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CN1264310A - Polymer based pharmaceutical compositions for targeted delivery of biologically active agents - Google Patents

Polymer based pharmaceutical compositions for targeted delivery of biologically active agents Download PDF

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Publication number
CN1264310A
CN1264310A CN 98807413 CN98807413A CN1264310A CN 1264310 A CN1264310 A CN 1264310A CN 98807413 CN98807413 CN 98807413 CN 98807413 A CN98807413 A CN 98807413A CN 1264310 A CN1264310 A CN 1264310A
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Prior art keywords
acid
serotonin
polymer
polymerization
construction
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J·R·劳
W·B·格霍
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SDG Technology Inc
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SDG Technology Inc
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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

This invention provides a polymeric construct for delivering a biologically active agent to a mammal comprising a first polymeric matrix, a biologically active agent contained within the polymeric matrix, and a second polymer chemically bound to the biologically active agent, said second polymer comprising an amino acid copolymer, said second polymer present in an amount effective to reduce leakage of the active agent from the polymeric construct prior to delivery to the desired situs.

Description

The pharmaceutical composition based on polymer of targeted delivery of biologically active agents
Background of invention
Technical field of the present invention
The present invention relates generally to the polymer construction thing that is used to transmit bioactivator.The invention particularly relates to the polymer construction thing that is used to transmit biogenic amine and pharmaceutical composition thereof and with the method for its treatment disease.
Correlation technique
Prior art has been put down in writing polymer formulations of multiple bioactivator and preparation method thereof.
United States Patent (USP) 3773919,3991776,4076779,4093709,4118470,4131648,4138344,4293539 and 4675189 discloses biocompatible, preparation and the application of biodegradable polymer as gathering (lactic acid), gathering the copolymer of (glycolic), glycolic and lactic acid, poly-(O-hydroxy carboxylic acid), polylactone, polyacetals, poe and poly-orthocarbonic ester that is used for encapsulated drug and medicament especially.These polymer are by the mechanical encapsulation active component, then by the dissolving of polymer or the release of degraded control active component." polymer communication " (Polymer Letters), 18,293 (1980) have described some condensation polymer that is formed by divinyl ether and polyhydric alcohol.Polymer has been proved to be the transmission utensil of the slow releasing pharmaceutical of success; Yet stability between the enhancing storage life and integrity and increase targeting specific will help its effect, and increase the therapeutic index that targeting specific will increase packaged medicine.
The publication of above-mentioned patent and publication and other patent publication and the publication that relate to this description are specially introduced with for referencial use at this.
The invention summary
The purpose of this invention is to provide and be used for improving the bioactivator that is encapsulated in polymer support, the storage stability of biological example amine and the method for transmission efficiency.
Therefore, the invention provides the polymerization construction that is used for bioactivator is passed to the host, comprise: first kind and basic polymeric matrices, bioactivator in first kind of polymeric matrices, with with the chemically combined second kind of polymers compositions of bioactivator, wherein second kind of polymer exists with the amount that can reduce this bioactivator effectively and spill from polymer support.The polymerization construction optionally further comprises the targeting moiety that links to each other with its surface, be used to guide this construction arrival predetermined site.Second kind of polymeric component is optionally with first kind of polymeric matrices copolymerization or otherwise combine with it.
The present invention also provides the Pharmaceutical composition of polymerization construction and pharmaceutically acceptable excipient, and the method for the treatment of mammalian diseases with said composition.Particularly preferably be, with the treatment of serotonin or combination of serotonin agonist to the disease of biogenic amine reaction, especially treat type ii diabetes.
Detailed Description Of The Invention
In a broad sense, the invention provides the polymerization construction that is used for bioactivator is passed to the host, comprise: first kind and basic polymeric matrices, bioactivator in first kind of polymeric matrices, with with the chemically combined second kind of polymers compositions of bioactivator, wherein second kind of polymer exists with the amount that can reduce this bioactivator effectively and spill from polymer support.The polymerization construction optionally further comprises the targeting moiety that links to each other with its surface, be used to guide this construction arrival predetermined site.Second kind of polymeric component is optionally with first kind of polymeric matrices copolymerization or otherwise combine with it.
The used concrete bioactivator of this description is not in addition any restriction of scope of the present invention, as long as activating agent can be encapsulated in or wrap and be trapped in the polymeric matrices and its inherent biological activity does not significantly reduce, so just can be used for the present invention.
First kind of polymeric matrices can be but be not limited to: poly-(lactide/glycolides) copolymer (PLGA), polylactic acid, polyglycolic acid, poly-(O-hydroxy carboxylic acid), polylactone, polyacetals, poe, poly-orthocarbonic ester, polyamino acid, the chitosan glutamate, polyacrylic acid, poly-divinyl glycol, albumin, Merlon, polyamine, poly butyric, scleroglucan (scleroglucans), polyoxypropylene-polyoxyethylene, polygalacturonic acid (partial esterification) and xanthan gum.In some embodiments of the present invention, these basic polymer use that can combine.
Second kind of polymers compositions comprises the polymer with negative charge functional group.In preferred embodiments, second kind of polymers compositions comprises that load has the polyamino acid of net negative charge.In another embodiment preferred, second kind of polymers compositions comprises the copolymer of polylysine and other aminoacid or chemical compound.Polymerization construction of the present invention optionally uses the auxiliary polymeric component of more than one closing property of anchor.
On the other hand, the present invention includes the method for preparing the polymerization construction, comprise with first kind can biocompatible polymer, copolymer, biogenic amine and the targeting moiety of second kind of polylysine-poly-(glutamic acid/aspartic acid) mix, thus, described first kind and second kind polymer formation contain the composite polymeric carrier of biogenic amine and targeting moiety.
In one embodiment, bioactivator comprises biogenic amine and acts on serotonin receptor to cause the autacoid of hepatic glucose depot reaction that wherein biogenic amine comprises sympathomimetic amine, the medicine of promptly natural catecholamine and its effect of simulation.Referring to Goodman and Gilman, the 9th edition .MacmillanPublishing Co. (1995) of " treatment pharmacological basis " (The Pharmacological Basis of Therapeutics).The example of biogenic amine includes but not limited to L-β-3,4-dihydroxyphenylalanine (L-DOPA), 3-(2-amino-ethyl)-5-oxyindole (5-hydroxy tryptamine or serotonin), 2-(4-imidazole radicals) ethamine (histamine), 4-[1-hydroxyl-2-(methylamino) ethyl]-1,2-Benzodiazepines (epinephrine), 1-[3,4-dihydroxy phenyl]-2-ethylaminoethanol (norepinephrine), gamma-amino n-butyric acie, acetylcholine and aminoacid.In preferred embodiments, biogenic amine is serotonin, serotonin analog or combination of serotonin agonist.The used term of this description " serotonin analog " and " combination of serotonin agonist " are meant can simulate the active chemical compound of serotonin, especially acts on the chemical compound of its hepatocyte 5-HT receptor of being blocked by desernil of interacting.
Be connected in the lip-deep targeted molecular guiding of polymerization construction polymerization construction and arrive suitable receptor, for example hepatic duct receptor.The target molecule of these directed liver and gall receptors is optional from the iminodiacetic acid, the ethylenediamine N that replace, the N '-substitutive derivative of N-oxalic acid (EDDA), liver and gall dyestuff, liver and gall contrast agent, bile salts, liver and gall mercaptan coordination compound, regulating liver-QI cholamine coordination compound.
In preferred embodiments, first kind of polymeric matrices is selected from polymer, for example polylysine, poly-(lactide/glycolides), chitosan glutamate, polyacrylic acid, poly-divinyl glycol, albumin, Merlon, polyamine, poly butyric, scleroglucan (scleroglucans), polyoxypropylene-polyoxypropylene, polygalacturonic acid (partial esterification) and xanthan gum, second kind of polymeric component is the copolymer of polylysine and poly-(glutamic acid/aspartic acid).
Polymerization construction of the present invention and pharmaceutical composition can be used for the treatment of the disease to biogenic amine that comprises sympathomimetic amine and autacoid reaction.These diseases can comprise, for example hypertension, shock, heart failure, arrhythmia, asthma, allergy, anaphylaxis and diabetes.Therefore, the invention provides the method for treatment mammalian diseases, comprise biogenic amine with the treatment effective dose in pharmaceutical composition to the mammal administration, wherein pharmaceutical composition comprises the polylysine of the polymerization construction that contains biogenic amine and second kind and the copolymer of poly-(glutamic acid/aspartic acid).
The present invention is particularly useful for transmitting biogenic amine, wherein biogenic amine as effective neurotransmitter should closely be sequestered in the polymerization construction with reduce or eliminate basically be not this construction the interaction of directed organ or tissue's receptor.The biogenic amine neurotransmitter is water miscible, and the polarity chemical functionality is arranged.Quaternary amine, for example epinephrine and acetylcholine all carry positive charge in very wide PH scope, and other biogenic amine neurotransmitter is a primary amine, and they only just carry positive charge at physiology PH with below the physiology PH.
Because biogenic amine shows the remarkable polarity that primary amine group caused of carrying positive charge by the quaternary amines that carries positive charge or under physiology PH, so they have unusual water activity.Therefore biogenic amine is difficult to rest in the polymerization construction, makes that its storage stability is very poor, can leak after having genotoxic potential and administration.Biogenic amine can be not treatment disease and multiple acceptor interaction that must will act on, on the dissimilar cells.These cells especially comprise neuron, platelet, mastocyte and enterochromaffin cell.
This situation can usually illustrate with hormone and neurotransmitter serum.
Research is for example put down in writing in the US 4761287 described researchs in early days, in order suitably to treat non-insulin diabetes (type ii diabetes), need serotonin be delivered in the hepatocyte of liver with the target liposomes construction.Signal so that blood glucose is stored as glycogen to liver with insulin after this hormone transmission.This effect makes that high glucose level descends in the blood circulation, and has alleviated the degree that other tissue and organ in the body are exposed to high glucose level.If this hormone spills from its carrier, just be difficult to this hormone of accurate dosage is delivered in the liver, use the original intention of this targeted delivery system just to be affected.
Therefore, in preferred embodiments, the present invention relates to biogenic amine for example serotonin and the reservation of combination of serotonin agonist in targeting polymerization construction.Why need the serotonin chelating, not still because its hormone function, and be because in vivo serotonin as neurotransmitter with the irrelevant polytype cell of liver in work.If therefore be encapsulated in the target polymer exogenous serotonin not with polymer architecture chelating or be retained in the polymer architecture very doughtily, serotonin will spill from polymer, and produces disadvantageous pharmacological reaction with other cell type with serotonin receptor.
New polymerization construction of the present invention provides to transmit and has been encapsulated in the means that chemically stable carries intravital bioactivator, and wherein the chemical stability of carrier is caused by strong ionic bond and the dipole-dipole interaction that a plurality of carriers constitute between the component.These chemical interactions have reduced the water activity that is encapsulated in the bioactivator biological example amine in the polymerization construction effectively, have therefore just reduced activating agent and have diffused out from polymeric carrier.Chemistry and physics interaction (especially when the different activities agent is used together) between the activating agent itself have also been alleviated.The active overall result who reduces of water is that fusion between the construction individuality, Colaesce, gathering and/or sedimentary probability have reduced in the polymerization construction.These interactions obviously increase shelf life and stability, have protected the integrity and the stability of biochemical transmitter in addition.
The present invention also provides complementary polymerization anchor, wherein bioactivator comprise biogenic amine as serotonin by as described in the polymerization anchor can in long-time, be sequestered in effectively in first kind of polymeric matrices and drain to the substrate external environment to reduce it.In preferred embodiments, the invention provides for example chelating of serotonin in liver and gall targeting polymerization construction of biogenic amine.In one embodiment, be serotonin and liver and gall targeted molecular to be retained in first kind of polymeric matrices with the auxiliary combined polymerization anchor that comprises polylysine-poly-(glutamic acid-aspartic acid).
Chelating and the transmission of using polymerization construction of the present invention to interact and to promote biogenic amine by above-mentioned specific functional group.For example, carbonyl on basic polymer and the auxiliary polyalcohol and amido functional group can be by the formation that participates in hydrogen bond and the biogenic amine effect.Also have, the polymerization carboxyl that carries negative charge can form ionic bond with primary amine class of carrying positive charge and quaternary ammonium biogenic amine.Therefore targeting and the molecule that transmitted can keep more firmly, and this has just stoped medicine to drain to outer aqueous phase effectively.
Can be used as in the polymer of polymeric carrier the copolymer that lactic acid and glycolic are arranged (PLGA) that can mention.These polymer are biocompatible, biodegradable and are suitable for human.According to the difference of the degree of polymerization, the PLGA diameter of micro ball is generally about 1500 dusts of about 200-.
The present invention relates to three interaction aspects.First aspect is, the copolymer of lysine and glutamic acid and aspartic acid (or glutamate and aspartate) closed molecule as the anchor of biogenic amine be added in first kind of polymeric matrices.Second aspect be, uses to combine with first kind of polymeric matrices or optionally close liver and gall targeted molecular that polymer combines so that biogenic amine is delivered in the hepatocyte of liver with anchor.Therefore, auxiliary copolymer can not only play chemical anchors and closes the function of liver and gall targeted molecular, but also works the function that keeps biogenic amine.The 3rd aspect relates to the interaction between basic polymer and the auxiliary polyalcohol, and this interaction provides the construction stability in basic polymeric matrices, auxiliary polymerization anchor, activating agent and other construction component.
The example of liver and gall targeted molecular comprises the iminodiacetic acid of replacement, for example N-(2,6-diisopropyl phenyl carbamyl ylmethyl) iminodiacetic acid, N-(2,6-diethyl phenyl carbamoyl methyl) iminodiacetic acid, N-(2,6-3,5-dimethylphenyl carbamyl ylmethyl) iminodiacetic acid, N-(4-isopropyl phenyl carbamyl ylmethyl) iminodiacetic acid, N-(4-butyl phenyl carbamyl ylmethyl) iminodiacetic acid, N-(2,3-3,5-dimethylphenyl carbamyl ylmethyl) iminodiacetic acid, N-(3-butyl phenyl carbamyl ylmethyl) iminodiacetic acid, N-(2-butyl phenyl carbamyl ylmethyl) iminodiacetic acid, N-(4-tert-butyl-phenyl carbamyl ylmethyl) iminodiacetic acid, N-(3-butoxy phenyl carbamyl ylmethyl) iminodiacetic acid, N-(2-hexyloxy phenyl amino formoxyl methyl) iminodiacetic acid, N-(4-hexyloxy phenyl amino formoxyl methyl) iminodiacetic acid; The iminodiacetic acid that azo replaces, imino-diacetic carboxyl methyl-2-naphthalenone, the phthalein complexon, N-(5-pregnene-3-β-alcohol-2-acyl amino formoxyl methyl) iminodiacetic acid, gallbladder alcohol falls in 3a:7a:12a: trihydroxy-24-: amyl group-23-iminodiacetic acid, N-(3-bromo-2,4,6-trimethylphenyl carbamyl ylmethyl) iminodiacetic acid, the benzimidazole methyliminodiacetic acid, N-(3-cyano group-4,5-dimethyl-2-pyrrole radicals carbamyl ylmethyl) iminodiacetic acid, other derivant of N-(3-cyano group-4-methyl-2-pyrrole radicals carbamyl ylmethyl) iminodiacetic acid, ethylenediamine-N, two (2-hydroxyl-5-bromophenyl) acetass of N-, N '-acyl group ethylenediamine-N, N-oxalic acid and N '-sulfonyl ethylenediamine-N, the N-oxalic acid; Ethylenediamine-N, the N '-substitutive derivative of N-oxalic acid (EDDA), N '-acetyl group EDDA, N '-benzoyl EDDA, N '-(p-toluenesulfonyl) EDDA, N '-(to the tert-butyl benzene formoxyl) EDDA, N '-(benzenesulfonyl) EDDA, N '-(to the chlorobenzene sulfonyl) EDDA, N '-(to the ethylo benzene sulfonyl) EDDA, N '-(to the n-propylbenzene sulfonyl) EDDA, N '-(naphthalene-2-sulfonyl) EDDA, N '-(2,5-dimethyl benzene sulfonyl) EDDA for example; N-(2 acetyl naphthalene base) iminodiacetic acid; N-(2-naphthyl methyl) iminodiacetic acid; The liver and gall dyestuff, for example rose-red, Congo red, bromosulfalein, bromophenol blue, phenolphthalein, toluidine blue, indocyanine green; Liver and gall contrast agent, for example adipiodone, ioglycamic acid; Bile salts is bilirubin, gallbladder acyl glycyl iodine histamine, thyroxine glucuronate for example; Liver and gall mercaptan coordination compound is penicillamine, β-mercaptoisobutyric acid, dihydroehioctic acid, Ismipur, U-2032 two (amithiozone) for example; The liver and gall amine complex is 1-hydralazine (hydrazine) sulfonylureas for example; Liver and gall amino-acid schiff base coordination compound, for example pyridoxin subunit (pyridoxylidene) glutamate, pyridoxin subunit isoleucine, pyridoxin subunit phenylalanine, pyridoxin subunit tryptophan, pyridoxin subunit 5-methyl tryptophan; Other pyridoxin subunit aminate; 3-hydroxyl-4-formoxyl pyridine glutamic acid; With various liver and gall coordination compounds for example tetracycline, 7-carboxyl-beta-hydroxy quinoline, phenolphthalein ketone (phenolphthalexon), eosin and verograffin.
Basic polymeric matrices and complementary polylysine-poly-(glutamic acid/aspartic acid) copolymer use together provide anchor not only share biogenic amine also anchor share the polymerization construction of liver and gall targeted molecular.This copolymer sheet reveals keeps the compound synergism of entire target to polymeric carrier system structure integrity.Above for example understand the notion and the advantage of bifunctional polymerizable thing construction, and described the specific interaction that taken place when different basic polymeric matrices mixes with auxiliary copolymer with several polymer.
An embodiment of polymerization construction of the present invention comprises that the basic polymeric matrices of polylysine and polylysine-poly-(glutamic acid/aspartic acid) anchor close auxiliary copolymer.Because each amino acid residue of polylysine all has an epsilon-amino functional group, so compare with the amino functionality of native protein, polylysine has more amino, and amino chemical reactivity is stronger.Therefore, can highly precisely control chemical interaction chemically derived or subsequently.Be rich in amino polylysine and produced favourable positive charge ion environment, this positive charge environment has promoted to carry on the basic polymeric matrices interaction of carboxyl under physiological condition of carrying negative charge on the amino of positive charge and the polyglutamic acid of the auxiliary polymerization construction-aspartic acid part.Therefore, the probability of formation significant polymer-polymer combination enlarges markedly between polylysine and auxiliary copolymerization construction.Carry on glutamic acid and the aspartic acid that the γ of negative charge-and β-carboxyl separately and carry the reserve capability that ionic interaction between the amino of positive charge has improved activating agent on the biogenic amine.Equally, carboxyl on the liver and gall targeted molecular and the ionic bonding effect between the amino on the polylysine have also strengthened targeted molecular in the lip-deep reserve capability of polymeric carrier.
Another embodiment of the present invention uses PLGA as basic polymeric matrices.By changing the mol ratio of Acetic acid, hydroxy-, bimol. cyclic ester and lactide, the hydrophilic of this copolymerization construction of scalable.Therefore basic polymeric matrices provides can participate in the carbonyl functional group that hydrogen bond forms in a large number.Polylysine-poly-(glutamic acid/aspartic acid) copolymerization piggy-back anchor provides a plurality of binding sites for the carrier all components.In addition, the ionic interaction that carries on the biogenic amine between the β-carboxyl of the γ-carboxyl of the nitrogen-atoms of positive charge and aspartic acid and glutamic acid has strengthened stability.
The 3rd embodiment of polymerization construction of the present invention uses the chitosan glutamate as basic polymeric matrices.The chitosan glutamate is the acetyl derivative that takes off of chitin, can make by chitosan and glutamic acid are mixed.The main distinction of chitosan glutamate and natural chitosan is, the chitosan glutamate is water miscible, and chitosan is only soluble in the rare organic acid usually.The chitosan glutamate is the polymerization amino sugar that free amine group is arranged on the carbon #2 of each glycosamine residue, and wherein each glycosamine is connected with β-(1 → 4) mode glycosides with other each glycosamine in linear order in the polymer.The chitosan glutamate has strong hydrogen bonding functional group, for example hydroxyl and amino.This molecule carries one group of positive charge at physiology PH with below the physiology PH, have high molecular, good polymeric chain pliability and the surface energy feature that helps and comprise other type polymer generation interaction of molecules of polylysine-poly-(glutamic acid/aspartic acid) auxiliary copolymer.This construction has the basic main chain of polysaccharide polymer.
Above-mentioned three kinds of representative example that the polymerization construction is different polymer, it for example understands the multiformity of polymer support.The example of other first kind and basic polymer includes but not limited to cross-linked polymer amount copolymer, albumin, Merlon, polyamine and the poly butyric of close organic polymer (polycarbophil), acrylic acid and divinyl glycol.Non-ionic polymers comprises the polysaccharide glucosan that for example hardens, and the equal polysaccharide with glucosan subunit is glucosan, starch and hetastarch for example.Polyoxyethylene polymer and copolymer also can be used as the basic polymer of the present invention.The anionic polymer that is applicable to basic polymer comprises some polysaccharide, and its representative example has pectin and xanthan gum.
Polymerization construction of the present invention is suitable for active agent delivery to the host.Therefore, construction of the present invention can be made pharmaceutical composition with pharmaceutically suitable carrier.Construction of the present invention can be used for the received administering mode administration that administration needs the bioactive substance of administration by arbitrary.These medications comprise oral administration, topical, parenteral administration, dosing eyes, transdermal administration, nose administration and other whole body or the molten administration of gas.
According to the administering mode that desire adopts, compositions can be solid, semisolid or liquid dosage form, and for example tablet, suppository, pill, capsule, powder, liquid agent, suspending agent etc. are preferably made the unit dose formulations that is suitable for the exact dose single-dose.Pharmaceutical composition contains above-mentioned polymerization construction and pharmaceutically acceptable excipient and optionally contains other activating agent, carrier, adjuvant etc.
Can use by different way by the local administration preparation that polymerization construction, penetration enhancer and other component are formed.Available suitable doser drips to the appropriate area of skin or mucosa with solution, and available hands friction or only carry out air drying.Suitable gel can be added in the solution, and the gained preparation can be coated in appropriate area, and rub in.Perhaps, in the sprayer unit of liquid preparation can being packed into, and as the spray administration.This doser is particularly suited for medicament administration in big regional skin, high susceptibility skin or nasal cavity or oral cavity.
The feature of parenteral administration generally is a drug administration by injection, both can pass through the subcutaneous injection administration, also can be by intramuscular injection or intravenous injection administration.Injection can be made conventional injection type, as liquid solution or suspending agent, be suitable for before injection the solid dosage forms or the Emulsion of in liquid wiring solution-forming or suspension.Suitable excipient has, for example water, saline, glucose, glycerol, ethanol etc.In addition, if necessary, the pharmaceutical composition of administration can also contain for example for example sodium acetate, anhydro sorbitol one lauric acid ester, Emulphor FM etc. of wetting agent or emulsifying agent, PH buffer agent and similar substance of a small amount of non-toxicity adjuvant.
The dosage of reactive compound depends on the type of treatment target, disease and the order of severity, administering mode and prescriber's judgement certainly.In addition, if dosage form is to be used for slow release, need be with the adapting total time of accumulated dose and delayed release device effect, to calculate required suitable dosage.Though the effective dosage ranges of concrete bioactive substance depends on several factors, and generally is well known by persons skilled in the art, can determine some dosage guidance principles usually.For most of form of administration, polymeric component is to be suspended in the aqueous solution, and its content is no more than 30% (w/v) of preparation total amount usually.The content most probable of the drug component in the preparation is less than 20% (w/v) of preparation total amount, and surpasses 0.01% (w/v) usually.
Local administration preparation is normally made gel, ointment or solution, wherein the content of active component is 0.001%-10% (w/v), preferred 0.01%-5% (w/v), most preferably from about about 5% (w/v) of 1%-is (certain, these dosage ranges will be renderd a service with biogenic amine and change, and can drop at the appropriate time in this scope of 0.001%-20%).In all these formulation examples and other topical formulations, accumulated dose will depend on the area in the pathogenic zone of skin and the administration number of times of every day.
For oral administration, pharmaceutically acceptable, non-toxic composite can make by adding usual excipients: described excipient has, for example mannitol, lactose, starch, magnesium stearate, saccharin sodium, Talcum, cellulose, cross-linking sodium carboxymethyl cellulose, glucose, gelatin, sucrose, magnesium carbonate etc.This based composition comprises solution, suspending agent, tablet, dispersible tablets, pill, capsule, powder, slow releasing preparation etc.
Orally administered composition preferably is pill or tablet.Therefore compositions contains active component and following component: diluent is lactose, sucrose, dicalcium phosphate etc. for example; Lubricant is magnesium stearate etc. for example; Binding agent is starch, arabic gum, gelatin, polyvinylpyrrolidine, cellulose and derivant thereof etc. for example.
Composition of liquid medicine can make to form suspension by for example above-mentioned polymerization construction and optional excipient substance being dispersed in or being suspended in the carrier, and described carrier has, for example water, saline, D/W, glycerol, ethylene glycol, ethanol etc.If necessary, pharmaceutical composition can also contain for example for example acetate, sodium citrate, cyclodextrin derivative, anhydro sorbitol one lauric acid ester, triethanolamine, sodium acetate, Emulphor FM etc. of wetting agent or emulsifying agent or solubilizing agent, PH buffer agent etc. of a small amount of nontoxic adjuvant.To those skilled in the art, the practical methods for preparing this class dosage form is known or conspicuous; Referring to, Remington: " (pharmacy science and put into practice " (The Science and Practice of Pharmacy), the 19th edition, 1995 (MackPublishing Co.Easton, PA).In either case, compositions or preparation all contain the disease of treatment target or the active bio amine for the treatment of dysfunction effective dose.
The dosage form or the compositions that can prepare the non-toxic carrier that contains 0.005%-95% active component and aequum.The accurate composition of these preparations can change according to the special properties of used biogenic amine.Yet for high-efficiency activated dose, its content is generally 0.01%-95%, is preferably 0.05%-10%, and for middle equivalent force activating agent, its content is generally 40%-85%.
For solid dosage forms, preferably with suspending agent, for example the suspending agent in carbonic acid trimethylene ester, vegetable oil or triglyceride is encapsulated in the gelatine capsule.This class suspension and preparation and capsule thereof can be according to disclosed method preparations among US 4328254, US 4409239 and the US 4410545.For liquid dosage form, the pharmaceutically acceptable liquid-carrier of available capacity, for example water dilute suspending agent, are beneficial to dosed administration.
Perhaps, liquid or semisolid oral formulations can be by with polymerization construction dissolvings or be dispersed in vegetable oil, glycol, triglyceride, the diol ester (for example carbonic acid trimethylene ester) etc., and these solution or suspension be encapsulated in firmly or in the Perle shell prepare.
Other suitable preparation is included in disclosed preparation among US 28819 and the US 4358603.
The feature of parenteral administration is drug administration by injection normally, comprises subcutaneous, intramuscular or intravenous injection.Injection can be made into conventional injection, for example solution or suspending agent, be suitable for before injection, becoming the solid dosage forms or the Emulsion of solution or suspension with liquid dosage.Suitable excipient has, for example water, normal saline, glucose, glycerol, ethanol etc.In addition, if necessary, pharmaceutical composition can also contain a small amount of nontoxic adjuvant, for example wetting agent or lubricant, PH buffer agent, solubilizing agent etc., for example sodium acetate, anhydro sorbitol one lauric acid ester, Emulphor FM, cyclodextrin etc.
The parenteral administration method of invention is to implant slow release or slow-released system recently, can keep constant dosage level like this.Referring to for example US 3710795.
Parenteral administration depends on the activity of its concrete feature and chemical compound and patient's needs with the percentage composition height of activating agent in the compositions.Yet, can contain the 0.01%-10% active component in the solution, if redilution became above-mentioned degree before compositions was to use, the content of active component will be higher.Compositions preferably contains the 0.2%-2% activating agent in solution.
Also can use the nose suspension administration of polymerization construction or polymerization construction and pharmaceutically acceptable excipient.
Also can be with the preparation of polymerization construction with the form administration of gaseous solvents in the aerosol apparatus to respiratory tract.In this case, the diameter of preparation granules less than 50 microns, preferably less than 10 microns.
Embodiment
Following specific embodiment is in order to demonstrate the invention, and should not be construed as limiting the scope of the invention.
Following all is to carry out in, PH buffered with HEPES are 7.0 solution in conjunction with experiment.Embodiment 1. bovine serum albumin combine with serotonin HCl's.
Experiment A. bovine serum albumin solution is to make in 7.0 the 10mM HEPES buffer agent by the 40mg albumin being dissolved in 10ml PH.Serotonin solution is by 10mg serotonin HCl (5-hydroxy tryptamine HCl) being dissolved in 10ml PH to be, to add trace (50 μ l) radiolabeled 5-hydroxy tryptamine creatinine sulfuric ester then and make in 7.0 the 10mM HEPES buffer agent.With 1.0ml albumin solution and 1.0ml serotonin solution, and vortex 20 seconds.From this mixture, take out 25 μ l aliquots and 50 μ l aliquots as standard.The final concentration of albumin in this mixed solution is 2mg/ml (0.03mM).The final concentration of serotonin in this mixed solution is 0.5mg/ml (2.4mM).
Remaining 1.925ml solution placed have the transparent centrifuge tube that molecular cut off is 30000 filter.With this centrifuge tube centrifugal 30 minutes with the rotating speed of 6500rpm.The filtrate of 3 part of 192.5 μ l aliquot is counted on scintillation counter.
The count results of scintillation counter shows, contains 924 μ g serotonin HCl (account for 963 μ g/l.925ml 95.9%) in filtrate.Therefore, have 4.1% serotonin to be retained in the filter, this is because with due to the albumin bound by inference.
Experiment B. tests the serotonin solution (1mg/ml) that albumin solution (4mg/ml) and 20 μ l among the A test among the A with 1ml and mixes, and vortex 20 seconds.From this mixture, take out 20 μ l aliquots as standard.The final concentration of albumin in this mixed solution is 4mg/ml (0.06mM).The final concentration of serotonin HCl in this mixed solution is 0.020mg/ml (0.094mM).
This solution of 1.0ml placed have the green centrifuge tube that molecular cut off is 10000 filter.Then this sample centrifugal 30 minutes with the rotating speed of 6500rpm.The filtrate of 2 part of 100 μ l aliquot is counted on scintillation counter.
The result shows, contains 16.3 μ g serotonin HCl (account for 20 μ g/l ml 81.5%) in filtrate, and has 18.5% serotonin to be retained in the centrifugal filter.
Experiment C. albumin solution (40mg/ml) is to make in 7.0 the 10mM HEPES buffer agent by the 120mg albumin being dissolved in 3.0ml PH.Use the serotonin solution (1mg/ml) among the experiment A.The 1ml albumin solution is mixed with 20 μ l serotonin solution, and vortex 20 seconds.From this mixture, take out 20 μ l aliquots as standard.Mixture was placed 20 minutes.Albumin and the final concentration of serotonin HCl in this mixed solution are respectively 40mg/ml (0.61mM) and 0.020mg/ml (0.094mM).
This solution of 1.0ml placed have the transparent centrifuge tube that molecular cut off is 30000 filter.Then this sample centrifugal 30 minutes with the rotating speed of 6500rpm.The filtrate of 2 part of 100 μ l aliquot is counted on scintillation counter.
The result shows, contains 9.3 μ g serotonin HCl (account for 20 μ g/l ml 47.5%) in filtrate, therefore has 52.5% serotonin to be retained in the centrifugal filter.
Just test the following table that the results are summarized in of A, B and C:
The serotonin that mol ratio keeps
The combination of 1 mole of 4.1% experiment of serotonin albumin experiment A:80 mole B:3 mole 1 mole of 18.5% experiment, 6.5 mole of 52.5% embodiment 2. serotonin of C:1 mole and phytic acid, polylysine, polylysine-succinyl and N-(2,6-diisopropyl phenyl carbamyl ylmethyl) iminodiacetic acid (DIDA)
With 5.6mg phytic acid and 10ml PH is that 7.0 10mM HEPES buffer agent mixes and prepares plant acid solution.With 5.6mg polylysine and 10ml PH is that 7.0 10mM HEPES buffer agent mixes and prepares polylysine solution.With 5.6mg polylysine-succinyl and 10ml PH is that 7.0 10mM HEPES buffer agent mixes and prepares polylysine-succinyl solution.With 8.4mg DIDA and 10ml PH is that 7.0 10mM HEPES buffer agent mixes and prepares DIDA solution.Serotonin solution (1mg/ml) among 20 μ l embodiment, the 1 experiment A is added in the 1.0ml plant acid solution (0.56mg/ml), and vortex.Add 1.0ml polylysine solution (0.56mg/ml) and vortex then.Add 1.0ml polylysine-succinyl solution (0.56mg/ml), with mixture vortex once more.At last 20 μ l DIDA solution (0.84mg/ml) are added in the mixture.
The final concentration of each component is as follows in the mixture:
Serotonin HCl:0.007mg/ml (0.033mM)
Phytic acid: 0.18mg/ml (0.20mM)
Polylysine: 0.18mg/ml (1.4mM)
Polylysine-succinyl: 0.18mg/ml (0.80mM)
DIDA： 0.006mg/ml(0.02mM)
This solution of 1.0ml placed have the yellow centrifuge tube that molecular cut off is 3000 filter.Then this sample centrifugal 2 hours with the rotating speed of 6500rpm.The original stock of 1 part of 100 μ l aliquot and the filtrate of 2 part of 100 μ l aliquot are counted on scintillation counter.
The content of serotonin HCl in filtrate is 5.0 μ g (account for 20 μ g/3.040ml 75.8%).This result shows, in this experiment, has 24.2% serotonin to be retained in the centrifugal filter, and this is owing to take place due to ion and/or the interaction of hydrogen bond between the polymeric component in serotonin and the solution mixture by inference.The combination of embodiment 3. serotonins and chitosan (Mr=70kD), polyglutamic acid-lysine and N-(2,6-diisopropyl phenyl carbamyl ylmethyl) iminodiacetic acid (DIDA).
The 10mg chitosan is dispersed in the 10ml distilled water, and dissolves with promotion with the titration of 0.6ml glacial acetic acid.10mg polyglutamic acid-lysine is dissolved in 10ml PH to be in 7.0 the 10mMHEPES buffer agent, and to prepare polyglutamic acid-lysine solution in ultrasonic 30 seconds.Serotonin HCl solution (1mg/ml) among 20 μ l embodiment, the 1 experiment A is added in 1.0ml polyglutamic acid-lysine solution (1.0mg/ml), and vortex.Add 10 μ l DIDA solution (0.84mg/ml) and vortexs then.Add 500 μ l chitosan soln (0.94mg/ml), vortexs then again.
The final concentration of each component is as follows in the mixture:
Chitosan: 0.31mg/ml (1.9mM)
Polyglutamic acid-lysine: 0.65mg/ml (2.7mM)
DIDA： 0.006mg/ml(0.002mM)
Serotonin HCl:0.013mg/ml (0.061mM)
This five equilibrium sample solution of 1.0ml placed have the centrifuge tube that molecular cut off is 30000 filter.Then centrifugal 30 minutes of this sample.From original sample and filtrate, take out 100 μ l aliquots and count at scintillation counter.
Found that, contain 11.4 μ g serotonin HCl (account for 20 μ g/1.53ml 85.1%) in the filtrate.Therefore, in this experiment, have 14.9% serotonin HCl to be retained in the centrifugal filter, this is because and due to the combination of the polymer in the mixture by inference.Embodiment 4. serotonins and the combination that gathers (L-lactide-copolymerization-Acetic acid, hydroxy-, bimol. cyclic ester), polyglutamic acid-lysine and N-(2,6-diisopropyl phenyl carbamyl ylmethyl) iminodiacetic acid (DIDA).
Poly-(L-lactide-copolymerization-Acetic acid, hydroxy-, bimol. cyclic ester) (PLGA) is insoluble to acetic acid, ethanol or NaOH, but is dissolved in dimethyl sulfoxine (DMSO).10mg PLGA was dissolved 30 seconds in 60 ℃ DMSO.Be that 7.0 10mM HEPES buffer agent is added among this polymer/DMSO then with 9.5ml PH, and with the mixture vortex.Polyglutamic acid-lysine solution among the 1ml embodiment 3 (1mg/ml) is mixed at clean test tube with the serotonin HCl solution (1mg/ml) that 20 μ l embodiment 1 test among the A, be heated to 60 ℃ and vortexs.The DIDA solution (0.84mg/ml) that adds 10 μ l aliquots is with mixture vortex once more.Add poly-(L-lactide-copolymerization-Acetic acid, hydroxy-, bimol. cyclic ester) solution (1mg/ml) of 0.5ml at last.With whole mixture heated and vortex.
The final concentration of each component is as follows in the mixture: poly-(L-lactide-copolymerization-Acetic acid, hydroxy-, bimol. cyclic ester): 0.33mg/ml (1.0mM)
Polyglutamic acid-lysine: 0.65mg/ml (2.7mM)
Serotonin HCl:0.013mg/ml (0.061mM)
DIDA： 0.005mg/ml(0.0014mM)
This solution mixture of 1.0ml placed have the green centrifuge tube that molecular cut off is 10000 filter.Then this sample centrifugal 1 hour with the rotating speed of 6500rpm.From primary sample and filtrate, take out 100 μ l aliquots and count at scintillation counter.
Detect 11.5 μ g serotonin HCl (account for 20 μ g/l.530ml 87.8%) in filtrate, this expression has the serotonin HCl in 12.2% solution mixture to be retained in the centrifugal filter.Embodiment 5. serotonins and polyoxypropylene-polyoxyethylene (PLUronic F-127), the combination of polyglutamic acid-lysine, poly-(tyrosine-glutamic acid) alanine-lysine and N-(2,6-diisopropyl phenyl carbamyl ylmethyl) iminodiacetic acid (DIDA).
1.0ml polyglutamic acid-lysine solution (1mg/ml) 100 ℃ of heating 2 minutes, is added the serotonin HCl solution (1mg/ml) among 20 μ l embodiment, the 1 experiment A then.Poly-(tyrosine-glutamic acid) alanine-lysine solution (1mg/ml) of 1.0ml is heated to 100 ℃ in separating test tube, adds above-mentioned solution then.Next 10 μ l DIDA solution (0.84mg/ml) are added in this solution mixture and mixing.With whole mixture vortex and be cooled to room temperature, be refrigerated to 4 ℃ then.Next with 0.5ml concentration polyoxypropylene-polyoxyethylene (PLUronic of 1mg/ml F-127) cold soln is added in this solution mixture.With the solution mixture vortex, store 64 hours at 4 ℃.
The final concentration of each component is as follows in the solution mixture:
Polyglutamic acid-lysine: 0.40mg/ml (1.7mM) gathers (tyrosine-glutamic acid) alanine-lysine: 0.40mg/ml (0.94mM)
Serotonin HCl:0.008mg/ml (0.04mM)
DIDA： 0.003mg/ml(0.001mM)
PLUronic F-127： 0.20mg/ml(1.7mM)
This solution mixture of 1.0ml placed have the green centrifuge tube that molecular cut off is 30000 filter.Then centrifugal 1 hour of this sample.From filtrate, take out 100 μ l aliquots and count at scintillation counter.
Found that the concentration of serotonin HCl in filtrate is 7.4 μ g/ml (account for 20 μ g/2.530ml 92.5%).This result represents have the serotonin HCl in the 7.5% original solution mixture to be retained in the centrifugal filter, is because and due to the polymer complex in the solution by inference.The combination of embodiment 6. serotonins and ATP, polyglutamic acid-lysine, polylysine and N-(2,6-diisopropyl phenyl carbamyl ylmethyl) iminodiacetic acid (DIDA).
10mg ATP and to be dissolved in 10ml PH be in 7.0 the 10mM HEPES buffer agent weighs.In separating test tube, be added in 1.13ml polyglutamic acid-lysine solution (1mg/ml) the serotonin HCl solution (1mg/ml) among 20 μ l embodiment, the 1 experiment A and vortex.The ATP solution (1mg/ml) and the vortex that add 26 μ l then.Add 1.07ml polylysine solution (0.56mg/ml) again.Then 10 μ l DIDA solution (0.84mg/ml) are added in this solution mixture and vortex.
The final concentration of each component is as follows in the solution mixture:
Serotonin HCl:0.009mg/ml (0.04mM)
Polyglutamic acid-lysine: 0.50mg/ml (2.0mM)
Polylysine: 0.27mg/ml (2.0mM)
ATP-Na 2： 0.012mg/ml(0.022mM)
DIDA： 0.0037mg/ml(0.01mM)
This solution mixture of 1.0ml placed have the green centrifuge tube that molecular cut off is 30000 filter.Then centrifugal 1 hour of this sample.From filtrate, take out 100 μ l aliquots and count at scintillation counter.
Found that the concentration of serotonin HCl in filtrate is 7.4 μ g/ml (account for 0.02mg/2.256ml 82%).Therefore, having 18% serotonin HCl to be retained in the centrifugal filter approximately, is that part is because and due to the polymer generation ion and/or hydrogen bond complexation in the solution mixture by inference.The combination of embodiment 7. serotonins and polyacrylic acid, polyglutamic acid-lysine and N-(2,6-diisopropyl phenyl carbamyl ylmethyl) iminodiacetic acid (DIDA).
1.3ml polyacrylic acid solution (25% aqueous solution) is added in the serotonin HCl solution (1.0mg/ml) among the 20 μ l embodiment 1 experiment A vortex 20 seconds.In separating bottle, with 1.13ml concentration be polyglutamic acid-lysine solution of 1.0mg/ml to be added to 10 μ l concentration be in the DIDA solution of 0.84mg/ml, vortex 20 seconds.Solution in above-mentioned two bottles is combined and vortex, take out 2 part of 200 μ l aliquot on scintillation counter, to be used as standard.
The final concentration of each component is as follows in the reactant mixture:
Polyacrylic acid: 0.13mg/ml (1.9mM)
Polyglutamic acid-lysine: 0.46mg/ml (1.9mM)
Serotonin HCl:0.01mg/ml (0.04mM)
DIDA： ＜0.01mg/ml(＜0.01mM)
This solution mixture of 0.5ml placed have the centrifuge tube that molecular cut off is 10000 filter.Then centrifugal 30 minutes of this centrifuge tube.From filtrate, take out 1 part of 200 μ l aliquot and count at scintillation counter.
The result shows that 74% serotonin is arranged in the filtrate approximately.Therefore, having 26% serotonin to be retained in the centrifugal filter approximately, is because and the polymeric component generation ions binding in the solution mixture and/or form due to the hydrogen bond by inference.The combination of embodiment 8. serotonins and polyvinyl sulfonic acid, polyglutamic acid-lysine and N-(2,6-diisopropyl phenyl carbamyl ylmethyl) iminodiacetic acid (DIDA).
3.3ml polyvinyl sulfonic acid solution (15% aqueous solution) is added in the serotonin HCl solution (1.0mg/ml) among the 20 μ l embodiment 1 experiment A vortex 20 seconds.In separating bottle, with 1.13ml concentration be polyglutamic acid-lysine solution of 1.0mg/ml to be added to 10 μ l concentration be in the DIDA solution of 0.84mg/ml, vortex 20 seconds.Solution in above-mentioned two bottles is combined and vortex, take out 3 part of 200 μ l aliquot on scintillation counter, to be used as standard.
The final concentration of each component is as follows in the reactant mixture:
Polyvinyl sulfonic acid: 0.10mg/ml (1.0mM)
Polyglutamic acid-lysine: 0.25mg/ml (1.0mM)
Serotonin HCl:0.0004mg/ml (0.02mM)
DIDA： ＜0.01mg/ml(＜0.01mM)
This mixture of 0.5ml placed have the centrifuge tube that molecular cut off is 10000 filter.Then centrifugal 30 minutes of this centrifuge tube.From filtrate, take out 1 part of 200 μ l aliquot and count at scintillation counter.
The result shows that serotonin has 88% approximately in filtrate.Therefore, have 12% serotonin to be retained in the centrifuge tube filter approximately, by inference this be since the polymeric component in serotonin and the solution mixture in conjunction with due to.The combination of embodiment 9. serotonins and poly-aspartate, polyglutamic acid-lysine and N-(2,6-diisopropyl phenyl carbamyl ylmethyl) iminodiacetic acid (DIDA).
0.62ml poly-aspartate solution (1.0mg/ml) is added in the serotonin HCl solution (1.0mg/ml) among the 20 μ l embodiment 1 experiment A vortex 20 seconds.In separating bottle, with 1.13ml concentration be polyglutamic acid-lysine solution of 1.0mg/ml to be added to 10 μ l concentration be in the DIDA solution of 0.84mg/ml, vortex 20 seconds.Solution in above-mentioned two bottles is combined and vortex, take out 2 part of 200 μ l aliquot as standard.
The final concentration of each component is as follows in the solution mixture behind this vortex:
Poly-aspartate: 0.35mg/ml (2.6mM)
Polyglutamic acid-lysine: 0.63mg/ml (2.6mM)
Serotonin HCl:0.01mg/ml (0.05mM)
DIDA： ＜0.01mg/ml(＜0.01mM)
This mixture of 0.5ml placed have the centrifuge tube that molecular cut off is 10000 filter.Then centrifugal 30 minutes of this sample.From filtrate, take out 2 part of 200 μ l aliquot and count at scintillation counter.
The result shows that initial serotonin has 92% approximately in filtrate.Therefore, have 8% serotonin to be retained in the centrifuge tube filter approximately, this is because the polymer generation ionic interaction in serotonin and the solution mixture and/or form due to the hydrogen bond by inference.The combination of embodiment 10. serotonins and polylysine, phytic acid, polyglutamic acid-lysine and N-(2,6-diisopropyl phenyl carbamyl ylmethyl) iminodiacetic acid (DIDA).
In this experiment, it is in the DIDA solution of 0.84mg/ml that 1.05ml polylysine solution (0.56mg/ml) is added to 10 μ l concentration, and vortex 20 seconds.In separating bottle, be that the plant acid solution of 0.56mg/ml is added in the serotonin HCl solution (1.0mg/ml) among 20 μ l embodiment, the 1 experiment A with 1.28ml concentration.With 1.13ml concentration is that polyglutamic acid-lysine solution of 1.0mg/ml also is added in second bottle.With second bottle vortex 20 seconds.Solution in above-mentioned two bottles is combined and vortex, take out 2 part of 200 μ l aliquot as standard.
The final concentration of each component is as follows in this mixed solution:
Polylysine: 0.17mg/ml (1.3mM)
Phytic acid: 0.21mg/ml (0.2mM)
Polyglutamic acid-lysine: 0.32mg/ml (1.3mM)
Serotonin HCl:＜0.01mg/ml (＜0.01mM)
DIDA： ＜0.01mg/ml(＜0.01mM)
This mixture of 0.5ml placed have the centrifuge tube that molecular cut off is 10000 filter.Then centrifugal 30 minutes of this sample.From filtrate, take out 2 part of 200 μ l aliquot and count at scintillation counter.
The data of scintillation counter show that initial serum have 86% in filtrate.This result shows, initial serotonin have approximately 14% and solution mixture in polymer scale merge therefore and be retained in the filter.The combination of embodiment 11. serotonins and polyglutamic acid, chitosan and N-(2,6-diisopropyl phenyl carbamyl ylmethyl) iminodiacetic acid (DIDA).
In this experiment, be that the polyglutamic acid solution of 0.5mg/ml is added in the serotonin HCl solution (1.0mg/ml) among 20 μ l embodiment, the 1 experiment A vortex 20 seconds with 1.06ml concentration.With 0.76ml concentration be then low-molecular-weight (MW) chitosan soln of 1.0mg/ml to be added to 10 μ l concentration be in the DIDA solution of 0.84mg/ml, vortex 20 seconds.Solution in above-mentioned two bottles is combined and vortex, take out 2 part of 200 μ l aliquot in scintillation counter, to be used as standard.
The final concentration of each component is as follows in this vortex solution mixture:
Polyglutamic acid: 0.29mg/ml (2.5mM)
Chitosan (low MW): 0.41mg/ml (2.5mM)
Serotonin HCl:0.01mg/ml (0.05mM)
DIDA： ＜0.01mg/ml(＜0.01mM)
This mixture of 0.5ml placed have the centrifuge tube that molecular cut off is 10000 filter.Then centrifugal 30 minutes of this sample.From filtrate, take out 2 part of 200 μ l aliquot and count at scintillation counter.
The result shows that initial serotonin has 95% approximately in filtrate.Initial serum have 5% and is retained in the centrifuge tube filter.The combination of embodiment 12. serotonins and polygalacturonic acid, polyglutamic acid-lysine and N-(2,6-diisopropyl phenyl carbamyl ylmethyl) iminodiacetic acid (DIDA).
Serotonin HCl solution (1.0mg/ml) among 20 μ l embodiment, the 1 experiment A is added in the 0.370ml polygalacturonic acid solution (2mg/ml), at 60 ℃ of heating several seconds and vortex.Then 1.0ml polyglutamic acid-lysine solution (1.0mg/ml) is added in the said mixture and vortex.Add 10 μ l DIDA solution (0.84mg/ml).By vortex once more solution is mixed.
The final concentration of each component is as follows in this solution mixture:
Polygalacturonic acid: 0.53mg/ml (3mM)
Polyglutamic acid-lysine: 0.71mg/ml (3mM)
Serotonin HCl:0.014mg/ml (0.07mM)
DIDA： 0.0006mg/ml(0.02mM)
This mixture of 1ml placed have the green centrifuge tube that molecular cut off is 10000 filter.Then this sample with the Sorvall refrigerated centrifuger centrifugal 1 hour of 10 ℃ of rotating speeds with 6500rpm.Respectively 100 μ l aliquots are counted on bright enumerator before filtration and after filtering.
The data of scintillation counter show that the serum in above-mentioned mixed solution have 90% in filtrate.Initial serotonin has 10% to be retained in the centrifugal filter approximately, by inference this be since serotonin with due to polymeric component in the solution mixture combines.Embodiment 13. do not have anchor close auxiliary polyalcohol in the presence of; serotonin and poly-(L-lactide-copolymerization-Acetic acid, hydroxy-, bimol. cyclic ester), chitosan (Mr=70kD) and N-(2,6-diisopropyl phenyl carbamyl ylmethyl) the bonded failure of iminodiacetic acid (DIDA).
In first bottle, poly-(L-lactide-copolymerization-Acetic acid, hydroxy-, bimol. cyclic ester) solution (1.0mg/ml) of 1.49ml embodiment 4 is added in the serotonin HCl solution (1.0mg/ml) among 20 μ l embodiment, the 1 experiment A, and vortex 20 seconds.8.4mg DIDA and to be dissolved in 10ml PH be with preparation DIDA solution in 7.0 the 10mM HEPES buffer agent weighs.In second bottle, the low-molecular-weight chitosan soln (1.0mg/ml) of 0.85ml embodiment 3 is added in the 10 μ l DIDA solution, mixture vortex 20 seconds.Solution in above-mentioned two bottles is combined, take out 2 part of 100 μ l aliquot as standard.
The final concentration of each component is as follows in this solution mixture:
Poly-(L-lactide-copolymerization-Acetic acid, hydroxy-, bimol. cyclic ester): 0.68mg/ml (2.1mM)
Chitosan: 0.39mg/ml (2.4mM)
Serotonin HCl:0.01mg/ml (0.04mM)
DIDA： ＜0.01mg/ml(＜0.01mM)
This mixture of 1.0ml placed have the yellow centrifuge tube that molecular cut off is 3000 filter.Then centrifuge tube and centrifugal 1 hour of sample wherein.From filtrate, take out 2 part of 100 μ l aliquot and count at bright enumerator.
The data of scintillation counter show that the serum in initial mixing solution have 100% and stays in the filtrate.Be retained in centrifugal filter without any serotonin.This result shows do not have suitable anchor to close for example existence of polyglutamic acid-lysine of auxiliary polyalcohol, and serotonin can not for example gather (L-lactide-copolymerization-Acetic acid, hydroxy-, bimol. cyclic ester) and chitosan with basic polymeric matrices and form stable conjugate.
Though described the present invention, should be appreciated that it all is conspicuous to those skilled in the art that its modification, equivalent have reached variation, and be and be included in the scope of protection of present invention with specific embodiments.

Claims (25)

1. be used for bioactivator is passed to mammiferous polymerization construction, comprising:
A) first kind of polymeric matrices;
B) bioactivator in this polymeric matrices; With
C) with the chemically combined second kind of polymer of bioactivator, described second kind of polymer is amino acid copolymer, and wherein second kind of polymer exists with the amount that can reduce this bioactivator effectively and spill from the polymerization construction before being delivered to desired area.
2. the polymerization construction of claim 1 wherein also comprises a kind of bonded targeting moiety with at least the first kind or second kind polymer.
3. the polymerization construction of claim 1, wherein said first kind of polymeric component are selected from copolymerization (lactide/glycolides), polylactic acid, polyglycolic acid, polyhydroxycarboxyliacid acid, polylactone, polyacetals, poe, Merlon, polyamino acid, chitosan glutamate, polyacrylate, poly-divinyl glycol, albumin, polyamine, poly butyric, scleroglucan (scleroglucans), polyoxyalkylene, polygalacturonic acid (partial esterification) and xanthan gum.
4. the polymerization construction of claim 1, wherein said second kind of polymer is lysine and other amino acid whose copolymer.
5. the polymerization construction of claim 1, wherein said bioactivator comprises biogenic amine.
6. the polymerization construction of claim 5, wherein said biogenic amine comprises sympathomimetic amine or autacoid.
7. the polymerization construction of claim 6, wherein said biogenic amine is selected from L-β-3,4-dihydroxyphenylalanine (L-DOPA), 3-(2-amino-ethyl)-5-oxyindole (5-hydroxy tryptamine or serotonin), 2-(4-imidazole radicals) ethamine (histamine), 4-[1-hydroxyl-2-(methylamino) ethyl]-1,2-Benzodiazepines (epinephrine), 1-[3,4-dihydroxy phenyl]-2-ethylaminoethanol (norepinephrine), gamma-amino n-butyric acie, acetylcholine, combination of serotonin agonist and aminoacid.
8. the polymerization construction of claim 7, wherein said biogenic amine is serotonin or combination of serotonin agonist.
9. the polymerization construction of claim 2, wherein said targeted molecular comprises the liver and gall oriented molecule.
10. the polymerization construction of claim 9, wherein said liver and gall oriented molecule is selected from iminodiacetic acid, the ethylenediamine N of replacement, the N '-substitutive derivative of N-oxalic acid (EDDA), liver and gall dyestuff, liver and gall contrast agent, bile salts, liver and gall mercaptan coordination compound, regulating liver-QI cholamine coordination compound.
11. the polymerization construction of claim 10, wherein said liver and gall oriented molecule is N-(2,6-diisopropyl phenyl carbamyl ylmethyl) iminodiacetic acid, N-(2,6-diethyl phenyl carbamoyl methyl) iminodiacetic acid, N-(2,6-3,5-dimethylphenyl carbamyl ylmethyl) iminodiacetic acid, N-(4-isopropyl phenyl carbamyl ylmethyl) iminodiacetic acid, N-(4-butyl phenyl carbamyl ylmethyl) iminodiacetic acid, N-(2,3-3,5-dimethylphenyl carbamyl ylmethyl) iminodiacetic acid, N-(3-butyl phenyl carbamyl ylmethyl) iminodiacetic acid, N-(2-butyl phenyl carbamyl ylmethyl) iminodiacetic acid, N-(4-tert-butyl-phenyl carbamyl ylmethyl) iminodiacetic acid, N-(3-butoxy phenyl carbamyl ylmethyl) iminodiacetic acid, N-(2-hexyloxy phenyl amino formoxyl methyl) iminodiacetic acid, N-(4-hexyloxy phenyl amino formoxyl methyl) iminodiacetic acid; The iminodiacetic acid that azo replaces, imino-diacetic carboxyl methyl-2-naphthalenone, the phthalein complexon, N-(5-pregnene-3-β-alcohol-2-acyl amino formoxyl methyl) iminodiacetic acid, gallbladder alcohol amyl group-23-iminodiacetic acid falls in 3a:7a:12a: trihydroxy-24-, N-(3-bromo-2,4,6-trimethylphenyl carbamyl ylmethyl) iminodiacetic acid, the benzimidazole methyliminodiacetic acid, N-(3-cyano group-4,5-dimethyl-2-pyrrole radicals carbamyl ylmethyl) iminodiacetic acid, ethylenediamine-N, two (2-hydroxyl-5-bromophenyl) ethyl acetate of N-, N '-acyl group ethylenediamine-N, N-oxalic acid and N '-sulfonyl ethylenediamine-N, the N-oxalic acid; N '-acetyl group EDDA, N '-benzoyl EDDA, N '-(p-toluenesulfonyl) EDDA, N '-(to the tert-butyl benzene formoxyl) EDDA, N '-(benzenesulfonyl) EDDA, N '-(to the chlorobenzene sulfonyl) EDDA, N '-(to the ethylo benzene sulfonyl) EDDA, N '-(to the n-propylbenzene sulfonyl) EDDA, N '-(naphthalene-2-sulfonyl) EDDA, N '-(2,5-dimethyl benzene sulfonyl) EDDA; N-(2 acetyl naphthalene base) iminodiacetic acid; N-(2-naphthyl methyl) iminodiacetic acid; Rose-red, Congo red, bromosulfalein, bromophenol blue, phenolphthalein, toluidine blue, indocyanine green; Adipiodone, ioglycamic acid, bilirubin, gallbladder acyl glycyl iodine histamine, thyroxine glucuronate, penicillamine, β-mercaptoisobutyric acid, dihydroehioctic acid, Ismipur, U-2032 two (amithiozone); 1-hydralazine (hydrazine) sulfonylureas; Pyridoxin subunit (pyridoxylidene) glutamate, pyridoxin subunit isoleucine, pyridoxin subunit phenylalanine, pyridoxin subunit tryptophan, pyridoxin subunit 5-methyl tryptophan; 3-hydroxyl-4-formoxyl pyridine glutamic acid; 7-carboxyl-beta-hydroxy quinoline, phenolphthalein ketone (phenolphthalexon), eosin and verograffin.
12. be used for biogenic amine is passed to mammiferous polymerization construction, comprising:
A) first kind of polymeric matrices;
B) biogenic amine in this polymeric matrices; With
C) with the chemically combined second kind of polymer of biogenic amine, described second kind of polymer comprises amino acid copolymer, and wherein second kind of polymer exists with the amount that can reduce this biogenic amine effectively and spill from the polymerization construction before being delivered to desired area.
13. the polymerization construction of claim 12 wherein also comprises a kind of bonded targeting moiety with at least the first kind or second kind polymer.
14. the polymerization construction of claim 12, wherein said biogenic amine comprises serotonin or combination of serotonin agonist.
15. the polymerization construction of claim 12, wherein said second kind of polymer are lysine and other amino acid whose copolymer.
16. be used for serotonin or combination of serotonin agonist are passed to the hepatocellular polymerization construction of mammalian liver, comprising:
A) first kind of polymeric matrices;
B) serotonin in this polymeric matrices or combination of serotonin agonist;
C) with serotonin or the chemically combined second kind of polymer of combination of serotonin agonist, described second kind of polymer comprises at least a amino acid whose copolymer in lysine and aspartic acid and the glutamic acid, and wherein second kind of polymer exists with the amount that can reduce serotonin or combination of serotonin agonist effectively and spill from the polymerization construction before being delivered to desired area; With
D) with a kind of bonded liver and gall targeting moiety of at least the first kind or second kind polymer.
17. contain the pharmaceutical composition of polymerization construction as claimed in claim 1 and pharmaceutically acceptable excipient.
18. contain the pharmaceutical composition of polymerization construction as claimed in claim 12 and pharmaceutically acceptable excipient.
19. contain the pharmaceutical composition of polymerization construction as claimed in claim 16 and pharmaceutically acceptable excipient.
20. the method for treatment mammalian diseases comprises and will treat the polymerization construction as claimed in claim 1 of effective dose to described mammal administration.
21. the method for the treatment disease that treatment responds to biogenic amine in mammal comprises and will treat the polymerization construction as claimed in claim 12 of effective dose to described mammal administration.
22. the method for the treatment disease that treatment responds to serotonin or combination of serotonin agonist in mammal, comprise will the treatment effective dose polymerization construction as claimed in claim 16 to described mammal administration.
23. the method for treatment type ii diabetes in mammal comprises and will treat the pharmaceutical composition as claimed in claim 19 of effective dose to described mammal administration.
24. the method for treatment type ii diabetes in mammal comprises that the pharmaceutical composition that contains following component with the treatment effective dose is to described mammal administration:
A) first kind of polymeric matrices;
B) serotonin in this polymeric matrices or combination of serotonin agonist;
C) with serotonin or the chemically combined second kind of polymer of combination of serotonin agonist, described second kind of polymer comprises at least a amino acid whose copolymer in lysine and aspartic acid and the glutamic acid, and wherein second kind of polymer exists with the amount that can reduce serotonin or combination of serotonin agonist effectively and spill from the polymerization construction before being delivered to desired area;
D) with a kind of bonded liver and gall targeting moiety of at least the first kind or second kind polymer; With
E) pharmaceutically acceptable excipient.
25. the method for claim 24, wherein the content of serotonin is the about 200 μ g of about 100 μ g-.
CN 98807413 1997-07-25 1998-07-24 Polymer based pharmaceutical compositions for targeted delivery of biologically active agents Pending CN1264310A (en)

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