CN105381469A - Medicine preparation for treating brain diseases - Google Patents
Medicine preparation for treating brain diseases Download PDFInfo
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- CN105381469A CN105381469A CN201510745787.9A CN201510745787A CN105381469A CN 105381469 A CN105381469 A CN 105381469A CN 201510745787 A CN201510745787 A CN 201510745787A CN 105381469 A CN105381469 A CN 105381469A
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Abstract
The invention relates to a medicine preparation, in particular to a medicine preparation for treating brain diseases. The medicine preparation is prepared from effective components and auxiliary materials. The effective components comprises one or a combination of Eevans blue, adriamycin, camptothecin, paclitaxel, camptothecin with the mass percentage different from the previous camptothecin, podophyllotoxin, echidnotoxin, indomethacin, guaianolide, parthenolide, arglabin, aFGF, BDNF, NGF, EPO, insulin, insulin amyloids, oxytocin or GLP-1. The invention discloses a medicine delivery method for treating brain diseases. The method has the advantages of innovativeness, high efficiency and targeting performance, toxic and side effects are reduced, a blood brain barrier way is not used, the amount of medicine entering the brain is increased, and the brain disease treatment effect is remarkable.
Description
Technical field
The present invention relates to a kind of medication, be specifically related to a kind of pharmaceutical preparation being used for the treatment of brain diseases.
Background technology
Brain diseases is as huge to human health risk in the cerebral tumor, viral infection, central nervous system trauma etc.But due to the native physiological barrier of cerebral tissue---blood brain barrier (blood-brainbarrier, BBB) existence, most of small-molecule drug and nearly all macromolecular drug all can not enter cerebral tissue smoothly, make the treatment of brain diseases be subject to a lot of restriction.Therefore, promote medicine especially macromolecular drug enter brain and become a key issue urgently to be resolved hurrily, be also the trend of international encephalopathy drug development in recent years.
Because medicine adopts conventional route application just need can enter brain by BBB, thus must strengthen dosage, thus cause and respectively organize higher drug level at whole body, considerably increase the risk that whole body toxicity occurs.Brain-targeted drug delivery arrives amount and the concentration of cerebral tissue because increasing medicine, improve curative effect, reduce whole body toxic and side effects, thus becomes emphasis and the focus of research at present.Most current Brain targeting method is conceived to the barrier action how overcoming BBB densification, mainly comprise following two kinds: the first is traditional method, namely ooze material or active substance by operation to carotid injection is high, make the of short duration opening of BBB, various material can take advantage of the occasion to enter brain.This mode allows medicine and other all molecules to enter, and its danger is self-evident, but also needs very superb surgical skills.The second is the method increasing agent permeates therethrough BBB, comprise esterified, the chemical movement system of medicine, nutrient substance movement system, receptor-mediated movement system, absorption mediate transport system and make colloidal drug delivery system, but said method respectively has certain limitation, limit its extensive use clinically.
The brain barrier maintaining central nervous system's stability is made up of three parts: BBB, blood-cerebrospinal fluid barrier and cerebrospinal fluid-brain barrier.Wherein BBB is made up of the capillary endothelial cell of densification, basement membrane and astrocyte, the barrier action that rises maximum.Cerebrospinal fluid fills the air in the ventricles of the brain, myelocoele, subarachnoid space room and vascular space, least complete with the barrier structure of brain, without anatomy obstacle, acts on the most weak, can and the outer liquid of neurocyte between carry out free mass exchange.So medicine can be walked around BBB and directly reach Brain targeting by the most weak cerebrospinal fluid-brain barrier of barrier action, the research of this respect makes some progress.In early days, clinician adopts neurosurgery to carry out intrathecal injection or the direct administration of ventricular puncture, directly injects cerebrospinal fluid, can obtain drug level higher in cerebrospinal fluid and cerebral tissue by medicine, and curative effect certainly.But this method cost intensive, technical requirement is high, also has obvious invasive to brain.After nasal-cavity administration, drug molecule is stranded in olfactory region mucosa, and absorbed by olfactory bulb and enter cerebrospinal fluid, this method comparatively safe ready, receives publicity in recent years.But enter body with nasal-cavity administration circulate and play compared with whole body therapeutic effect, nasal-cavity administration targeting is still in the exploratory stage in the research of central nervous system, and effect is not very desirable up to now.Send 1% of the not enough dosage of medication amount into brain from nasal, be difficult to the requirement meeting clinical practice; And great majority research is at present model with rat, and the regio olfactoria of rat covers the major part of nasal mucosa, and the mankind cover only a pocket at nasal cavity top, therefore the possibility of result that medicine obtains with it in muroid is much more remarkable than human body.In prior art, make drug percutaneous skin nervi trigeminus position, nervus facialis, striatum, rhinencephalon, it is main path that Hippocampus or oblongata enter brain administration, but still also exist that to enter brain efficiency by the medicine of blood brain barrier low, the shortcoming of therapeutic effect difference, as can be seen here, a kind of pharmaceutical preparation being used for the treatment of brain diseases can be invented, it is made to be applicable at face, oral cavity, the skin surface of nasal cavity, Intradermal and subcutaneous administration, make drug percutaneous skin nervi trigeminus position, nervus facialis, striatum, rhinencephalon, Hippocampus or oblongata enter brain administration, become the technical barrier that those skilled in the art are urgently to be resolved hurrily.
Summary of the invention
An object of the present invention is large for solving treatment brain diseases drug-delivery preparation dosage of the prior art, toxic and side effects is obvious, the problem of therapeutic effect difference, a kind of pharmaceutical preparation being used for the treatment of brain diseases is provided, be used for the treatment of the Chinese medicine of brain diseases, chemicals and biopharmaceutical macromolecular drug preparation are at face, oral cavity, the skin surface of nasal cavity, Intradermal and subcutaneous administration, make drug percutaneous skin nervi trigeminus position, nervus facialis, striatum, rhinencephalon, Hippocampus or oblongata enter brain administration, promote that some does not enter brain by the medicine of blood brain barrier, adding does not have at present, the treatment new way of brain diseases and the new method of new treatment brain diseases.This kind of approaches and methods can promote that some does not enter brain, as biopharmaceutical macromolecular drug by the medicine of blood brain barrier.
In order to reach above-mentioned technique effect, technical scheme of the present invention comprises:
A kind of pharmaceutical preparation being used for the treatment of brain diseases, described pharmaceutical preparation includes effective constituent and adjuvant, and described active ingredient comprises any one or several combinations in azovan blue, amycin, camptothecine, paclitaxel, camptothecine, podophyllotoxin, echidnotoxin, indomethacin, guaianolide, parthenolide, Arglabine, aFGF, BDNF, NGF, EPO, insulin, insulin starch peptide, oxytocin or GLP-1; Described adjuvant comprises several combinations in surfactant, cosurfactant, acid-base modifier, stabilizing agent, organic solvent, coemulsifier, hydrogel matrix material, subnano-emulsion oil phase, solid lipid nanoparticle material, buffer, liposome phospholipid capsule material or tackifier, and described pharmaceutical preparation also comprises for promoting that targeting enters brain material hyaluronic acid and lanosterol.
Further, described pharmaceutical preparation is the targeting preparation entering brain through nervi trigeminus.
Further, the dosage form of described pharmaceutical preparation is any one in hydrogel, liposome, nanoparticle or solid nano liposome.
Further, described hydrogel comprises the component of following mass percent:
Further, described liposome comprises the component of following mass percent:
Further, the dosage form of described pharmaceutical preparation is subnano-emulsion, and described subnano-emulsion comprises the component of following mass percent:
Further, the dosage form of described pharmaceutical preparation is solid nano liposome, and described solid nano liposome comprises the component of following mass percent:
Further, it is 5 ~ 20% phosphate buffers that described solid nano liposome also comprises mass percent.
Further, described hydrogel matrix material is any one or several combinations in poloxamer, carbomer, methylcellulose, hypromellose, gelatin;
Described surfactant comprises tween, lecithin, polyethers, double stearic acid aluminium, sodium laurylsulfate, Myrij class, brejs, polyoxyethylene castor oil condensation substance, polyoxyethylene hydrogenated Oleum Ricini condensation substance, the phospholipid of natural or synthesis and hydroderivating thing or its mixture, polyethyleneglycol modified derivative of phosphatidylcholine, sphingolipid and glyceride type thereof, biological gallbladder salt, saturated, unsaturated fatty acid or fatty alcohol, ethoxylated fatty acid or fatty alcohol and ester thereof or ethers, acetylation or hydroxyethylated single sour or Diglyceride, alkylation Aethoxy Sklerol, with fatty acid or the sugar of fatty alcohol or the ethers of sugar alcohol or esters, the biological degradation polyalcohol such as polyoxyethylene and the rare block copolymer of polyoxy third of synthesis, ethoxy Pyrusussuriensis sugar ether or Pyrusussuriensis sugar ester, aminoacid, gather one or more combination in peptide or protein such as gelatin or albumin,
Described cosurfactant comprises ethanol, ethanol, middle short chain butanols, any one or several combinations in amylalcohol, hexanol, propylene glycol, glycerol, Polyethylene Glycol or benzyl alcohol;
Described acid-base modifier comprises any one or several combinations in triethanolamine, sodium hydroxide or triethanolamine stearate;
Described liposome phospholipid capsule material comprises the one or more combination in the polyethylene glycol derivative of phosphatidylcholine of lecithin, fabaceous lecithin, hydrolecithin, hydrogenated soybean lecithin, the derivative of phosphatidylcholine of polyethylene glycol modification, ligand modified phosphatidylcholine, the phosphatidylcholine of antibody modification, ligand modified polyethylene glycol derivative of phosphatidylcholine, antibody modification;
Described stabilizing agent comprises the one or more combination in cholesterol and derivant, polyvinyl alcohol, sodium tripolyphosphate, dimethyl formamide, glycine, vitamin C or vitamin E;
Described tackifier comprises the one or more combination in cellulose derivative, castor oil hydrogenated derivant, gelatin;
Described organic solvent comprises the one or more combination in ethanol, propylene glycol, glycerol, chloroform, ether, dehydrated alcohol, acetone;
Described nanoparticle material comprises nanoparticle material PBCA, chitosan, gelatin, albumin, sodium alginate, polylactic acid, the one or more combination in PVP with targeting;
Described buffer is phosphate buffer.
Subnano-emulsion oil phase comprises Oleum Glycines, isopropyl myristate, isopropyl palmitate, the triglyceride of medium chain, crude vegetal or in, one or more combination in the fatty glyceride of long-chain.
Described have Brain targeting and nervi trigeminus has the material of special affinity to be hyaluronic acid and lanosterol.
Beneficial effect of the present invention comprises: a kind of pharmaceutical preparation being used for the treatment of brain diseases provided by the invention, have novelty, high efficiency, targeting, minimizing toxic and side effects, without blood brain barrier approach, medicine enters brain volume to be increased, treatment brain diseases successful.
Detailed description of the invention
Hereafter in detail the specific embodiment of the invention will be described.It should be noted that the combination of technical characteristic or the technical characteristic described in following embodiment should not be considered to isolated, they can mutually be combined thus be reached better technique effect.
Embodiment 1
Be used for the treatment of a pharmaceutical preparation for brain diseases, described medication comprises the following steps: medicine being made the targeting preparation entering brain through nervi trigeminus is that one can external and injectable hydrogel, and its component and mass percent content comprise:
Above-mentioned a kind of pharmaceutical preparation being used for the treatment of brain diseases, its preparation method comprises the following steps: at 20 DEG C of temperature, by mass percent be 23% poloxamer soluble in water, be that 0.1%aFGF adds in poloxamer aqueous solution by mass percent, continue the Tween 80,0.1% propylene glycol, the triethanolamine of 5%, hyaluronic acid, 1.5% lanosterol of 1.5% that add 5%, add deionized water and complement to 100%, temperature is added to 37 DEG C, form immobilising gel.
Embodiment 2
Be used for the treatment of a pharmaceutical preparation for brain diseases, described medication comprises the following steps: medicine being made the targeting preparation entering brain through nervi trigeminus is that one can external and injectable hydrogel, and its component and mass percent content comprise:
Deionized water complements to 100%.
Be that the carbomer dispersion of 2% is in water by mass percent, can suitably heat, all be dissolved into carbomer aqueous solution, in carbomer aqueous solution, add mass percent is 4% glycerol, the sodium laurylsulfate of 3%, the lanosterol of Polyethylene Glycol 1% of 1% and the hyaluronic acid of 1%, be uniformly dispersed, add the BFGF that mass percent is 1%, be uniformly dispersed, at ambient temperature, add the triethanolamine stearate that mass percent is 2%, add deionized water and complement to 100%, become immobilising gel.
Embodiment 3
Be used for the treatment of a pharmaceutical preparation for brain diseases, described medication comprises the following steps: medicine being made the targeting preparation entering brain through nervi trigeminus is that one can external and injectable hydrogel, and its component and mass percent content comprise:
Getting mass percent is that the methylcellulose of 2.5% is in mortar, add that mass percent is the glycerol of 5%, the double stearic acid aluminium of 0.1% grinds well, adding mass percent is that the lanosterol of 1% and the hyaluronic acid of 1% grind well, adding deionized water to 100% grinds evenly, add recipe quantity medicine, stir, become immobilising gel.
A kind of pharmaceutical preparation being used for the treatment of brain diseases described in embodiment 1 ~ 3, wherein active ingredient also can be EPO and has the nerve growth factor for the treatment of brain diseases;
Hydrogel matrix material can also be the one in hypromellose, gelatin;
Surfactant also can be the one or more combination of lecithin, polyethers (Pluronics), moon Myrij class (Myrjs), brejs (Brijs), polyoxyethylene castor oil condensation substance and polyoxyethylene hydrogenated Oleum Ricini condensation substance (Cremophors);
Cosurfactant also can be the one in ethanol, propylene glycol, Polyethylene Glycol;
Acid-base modifier also can be the one in triethanolamine, sodium hydroxide.
Described have Brain targeting and nervi trigeminus has the material of special affinity to be hyaluronic acid and lanosterol.
Embodiment 4
Be used for the treatment of a pharmaceutical preparation for brain diseases, described medication comprises the following steps: medicine being made the targeting preparation entering brain through nervi trigeminus is a kind of injectable liposome, and its component and mass percent content comprise:
Take sodium hydrogen phosphate and sodium dihydrogen phosphate, add the deionized water of 50%, dissolving the phosphate buffer being prepared into pH about 5.7 is aqueous phase, in water-bath 50 ~ 60 DEG C, add stand-by heat.Get mass percent be 1% BDNF, 5% lecithin, 10% hydrolecithin, 0.1% cholesterol, the sodium carboxymethyl cellulose of 0.1%, the hyaluronic acid of 0.5% and 0.5% lanosterol mix homogeneously, adding mass percent is in the ethanol of 10%, dissolve to obtain organic facies, heat 50 DEG C, under agitation, complement to 100% to organic addition deionized water, stir 3 hours, lyophilization both obtained.
Embodiment 5
Be used for the treatment of a pharmaceutical preparation for brain diseases, described medication comprises the following steps: medicine being made the targeting preparation entering brain through nervi trigeminus is a kind of injectable liposome, and its component and mass percentage comprise:
Above-mentioned a kind of preparation method being used for the treatment of the pharmaceutical preparation of brain diseases comprises the following steps: get Arglabine, the hydrolecithin of 3%, cholesterol, the cholesterol of 1%, the carboxymethyl cellulose mix homogeneously of 0.3% of 0.3% that mass percent is 10%, add the lanosterol of 0.5% and the hyaluronic acid of 0.5%, add the propylene glycol that mass percent is 12%, dissolve to obtain organic facies, heat 50 DEG C, under agitation, 100% is complemented to organic addition deionized water, stir 3 hours, lyophilization both obtained.
Embodiment 6
Be used for the treatment of a pharmaceutical preparation for brain diseases, described medication comprises the following steps: medicine being made the targeting preparation entering brain through nervi trigeminus is a kind of injectable liposome, and its component and mass percentage comprise:
Above-mentioned a kind of preparation method being used for the treatment of the pharmaceutical preparation of brain diseases comprises the following steps: get camptothecine, the lecithin of 0.3%, the polyethylene glycol phosphatidylcholine of 2.7% ligand modified, the cholesterol of 1%, gelatin, the lanosterol of 0.5%, the hyaluronic acid mix homogeneously of 0.5% of 2% that mass percent is 3%, add the ethanol that mass percent is 10%, dissolve to obtain organic facies, heat 50 DEG C, under agitation, 100% is complemented to organic addition deionized water, stir 3 hours, lyophilization both obtained.
A kind of pharmaceutical preparation being used for the treatment of brain diseases described in embodiment 4 ~ 6, wherein active ingredient: antibiotic doxorubicin, flexible mycin, nystatin, the cytosine arabinoside with treatment brain diseases; There is the treatment Chinese medicine extraction monomeric substance camptothecine of brain diseases, paclitaxel and Chinese medicine extract monomer and test one or more combination in biological guaianolide, parthenolide, Arglabine (Arglabin).Matrix material: the derivative of phosphatidylcholine that the phospholipid material with Brain targeting includes lecithin, fabaceous lecithin, hydrolecithin, hydrogenated soybean lecithin, polyethylene glycol are modified, the phospholipid material with Brain targeting also comprises the one or more combination in the polyethylene glycol derivative of phosphatidylcholine of ligand modified phosphatidylcholine, the phosphatidylcholine of antibody modification, ligand modified polyethylene glycol derivative of phosphatidylcholine, antibody modification.There is Brain targeting and nervi trigeminus has the material of special affinity to be hyaluronic acid and lanosterol.Stabilizing agent: the one or more combination in cholesterol and derivant thereof, vitamin E.Tackifier: the one or more combination in cellulose derivative, castor oil hydrogenated derivant, gelatin.Organic solvent: the one or more combination in ethanol, propylene glycol, glycerol, chloroform, ether.
Embodiment 7
Be used for the treatment of a pharmaceutical preparation for brain diseases, described medication comprises the following steps: subnano-emulsion medicine being made the targeting preparation entering brain through nervi trigeminus, and its component and mass percentage comprise:
A kind of preparation method being used for the treatment of the pharmaceutical preparation of brain diseases described above comprises the following steps: go mass percent be 0.1% azovan blue, the oleic acid of 40%, the Tween 80 mix homogeneously of 25%, add the vitamin E that mass percent is 0.5%, add the lanosterol of 1% and the hyaluronic acid of 0.5%, under agitation, be added dropwise to deionized water and complement to 100%, after stirring, in high pressure homogenizer after homogenize and get final product.
Embodiment 8
Be used for the treatment of a pharmaceutical preparation for brain diseases, described medication comprises the following steps: subnano-emulsion medicine being made the targeting preparation entering brain through nervi trigeminus, and its component and mass percentage comprise:
A kind of preparation method being used for the treatment of the pharmaceutical preparation of brain diseases described above comprises the following steps: go mass percent be 5% Arglabine, 12% ethyl oleate, 17% PEG modify lecithin, the cholesterol of 5%, the lanosterol of 1% and 1% hyaluronic acid mix homogeneously, add the vitamin E that mass percent is 3%, under agitation, be added dropwise to deionized water and complement to 100%, after stirring, in high pressure homogenizer after homogenize and get final product.
Embodiment 9
Be used for the treatment of a pharmaceutical preparation for brain diseases, described medication comprises the following steps: subnano-emulsion medicine being made the targeting preparation entering brain through nervi trigeminus, and its component and mass percentage comprise:
A kind of preparation method being used for the treatment of the pharmaceutical preparation of brain diseases described above comprises the following steps: mass percent is the ciclosporin of 3%, isopropyl myristate, 1% polyoxyethylene castor oil, the pegylated phospholipids phatidylcholine derivant of 2%, cholesterol, the lanosterol of 1%, the hyaluronic acid mix homogeneously of 1% of 3% of 15%, add the vitamin E that mass percent is 5%, under agitation, be added dropwise to deionized water and complement to 100%, after stirring, in high pressure homogenizer after homogenize and get final product.
A kind of pharmaceutical preparation being used for the treatment of brain diseases described in any one of embodiment 7 ~ 9, wherein active ingredient is: the dyestuff azovan blue with identification targeting brain; There is monomeric compound camptothecine, Arglabine, paclitaxel, the vincristine of the Chinese medicine extraction for the treatment of brain diseases; Have the treatment chemical synthetic drug ciclosporin of brain diseases, flurbiprofen,
Subnano-emulsion oil phase is: have larger deliquescent nontoxic non-irritating Oleum Glycines, isopropyl myristate, isopropyl palmitate to medicine, the triglyceride of medium chain; Crude vegetal, in, the fatty glyceride of long-chain.
Surfactant is: have reduction surface activity, makes the phospholipid of stable natural of skin covering of the surface or synthesis and hydroderivating thing thereof or its mixture, polyethyleneglycol modified derivative of phosphatidylcholine; (nerve) sphingolipid and glyceride type thereof; Biological gallbladder salt; Saturated, unsaturated fatty acid or fatty alcohol; Ethoxylated fatty acid or fatty alcohol and ester thereof or ethers; Acetylation or hydroxyethylated single sour or Diglyceride; Alkylation Aethoxy Sklerol: band fatty acid or the sugar of fatty alcohol or the ethers of sugar alcohol or esters; The biological degradation polyalcohol such as polyoxyethylene and the rare block copolymer of polyoxy third of synthesis; Ethoxy Pyrusussuriensis sugar ether or Pyrusussuriensis sugar ester; Aminoacid; In poly-peptide or protein such as gelatin, albumin one or more.
Cosurfactant is: increase emulsifying capacity, increases the mobility of interfacial film, reduces the rigidity of film, is conducive to the micromolecular ethanol, the middle short chain butanols that increase emulsion stability, amylalcohol, hexanol; Low-molecular-weight polyethylene glycol, has the surfactant of insatiable hunger double bond.
Stabilizing agent is: vitamin E, vitamin C
To there is Brain targeting and nervi trigeminus has the material of special affinity to be hyaluronic acid and lanosterol.
Embodiment 10
Be used for the treatment of a pharmaceutical preparation for brain diseases, described medication comprises the following steps: medicine is made the solid nano liposome entering the targeting preparation of brain through nervi trigeminus, its component and mass percentage comprise:
Get mass percent be 0.1% berberine hydrochloride, 10% hard amine, the hyaluronic acid of 1% and the lecithin of 1%, joining mass percent is in the dehydrated alcohol of 10%, and 45 DEG C of water-baths are dissolved, and are cooled to room temperature, form organic facies; Get mass percent be 0.1% PVA add the phosphate buffer that people's mass percent is 20%, join under magnetic stirring in organic facies, add the lanosterol of 1% and the hyaluronic acid of 1%, continue stir 1h, centrifugal 30min, collect supernatant.Precipitation adds deionized water and complements to 100%, and water bath sonicator disperses, and obtains solid lipid nanoparticle suspension.
Embodiment 11
Be used for the treatment of a pharmaceutical preparation for brain diseases, described medication comprises the following steps: medicine is made the solid nano liposome entering the targeting preparation of brain through nervi trigeminus, its component and mass percentage comprise:
Get mass percent be 1% insulin starch peptide, 8% glyceryl monostearate, 3% lecithin, 1% hyaluronic acid and 1% lanosterol, join mass percent be 10% dehydrated alcohol and 5% acetone in, 45 DEG C of water-baths are dissolved, and are cooled to room temperature, form organic facies; Get mass percent be 1% PVA add the phosphate buffer that people's mass percent is 10%, join under magnetic stirring in organic facies, continue stir 1h, centrifugal 30min, collect supernatant.Precipitation adds deionized water and complements to 100%, and water bath sonicator disperses, and obtains solid lipid nanoparticle suspension.
Embodiment 12
Be used for the treatment of a pharmaceutical preparation for brain diseases, described medication comprises the following steps: medicine is made the solid nano liposome entering the targeting preparation of brain through nervi trigeminus, its component and mass percentage comprise:
Get mass percent be 5% insulin starch peptide, 1% glyceryl monostearate, the lanosterol of 1%, the hyaluronic acid of 1% and 10% lecithin, join mass percent be 25% dehydrated alcohol and 25% acetone mixed solution in, 45 DEG C of water-baths are dissolved, be cooled to room temperature, form organic facies; Get mass percent be 4% polyvinyl alcohol add the phosphate buffer that people's mass percent is 5%, join under magnetic stirring in organic facies, continue stir 1h, centrifugal 30min, collect supernatant.Precipitation adds deionized water and complements to 100%, and water bath sonicator disperses, and obtains solid lipid nanoparticle suspension.
In claim 10 ~ 12, described effective ingredient can be: the treatment biomacromolecule material of brain diseases, proteinaceous components as insulin and insulin starch peptide, BDNF, there is the Chinese medicine extraction effective monomer compound for the treatment of brain diseases as paclitaxel, camptothecine, podophyllotoxin, echidnotoxin.
Solid lipid nanoparticle material can be: have physiological compatibility strong, the glyceryl tristearate of easy degraded and the low material of toxicity, stearic acid, stearylamine, Palmic acid, docosanoic acid, spermol cetylate, chitosan, sad or capric acid three ester (Miglyol812) of liquid oils, vitamin E, PBCA, chitosan, gelatin, albumin, sodium alginate, there is biodegradable nanoparticle material polylactic acid, one or more that can increase in the PVP of viscosity select suitable lipid carrier material mixing preparation to reach stabilized nanoscale particle.
Surfactant can be: the phospholipid of natural or synthesis and hydroderivating thing or its mixture; (nerve) sphingolipid and glyceride type thereof; Biological gallbladder salt; Saturated, unsaturated fatty acid or fatty alcohol; Ethoxylated fatty acid or fatty alcohol and ester thereof or ethers; Acetylation or hydroxyethylated single sour or Diglyceride; Alkylation Aethoxy Sklerol; With fatty acid or the sugar of fatty alcohol or the ethers of sugar alcohol or esters; The biological degradation polyalcohol such as polyoxyethylene and the rare block copolymer of polyoxy third of synthesis; Ethoxy Pyrusussuriensis sugar ether or Pyrusussuriensis sugar ester; Aminoacid; In poly-peptide or protein such as gelatin, albumin one or more.
Stabilizing agent can be: increase prescription medium viscosity, to increase synthesis or natural macromolecular material, polyvinyl alcohol, sodium tripolyphosphate (TPP), dimethyl formamide, glycine, the PVA of stability.
There is Brain targeting and nervi trigeminus has the material of special affinity to be hyaluronic acid and lanosterol.
Organic solvent can be: in dehydrated alcohol, acetone one or more.
Embodiment 13
Blood drug level testing result in Evans Blue solution agent-employing approach-brain:
The distribution of Head And Face cranial nerve is adopted to draw medicine, the mainly Head And Face areal area administration of nervi trigeminus, nervus facialis and other cranial nerves, for nervi trigeminus, we illustrate that percutaneous drug delivery enters the effect of brain, study, comprise intradermal administration, subcutaneous administration compares to administration.Take azovan blue as instrument medicine, 200ug azovan blue must pad and administration in the skin of hind leg vola at mouse back skin, nose respectively, in different dosing position, during 6h, only Head And Face administration can enter in brain (1823.04 ± 203.64ng/mL), skin of back administration and normal group indifference (106.92 ± 42.17ng/mL).In cardiac perfusion tissues following MCAO in rats, occur azovan blue fluorescence, be distributed widely in brain in each region, in Hippocampus, striatum, rhinencephalon and thalamus, distribution is strong.In the dynamics research reaching 7d, comparatively nasal-cavity administration and sublingual vein administration improve about 3-4 doubly (Hippocampus AUC:148.516 ± 21.966,53.329 ± 18.38 and 41.732 ± 9.106 μ g/mLh to the area under curve of brain, Hippocampus, striatal cortex; Striatum AUC:155.052 ± 20.774; 41.091 ± 7.275 and 44.832 ± 7.201 μ g/mL*h; Cortex AUC:152.423 ± 11.092; 68.567 ± 4.369 and 91.875 ± ± 11.191 μ g/mLh, n=5).Point out to soluble small molecular medicine rat nose must pad in administration can enter in brain, and comparatively nasal-cavity administration and sublingual vein operational efficiency high.
Embodiment 14
Blood drug level testing result in BDNF solution and liposome-employing approach-brain:
Left side antenna pad (the main areal area of nervi trigeminus) the 200ng intradermal injection of BDNF rat, in the pharmacokinetic drug determination study of seven days by a definite date, Hippocampus, striatum and cortex changes of contents comparatively nasal-cavity administration, intravenously administrable are obviously high; Namely appear in striatum, rhinencephalon, Hippocampus and cortex in BDNF administration 5min, left side is apparently higher than right side; Intradermal administration is higher than being better than nasal-cavity administration and intravenously administrable; BDNF content in blood is significantly lower than nasal cavity and intravenous administration approach.The area under curve AUC of BDNF in Hippocampus: left side 531.514 ± 27.759,235.298 ± 11.340 and 220.871 ± 4.505ng/mLh; Right side, 347.453 ± 19.228,211.353 ± 14.206 and 221.556 ± 5.481ng/mLh, n=4.The left side of striatal BDNF: AUC:411.601 ± 21.774,256.891 ± 9.430 and 69.586 ± 26.54ng/mLh; Right side: 344.999 ± 18.350,236.973 ± 20.877 and 67.201 ± 3.329ng/mLh.And in blood, 3.213 ± 0.418,3.422 ± 1.226 and 27.132 ± 2.890ng/mLh; N=4.Can enter in cerebral tissue after this result prompting protein drug antenna pad intradermal administration, significantly be better than nasal-cavity administration and intravenously administrable.Head And Face intradermal administration is also applicable to macromolecular substances and sends into brain.
After the polyoxyl 40 stearate plastid Head And Face administration of BDNF liposome and BDNF, the distribution in each region of cerebral tissue significantly improves.When 24h, 96h and 7d, BDNF liposome and polyoxyl 40 stearate plastid significantly improve and improve medicine and enter brain efficiency, all significantly improve extend the holdup time at Hippocampus, striatum and cortex.As: medicine Hippocampus BDNF content during 2h: left side 3735.101 ± 474.514,3090.3539 ± 429.542 and 2853.981 ± 201.639; Right side: 3632.047 ± 313.143,2695.337 ± 203.306 and 1642.765 ± 174.909ng/mL.Left hippocampus BDNF content 3620.247 ± 620.706,3260.824 ± 202.901 and 1713.701 ± 105.263ng/mL during 96h; 1839.0812 ± 89.652,2720.158 ± 738.791 and 1699.335 ± 135.482ng/mL.And when 7d, in left hippocampus, BDNF content is significantly higher than nasal-cavity administration and intravenously administrable, 3494.894 ± 227.926,2975.637 ± 229.488 and 1382.228 ± 146.883ng/mL; Right side is then close there is no marked difference.
Embodiment 15
Insulin Head And Face administration hypoglycemic activity and enter brain and improve diabetes mellitus encephalopathy testing result:
0.25IU-2IU insulin is fasting glucose and the diabetic mice blood glucose of the reduction rat of dose dependent, and during normal rat, the maximum range of decrease is 3.8,4.2,4.7 and 4.8mmol/L, and the persistent period is respectively 1.5h, 4h, 6h and 6h.It is that dose dependent, Hippocampus, striatum are then for the shape of falling V changes that insulin enters cortex.To diabetes rat, insulin effectively can reduce blood glucose (normal 7.90 ± 2.62mmol/L, model 28.94 ± 3.61mmol/L), after maintaining the continuous 2w injection of 1 time/2d, effectively can reduce the former tune of hippocampal neural and die, improves neuron morphology.
Embodiment 16
BDNF solution, liposome and polyoxyl 40 stearate plastid Head And Face drug treatment bilateral common carotid arteries block caused reperfusion injury testing result:
Adopt bilateral ligation legal system for vascular dementia model.Specific as follows, dissociation anesthesia rats with bilateral common carotid artery, unclamps after it folder is closed 20min and realizes reperfusion injury.Rear 15min Head And Face Intradermal, nasal cavity and intravenous injection 200ng is started in Reperfu-sion.After 72h, pathologyofbraintissue inspection, display intradermal administration improves Hippocampus and cortex neural survival rate significantly, preferably preserves Hippocampus and cortex construction, and cell number significantly matches more than intravenously administrable group and nasal-cavity administration group and above-mentioned kinetic results.Beginning in the 3rd day prepared by model, carries out three atmospheric electricity, acousto-optic stimulating exercise, and namely the electricity irritation the same several seconds carries out acousto-optic stimulation, forms the contact of acousto-optic and electricity irritation, the reaction measuring animal and stimulate acousto-optic for the 4th day.Model group animal obviously weakens electricity irritation aspect, and three kinds of administering modes can promote reaction, and after acousto-optic stimulates, the dead time reduces significantly, and BDNF intradermal administration can improve locomotor activation simultaneously, and intradermal administration group is all higher than nasal cavity and vein group.
A kind of pharmaceutical preparation being used for the treatment of brain diseases provided by the invention, has novelty, high efficiency, targeting, minimizing toxic and side effects, without blood brain barrier approach, medicine enters brain volume to be increased, treatment brain diseases successful.
Above-mentioned detailed description is the illustrating of possible embodiments for invention, and this embodiment is also not used to limit the scope of the claims of the present invention, does not allly depart from equivalence of the present invention and implements or change, and all should be contained in the scope of the claims of the present invention.
In addition, those skilled in the art also can make various amendments in other form and details, interpolation and replacement in the claims in the present invention scope of disclosure and spirit.Certainly, the changes such as these various amendments made according to the present invention's spirit, interpolation and replacement, all should be included within the present invention's scope required for protection.
Claims (9)
1. one kind is used for the treatment of the pharmaceutical preparation of brain diseases, it is characterized in that, described pharmaceutical preparation includes effective constituent and adjuvant, and described active ingredient comprises any one or several combinations in azovan blue, amycin, camptothecine, paclitaxel, camptothecine, podophyllotoxin, echidnotoxin, indomethacin, guaianolide, parthenolide, Arglabine, aFGF, BDNF, NGF, EPO, insulin, insulin starch peptide, oxytocin or GLP-1; Described adjuvant comprises the one or more combination in surfactant, cosurfactant, acid-base modifier, stabilizing agent, organic solvent, coemulsifier, hydrogel matrix material, subnano-emulsion oil phase, solid lipid nanoparticle material, buffer, liposome phospholipid capsule material or tackifier, and described pharmaceutical preparation also comprises for promoting that targeting enters brain material hyaluronic acid and lanosterol.
2. a kind of pharmaceutical preparation being used for the treatment of brain diseases according to claim 1, is characterized in that, described pharmaceutical preparation is the targeting preparation entering brain through nervi trigeminus.
3. a kind of pharmaceutical preparation being used for the treatment of brain diseases according to claim 2, is characterized in that, the dosage form of described pharmaceutical preparation is any one in hydrogel, liposome, nanoparticle or solid lipid nanoparticle.
4. a kind of pharmaceutical preparation being used for the treatment of brain diseases according to claim 3, it is characterized in that, described hydrogel comprises the component of following mass percent:
5. a kind of pharmaceutical preparation being used for the treatment of brain diseases according to claim 3, it is characterized in that, described liposome comprises the component of following mass percent:
6. a kind of pharmaceutical preparation being used for the treatment of brain diseases according to claim 3, is characterized in that, the dosage form of described pharmaceutical preparation is subnano-emulsion, and described subnano-emulsion comprises the component of following mass percent:
7. a kind of pharmaceutical preparation being used for the treatment of brain diseases according to claim 3, is characterized in that, the dosage form of described pharmaceutical preparation is solid lipid nanoparticle, and described solid lipid nanoparticle comprises the component of following mass percent:
8. a kind of pharmaceutical preparation being used for the treatment of brain diseases according to claim 7, is characterized in that, it is 5 ~ 20% phosphate buffers that described solid nano liposome also comprises mass percent.
9. a kind of medication being used for the treatment of brain diseases according to any one of claim 1 ~ 8, is characterized in that: described hydrogel matrix material is any one or several combinations in poloxamer, carbomer, methylcellulose, hypromellose, gelatin;
Described surfactant comprises tween, lecithin, polyethers, double stearic acid aluminium, sodium laurylsulfate, Myrij class, brejs, polyoxyethylene castor oil condensation substance, polyoxyethylene hydrogenated Oleum Ricini condensation substance, the phospholipid of natural or synthesis and hydroderivating thing or its mixture, polyethyleneglycol modified derivative of phosphatidylcholine, sphingolipid and glyceride type thereof, biological gallbladder salt, saturated, unsaturated fatty acid or fatty alcohol, ethoxylated fatty acid or fatty alcohol and ester thereof or ethers, acetylation or hydroxyethylated single sour or Diglyceride, alkylation Aethoxy Sklerol, with fatty acid or the sugar of fatty alcohol or the ethers of sugar alcohol or esters, the biological degradation polyalcohol such as polyoxyethylene and the rare block copolymer of polyoxy third of synthesis, ethoxy Pyrusussuriensis sugar ether or Pyrusussuriensis sugar ester, aminoacid, gather one or more combination in peptide or protein such as gelatin or albumin,
Described cosurfactant comprises ethanol, middle short chain butanols, any one or several combinations in amylalcohol, hexanol, propylene glycol, glycerol, Polyethylene Glycol or benzyl alcohol;
Described acid-base modifier comprises any one or several combinations in triethanolamine, sodium hydroxide or triethanolamine stearate;
Described liposome phospholipid capsule material comprises the one or more combination in the pegylated phospholipids phatidylcholine derivant of lecithin, fabaceous lecithin, hydrolecithin, hydrogenated soybean lecithin, polyethyleneglycol modified derivative of phosphatidylcholine, ligand modified phosphatidylcholine, the phosphatidylcholine of antibody modification, ligand modified pegylated phospholipids phatidylcholine derivant, antibody modification;
Described stabilizing agent comprises the one or more combination in cholesterol and derivant, polyvinyl alcohol, sodium tripolyphosphate, dimethyl formamide, glycine, vitamin C or vitamin E;
Described tackifier comprises the one or more combination in cellulose derivative, castor oil hydrogenated derivant, gelatin;
Described organic solvent comprises the one or more combination in ethanol, propylene glycol, glycerol, chloroform, ether, dehydrated alcohol, acetone;
Described nanoparticle material comprises nanoparticle material PBCA, chitosan, gelatin, albumin, sodium alginate, polylactic acid, the one or more combination in PVP with targeting;
Described buffer is phosphate buffer.
Subnano-emulsion oil phase comprises Oleum Glycines, isopropyl myristate, isopropyl palmitate, the triglyceride of medium chain, crude vegetal or in, one or more combination in the fatty glyceride of long-chain.
Described have Brain targeting and nervi trigeminus has the material of special affinity to be hyaluronic acid and lanosterol.
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| CN112972653A (en) * | 2021-02-23 | 2021-06-18 | 温州医科大学附属第二医院（温州医科大学附属育英儿童医院） | Application of CHBP in promotion of ultra-long random flap survival |
| CN114983927A (en) * | 2021-03-02 | 2022-09-02 | 复旦大学 | Temperature-sensitive instant gel system and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114983927A (en) * | 2021-03-02 | 2022-09-02 | 复旦大学 | Temperature-sensitive instant gel system and preparation method and application thereof |
| CN114983927B (en) * | 2021-03-02 | 2024-03-29 | 复旦大学 | Temperature-sensitive in-situ gel system and preparation method and application thereof |
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