymers for removal of phosphate

Family Applications After (2)

Application Number Title Priority Date Filing Date
PCT/CN2016/076715 WO2016150341A1 (zh) 2015-03-20 2016-03-18 多糖-聚氨共聚物及其在降低血浆中尿酸浓度的应用
PCT/US2016/023237 WO2016154043A1 (en) 2015-03-20 2016-03-18 Polysaccharide-polyamine copolymers for removal of phosphate

Country Status (6)

Country Link
US (4) US10925893B2 (zh)
EP (1) EP3270933B1 (zh)
CN (3) CN107406523B (zh)
CA (1) CA2980468C (zh)
HK (1) HK1244829A1 (zh)
WO (3) WO2016150342A1 (zh)

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2980472C (en) 2015-03-20 2023-08-29 Howard University Microcarriers, matrices and scaffolds for culturing mammalian cells and methods of manufacture
WO2016150342A1 (zh) * 2015-03-20 2016-09-29 杨达志 多糖-聚氨共聚物及其在降低血浆中低密度脂蛋白浓度的应用
CN107754773A (zh) * 2017-09-29 2018-03-06 周玲玲 一种环氧化纤维‑二氧化锰交联海藻酸钠微球吸附剂的制备方法
CN108219009B (zh) * 2018-01-05 2020-10-09 中海石油(中国)有限公司 一种改性纳米纤维素及其制备方法与应用
CN108383917B (zh) * 2018-01-30 2020-06-05 浙江理工大学 一种多功能纤维素膜及其制备方法
CN108926714B (zh) * 2018-06-28 2021-11-26 哈尔滨医科大学 一种用于膀胱灌注靶向膀胱癌递送药理活性物质的高分子凝胶及其制备方法
CN113426423B (zh) * 2018-09-29 2023-10-27 健帆生物科技集团股份有限公司 用于血液体外循环去除ldl的吸附剂及其制备方法和灌流器
CN109988314B (zh) * 2019-04-04 2021-07-02 大连民族大学 一种超支化聚壳多糖及其制备方法和应用
CN110038529A (zh) * 2019-04-25 2019-07-23 广西科技大学 一种三维纤维基复合气凝胶型吸附剂的制备方法
CN110038528A (zh) * 2019-04-25 2019-07-23 广西科技大学 一种纤维素/壳聚糖复合抗菌吸附剂的制备方法
US20210361570A1 (en) * 2020-05-19 2021-11-25 Mcmaster University In situ gelling polysaccharide-based nanoparticle hydrogel compositions, and methods of use thereof
CN112830979A (zh) * 2021-01-15 2021-05-25 江南大学 一种改性黄原胶及其制备方法与应用
CN114874619B (zh) * 2022-05-11 2023-06-16 浙江大学 一种聚乙烯亚胺/氧化纤维素纳米凝胶、制备方法及用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000021572A2 (en) * 1998-10-09 2000-04-20 The University Of Michigan Hydrogels and water soluble polymeric carriers for drug delivery
CN101791408A (zh) * 2009-11-12 2010-08-04 中山大学附属第一医院 一种具有低细胞毒性、高转染效率的阳离子聚合物基因载体及其制备方法和应用
CN102154351A (zh) * 2010-12-30 2011-08-17 江苏大学 阳离子化当归多糖纳米粒基因传递系统及其制法
CN102154350A (zh) * 2010-12-30 2011-08-17 江苏大学 阳离子化枸杞多糖纳米粒基因传递系统及其制法
CN103113594A (zh) * 2013-01-25 2013-05-22 暨南大学 琼脂糖-聚乙烯亚胺-透明质酸接枝物及其制备方法与应用

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4663163A (en) * 1983-02-14 1987-05-05 Hou Kenneth C Modified polysaccharide supports
US4788280A (en) 1987-03-19 1988-11-29 National Starch And Chemical Corporation Polysaccharide derivatives containing aldehyde groups on an aromatic ring, their preparation from the corresponding acetals and use in paper
US5340731A (en) * 1988-07-08 1994-08-23 University Of British Columbia Method of preparing a B-1,4 glycan matrix containing a bound fusion protein
US5496545A (en) 1993-08-11 1996-03-05 Geltex Pharmaceuticals, Inc. Phosphate-binding polymers for oral administration
WO1996027614A1 (en) 1995-03-08 1996-09-12 Elias Klein Surface modified affinity separation membrane
IL131074A0 (en) 1999-07-23 2001-03-19 Polygene Ltd A biodegradable polycation composition for delivery of an anionic macromolecule
DE19953589B4 (de) 1999-11-08 2005-05-25 Sca Hygiene Products Gmbh Polysaccharid mit funktionellen Gruppen, Verfahren zu dessen Herstellung und daraus hergestellte Produkte
DE10152407A1 (de) * 2001-10-24 2003-05-08 Aesculap Ag & Co Kg Zusammensetzung aus mindestens zwei biokompatiblen chemisch vernetzbaren Komponenten
WO2006091894A2 (en) 2005-02-25 2006-08-31 The Regents Of The University Of California New polymeric materials and methods
ITFI20060132A1 (it) * 2006-05-31 2007-12-01 Golden Lady Co Spa Metodo e dispositivo per distendere pneumaticamente un manufatto flessibile allungato, come una calza o un calzino
US8425887B2 (en) 2006-09-29 2013-04-23 Genzyme Corporation Amide dendrimer compositions
US8163799B2 (en) 2006-12-14 2012-04-24 Genzyme Corporation Amido-amine polymer compositions
CN101224413A (zh) * 2007-09-29 2008-07-23 大连理工大学 水溶性阳离子多聚物吸附材料及其应用
WO2009064963A2 (en) 2007-11-14 2009-05-22 E. I. Du Pont De Nemours And Company Oxidized cationic polysaccharide-based polymer tissue adhesive for medical use
US20110142952A1 (en) * 2008-06-20 2011-06-16 Harris David J Pharmaceutical Compositions
CN102030908A (zh) * 2009-09-25 2011-04-27 天津大学 聚乙烯亚胺接枝瓜尔胶阳离子聚合物及其制备方法和应用
CN101864078B (zh) 2010-06-01 2011-12-07 浙江大学 聚乙烯亚胺-壳聚糖-硬脂酸嫁接物及制备与应用
CN103083718B (zh) * 2011-11-02 2015-06-10 中国人民解放军军事医学科学院毒物药物研究所 一种可生物降解的医用粘合剂及其制备方法和用途
EP2888223A2 (en) 2012-08-24 2015-07-01 Université de Strasbourg Branched or macrocyclic polyamines and uses thereof
EP2925432A4 (en) 2012-11-29 2016-08-31 Affigel Ab SUPER-HYDROXYLATED ADSORBENTS AND USES THEREOF
CN103030813B (zh) 2012-12-21 2015-08-05 深圳先进技术研究院 一种壳聚糖接枝聚乙烯亚胺非病毒转基因载体的制备方法
CN103041403B (zh) 2012-12-26 2015-04-08 深圳先进技术研究院 含葡聚糖的药物组合物及其制备方法
WO2016150342A1 (zh) 2015-03-20 2016-09-29 杨达志 多糖-聚氨共聚物及其在降低血浆中低密度脂蛋白浓度的应用
KR101965735B1 (ko) 2015-04-15 2019-04-04 가부시키가이샤 고마쓰 세이사쿠쇼 금속 부재의 제조 방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000021572A2 (en) * 1998-10-09 2000-04-20 The University Of Michigan Hydrogels and water soluble polymeric carriers for drug delivery
CN101791408A (zh) * 2009-11-12 2010-08-04 中山大学附属第一医院 一种具有低细胞毒性、高转染效率的阳离子聚合物基因载体及其制备方法和应用
CN102154351A (zh) * 2010-12-30 2011-08-17 江苏大学 阳离子化当归多糖纳米粒基因传递系统及其制法
CN102154350A (zh) * 2010-12-30 2011-08-17 江苏大学 阳离子化枸杞多糖纳米粒基因传递系统及其制法
CN103113594A (zh) * 2013-01-25 2013-05-22 暨南大学 琼脂糖-聚乙烯亚胺-透明质酸接枝物及其制备方法与应用

Also Published As

Publication number Publication date
US10925893B2 (en) 2021-02-23
HK1244829A1 (zh) 2018-08-17
US20210038638A1 (en) 2021-02-11
WO2016150341A1 (zh) 2016-09-29
EP3270933B1 (en) 2020-08-19
CN107406523B (zh) 2020-09-22
US20180099007A1 (en) 2018-04-12
CN105985448B (zh) 2018-09-18
CN107428850B (zh) 2019-10-11
EP3270933A1 (en) 2018-01-24
US10849927B2 (en) 2020-12-01
CA2980468C (en) 2023-09-26
US20180071331A1 (en) 2018-03-15
EP3270933A4 (en) 2018-12-19
US10639325B2 (en) 2020-05-05
CN105985448A (zh) 2016-10-05
CA2980468A1 (en) 2016-09-29
US20180110801A1 (en) 2018-04-26
CN107428850A (zh) 2017-12-01
CN107406523A (zh) 2017-11-28
WO2016154043A1 (en) 2016-09-29

Similar Documents

Publication Publication Date Title
WO2016150342A1 (zh) 多糖-聚氨共聚物及其在降低血浆中低密度脂蛋白浓度的应用
Pushpamalar et al. Biodegradable polysaccharides for controlled drug delivery
US7740883B2 (en) Nanoparticles from chitosan
Pal et al. Interpenetrating polymer network hydrogels of chitosan: applications in controlling drug release
JP2009510233A (ja) 架橋シェルを有するコア−シェルコンポジットを製造する方法および該方法によって生じたコア−シェルコンポジット
Yan et al. Formation and characterization of polyelectrolyte complex synthesized by chitosan and carboxylic curdlan for 5-fluorouracil delivery
CN112933286B (zh) 一种用于止血并承载抗癌药物的晶胶及其制备方法
Bhosale et al. Design and development of polymethylmethacrylate-grafted gellan gum (PMMA-g-GG)-based pH-sensitive novel drug delivery system for antidiabetic therapy
TWI374742B (zh)
CN105749296A (zh) 一种溃疡性结肠炎组织靶向分子及其应用
Singh et al. Chitosan: A novel excipient in pharmaceutical formulation: A review
Dey et al. Cross-linking of chitosan in drug delivery
CN1203119C (zh) 一种离子交联壳聚糖微球的制备方法
Mahmoodi et al. Synthesis and Characterization of Alginate-Chitosan Nanocarrier System for Empagliflozin Delivery
Ramazanzadeh et al. Drug delivery system for controlled release of empagliflozin from alginate-chitosannanocarrier system
Mulia et al. Effect of sodium tripolyphosphate concentration and simulated gastrointestinal fluids on release profile of paracetamol from chitosan microsphere
Stavarache et al. k-Carrageenan/Sodium Alginate interpenetrating Network beads for the incorporation of Ketoprofen as a potential drug delivery system
Dotto et al. Frontiers in Biomaterials
Musa et al. Functional Chitosan Carriers for Oral Colon-Specific Drug Delivery
Aiedeh et al. Application of novel chitosan derivatives in dissolution enhancement of a poorly water soluble drug
Prabaharan Chitosan and its derivatives as promising drug delivery carriers
Vedavahini et al. Comparative Study of Chitosan and Carboxy Methyl Chitosan Nanoparticles in Mefenamic Acid Drug Delivery
Pistone et al. Effect of Cross‐Linking Agent on Curcumin Release from Chitosan‐Based Macroparticles
KR20090056314A (ko) 시플로플록사신이 담지된 저분자량 수용성 키토산 미립자에고분자가 코팅된 다중입자 및 이의 제조방법
Vaidya A Review of Chitosan in Oral Drug Delivery Formulations

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16767719

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 15559221

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16767719

Country of ref document: EP

Kind code of ref document: A1